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5,272,971,680,948,108,000 | Cindy R. Gunn
Why you need to End up being Asleep in the Nude
Why you need to End up being Asleep in the Nude
. to possess improved sleep and you will overall health benefits as well as weight loss.
What is their bed consistent? Might you clad your self for the comfortable pajamas? Sleep-in undergarments and you will an excellent T-shirt? Layer-up from inside the sweatpants?
There are certain reasons and come up with a practice of oneβs latter, because this latest post points out. Asleep naked should be perfect for their dating, your wellbeing, plus the quality of your bed.
If one current survey try perfect, not too many People in america try capitalizing on the many benefits of asleep regarding follower. Regarding national questionnaire from step 3,700 visitors, only 8% claimed sleep naked, when you find yourself nearly 75%-74%-decided to go to bed for the sleepwear. Letβs evaluate a number of the root advantages of ditching bedclothes.
Itβs not hard to imagine the positive effects you to definitely sleep nude can have to the relationship: Resting facial skin-to-facial skin can raise emotions regarding intimacy and you can closeness, each other physical and emotional. In lieu of relying on clothes for additional love, naked sleepers may sleep better along with her to store both warm-and still take some range to store chill. Are naked and you may directly close in sleep with her may generate sex-particularly the impulsive, unplanned type-apt to be and frequent.
Sleep naked may sign up to better feelings regarding contentment inside dating. A study conducted of the Cotton fiber United states of america, and that encourages the use of U.S. pure cotton facts global, checked-out the sleep designs in excess of step one,100000 United kingdom people. People you to definitely made a practice out-of sleeping nude was more likely to help you report becoming happy within relationship, than the people whom slept dressed up.
Why you ought to Getting Sleeping about Nude
Skin-to-surface contact causes the production away from oxytocin, sometimes referred to as the βlike hormone.β Oxytocin influences ideas one drive societal decisions and social partnership, engendering feelings of believe, simplicity, and stability anywhere between partners. Research shows you to definitely an increase in oxytocin account causes us to be even more responsive to othersβ thoughts (also, maybe, very sensitive), and may also increase levels of interest anywhere between people into the enough time-identity matchmaking. Oxytocin plenty of fish PΠβ’ihlΠΠsit se will not simply render self-confident, relationship-enhancing feelings-moreover it confers positive points to future health, cutting anxieties account, and lowering blood pressure level.
There are other health and fitness benefits that can come from asleep for the brand new naked, regardless if you are which have somebody or alone. By improving the looks to keep cooler at once, asleep naked could help you improve the locations off brownish body weight, the kind of lbs that basically injury times, in the way of fat, in place of storage space it as ordinary pounds really does. Children have brownish pounds to keep them loving, and you may has just experts discovered that adults will also have they, with triggered many appeal towards possible therapeutic professionals inside managing weight and to prevent metabolic ailment along with diabetes. We do not yet know what masters there is certainly inside manipulating brownish weight-there was nevertheless too much to discover how it characteristics during the grownups, and you may if it makes sense to try to increase or trigger brown weight to possess health benefits. Early research suggests that contact with cooler-including asleep from inside the a cool bedroom-will get end in brownish weight as effective in the burning calories, and you may ounts. Increasing brown body weight could possibly get consequently make it easier to reduce and boost glucose levels and you may insulin mode. Also keeping heat off in your rooms, the cooling effects of sleep versus gowns may be an easy method to help you contribute to increasing the way brownish fat performs from the body.
Regulating bodyβs temperature downward, and never overheating during the night, is just one obvious treatment for help to improve bed. Bodyβs temperature needless to say minimizes during the night time, essential parts of your own bodyβs transition to sleep. Asleep nude causes it to be more comfortable for the body so you can effortlessly perform which gradual downwards turn. To stop getting as well loving whilst in bed and you will bed-and you will enabling you to control heat because it requires-can make it more straightforward to go to bed that assist your bed alot more peacefully.
1. Purchase a beneficial bedding and you can wash they apparently. When youβre sleep epidermis-to-sheet, you desire that bed linen to get comfortable. Fool around with absolute fibers instance pure cotton otherwise silk, and you may tidy and alter your sheet sets appear to.
2. Maintain your room temperature with the cool top. A few of the great things about sleeping naked could possibly get disappear whenever you are getting undressed in order to sleep-in a spa. In addition, your bed is experience when you look at the a room thatβs too warm, having otherwise as opposed to clothes. For most people, a fever in the neighborhood regarding 65 stages is best.
3. Make sure your feet and hands is enjoying. Oneβs body releases temperatures employing extremities as an element of the sleep-associated cool down. Having cold hands and feet is affect this action. Keep feet and hands loving regarding the circumstances before bed-a shower ninety minutes before going to sleep is one long distance-and make certain you have got enough bed linen to cease becoming cooler in your hands and feet through the night.
4. Don as little as youβll be able to. When the resting naked actually to you, you will need to don very little attire as you are able to for your night of people. Youβll be able to prevent overheating, and you may sleep a whole lot more soundly consequently.
Is actually resting nude prior to deciding it is not for you. You might be surprised at how natural and you may safe it feels. | {
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-6,427,989,513,668,166,000 | Article Text
Original research
Src/lck inhibitor dasatinib reversibly switches off cytokine release and T cell cytotoxicity following stimulation with T cell bispecific antibodies
1. Gabrielle Leclercq1,2,
2. Hélène Haegel1,
3. Anneliese Schneider1,
4. Anna Maria Giusti1,
5. Estelle Marrer-Berger3,
6. Christophe Boetsch3,
7. Antje-Christine Walz3,
8. Vesna Pulko1,
9. Johannes Sam1,
10. John Challier1,
11. Cristiano Ferlini1,
12. Alex Odermatt2,
13. Pablo UmaΓ±a1,
14. Marina Bacac1 and
15. Christian Klein1
1. 1Roche Pharma Research and Early Development, Roche Innovation Centre Zurich, Schlieren, Switzerland
2. 2Department of Pharmaceutical Sciences, Division of Molecular and Systems Toxicology, University of Basel, Basel, Switzerland
3. 3Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
1. Correspondence to Gabrielle Leclercq; gabrielle.leclercq{at}roche.com
Abstract
Background T cell engagers are bispecific antibodies recognizing, with one moiety, the CD3Ξ΅ chain of the T cell receptor and, with the other moiety, specific tumor surface antigens. Crosslinking of CD3 upon simultaneous binding to tumor antigens triggers T cell activation, proliferation and cytokine release, leading to tumor cell killing. Treatment with T cell engagers can be associated with safety liabilities due to on-target on-tumor, on-target off-tumor cytotoxic activity and cytokine release syndrome (CRS). Tyrosine kinases such as SRC, LCK or ZAP70 are involved in downstream signaling pathways after engagement of the T cell receptor and blocking these kinases might serve to abrogate T cell activation when required (online supplemental material 1). Dasatinib was previously identified as a potent kinase inhibitor that switches off CAR T cell functionality.
Methods Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of dasatinib combined with 2+1βT cell bispecific antibodies (TCBs) including CEA-TCB, CD19-TCB or HLA-A2 WT1-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. To determine the effective dose of dasatinib, the Incucyte system was used to monitor the kinetics of TCB-mediated target cell killing in the presence of escalating concentrations of dasatinib. Last, the effects of dasatinib were evaluated in vivo in humanized NSG mice co-treated with CD19-TCB. The count of CD20+ blood B cells was used as a readout of efficacy of TCB-mediated killing and cytokine levels were measured in the serum.
Results Dasatinib concentrations above 50βnM prevented cytokine release and switched off-target cell killing, which were subsequently restored on removal of dasatinib. In addition, dasatinib prevented CD19-TCB-mediated B cell depletion in humanized NSG mice. These data confirm that dasatinib can act as a rapid and reversible on/off switch for activated T cells at pharmacologically relevant doses as they are applied in patients according to the label.
Conclusion Taken together, we provide evidence for the use of dasatinib as a pharmacological on/off switch to mitigate off-tumor toxicities or CRS by T cell bispecific antibodies.
β’ drug therapy
β’ combination
β’ cytokines
β’ inflammation
β’ t-lymphocytes
β’ cytotoxicity
β’ immunologic
β’ preclinical
β’ immunotherapy
β’ lymphocyte activation
β’ drug evaluation
Data availability statement
The authors declare that all relevant data to the study are included in the article or uploaded as online supplemental information.
http://creativecommons.org/licenses/by-nc/4.0/
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
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Background
T cell bispecific antibodies (TCBs) or T cell engagers are bispecific antibodies that, with one binding moiety, recognize a tumor antigen expressed on tumor cells and, with the other binding moiety, the T cell receptor resulting in T cell activation and subsequent tumor cell killing.1β5 We have described potent 2+1 TCBs, for example, cibisatamab (CEA-TCB)6 7 or glofitamab (CD20-TCB),8 based on a 2+1 format with one binder to the CD3Ξ΅ chain of the T cell receptor and two binders to the specific tumor antigens. Their Fc region enables a longer half-life and is engineered with P329G LALA mutations to prevent FcΞ³R signaling.9 10 Crosslinking of the CD3Ξ΅ chain with tumor antigens by simultaneous TCB binding triggers T cell activation, proliferation and cytokine secretion.6 7 In contrast to chimeric antigen receptor (CAR) T cells, TCBs represent an βoff the shelfβ therapy to eradicate tumors.1 11 12 While lineage-specific antigens like CD19, CD20 or BCMA can be targeted with CAR T cells or TCBs as the respective cell types expressing these antigens are non-essential, the targeting of solid tumor antigens in epithelial tumors is more challenging due to their broader expression in normal tissues resulting in potential undesired on-target off-tumor toxicity.13
One of the most common mode-of-action related toxicities reported with T cell engagers is cytokine release syndrome (CRS).14 This complex clinical syndrome is featured by fever and in the most severe cases by hypotension and/or hypoxia.15 CRS is linked to a strong release of pro-inflammatory cytokines by T cells producing TNF-Ξ±, IFN-Ξ³ and GM-CSF16 17 and by myeloid cells producing TNF-Ξ±, IL-1Ξ² and IL-6.18β21
Several problems of toxicity grading of CRS were addressed as summarized in a recent publication of a consensus grading scale,22 mainly driven by treatment interventions, with severe cases easily classified if managed with pressors and/or high-flow oxygen devices. Management of severe CRS also requires appropriate supportive care, high-dose glucocorticoids and benefit from anti-IL-6R/IL-6 treatment such as tocilizumab or silixumab.16 23 24
Another problematic toxicity to manage in the clinic is represented by off-tumor off-target toxicity as observed with TCRs in the context of adoptive T cell therapy. A clinically relevant example of the risks associated with TCR-based therapies in the context of adoptive T cell therapy was identified when an unexpected cross-reactivity of an enhanced affinity TCR targeting an HLA-A*01-restricted epitope from MAGE-A3 resulted in severe cardiovascular toxicity through recognition of an unrelated HLA-A*01-associated peptide, A1-Titin.25 Similarly, a MAGE-A3 peptide-specific TCR for adoptive T cell therapy demonstrated an undetected cross-reactivity with MAGE-A12 responsible for severe neurotoxicity.26 A rapid blockade of T cell activation/proliferation at onset of the off-target toxicity would have been essential to stop such life-threatening toxicities. Recombinant TCR-based T cell engagers or TCR-like TCBs targeting intracellular proteins presented by MHC class I have the potential inherent risk of recognizing related undesired peptides in the context of MHC presentation. Furthermore, on-target off-tumor toxicity may also occur when the tumor-associated antigens (TAAs) are expressed on healthy cells like in epithelial tissues, which may potentially trigger cell death and inflammation, resulting in irreversible tissue damage and compromising the patientβs safety.
Tyrosine kinases such as Lck, Fyn (Src family of protein kinases) or ZAP70 are involved in downstream T cell activation signaling pathways after engagement of the CD3Ξ΅ chain of the T cell receptor.27 Blocking these kinases might counteract T cell activation. Recently, screening of tyrosine kinase inhibitor (TKI) libraries was performed in an effort to identify TKI candidates inhibiting CAR T cell proliferation and activation.28 Mestermann et al29 and Weber et al30 identified dasatinib as a potent candidate that switches off CAR T cell functionality by inhibiting Src/Lck phosphorylation and NFAT signaling.31 Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the reversible effects of dasatinib combined with CEA-TCB, as an example of a solid-tumor targeting TCB,7 CD19-TCB, as an example of blood cancer targeting TCB, or HLA-A2 WT1-TCB, as an example of TCR-like TCB on T cell activation and proliferation, target cell killing and cytokine release. βKilling assaysβ testing the dose-response effects of dasatinib were conducted to define the threshold at which TCB-induced T cell activation was fully inhibited. In humanized NSG mice, the combination of dasatinib with CD19-TCB successfully prevented TCB-mediated B cell depletion. These counteracting effects can be obtained at dasatinib concentrations corresponding to clinically relevant doses. Our data show that dasatinib can act as a reversible on/off switch for TCB-mediated T cell cytotoxicity and cytokine release. Dasatinib could be used either to block TCB-induced T cell activation in case of tissue toxicities or to reduce cytokine release if CRS symptoms are not manageable with standard interventions, as an alternative to TNF-Ξ± or IL-6R blockade.19 32 Graphical Abstract has been provided as online supplemental material 1.
Supplemental material
Methods
Reagents and antibodies
CEA-TCB (cibisatamab), HLA-A2 WT1-TCB (RG6007), CD19-TCB and DP47-TCB were produced internally in the 2+1βTCB format previously described (Bacac et al, CCR for CEA and CD20-TCBs). Dasatinib (S1021) was purchased from Selleckchem.
Cell culture
The SKM-1 cell line (DSMZ# ACC547) is a human acute myeloid leukemia cell line. The cells were cultured in RPMI (11875101; Gibco) containing 20% FBS (26140079; Gibco) and split every 3 to 4βdays (to 0.6βmillion cells/mL). To ensure sufficient MHC I levels, cells were used in an assay 1β2βdays after passaging. For the Incucyte experiment, SKM-1 labeled with NucLightRed (NLR) were used.
The NLR-labeled A375 cell line is an adherent melanoma cell line which is HLA-A2 and WT1 positive. It was transduced with a vector coding for histone-staining red fluorescent protein. The cells were cultured in DMEMF12 (11320033; Gibco) containing 10% FBS (26140079; Gibco) supplemented with 6βΒ΅g/mL puromycin and split every 3 to 4βdays (to 20,000βcells/cm2). Cells were plated 1βday prior to the assay and pulsed with RMF peptides 2βhours before starting the assay.
The NLR-labeled MKN45 cell line is an adherent human gastric cancer cell line, which expresses high levels of the CEA antigen. It was transduced with a vector coding for histone-staining red fluorescent protein. The cells were cultured in RPMI Glutamax (61870036; Gibco) containing 10% FCS and split every 3 to 4βdays (50,000βcells/cm2). The cells were plated 1βday prior to the assay.
The SU-DHL-8 cell line is a human large cell lymphoma cell line derived from peritoneal effusion in a 59-year-old male Caucasian patient (ATCC catalog number CRL-2961). The cells were cultured in RPMI (11875101; Gibco) containing 10% FBS (26140079; Gibco) and split every 3 to 4βdays (to 0.8βmillion cells/mL).
Cell line authentication was performed at Microsynth.
PBMCs isolation
Peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats donated by healthy donors (blood donation center in ZΓΌrich, in accordance with the Declaration of Helsinki) by Ficoll density gradient. Briefly, blood from buffy coat was diluted 1:1 with PBS and about 25βmL was layered on 15βmL of Ficoll (17-5442; GE-Healthcare) and centrifuged for 30βmin at 2000βrpm without break. Lymphocytes were collected with a 10βmL pipette in a 50βmL tube, rinsed with PBS, and successively centrifuged at 1700 rpm (5βmin), 1500βrpm (5βmin), 1100βrpm (10βmin) and 900βrpm (10βmin) to remove remaining platelets.
Preparation of effector cells
PBMCs were counted and then adjusted to either 0.4Γ106βcells/mL, 1.0Γ106βcells/mL, 2.0Γ106βcells/mL or 6.0Γ106/mL in assay medium. Then 50βΒ΅L of the cell suspension was transferred to the wells of the assay plates, corresponding to 20,000, 50,000, 100,000 or 300,000βcells/well.
Preparation of antibodies and dasatinib solution
HLA-A2 WT1-TCB, CEA-TCB, DP47-TCB and CD19-TCB were diluted in assay medium. A series of eight dilutions (1:10) was prepared by transferring and mixing 100βΒ΅L of 400βnM TCB solution to the subsequent wells containing 900βΒ΅L of assay medium. A 20Γ dasatinib solution was prepared in PBS from a 10βmM DMSO stock solution and transferred into the wells (10βΒ΅L/well).
For in vivo administration, dasatinib was formulated in 10% DMSO, 30% PEG300, 5% Tween 80% and 55% H2O in a stock solution of 10βmg/mL
Preparation of adherent tumor target cells
Oneβday before the assay, adherent NLR-labeled A375 or NLR-labeled MKN45 target tumor cells were detached from the plate using 0.05% trypsin (25300096; Gibco). Cells were washed with PBS and the counts of viable cells (>90%) were determined by Trypan Blue staining using an EVE cell counter. Cells were re-suspended in pre-warmed assay medium (37Β°C) to obtain a cell density of 50,000βcells/mL. Then 100βΒ΅L of the cell suspension was transferred into a 96-flat-bottom well plate, corresponding to 5000 target cells per well.
Preparation of non-adherent tumor target cells
On the day of the assay, SKM-1 or SU-DHL-8 tumor cells were washed with PBS and the counts of viable cells were determined by Trypan Blue staining using an EVE cell counter (>90%). If required, the cells were labeled with Cell Trace CTV (C34557; Thermo Fisher) or CFSE (C34554; Thermo Fisher). Cells were re-suspended in pre-warmed assay medium (37Β°C) to obtain a cell density of 200,000βcells/mL. Then 100βΒ΅L of the cell suspension was transferred into a 96 U-bottom well plate, corresponding to 20,000 target cells per well.
For the Incucyte experiments, NLR-labeled SKM-1 cells were attached to a 96-well plate using rectronectin from Takara. Flat-bottom 96-well plates were coated with 50βΒ΅L of a rectronectin stock solution of 10βΒ΅g/mL (45βmin, RT). The plates were washed with PBS, and the cells were plated (45βmin, 37Β°C) before the assay.
Labeling of tumor cells
SKM-1 tumor cells were washed once with sterile PBS and labeled with Cell Trace CTV (C34557; Thermo Fisher) or CFSE dye (C34554; Thermo Fisher) (5βΒ΅M, 20βmin at RT), washed with RPMI+20%βFBS and counted.
Preparation of the killing assay
In assays with 20,000 SKM-1 tumor cells/well, 50βΒ΅L of the effector cell suspension (20,000, 100,000 or 200,000βcells/well) were added, followed by 50βΒ΅L of the antibody solutions. The final E:T ratio was 1:1, 5:1 or 10:1 and the total volume per well was 200βΒ΅L. The assay plates were covered with lids, and placed in the incubator, 37Β°C, 5% CO2.
Preparation of the killing assay using the Incucyte
The assay medium of tumor cells was replaced with fresh medium (100βΒ΅L/well). Then 50βΒ΅L of the effector cell suspension (50,000 cells/well) followed by 50βΒ΅L of the antibody dilutions were added to the assay plates containing 5000 adherent target cells/well. The E:T was approximately 10:1 and the total volume per well was 200βΒ΅L. The assay plates were incubated in the Incucyte for measurements of total red area/well every 3βhours, at 37Β°C, 5% CO2.
Flow cytometry readout: T cell activation and B cell count
At the assay endpoint, PBMCs were washed twice in PBS (1500βrpm, 5βmin, RT) and stained with the following markers: CD4 (APC-Cy7, 317418; Biolegend), CD8 (BV605, 344742; Biolegend), CD25 (BUV395, 564034; BD), CD69 (PE, 310306; Biolegend) and Live Dead Near Infra Red (NIR) (L10119; Thermo Fisher) for 30βmin at 4Β°C in FACS buffer. For blood staining, 25βΒ΅L of blood was lysed twice using BD Pharm Lyse buffer (555899; BD) (200βΒ΅L, 10βmin, RT) and stained with the following markers: CD45 (Alexa 700, 304119; Biolegend), CD20 (APC, 302309; Biolegend) and Live Dead NIR (L10119; Thermo Fisher) for 30βmin at 4Β°C in FACS buffer. Cells were then washed twice in FACS buffer (1500βrpm, 5βmin, RT) and re-suspended in 100βΒ΅L/well FACS buffer for analysis. Sample acquisition was performed using an HTS plate reader connected to a BD Fortessa Flow cytometer.
Flow cytometry readout: intracellular cytokine staining
To block cytokine secretion, 20βΒ΅L of culture medium containing 1/150 (final concentration: 1/1500) Brefeldin A (Golgiplug, 555029; BD) and 1/100 (final concentration: 1/1000) Monensin A (Golgistop, 554724; BD) and CD107a (Alexa 647, 562622; BD) was transferred to each well for 24βhours. At the assay endpoint, PBMCs were collected, washed twice in PBS (5βmin, 1500βrpm, RT) and stained with a mix of antibodies to the following surface markers: CD4 (BUV395, 564724; BD), CD8 (BV605, 344742; Biolegend) and live dead NIR (L10119; Thermo Fisher) in PBS (30βmin, 4Β°C, no light) in PBS. PBMCs were centrifuged (5βmin, 1500βrpm, RT) and fixed with Cytofix/Cytoperm buffer (554722; BD) (80βΒ΅L/well, 30βmin, 4Β°C). PBMCs were centrifuged and then washed with Perm/Wash buffer (554723; BD) (5βmin, 1500βrpm, RT). PBMCs were incubated in Perm/Wash buffer (30βmin, 4Β°C, no light) and then stained with a mix of antibodies to cytokines: TNF-Ξ± (APC-Cy7, 502944; Biolegend) and IFN-Ξ³ (BV795, 612845; BD) in Perm/Wash buffer (50βΒ΅L/well, 30βmin, 4Β°C, in the dark). PBMCs were centrifuged and washed with FACS buffer (5βmin, 1500βrpm, RT). Last, they were re-suspended in 100βΒ΅L FACS buffer and sample acquisition was performed using and HTS plate reader connected to a BD Fortessa Flow cytometer.
Cytokine measurement
Cytokines were analyzed in the culture supernatants from the killing assays (stored at β80Β°C) by Luminex using a human8Plex Assay kit (M50000007A; Bio-Rad) and additional reagents for IL-1Ξ² (171B5001M; Bio-Rad) and MCP-1 (171B5021M) measurement. Pre-diluted supernatants were incubated with beads in a 96-well filter plate (1βhour, 800βrpm, RT, in the dark). The plate was washed twice using a vacuum manifold and the detection antibody solution was added (1βhour, 800βrpm, RT, no light). The plate was vacuumed and washed twice and the streptavidin solution was added (30βmin, 800βrpm, RT, in the dark). The plate was vacuumed and washed twice and the samples were re-suspended in assay buffer. Sample acquisition was conducted using the Luminex equipment from Bio-Rad.
In vivo experiment
Humanized NSG mice were ordered from the Jackson Laboratory. The Cantonal Veterinary Office, Zurich, Switzerland, approved the protocol (ZH225-17) in accordance with the Swiss Animal Protection Law. One day before treatment, humanized NSG mice were randomized based on their T cell counts into three groups of four mice. One group was treated with dasatinib (50βmg/kg, orally) 1βhour before injection of CD19-TCB (0.5βmg/kg, intravenously) on day 0 and again 5βhours and 8βhours after injection. On days 1 and 2, dasatinib was given twice per day with intervals of 10β11βhours. Blood was collected by tail-vein bleedings or by terminal retro-orbital bleeding at 72βhours.
Data analysis
Flow cytometry data were analyzed using FlowJo V.10. Cytokine data were analyzed using the Bio-Plex software. GraphPad Prism V.8 was used to generate the graphs and for statistical analysis. For doseβtitration curves, AUC were calculated and used for statistical comparison. Data are shown as means with SD or SEM or as individual curves. The statistical tests used are indicated in the figure legends for each experiment.
Results
Dasatinib is a potent inhibitor of TCB-mediated target cell killing at pharmacologically relevant doses
To assess the inhibitory effect of dasatinib on TCB-mediated target-cell killing, PBMCs were co-cultured with NLR-labeled SKM-1 cells and HLA-A2 WT1-TCB, in medium supplemented with escalating concentrations of dasatinib. The Incucyte system was used to capture the loss of red fluorescent protein signal over time as a readout of target-cell killing. A concentration of 100βnM (48.8βng/mL) and 50βnM (24.4βng/mL) dasatinib resulted in 92.2% and 95.5% inhibition of target-cell killing induced by 10βnM HLA-A2 WT1-TCB (figure 1A and table 1), while not directly affecting NLR-labeled SKM-1 growth (online supplemental figure 2A). A concentration of 25βnM (12.2βng/mL) and 12.5βnM (6.1βng/mL) dasatinib resulted in 87.1% and 80.2% inhibition of target-cell killing for 10βnM HLA-A2 WT1-TCB (table 1). The lower concentration of 6.25βnM dasatinib combined with 10βnM HLA-A2 WT1-TCB only partially inhibited killing (figure 1A and table 1). Similarly, 100βnM and 50βnM dasatinib significantly prevented HLA-A2 WT1-TCB-induced SKM-1 killing as well as T cell proliferation and activation in a killing assay using CSFE-labeled SKM-1 tumor cells co-cultured with PBMCs and HLA-A2 WT1-TCB (figure 1BβE and online supplemental figure 4A,B). Dasatinib did not affect T cell nor SKM-1 cell viability, nor the target expression on SKM-1 cells (online supplemental figures 2A,D,E and 3). Moreover, treatment with a concentration of dasatinib above 25βnM totally prevented the release of IFN-Ξ³, IL-2 and to a lower extent TNF-Ξ± (figure 1FβH and online supplemental figure 8AβD). The lower concentration of 12.5βnM and 6.25βnM dasatinib decreased but did not fully suppress cytokine release (figure 1FβH). Overall, these data show that dasatinib can fully prevent T cell mediated target-cell lysis triggered by PBMCs stimulated with HLA-A2 WT1-TCB at in vitro concentrations of 50βnM and above. The inhibitory effect of dasatinib on HLA-A2 WT1-TCB-induced T cell cytotoxicity and cytokine release was confirmed using another target cell line (A375) for HLA-A2 WT1-TCB. (online supplemental figures 1 and 2B).
Supplemental material
Table 1
Percentage of inhibition of tumor cell killing for each concentration of dasatinib was calculated over that in the absence of dasatinib for a fixed HLA-A2 WT1-TCB concentration of 10βnM in the assay of figure 1A, mean of n=2 donors
Figure 1
Dasatinib is a potent inhibitor of TCB-mediated target cell killing at the label pharmacological dose. (A) Real-time killing of NLR-labeled SKM-1 tumor cells by 10βnM HLA-A2 WT1-TCB in the presence of escalating concentrations of dasatinib. NLR-labeled SKM-1 tumor cells were co-cultured with peripheral blood mononuclear cells (PBMCs) and HLA-A2 WT1-TCB in media supplemented with dasatinib, E:T=2.5:1. Killing was followed by Incucyte (1 scan every 3βhours, zoom Γ10, phase and red 400 ms acquisition time), mean of n=2 donorsΒ±SD with *pβ€0.05, **pβ€0.01 by one-way ANOVA (Friedman test). Effects of escalating concentrations of dasatinib on HLA-A2 WT1-TCB-induced killing (B), T cell proliferation (C) and T cell activation (D, E) in a killing assay where CFSE-labeled SKM-1 tumor cells were co-cultured with CTV-labeled PBMCs and HLA-A2 WT1-TCB, E:T=5:1. (B) The killing of CFSE-labeled SKM-1 cells was measured by flow cytometry at t=24βhours using a Live/Dead stain allowing exclusion of dead cells. (C) To assess the effect of dasatinib on T cell proliferation, the dilution of the CTV dye in CD4+ andβCD8+ T cells was measured by flow cytometry at t=72βhours, histogram plots for 1 donor representative of 3. (D, E) The expression of CD25 and CD69 on CD4+ andβCD8+ T cells was measured by flow cytometry (t=24βhours), mean of n=3 donors+SD with *pβ€0.05, **pβ€0.01 1 by one-way ANOVA (Friedman test). (F, G, H) The levels of IFN-Ξ³, TNF-Ξ± and IL-2 were measured by Luminex in the supernatants after 24βhours. The dasatinib doseβresponse curves depict the data from 1 donor representative of 3. The graphs show the individual values for n=3 donors treated with 10βnM HLA-A2 WT1-TCB in the presence of escalating concentrations of dasatinib, mean of n=3 donorsΒ±SEM with *pβ€0.05, **pβ€0.01 by one-way ANOVA (Friedman test).
Dasatinib rapidly switches off TCB-induced T cell functionality
To evaluate if dasatinib could act as a rapid and potent inhibitor of activated T cells, we first stimulated PBMCs cultured with SKM-1 tumor cells and HLA-A2 WT1-TCB for 24βhours before adding 100βnM dasatinib to the co-culture (figure 2A).
Figure 2
Dasatinib is a rapid and potent inhibitor of TCB-induced T cell functionality. (A) In vitro killing assay set-up and timelines. CTV-labeled peripheral blood mononuclear cells (PBMCs) were co-cultured with SKM-1 tumor cells (E:T=1:1) and HLA-A2 WT1-TCB. Dasatinib was added after 24βhours of activation. (B, C) The expression of CD25 and CD69 on CD8+ andβCD4+ T cells was measured by flow cytometry after 24βhours and 48βhours of activation in the presence and absence of dasatinib. (D, E, F) The supernatants were collected at 24βhours and 48βhours, and the levels of IL-2, IFN-Ξ³ and TNF-Ξ± were measured by Luminex. (G) At 144βhours, the absolute T cell counts were measured by flow cytometry to assess the effect of dasatinib on CD4+ andβCD8+ Tβcell proliferation. The doseβresponse curves depict the data from 1 donor representative of 3, mean of technical replicatesΒ±SD (B, C). The graphs show the meansΒ±SD of individual values from 3 donors treated with 10βnM HLA-A2 WT1-TCB with *pβ€0.05, **pβ€0.01 by one-way ANOVA (Friedman test). ns, not significant.
The expression of CD69 and CD25 on CD8+ andβCD4+ T cells at 24βhours showed a partially activated phenotype for T cells stimulated with HLA-A2 WT1-TCB in the absence of dasatinib (figure 2B,C). Along with activation of T cells, IFN-Ξ³, TNF-Ξ± and IL-2 were also found in the culture supernatants after 24βhours of stimulation (figure 2DβF).
Following a further 24βhours of incubation, this time in the presence of 100βnM dasatinib, the expression of the early activation marker CD69 and the late activation marker CD25 on CD4+ andβCD8+ T cells at 48βhours were lower than those measured at 48βhours in absence of dasatinib (figure 2B,C). Thus, treatment with 100βnM dasatinib rapidly inhibited further induction of activation markers in pre-activated T cells.
We also measured the cytokine levels in the killing assay supernatants at 48βhours, to assess the impact of dasatinib on T cell-mediated cytokine release. No differences were observed for IFN-Ξ³, TNF-Ξ± and IL-2 levels measured at 24βhours and 48βhours, as opposed to the dasatinib-untreated control where cytokine levels had largely increased at 48βhours (figure 2DβF). This indicated that the addition of 100βnM dasatinib at 24βhours had rapidly prevented the release of cytokines by activated T cells.
We also assessed T cell proliferation 120βhours after addition of 100βnM dasatinib in the killing assay, measuring the CTV dye dilution peaks by flow cytometry. The treatment with 100βnM dasatinib decreased the proliferation of CD4+ andβCD8+ T cells induced by 10βnM HLA-A2 WT1-TCB, with a stronger effect on CD4+ T cells (online supplemental figure 4C). In addition, CD4+ andβCD8+ Tβcell counts were significantly higher in untreated cultures than in those treated with 100βnM dasatinib (figure 2G). Dasatinib appeared to impact more strongly the CD4+ thanβthe CD8+ Tβcell proliferation (figure 2G and online supplemental figure 4C). These results showed that 100βnM dasatinib added to the killing assay inhibited TCB-induced T cell proliferation with an apparent stronger impact on CD4+ than on CD8+ T cells.
As demonstrated in these experiments, dasatinib treatment rapidly resulted in the blockade of T cell activation, cytokine release and proliferation indicating a loss of T cell functionality.
Dasatinib prevents TCB-induced cytotoxicity of activated T cells
To assess whether dasatinib could efficiently prevent TCB-mediated target cell killing by activated T cells, we set up an in vitro killing assay with two stimulation steps, in an attempt to mimic an ON/OFF switch of T cell cytotoxicity. PBMCs were first activated with HLA-A2 WT1-TCB for 20βhours in the presence of SKM-1 target cells labeled with CFSE in the absence of 100βnM dasatinib (ON). The PBMCs were then washed and re-stimulated with the TCB on SKM-1 cells labeled with CTV in the presence of 100βnM dasatinib (OFF switch). The use of CFSE-labeled and CTV-labeled SKM-1 tumors allowed to differentiate the tumor cells used in the first or second stimulation by flow cytometry (figure 3A).
Figure 3
Dasatinib is a potent inhibitor of TCB-induced T cell cytoxicity. (A) In vitro killing assay set-up and timelines. Peripheral blood mononuclear cells (PBMCs) were co-cultured with CFSE-labeled SKM-1 tumor cells (E:T=5:1) and HLA-A2 WT1-TCB. After 20βhours, the cells were washed and re-stimulated with HLA-A2 WT1-TCB on fresh CTV-labeled SKM-1 cells (E:T=5:1) in the presence or absence of 100βnM dasatinib for 24βhours. (B) The killing of SKM-1 cells was measured by flow cytometry at 20βhours (after 1st stimulation) and 44βhours (after 2nd stimulation) by exclusion of dead CFSE-labeled and CTV-labeled SKM-1 cells using a Live/Dead NIR dye. The flow cytometry dot plots are from 1 donor representative of 3 treated with 10βnM HLA-A2 WT1-TCB. (C) CTV-labeled and CFSE-labeled SKM-1 tumor cell killing before and after restimulation with HLA-A2 WT1-TCB in the presence or absence of dasatinib, mean of n=3 donorsΒ±SD with *pβ€0.05, **pβ€0.01 by one-way ANOVA (Friedman test). (D, E) IFN-Ξ³, IL-2, TNF-Ξ±, IL-8, GM-CSF and IL-6 levels were measured by Luminex in the culture supernatants. The doseβresponse curves depict the data from 1 donor representative of 3 and the graphs show the meanΒ±SD of the individual values from 3 donors treated with 10 nM HLA-A2 WT1-TCB with *pβ€0.05, **pβ€0.01 by one-way ANOVA (Friedman test).
The first treatment with HLA-A2-WT1-TCB induced an upregulation of the early and late T cell activation markers CD69 and CD25 on CD8+ andβCD4+ T cells (online supplemental figure 5), as well as the killing of CFSE-labeled SKM-1 target cells (figure 3B,C), while a non-targeted TCB, DP47-TCB, did not show any activity (online supplemental figure 6). T cells were therefore activated by HLA-A2 WT1-TCB and functional before the addition of dasatinib in the system. Following the second stimulation in the presence of 100βnM dasatinib, 87.30% of CTV-labeled SKM-1 cells were alive while only 2.04% were still alive following re-stimulation in the absence of dasatinib (figure 3B). Thus, addition of dasatinib on the second stimulation prevented HLA-A2 WT1-TCB-mediated killing (figure 3B,C). In addition, the release of IFN-Ξ³, IL-2 and GM-CSF (known to be produced by T cells) and of TNF-Ξ±, IL-6 and IL-8 (produced by T cells and monocytes) was fully inhibited on re-stimulation in the presence of 100βnM dasatinib (figure 3D,E).18 19 This result emphasizes that dasatinib can switch off activated T cells, rapidly blocking TCB-mediated cytokine release as well as T cell cytotoxicity.
To investigate how dasatinib could prevent T cell cytotoxicity, we measured the expression of CD107a by intracellular staining as a readout for T cell degranulation (online supplemental figure 7A) after stimulation with 10βnM HLA-A2 WT1-TCB in the presence or absence of 100βnM dasatinib. The addition of dasatinib prevented T cell degranulation, as indicated by the inhibition of CD107a (online supplemental figure 7B,C). This result shows that dasatinib can prevent T cell degranulation and potentially the release of perforin and granzyme B that mediate the killing of target cells.
Dasatinib reversibly stops TCB-induced tumor cell killing
We then verified whether the effect of dasatinib was reversible on its removal. To this aim, we set up a killing assay with repeated stimulations in the presence or absence of dasatinib and followed the killing kinetics using the Incucyte system (figure 4A). After each stimulation, effector cells were washed and re-stimulated on fresh NLR-labeled MKN45 target cells with 1βnM CEA-TCB in the presence or absence of dasatinib, in order to mimic an OFF/ON/OFF or ON/OFF/ON switch. A dose titration of dasatinib was conducted in this system, showing that 100βnM and 50βnM significantly prevented the killing of NLR-labeled MKN45 cells by 1βnM CEA-TCB (figure 4B and online supplemental figure 2C). In addition, dasatinib blocked CEA-TCB-mediated cytokine release (online supplemental figure 9).
Figure 4
Dasatinib reversibly switches off TCB-induced T cell functionality. (A) Restimulation assay set-up. Peripheral blood mononuclear cells (PBMCs) were co-cultured with NLR-labeled MKN45 (E:T=10:1) target cells and CEA-TCB for 3 consecutive stimulations in the presence or absence of 100βnM dasatinib, mimicking an ON/OFF/ON switch (C) or OFF/ON/OFF switch (D), mean of n=3 donors+SD. (B) Effects of escalating concentrations of dasatinib on NLR-labeled MKN45 killing by 1βnM CEA-TCB on the first stimulation, mean of n=3 donors+SEM with *pβ€0.05 by one-way ANOVA (Friedman test). Real-time killing was followed by Incucyte (1 scan every 3βhours, zoom Γ10, phase and red 400 ms acquisition time). (E, F) The levels of IFN-Ξ³, IL-2 and TNF-Ξ± were measured by Luminex in the culture supernatants after each stimulation of the ON/OFF and OFF/ON switch assays for a dose response of CEA-TCB, mean of n=2 donors+SEM.
Adding 100βnM dasatinib in the co-culture during the first stimulation resulted in the inhibition of target cell killing, which was then reversed after dasatinib removal for the second stimulation (OFF/ON) (figure 4C). IFN-Ξ³, IL-2 and TNF-Ξ± were not detected in the supernatants after the first stimulation in the presence of 100βnM dasatinib, indicating a full inhibition of T cell derived cytokine release (figure 4E). Removal of dasatinib after 3βdays and re-stimulation with 1βnM CEA-TCB resulted in the release of IFN-Ξ³, IL-2 and TNF-Ξ±, indicating that T cell functionality was restored on dasatinib removal (figure 4E). Subsequent addition of dasatinib at day 6 again inhibited T cell cytotoxicity until day 9 (figure 4C), showing an overall OFF/ON/OFF switch effect during the time course of this experiment.
When dasatinib (100βnM) was added to the culture medium only on the second stimulation with CEA-TCB to prevent T cell cytotoxicity and then removed for the third stimulation, target cell killing was finally restored (figure 4D and online supplemental file 1), mimicking an ON/OFF/ON switch. Addition of 100βnM dasatinib for the second TCB stimulation prevented the release of IFN-Ξ³, IL-2 and TNF-Ξ±, as expected (figure 4F).
Cytokine release has been shown to occur on initial exposure to T cell bispecific antibodies, but not or much less on subsequent dosing. Interestingly, low doses of dasatinib (<25βnM) added for the first TCB stimulation in the OFF/ON assay described in figure 4A partially inhibited target cell killing but seemed to equilibrate cytokine release between the first and second stimulation (online supplemental figure 10AβC).
Dasatinib prevents CD19-TCB-induced B cell depletion and cytokine release in humanized NSG mice
In line with the previous observations with CEA-TCB and HLA-A2 WT1-TCB, 100βnM dasatinib prevented CD19-TCB-dependent killing of SU-DHL-8 tumor cells and T cell activation as well as the release of TNF-Ξ±, IFN-Ξ³ and IL-2 in vitro (figure 5A,B and online supplemental figure 11A,B). To verify whether dasatinib could prevent CD19-TCB-induced B cell depletion and cytokine release in vivo, humanized NSG mice were either treated with vehicle or with 0.5βmg/kg CD19-TCB as a monotherapy or combined with 50βmg/kg dasatinib (figure 5C). To best translate the clinical pharmacodynamics and pharmacokinetics profile of dasatinib and to verify if the resulting exposure would be sufficient to prevent CD19-TCB-induced T cell cytotoxicity and cytokine release, dasatinib was given orally three times on day 0 and twice on days 1 and 2. As shown by the CD20+ Bβcell count measured in the blood at 48βhours, dasatinib prevented the killing of CD20+ B cells by CD19-TCB (figure 5D). At 72βhours, partial killing of B cells was nevertheless observed (figure 5D). The half-life of dasatinib being around 6βhours, the exposure of dasatinib was probably not sufficient any longer to continuously inhibit T cell cytotoxicity at the later timepoint. This is another indication that the inhibitory effect of dasatinib is rapidly reversible in vivo, as observed by Mestermann et al29 and Weber et al30 for CAR T cells.33
Figure 5
Dasatinib prevents CD19-TCB-induced B cell depletion and cytokine release in vivo. Effect of 100βnM dasatinib on CD19-TCB-dependent SU-DHL-8 killing and cytokine release. Peripheral blood mononuclear cells were co-cultured with CTV-labeled SU-DHL-8 tumor cells (E:T=10:1) and escalating concentrations of CD19-TCB in the presence or absence of 100βnM dasatinib. (A) The killing of CTV-labeled SU-DHL-8 cells was measured by flow cytometry (t=24βhours) using a Live/Dead stain allowing exclusion of dead cells. (B) The levels of IFN-Ξ³, TNF-Ξ± and IL-2 were measured in the culture supernatants by Luminex (24βhours, 10βnM CD19-TCB). (A, B) Mean of n=3 donors+SD with *pβ€0.05, **pβ€0.01, paired t-test. (C) Humanized NSG mice were co-treated with 0.5βmg/kg CD19-TCB (intravenously) and 50βmg/kg dasatinib (orally). (D) CD20+ Bβcell counts were measured by flow cytometry in blood collected at 48βhours and 72βhours. (E, F) The levels of IFN-Ξ³, TNF-Ξ±, IL-2 and IL-6 were measured by Luminex in serum collected 1βhour 30βmin and 6βhours post-treatment with CD19-TCB. (DβF) Mean of n=4 mice per groupΒ±SD with *pβ€0.05, **pβ€0.01 by one-way ANOVA (Kruskal-Wallis test). ns, not significant.
Dasatinib blocked the release of IL-2, TNF-Ξ±, IFN-Ξ³ and IL-6 measured 1βhour 30βmin and 6βhours after CD19-TCB treatment, indicating that dasatinib could also rapidly switch off CD19-TCB-dependent cytokine release (figure 5E,F).
In line with the in vitro findings, the rapid onset of the activity of dasatinib allowed to prevent B cell depletion and cytokine release induced by the first infusion of CD19-TCB in humanized NSG mice. Collectively, these data demonstrate the favorable pharmacodynamic profile of dasatinib, efficiently preventing CD19-TCB-induced T cell cytotoxicity and cytokine release for at least 48βhours when administered twice per day at the dose of 50βmg/kg.
Discussion/conclusion
In recent studies, Mestermann et al29 and Weber et al30 showed that the kinase inhibitor dasatinib allowed pharmacological control over activated CD19 CAR T cells. They demonstrated that dasatinib could reversibly switch off activated CAR T cells, enabling the mitigation of CRS and CAR T cellβassociated neurotoxicity (CRES).24 The authors suggested that the use of dasatinib would represent a more efficient approach to mitigate these life-threatening toxicities than the current approaches consisting of treatment with glucocorticoids or tocilizumab blocking IL-6R, which do not always result in recovery of symptoms in patients treated with CAR T cells.34 Our work demonstrates that dasatinib reversibly suppresses T cell bispecific antibody-dependent cytotoxicity and cytokine release in vitro and in vivo, in line with recent in vitro findings of Leonard et al35 with blinatumomab. Dasatinib therefore represents an attractive way to improve the safety profile and tolerability of T cell engagers.
We show that the rapid blockade of T cell activities with dasatinib could be a way to revoke inflammation and tissue damage in cases of severe TCB-mediated off-tumor toxicity. In vitro, 50βnM dasatinib was found to prevent the killing of TAA-expressing cells by CEA-TCB-stimulated or HLA-A2 WT1-TCB-stimulated T cells. To verify whether these in vitro concentrations would translate into pharmacologically active doses, we compared the in vitro dose with the Cmin, Cmax and steady-state concentrations measured in patients exposed to labeled pharmacological doses of dasatinib. Wang et al reported that the PK parameters derived from 146 patients treated with 100βmg dasatinib QD were a Cmin value of 2.61βng/mL and a Cmax value of 54.6βng/mL.36 Hence, the in vitro doses of 50βnM (24.4βng/mL) and 100βnM (48.8βng/mL) appear translatable to the dasatinib dosing regimen of 100βmg QD.36 In humanized NSG mice, the PK/PD profile of dasatinib seemed favorable as it prevented CD19-TCB-induced B cell depletion and cytokine release.
Addition of dasatinib 20βhours or 4βdays after T cell stimulation with HLA-A2 WT1-TCB or CEA-TCB in killing assays was shown to rapidly stop further T cell activation and proliferation, as well as the release of cytokines including IFN-Ξ³, IL-2 and TNF-Ξ±. Moreover, the presence of dasatinib on restimulation of activated T cells on fresh SKM-1 cells totally averted HLA-A2 WT1-TCB-mediated target cell killing and T cell degranulation. Altogether, these data reveal that dasatinib can quickly switch off TCB-mediated T cell cytotoxicity at pharmacological label doses in cases where undesired side effects occur, such as tissue toxicity.
Another application for dasatinib could be the mitigation of severe T cell engagerβinduced CRS.37 The cytokine cascade is first initiated by T cells, which release cytokines that trigger activation of other immune cells, thus amplifying the cascade.19 Myeloid cells were shown to be key mediators of IL-6 and IL-1Ξ² release and to be activated via TNF-Ξ±. Li et al19 also showed that blocking TNF-Ξ± decreased cytokine release following treatment with a HER2 T cellβdependent bispecific antibody.32 In vitro, TNF-Ξ± blockade partially inhibited the release of IL-6 and IL-1Ξ² but not of the T cellβderived cytokines IL-2 or IFN-Ξ³, and did not block T cell cytotoxic activity (19 and manuscript in preparation). In our study, dasatinib rapidly and fully switched off the release of IL-2, IFN-Ξ³, IL-6, TNF-Ξ± and IL-1Ξ², in addition to blocking T cell cytotoxicity. Importantly, dasatinib was also able to rapidly stop both the cytokine release and cytotoxicity of pre-activated T cells, which might be important for the mitigation of high-grade CRS as well as tissue toxicities.
Tumor-associated antigen distribution in healthy and malignant tissues as well as the susceptibility of developing CRS is very heterogeneous among individuals and personalized prediction is not yet optimal. Consequently, dasatinib represents an attractive potential antidote against TCB-induced life-threatening safety liabilities like off-tumor related toxicities or high-grade CRS. Due to its short half-life as a small molecule, it can be tightly regulated in contrast to the administration of TNF-Ξ± or IL-6R blocking antibodies. Dasatinib (Sprycel) is indicated for the first-line treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphoblastic leukemia.36 The dasatinib regimen of 100βmg once a day is associated with favorable PK parameters and a fast absorption rate of 30βmin to 4βhours, suggesting that it could rapidly induce a pharmacological on/off switch after administration.36 Furthermore, dasatinibβs toxicity profile is well characterized and treatment-associated adverse events, including cytopenias and pleural effusions, are manageable by dose modification or interruption.38 Overall, this may support a straightforward implementation of dasatinib for the management of extreme cases of life-threatening CRS and on-target tissue toxicities.
Other Src kinase inhibitors were reported to block CAR T cell functionality like nintedanib, imatinib, ponatinib or saracatinib as well as the BTK inhibitor ibrutinib. However, none of them appeared as potent as dasatinib.28 35 39 40 Our work highlights that a short-term intervention with dasatinib could be used as a rapid safety switch to mitigate high-grade CRS and/or adverse events related to on-target off-tumor activity of T cell engagers. We showed that dasatinib blocked TCB-mediated target cell killing on first infusion in a mouse model, but whether intermittent dosing of dasatinib would negatively affect T cell engagersβ efficacy in a tumor model, as can be anticipated from the data presented, remains to be investigated. Indeed, the combination of blinatumomab and dasatinib to treat patients with relapsed or MRD-positive Philadelphia chromosome-positive leukemia was found to be safe and associated with efficacious responses.41 42 Recently, Weber et al33 showed that treatment with dasatinib could improve CAR T cell functionality, by inducing rapid and transient ON/OFF switches preventing exhaustion. While, for TCBs, our results suggest that dasatinib treatment would have a reversible but detrimental effect on efficacy, it is reasonable to assume that, like for CAR T cells, pulsed treatment with dasatinib may be able to reduce T cell engagerβinduced T cell exhaustion as well. To specifically reduce the risk of CRS and improve its mitigation, further mechanistic studies are required to identify kinase inhibitors that might differentially regulate T cell activation and cytokine release induced by CD3 bispecific antibodies.
Data availability statement
The authors declare that all relevant data to the study are included in the article or uploaded as online supplemental information.
Ethics statements
Ethics approval
The Institutional Animal Care and Use Committee of RICZ and the Cantonal Veterinary Office of Zurich approved the study protocol (license ZH225-17) in accordance with the Swiss Animal Protection Law. All the experiments were performed according to committed guidelines (GV-Solas; Felasa; TierschG) and under the AALAC accreditation.
Acknowledgments
The authors thank all the members of the HLA-A2 WT1-TCB and CEA-TCB team for reviewing the article as well as all members from Cancer Immunotherapy, Oncology, Large Molecule Research, and Pharmaceutical Sciences at Roche Pharma Research and Early Development (pRED) who contributed to the development of these programs; Oncology DTA, Pharmaceutical Science and pRED leadership for support during all phases of this project.
References
Supplementary materials
Footnotes
β’ Contributors Concept and experimental design: GL, HH, VP, CF, JS, CK. Acquisition of data: GL. Data analysis and interpretation: GL, HH, AS, AMG, VP, CF, CK, CB, A-CW, EM-B. Writing, review and/or revision of the manuscript: GL, HH, EM-B, CF, AO, CK, MB. Administrative, technical or material support: JC. Study supervision: CK, HH, AS, MB, PU.
β’ Funding All funding for the studies were provided by Roche.
β’ Competing interests GL, HH and CK declare patent application related to the work described. All authors, except AO, are employees of Roche or were employed by Roche at the time of this study. All the authors, except AO, GL and HH, declare ownership of Roche stock.
β’ Provenance and peer review Not commissioned; externally peer reviewed.
β’ Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | {
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5,867,576,976,267,964,000 | Skip to main content
Table 3 Survival for the Patients with high SCC level
From: Preoperative SCC-Ag as a predictive marker for the use of adjuvant chemotherapy in cervical squamous cell carcinoma with intermediate-risk factors
Group
Adjuvant chemo-radiotherapy (nβ=β84)
Adjuvant radiotherapy (nβ=β67)
p value
3-year
5-year
3-year
5-year
OS
94.05%
90.72%
86.57%
73.41%
0.015
DFS
89.16%
86.03%
77.61%
69.40%
0.007
1. Abbreviations: OS overall survival, DFS disease-free survival
2. #: calculated by KaplanβMeier method | {
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7,740,751,997,318,403,000 | Skip to content
Herbal Medicine
How to Treat Graves Disease With Acupuncture and TCM
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By Qineng Tan, L.Ac., Ph.D. and Xiaomei Cai, L.Ac., Ph.D.
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checking for goiter
Checking for goiter, or enlarged thyroid gland.
Goiter? Bulging eyes? Red eyes, eye pain? Feeling anxious and irritable? Hand tremor? These can all be signs of Graves disease, an autoimmune disorder that causes hyperthyroidism. Acupuncture and TCM can help relieve Graves disease symptoms.
Graves disease is an autoimmune disorder in which the immune system creates antibodies that make the thyroid produce too much thyroid hormone. This is known as an βoveractive thyroid,β or hyperthyroidism.
Many different conditions can lead to excessive levels of thyroid hormone, but Graves disease is the most common cause of hyperthyroidism. About 80% of people with hyperthyroidism have Graves disease. Graves disease tends to affect women more often than men.
A person is more likely to have Graves disease if other people in their family have it, or have Hashimotoβs disease. People who have Graves may also have other autoimmune disorders, like Rheumatoid arthritis, autoimmune gastritis, Type 1 diabetes, or vitiligo (an autoimmune skin condition).
As with other autoimmune diseases, there is still limited understanding from a medical research perspective about what exactly causes Graves disease. Graves disease requires attention, as it can lead to serious health issues.
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What Is Overactive Thyroid?
The thyroid gland is located in the front of the throat and is responsible for producing hormones that control metabolism, or how the body converts food into energy. The main thyroid hormones are thyroxine (T3) and triiodothyronine (T4).
The thyroid hormones impact many processes in the body, including your metabolic rate (how you use calories), how quickly food passes through your digestive tract, your heart rate, maintenance of body temperature, and the production of new cells to replace dying ones.Β
Thyroid function can have a big impact on your weight and digestion. Thyroid hormone imbalances can cause skin problems, vision problems, and problems with menstrual cycles, libido, and fertility.
Acupuncture can be an effective treatment for managing hyperthyroidism symptoms.
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Top 10 Graves Disease Symptoms
Graves disease most typically begins to show up in midlife, between the ages of 30 and 50. Signs of Graves disease may develop slowly over several weeks or months. Each individualβs experience with symptoms may be different; you may have some of the following symptoms, but not others.
Common symptoms of Graves disease include:
1. Rapid weight loss
2. Increased appetite
3. Diarrhea, more frequent bowel movements
4. Rapid heartbeat, heart palpitations
5. Feeling shaky, hand tremor, tremor in fingers
6. Clammy skin, sweating, feeling hot
7. Insomnia, trouble sleeping
8. Goiter, enlarged thyroid gland on the front of the throat
9. Changes in menstrual cycle
10. Muscle weakness
About a third of people with Graves disease will also develop Graves ophthalmopathy, or thyroid eye disease. This happens due to inflammation and swelling of the muscles and tissues around the eyes. This can happen in both eyes, or just one eye.
Graves disease eye symptoms can include:
1. Bulging eyes
2. Eyelids donβt close all the way
3. Puffy eyes, swelling around the eyes
4. Eye pain, eye pressure
5. Sensitive to light
6. Eye irritation, gritty eyes
7. Double vision
8. Blurred vision
9. Red eyes
10. Trouble moving the eyes
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Treatment for Graves Disease
thyroid testing Graves
Testing for thyroid disorders
Diagnosis of Graves disease will usually involve blood tests to check for elevated thyroid hormones and the presence of antibodies that stimulate thyroid hormone production. A thyroid uptake scan will show how much iodine your thyroid absorbs; high absorption of iodine is a sign of Graves disease. A Doppler ultrasound may also be done to see if there is extra blood flow to your thyroid gland.
Graves disease is considered a chronic condition with no cure. However, medications and other interventions can help control thyroid hormone levels. Antithyroid medications like Tapazole block the overproduction of T3 and T4. Side effects of these medications can include itchy skin rashes, nausea, hair loss, muscle pain or joint pain, headaches, dizziness, and other problems. Some people can develop serious liver problems.
Radioiodine therapy, or radioactive iodine ablation (RAI),Β is a treatment for Graves disease that involves taking radioactive iodine, which, as it is absorbed by the thyroid, will destroy the overactive cells of the thyroid gland. Many patients who undergo this treatment will end up being hypothyroid (low thyroid levels) and will have to have thyroid hormone replacement treatment. RAI treatment can affect the salivary glands, causing dry mouth and sometimes a loss of the ability to taste.
A thyroidectomy is a surgical option, which involves the removal of some or all of the thyroid gland. This may be recommended if a person has a very enlarged goiter, or thyroid gland. As with RAI, this may require that a person takes thyroid hormone replacement in the future. There is a risk that the vocal cords can suffer damage during this procedure, which may affect a personβs voice long-term.
Acupuncture and TCM offers an alternative or adjunct treatment for Graves disease that can help address the root cause of hyperthyroidism as well as help to manage symptoms.
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Can Acupuncture Help Graves Disease?
Chinese herbs in powder form
Chinese herbs can help relieve hyperthyroid symptoms.
According to TCM theory, hyperthyroidism and Graves disease are related to imbalances in Qi: typically, yin deficiency is the result of excessive yang energy. Stagnation of phlegm in the liver meridian around the throat area can also have an impact on the thyroid gland.
Herbal formulations that help address liver qi stagnation can help relieve many of the symptoms associated with Graves disease, including palpitations, increased heart rate, and insomnia. Other Chinese herb treatments can help to reduce thyroid hormone levels and even the size of an enlarged thyroid.
One study that compared patients who were treated with acupuncture and herbs versus those who were treated with antithyroid medications. Over 95% of the group who received TCM treatment had positive outcomes, while 73% of the group who were given medications saw positive improvement.
Another independent study showed a similar result, with some patients given acupuncture plus conventional medications, while another group received medication only. The acupuncture group had a 96% positive outcome, while the medication only group had a 64% success rate.
One case study of a woman who had tried antithyroid medications but had suffered from hives as a side effect had good results after taking TCM herbs. Her thyroid levels returned to normal and remained in the normal range even after she discontinued the herbs.
An overview of research shows that acupuncture and herbs have the potential to help patients with Graves disease and hyperthyroidism by lowering thyroid hormone levels, relieving stress, improving sleep, and relieving symptoms like tremors and muscle weakness, as well as IBS-like symptoms of diarrhea.
A TCM practitioner can also give personalized advice regarding dietary and other lifestyle changes that can further help to alleviate symptoms and strengthen Qi.
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Acupuncture Near Me for Graves Disease in West Los Angeles
Acupuncture and herbal medicine can be excellent modalities for hard-to-treat disorders, because TCM offers a different lens through which we can see health issues like autoimmune disorders and hormonal imbalances. TCM treatments can strengthen a personβs health on the deepest levels, while also relieving a wide variety of symptoms. Acupuncture can be very helpful for thyroid disorders like Graves disease and hyperthyroidism, as well as Hashimotoβs thyroiditis (Hashimoto) and hypothyroidism.Β
*This article is for education from the perspective of Traditional Chinese Medicine only. The education provided by this article is not approved by FDA to diagnose, prevent, treat and cure human diseases. It should not stop you from consulting with your physician for your medical conditions. Traditional Chinese Medicine is based on Qi, which is an invisible force that usually cannot be observed by modern science. Because science focuses on testing ideas about the natural world with evidence obtained through observation, these aspects of acupuncture canβt be studied by science. Therefore acupuncture and Chinese herbs are often not supported by double-blind, randomized trials, and they are considered alternative medicine therapies in the United States.
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How to Treat Hay Fever With Acupuncture and TCM
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By Qineng Tan, L.Ac. Ph.D. & Xiaomei Cai, L.Ac., Ph.D.
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hay fever, seasonal allergies, pollen
Seasonal allergies are usually triggered by pollen from plants.
Itchy eyes, runny nose and sneezing? These are some of the classic seasonal allergy symptoms, also known as allergic rhinitis, or hay fever. Acupuncture and TCM herbs can help relieve allergies, including pollen allergy symptoms.
Seasonal allergies affect about 20% of Americans. Allergic rhinitis is an immune system reaction to an allergen in the air that can be inhaled, like pollen from budding trees, growing grass, and plants like ragweed. Hay fever is a common term that typically describes being allergic to pollen.
βPollenβ are tiny seeds from plants that can be carried by the wind. When there is lots of pollen in the air, this is called a high pollen count. You can check the pollen count, like a weather report, to see when it is particularly high, and thus may affect people who suffer from seasonal allergies and asthma
While having an allergic reaction to common airborne allergens happens most often during the spring, summer, and early fall, when plants are giving off a lot of pollen, people can actually experience hay fever at any time of the year.
Similar allergy symptoms can occur due to exposure to dust mites, molds, and pet dander.
Acupuncture and TCM can help relieve the irritating symptoms caused by allergic reactions by helping to strengthen and balance the immune system so that it is not so easily triggered.Β
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Top 10 Seasonal Allergy Symptoms
Itchy eyes, watery eyes, allergy
Itchy eyes are a pollen allergy symptom.
The bodyβs histamine response causes inflammation of the mucus membranes in the sinuses and throat. The increased mucus production occurs in order to drive out the offending allergens.Β Β
Pollen allergy symptoms are similar to those of the common cold. Signs of hay fever include:
1. Sneezing
2. Nasal congestion
3. Runny nose, itchy nose
4. Itchy eyes, watery eyes (allergic conjunctivitis)
5. Itchy throat
6. Postnasal drip
7. Headaches, sinus pain
8. Dark circles under eyes, puffy eyes, βallergic shinersβ
9. Fatigue, malaise, generally feeling under the weather
10. Wheezing, coughing, trouble breathing
Skin rash is a less common symptom of seasonal allergies, but some people do develop a hay fever rash. The itchy allergy rash may look similar to hives: raised red welts on the skin.
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Treatment for Hay Fever
The common medical treatment for hay fever is an antihistamine. Histamines are chemicals that occur naturally in the body as part of the immune response to allergens in the environment. The release of histamines is what leads to allergy symptoms like a runny nose and itchy eyes.
Antihistamines come in pill or spray form, and they block the histamine response, which can temporarily relieve the hay fever symptoms. However, these medications do have side effects, the most common of which is drowsiness.Β
If someone is not getting relief from antihistamines, then corticosteroids, or steroids, may be prescribed. These work as anti-inflammatories, which in this case means that they reduce the swelling of mucous membranes. Steroids, too, can have significant side effects, especially when used over a long period of time.
Nasal sprays for allergies, like Flonase or Mucinex, are decongestants that are designed to be sprayed into the nose to help reduce allergy runny nose. Again, these may provide some temporary relief, but people can quickly get used to them, so they stop being effective.
Acupuncture and TCM offer an alternative treatment for allergies that can help relieve hay fever symptoms without side effects.
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Can Acupuncture Help Hay Fever?
sneezing hay fever
Sneezing and nasal congestion are signs of hay fever.
According to TCM theory, allergies fall under the category of illnesses that are caused by βwindβ as a pathogenic force that can invade the body. In the TCM view, hay fever occurs due to wind-heat getting into the lungs.Β
Weakness of the kidneys and spleen can also contribute to hay fever; when they are sluggish, mucus tends to build up, and we become more easily fatigued.
When the defensive Qi is strong, it can protect us from cold, heat, wind, and dampness getting into the body and causing problems. Defensive Qi is roughly analogous to what we think of as the immune system in conventional medicine.Β
TCM treatment for allergic rhinitis may include acupuncture, herbal supplements, moxibustion, and nutrition counseling. TCM can be used either as an alternative therapy for allergies, or as an adjunct treatment for hay fever, along with pharmacological treatment.
Chinese herbs have been used for many centuries to treat allergy symptoms. Now, we are able to see scientific evidence that these herbs, such as astragalus, magnolia flower, and licorice root, do actually have an effect on the immune response and histamine function by helping to regulate the production of chemicals like cytotoxic T-cells and immunoglobulin G. Compounds found in scutellaria root have been found to inhibit the production of inflammatory cytokines, and stephania root can help prevent anaphylaxis.
With Chinese herbal medicine, we are able to create customized formulas for each patient, depending on their particular presentation of symptoms.
Acupuncture is a highly effective modality for all types of allergies, from allergic rhinitis to atopic dermatitisΒ or eczema, and can help relieve the nasal sinus symptoms that affect the eyes, nose and mouth if someone is allergic to pollen. It can also help reduce itching due to allergic skin rashes.
A clinical trial conducted at a hospital in China showed that a regimen of acupuncture and herbs resulted in over 90% of patients reporting that their nasal symptoms were greatly reduced.
Another published study showed that acupuncture reduced levels of Immunoglobulin-E, an antibody that is associated with allergy responses.Β
A review of studies of acupuncture for allergic rhinitis showed that this treatment has both short-term and long-term efficacy.
TCM treatment for seasonal allergies allows us to get to the root cause of allergy symptoms and help prevent them from happening. In this way, acupuncture and herbs can function as preventive medicine for hay fever. Getting acupuncture periodically throughout the year can help you avoid allergy attacks when the pollen count is high.
Top 3 Tips for Hay Fever Prevention
Here are some things you can do to help prevent spring hay fever and relieve pollen allergy symptoms:Β
1. Avoid dairy food and cold foods, which promote more mucus production.
2. Apply warm compresses to the face to soothe the eyes and nasal area.
3. Use an air purifier in your home to keep allergens out of the environment.
To relieve allergies, emphasize more cooked foods that help warm the body.
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Acupuncture Near Me for Hay Fever in Los Angeles Area, Santa Monica
The multifaceted approach of TCM makes it uniquely suited to help relieve seasonal allergy symptoms. Acupuncture can help reduce hay fever symptoms right away and help prevent allergies from knocking you down every time the pollen count is high. Please do not hesitate to seek relief from hay fever by giving acupuncture and herbs a try.
*This article is for education from the perspective of Traditional Chinese Medicine only. The education provided by this article is not approved by FDA to diagnose, prevent, treat and cure human diseases. It should not stop you from consulting with your physician for your medical conditions. Traditional Chinese Medicine is based on Qi, which is an invisible force that usually cannot be observed by modern science. Because science focuses on testing ideas about the natural world with evidence obtained through observation, these aspects of acupuncture canβt be studied by science. Therefore acupuncture and Chinese herbs are often not supported by double-blind, randomized trials, and they are considered alternative medicine therapies in the United States.
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How to Treat Bronchitis With Acupuncture and TCM
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By Xiaomei Cai, L.Ac., Ph.D. & Qineng Tan, L.Ac., Ph.D.
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man coughing
A persistent, productive cough can be a sign of bronchitis.
Chest cold with a productive cough, shortness of breath, coughing up mucus? These could be acute bronchitis symptoms. Acupuncture and TCM herbs can provide an alternative bronchitis treatment to help relieve chest congestion and a chronic cough.
Bronchitis is a respiratory infection in which the bronchial tubes, or airways, become inflamed. It typically causes chest congestion, a wet cough, coughing up phlegm, and difficulty breathing. Acute bronchitis usually develops due to the same kinds of viral infections that cause the common cold or pneumonia.
Chronic bronchitis refers to long-term inflammation of the lungs and bronchial tubes that is not related to an infection. If a person has a cough with mucus that lasts for months, or happens year after year, it is considered chronic bronchitis. This can happen as a result of smoking, and/or exposure to air pollution.
Like emphysema, chronic bronchitis is considered a chronic obstructive pulmonary disease (COPD). There are other lung conditions that can cause symptoms similar to those of bronchitis, including: asthma, sinusitis, whooping cough (pertussis) and tuberculosis.
Acute bronchitis usually clears up within a few weeks, but the persistent cough may linger. Antibiotics do not help treat viral infections, so the treatment for bronchitis is usually just to help suppress the cough and reduce aches and pains.Β
TCM treatment with acupuncture and herbs can help relieve bronchitis symptoms without side effects. It can also help remove pathogens and blockages affecting the lungs, so that bronchitis doesnβt turn into a chronic, recurrent condition.
Bronchitis Symptoms
woman in bed coughing
Bronchitis cough may get worse when you lie down to sleep.
Acute bronchitis causes the airways of the lungsβthe bronchial tubesβto swell, and the lungs to produce extra mucus. Coughing, with clear or yellowish phlegm, is the primary symptom of bronchitis.
The most commons symptoms of bronchitis include:
β’ Cough, phlegmy cough, cough with mucus, productive cough, persistent cough
β’ Chest soreness, tightness in chest, chest pain
β’ Fatigue, feeling tired
β’ Shortness of breath, trouble breathing, wheezing
β’ Sore throat
β’ Stuffy nose, runny nose
β’ Body ache, headache, back pain, muscle pain
β’ Low grade fever
Is bronchitis contagious? It is not so much bronchitis as a conditionβthat is, inflammation and congestion in the lungsβis contagious, as the virus or bacterial infection that caused bronchitis to develop is contagious for a period of time. The coughing may last for a while beyond the infectious period. Sleeping can be difficult, because the cough tends to worsen when a person lies down.
Bronchitis Treatment
When you seek treatment for acute bronchitis from a physician, it is generally treated in the same way as the common cold. Recommendations will include:
β’ Rest
β’ Increase fluid intake, drink more water
β’ Take OTC pain relievers
β’ Take expectorants or cough suppressants to manage coughing
β’ Use a humidifier or sit in a steamy shower room to help relieve congestion
These remedies may help to temporarily relieve symptoms while a person gets over the infection. However, some of these medications can cause side effects, and they do not do much to help prevent bronchitis from coming back the next time a virus is going around.
Chronic bronchitis, as a COPD, is considered a chronic illness that must be managed, so as to slow its progression. Quitting smoking is the first recommendation. Then, bronchodilators, steroids, and/or antibiotics may be prescribed to help open the airways, reduce inflammation, and prevent recurrent infections.
These medical interventions, too, can come with significant side effects. Corticosteroids, in particular, if taken over a long period of time, can cause liver damage.Β
Making a major lifestyle change, like getting rid of a nicotine addiction, is easier said than done.Β
Fortunately, acupuncture and TCM herbs offer a complementary medicine to help relieve bronchitis symptoms, treat the deeper root causes, and also help with quitting smoking, if necessary.
Can Acupuncture Help Bronchitis?
acupuncture treatment for bronchitis
Acupuncture can help relieve bronchitis symptoms.
According to TCM theory, bronchitis is the result of pathogenic forces like Wind and Dampness affecting the lungs and other organs systems that are interrelated. An acupuncturist looks for the particular patterns of symptoms in each individual, and tailors acupuncture treatment and herbal supplements, according to which organ system patterns are involved. These may include:
β’ Lung dampness
β’ Lung deficiency
β’ Lung dryness
β’ Phlegm-heat obstructing lung
β’ Wind invasion
β’ Spleen Qi deficiency
β’ Spleen/Kidney Yang deficiency
β’ Qi and/or Yin deficiency
Multiple studies have shown that acupuncture treatment and herbal cough preparations can be even more effective than conventional medicines when helping to relieve post-infectious chronic coughing.
Studies have shown that acupuncture can help reduce bronchial inflammation and damage, relieve coughing and reduce phlegm production. It can also help boost immune function.
One study detailed how patients with chronic bronchitis, who had been taking steroids for years, were able to reduce or entirely stop their use of steroids after receiving acupuncture treatments for a few months.
Chinese herbs, used in combination, can help relieve bronchitis symptoms and work on other levels, too. They can help clear toxins from the tissues and promote regeneration of new, healthy tissue, and improve immunity, so that the next time a virus is going around, the body is better equipped to fight it off quickly.
Top 5 Tips for Getting Rid of Bronchitis Naturally
fresh ginger tea
Fresh ginger tea can help reduce inflammation.
Getting acupuncture treatment and specific herbs for your condition will be helpful. In addition, you can help strengthen your lung health by practicing these habits:
1. Avoid dairy products, which increase mucus production
2. Drink warm herbal teas, fresh ginger tea, and lemon water to help stay hydrated and thin phlegm. Avoid caffeine and alcohol, which dehydrate you. Ginger helps reduce inflammation.
3. Steam an asian pear until very soft, and eat like applesauce. This helps clear mucus.
4. Breathing exercises can be helpful; ask your acupuncture practitioner to show you some good breathing techniques.
5. Take Yin Qiao pills at the very first sign of a cough or sore throat. This is a traditional Chinese formulation that helps ward off colds and coughs if taken early.Β
Acupuncture Near Me for Bronchitis in West Los Angeles
When a respiratory infection turns into a nagging cough, or worse, into chronic bronchitis that keeps coming back, year after year, it is important to seek treatment. With acupuncture and TCM herbs, it is possible to recover from a bronchial infection more quickly and comfortably. With regular acupuncture βtune-ups,β you can end the cycle of a chronic cough.
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*This article is for education from the perspective of Traditional Chinese Medicine only. The education provided by this article is not approved by FDA to diagnose, prevent, treat and cure human diseases. It should not stop you from consulting with your physician for your medical conditions. Traditional Chinese Medicine is based on Qi, which is an invisible force that usually cannot be observed by modern science. Because science focuses on testing ideas about the natural world with evidence obtained through observation, these aspects of acupuncture canβt be studied by science. Therefore acupuncture and Chinese herbs are often not supported by double-blind, randomized trials, and they are considered alternative medicine therapies in the United States.
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How to Treat Chronic Fatigue Syndrome With Acupuncture and TCM
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By Xiaomei Cai, L.Ac., Ph.D. & Qineng Tan, L.Ac., Ph.D.
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chronic fatigue syndrome
When you have CFS, sleep doesnβt feel refreshing.
Chronic fatigue syndrome (CFS), also known as myalgic encephalitis (ME/CFS), is a condition marked by extreme fatigue that doesnβt get better, even with rest, and gets worse with physical and mental exertion. Chronic fatigue is not well understood by medical science, but acupuncture and Chinese medicine for chronic fatigue syndrome symptoms can be an effective treatment option.
People with chronic fatigue syndrome are always tired, even after getting a normal amount of sleep, and the condition persists for weeks, months, or years. Other chronic fatigue symptoms include body aches, cognitive problems, vision problems, and emotional or mental health problems, like depression and anxiety.
If a person feels tired all the time, with no medical explanation, for six months or more, and has several other chronic fatigue syndrome symptoms like dizziness, difficulty concentrating, headaches, or sensitivity to light, then they might be diagnosed with CFS, or myalgic encephalitis (ME CFS).
By definition, a syndrome is a collection of symptoms that often appear together in combination, for which the exact explanation is unknown. Chronic fatigue has been considered a syndrome for some time, but has more recently been given the designation of a βdisease;β hence, the newer term βmyalgic encephalitis,β which refers to muscle pain and inflammation of the brain and spinal cord.
Chronic fatigue syndrome symptoms can be very similar to those of fibromyalgia. People with fibromyalgia also experience severe fatigue, but the primary symptoms of fibromyalgia are musculoskeletal pain that comes and goes all over, especially in βtender pointsβ around the major muscles and joints, along with swelling and inflammation. It is possible to have both ME/CFS and fibromyalgia.
Women are much more likely to have chronic fatigue than men. MECFS can begin to appear at any stage of life, but most usually develops in adulthood. It is estimated that up to 90% of people who have chronic fatigue go undiagnosed.
ME/CFS is a serious and disabling condition that can interfere with even the most basic daily activities. People with chronic fatigue may be able to participate in some events where they exert themselves mentally and/or physically, but afterwards, they will feel completely wiped out and have to take time to recover, often confined to bed. This is called post-exertional malaise (PEM).
Top 10 Chronic Fatigue Syndrome Symptoms
ME CFS chronic fatigue
Dizziness and headaches can be signs of chronic fatigue.
The most common ME/CFS symptoms include:
1. Fatigue, tired all the time, weakness
2. Sensitivity to light
3. Trouble concentrating, hard to focus, memory problems, confusion
4. Dizziness, especially when getting up from lying down
5. Headaches
6. Muscle aches, body ache, muscle weakness, joint pain
7. Enlarged lymph nodes in neck or armpit area, sore throat
8. Tired after exercise or mental exertion (post-exertional malaise)
9. Depression, mood swings, moodiness
10. Insomnia, sleep problemsΒ
Other signs of chronic fatigue syndrome may include: fever, abdominal pain, weight loss or weight gain, allergies, rash, rapid heart beat, and night sweats/hot flashes.
What Causes Chronic Fatigue?
The cause of ME/CFS is not known. Immune system dysfunction, the aftereffects of having a virus, and psychological factors have all been associated with the development of chronic fatigue.
Some people begin to have symptoms of chronic fatigue after having a viral infection, such as Epstein Barr, mononucleosis, or herpes. Postural orthostatic tachycardia syndrome (POTS) is also strongly associated with chronic fatigue.
While it does seem that some people who suffer from CFS also have immune system problems, chronic fatigue is not considered to be an autoimmune disorder in and of itself.Β As with other conditions like lupus or fibromyalgia, CFS sometimes appears after a person has gone through some sort of emotional trauma or physical injury.Β
Some people with chronic fatigue have hormone imbalances related to pituitary hormone, adrenal hormone, or hypothalamus hormones, but it is not understood how these might be related to their condition. Diabetes, anemia, or hypothyroidism can also create hormonal imbalances that can contribute to chronic fatigue.
In some cases, chronic fatigue could be due to a sleep disorder, such as sleep apnea or chronic insomnia. Long-standing mental health issues like depression, anxiety, or PTSD can interfere with sleep and hormone responses, contributing to the chronic fatigue syndrome symptoms.
Treatment for Chronic Fatigue Syndrome Symptoms
tired all the time fatigue
Feeling exhausted after mental or physical activity is called post exertional malaise (PEM).
There is no clear treatment protocol within conventional Western medicine for ME/CFS. A doctor may diagnose myalgic encephalitis if they have ruled out other possibilities and then try to recommend medications or various types of therapy to help people deal with the symptoms of chronic fatigue.
Pain relievers or NSAIDs will often be the standard recommendation for handling ME/CFS related pain like headaches or muscles aches.Β
Doctors may prescribe antidepressants as a way of helping patients cope with depression and anxiety related to chronic fatigue. However, these medications can sometimes cause side effects that will exacerbate the chronic fatigue rather than helping it.
Some doctors have tried treating CFS with antiviral medications, corticosteroids, or thyroid hormone medications. None of the pharmacological interventions that have been used to treat chronic fatigue syndrome have proved to be very effective.
Thus, many patients with ME/CFS consider turning to alternative medicine or complementary therapies to relieve CFS symptoms. Acupuncture is now widely recognized as an alternative therapy for chronic fatigue.Β
Can Acupuncture and Chinese Medicine Help Chronic Fatigue Syndrome?
Traditional Chinese medicine is well suited to treatment for ME/CFS. Overall, TCM philosophy pays close attention to the subtle balance of energy, known as Qi, within the body as a whole, as well as within the various organ systems. By observing the specific symptoms each person experiences as part of chronic fatigue syndrome, we can pinpoint which organ systems are deficient and need strengthening.Β
Classic TCM patterns related to chronic fatigue diagnosis include:
β’ Spleen Qi deficiency
β’ Liver Qi stagnation
β’ Kidney deficiency
β’ Yin deficiency
β’ Heat toxicity
β’ Phlegm obstruction/dampness
Latent heat and dampness are sometimes the long-term effects of a viral infection or other illness, or a long period of emotional stress. These conditions originate from an external pathogenic factor, but then cause a series of imbalances which weaken the kidneys and other organs over time. Acupuncture treatment and herbs can help reduce inflammation and strengthen Qi.
A TCM doctor will choose acupuncture points and a combination of herbs that will help harmonize the affected systems. With herbs, we are able to get nutrients into the body beyond what you can do with foods alone. A balanced diet that cools heat and tonifies the organs will also be important for recovering strength and energy.
One controlled trial found that four weeks of acupuncture treatment led to improvements in CFS symptoms.Β
A systematic review of studies regarding acupuncture treatment for ME CFS showed a reduction in the severity of fatigue.
A study using acupuncture and moxibustion treatment for CFS showed a 90% effective rate, with half of the patients feeling that their CFS was βcured.β
Another study involving acupuncture and moxibustion found that the moxa treatment in particular became more and more effective as treatment sessions continued past the 10th treatment. Moxibustion was shown to have an effect on the vagus nerve, which controls the parasympathetic nervous system.
How long it takes to get results from acupuncture treatment for chronic fatigue will vary from person to person, depending on how long the person has been experiencing CFS, and how deeply the organ systems are affected. TCM treatment has a cumulative effect which strengthens over time and several sessions.
Acupuncture Near Me for Chronic Fatigue Syndrome (ME/CFS) in the Los Angeles Area
ME CFS is far more common than statistics show, because many people suffer in silence and invisibility. Now, many people are struggling with chronic fatigue after having COVID-19. TCM modalities like acupuncture, Chinese herbs, and moxibustion, can help relieve fatigue, depression, mental fogginess, poor sleep, and other symptoms of CFS. If you or someone you love has been feeling exhausted for months without improvement, it may be time to consider trying acupuncture for chronic fatigue.
*This article is for education from the perspective of Traditional Chinese Medicine only. The education provided by this article is not approved by FDA to diagnose, prevent, treat and cure human diseases. It should not stop you from consulting with your physician for your medical conditions. Traditional Chinese Medicine is based on Qi, which is an invisible force that usually cannot be observed by modern science. Because science focuses on testing ideas about the natural world with evidence obtained through observation, these aspects of acupuncture canβt be studied by science. Therefore acupuncture and Chinese herbs are often not supported by double-blind, randomized trials, and they are considered alternative medicine therapies in the United States.
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How to Treat Emphysema With Acupuncture and TCM
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By Qineng Tan, L.Ac., Ph.D. & Xiaomei Cai, L.Ac., Ph.D.
smoking emphysema
Smoking is the number one cause of emphysema.
Pulmonary emphysema is a kind of chronic obstructive pulmonary disease (COPD) that causes coughing and wheezing. Symptoms of emphysema are similar to those of chronic bronchitis and pneumonia. Acupuncture treatment and TCM herbs can help relieve emphysema symptoms and other COPD symptoms.
COPD refers to a group of progressive lung diseases, where damage to the lungs causes serious breathing problems and a chronic cough. Emphysema and chronic bronchitis are both considered COPDs, and it is possible to have both of these conditions at the same time.
Bronchitis is when there is inflammation in the bronchial tubes that bring airflow into the lungs, so they get swollen and have too much mucus buildup. Emphysema is what happens when there is damage to the alveoli, the small air sacs that make up the bottom part of the lungs. This makes it difficult to draw a full breath and get enough oxygen into your bloodstream.
Smoking is the primary thing that causes emphysema. Exposure to toxic chemicals or air pollution, repeated respiratory infections, or a genetic predisposition could also be causes of emphysema.Β
The number one thing people can do to prevent or help emphysema is to quit smoking. Acupuncture treatment can help people overcome nicotine addiction.
Acupuncture and other TCM treatment can also help to clear the lungs, reduce inflammation and shortness of breath, and improve quality of life for people suffering from emphysema and other types of COPD.
Top 10 Symptoms of Emphysema
smoker
A persistent cough can be a sign of emphysema.
In many cases, people do not realize that they have emphysema; they may only be feeling some fatigue and shortness of breath and not take much notice. By the time symptoms have become severe enough that they seek medical help, they may have already suffered a lot of lung damage.
Emphysema symptoms are similar to those of bronchitis; although, with acute bronchitis, there may also be chills and fever, and a sense of tightness in the chest.Β
The most common symptoms of emphysema include:
1. Chronic cough, coughing up phlegm, cough with mucus, smokerβs cough, persistent cough
2. Shortness of breath, especially with activity or exercise (dyspnea)
3. Rapid breathing, breathing fast
4. Wheezing
5. Sputum, mucus, mucous, phlegm
6. Fatigue, chronic fatigue
7. Sleep problems, trouble sleeping, insomnia
8. Heart problems
9. Depression, anxiety
10. Weight loss
Other signs of emphysema or COPD include: blue fingernails or lips, enlarged glands, broken capillaries under the skin, enlarged veins around the neck, enlargement of the chest or rib cage (emphysema barrel chest), and repeated respiratory infections.
Β
4 Stages of COPD
As a COPD, emphysema is a progressive lung disease. Sometimes symptoms worsen and breathing becomes more difficult over a short period of time; this is known as an βemphysema exacerbation.β As a personβs respiratory function decreases, they are said to enter the later stages of COPD. Interventions and treatments may help to slow COPD progression.
Emphysema can greatly increase the risk of a person having heart problems, due to extra pressure on the blood vessels around the heart. It can also eventually lead to there being actual holes in the lung tissues, or a collapsed lung (pneumothorax).
Medical Treatment for Emphysema
emphysema, COPD, lung damage
Imaging may show damage to the lungs due to COPD/emphysema.
In order to diagnose emphysema, doctors may look at X-ray or CT scans imaging to see damage to the lungs. Blood tests and other lung function tests like spirometry may show the level of oxygen in your bloodstream.
Medical science has no cure for the lung damage caused by emphysema. Bronchodilators or inhaled corticosteroids may be prescribed, which can help open airways and reduce shortness of breath. Antibiotics may be used to keep infections like the flu or pneumonia at bay. If emphysema gets to a severe stage, some people may need supplemental oxygen. Some patients may be able to have a major surgery, such as lung volume reduction (removal of damaged lung tissue) or a lung transplant.
TCM modalities like acupuncture and herbal medicine can help relieve shortness of breath and coughing, improving quality of life, while staving off further decline in lung function. Acupuncture, herbs, and moxibustion can be used effectively as adjuncts to regular medical treatments for emphysema.
Can Acupuncture Help Emphysema?
moxibustion TCM treatment
Moxibustion may be a part of TCM treatment for emphysema.
According to TCM theory, emphysema is considered to be caused by Lung deficiency, which can lead to βfei zhang,β distension of the lungs, and/or βchuan zheng,β which means βpanting.β TCM can help COPD in several ways: by clearing lung congestion and opening the bronchial airways, helping to boost immune function so that a person can better avoid infections, and providing more nutrient-rich blood flow to the whole body.
One study found that COPD patients who were given acupuncture treatment had improved breathing when doing a six minute walk.
A systematic review comparing TCM treatment and convention treatment for COPD showed that acupuncture, acupressure massage, and moxibustion were all effective interventions and concluded that TCM works well as a complementary medicine/adjunct therapy for COPD.
Many Chinese herbs and herbal formulations are useful for helping to dissolve phlegm and reduce inflammation of lung tissues. TCM herbal preparations can help reduce phlegm and clear heat, relieve inflammation of airways and improve lung function.
Nutrition is also very important for patients with emphysema, who may suffer weight loss due to lack of proper nutrients in the bloodstream. An acupuncture practitioner will work with each individual to determine what kind of food program will help to reduce inflammation and provide adequate nourishment for the organ systems.
Acupuncture Near Me for Emphysema COPD in Los Angeles
TCM is a good way to help people breathe easier, whether they are suffering from allergies, asthma, pneumonia, Cystic Fibrosis, the common cold or a sore throat, or COPDs like bronchitis and emphysema. If you or someone one you love needs to quit smoking, or has been exposed to chemical pollution through their work, acupuncture can help to detoxify and strengthen the lungs.
*This article is for education from the perspective of Traditional Chinese Medicine only. The education provided by this article is not approved by FDA to diagnose, prevent, treat and cure human diseases. It should not stop you from consulting with your physician for your medical conditions. Traditional Chinese Medicine is based on Qi, which is an invisible force that usually cannot be observed by modern science. Because science focuses on testing ideas about the natural world with evidence obtained through observation, these aspects of acupuncture canβt be studied by science. Therefore acupuncture and Chinese herbs are often not supported by double-blind, randomized trials, and they are considered alternative medicine therapies in the United States.
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-9,010,945,881,264,296,000 | ο»Ώ
Health Benefits of Cranberry Juice
You may have heard that drinking cranberry juice can help with a urinary tract infection (UTI), but thatβs not the only benefit.Β It is also beneficial in preventing stomach disorders and diabetes, as well as gum diseases caused by dental plaque. Phytonutrients, which are naturally derived plant compounds, are present in the fruit juice and have been found to prevent a wide range of health problems.
Cranberries are water-harvested fruits. They are packed with nutrients to help your body ward off infections and boost overall health. In fact, throughout history, theyβve been used to treat urinary issues, upset stomachs, and liver problems.
Cranberries grow in marshes. When the berries are ripe and ready to pick, they float in the water. Being on the waterβs surface exposes them to more sunlight. This may increase their nutritional value.
Like most fruits, you get the highest level of nutrition when you eat cranberries whole. But the juice is still chock-full of benefits.
Β
What is Cranberry Juice?
Cranberry juice is the juice made from cranberries, which are one of the native fruits of North America. The juice is rich in nutrients and is useful in food as well as in medicinal products.
The Latin name for the cranberry plant is Vaccinium macrocarpon. Cranberries have a tremendous amount of antioxidant capacity as compared to other vegetables and fruits like broccoli, spinach, and apples. One cup of cranberries measures a total 8983 antioxidant capacity.
Read on to find out how drinking cranberry juice can benefit your health.
Uses of Cranberry Juice
Cranberry juice, made from the fruit extract or cranberry concentrate, is used to make various sauces and cranberry juice cocktail. About one liter of juice can be extracted from 1500 grams of fresh cranberries. Cranberry juice cocktails are approximately 30% pure cranberry juice mixed with artificial sweetener or fructose.
The fruit extract is also used to make medicines, gels, and tonics for its healing benefits. Dried cranberries are also very healthy and can be enjoyed with breakfast cereals, energy bars, granola bars, trail mixes, or can be added to muffins.
Nutritional Value of Cranberry Juice
Cranberry juice is rich in antioxidants, vitamin C, and salicylic acid. By containing only 45 calories per cup, cranberry juice fits very well within the dietary guidelines. Cranberry juice also contains 87.13 g water per 100 g. It provides energy, protein, and carbohydrates. In terms of minerals, it contains calcium, magnesium, iron, phosphorus, sodium, potassium, and zinc. It also contains vitamins like thiamin, riboflavin, niacin, vitamin B6, vitamin E (alpha-tocopherol), and vitamin K (phylloquinone). Cranberries are members of the Ericaceae family and are native to North America.
Health Benefits of Cranberry Juice
Cranberry juice has long been used for curing various illnesses. The health benefits of cranberries include the following.
Β
Prevent Urinary Tract Infections
Cranberries contain proanthocyanidins, a compound commonly found in plants. Itβs believed that this compound can help prevent UTIs by stopping bacteria from attaching itself to the lining of the urinary tract. If the bacteria canβt grow and spread, it canβt cause an infection.
Unfortunately, research about cranberry juice has been mixed. Some studies show cranberry juice to be effective in reducing the risk for UTIs, while others have found that it isnβt an effective treatment.
More research is still needed to determine the exact benefits.
Β
Antitumor Effects
The anti-tumor efficacy offered by cranberry juice is attributed to the presence of polyphenolic compounds within the fruit. Studies have suggested that regular consumption of cranberry juice inhibits the development and spread of lung, breast, colon, prostate, and other cancers. Cranberry juice contains a high amount of salicylic acid which can help reduce swelling, prevent blood clots, and eliminate tumors.
Β
Heart Health
Cranberries also contain phytonutrients. This gives them an anti-inflammatory property. Inflammation plays a role in damaging blood vessels over time. The damaged vessels then attract plaque, causing atherosclerosis.
Phytonutrients in cranberries could help guard against inflammation, delaying the process and offering protection against heart disease.
There is also some evidence that cranberry juice can help to prevent dental plaque that builds up on teeth and causes gum disease.
Β
Prevents Tooth Decay
According to new research studies, cranberry juice prevents tooth cavities. Proanthocyanidins, a chemical compound present in cranberries, inhibits harmful bacteria from clinging to teeth. These components inhibit acid production and protect the teeth from periodontal diseases by preventing the growth of plaque. Good oral hygiene, along with the consumption of cranberries, disrupts the pathogenic mechanism of dental caries and generally makes for good dental health. At the same time, one should watch out for the soaring sugar content and the acidity of some commercially available cranberry juices β natural juice is always better!
Β
Protect Against Cancer
Cranberries also contain powerful phytochemicals that act as antioxidants. Antioxidants help to protect your body from cell damage due to free radicals. Free radicals contribute to the aging process and may also be risk factors for developing chronic diseases like cancer and heart disease.
Research published in the Journal of Nutrition found that cranberries might have a role in preventing cancer through dietary changes.
Β
Avoids Respiratory Infections
According to conducted studies, cranberry juice helps inhibit certain strains of the Haemophilus influenza, which is a common cause of ear and respiratory infections in children. The juice inhibits the bacteriaβs hair-like structures, inhibiting them from adhering to the surface of the skin.
Β
Improve Digestive Health
The same compounds that help protect the heart also improve your digestive system function.
They can prevent the bacteria, Helicobacter pylori (H. pylori), from growing and multiplying in the stomach lining. This is important because when H. pylori are allowed to grow out of control, stomach ulcers may form.
The antioxidants and other anti-inflammatory substances in cranberries may provide protection against colon cancer, too.
Β
Strengthens Bones and Teeth
Although cranberry juice is a natural source of calcium, many juice companies add extra calcium to cranberry juice. Natural or otherwise, calcium reduces the risk of getting osteoporosis.
Β
Cures Cold
Fresh cranberry juice is effective in fighting infections. It cures sore throats and colds.
Β
Weight Loss
Cranberry juice is rich in organic acids, which have an emulsifying effect on the fat deposits in our body. So, it is good for people who want to shed those extra kilos.
Β
Prevents Kidney Stones
The high amount of acid components in cranberry juice prevent kidney stone formation.
Β
Prevents Scurvy
Deficiency of vitamin C in an individual can result in scurvy. [18] Cranberries provide high levels of vitamin C, which is also vital for the body to make collagen, the main component responsible for the healthy functioning of tissues.
Β
Treats Lung inflammation
The anti-inflammatory effects of cranberry juice have been proven to be effective against the inflammation caused in the lungs by the influenza virus. A substance called nondialyzable material or NDM present in cranberries prevent the influenza virus from sticking to the cells, hence preventing a flu infection.Β
Β
Anti-aging Benefits
The USDA scientists at the human research center suggest that the wealth of phytonutrients and antioxidants present in cranberries play a vital role in providing protection against the problems that develop with age, such as memory loss and lack of coordination. Cranberries have a multitude of therapeutic properties that protect the cells from damage caused by unstable molecules called free radicals that contribute to aging, thereby making the skin look younger.
Β
Choice Your Juice Wisely
When youβre looking for healthy cranberry juice, itβs important not to fall for labeling traps. Thereβs a big difference between cranberry juice cocktail (or cranberry drink) and real cranberry juice.
Juice cocktails contain added sugars like high fructose corn syrup. This isnβt good for you. These cocktails are often made with only a small amount of actual cranberry juice.
Look for labels that say βmade with 100 percent real juiceβ or that list other natural sweeteners like apple or grape juice.
Side Effects of Cranberry Juice
Cranberry is LIKELY SAFE for most people when taken by mouth appropriately. Cranberry juice and cranberry extracts have been used safely in people. However, drinking too much cranberry juice can cause some side effects such as mild stomach upset and diarrhea. Drinking more than 1 liter per day for a long period of time might increase the chance of getting kidney stones.
Special Precautions & Warnings:
β’ Pregnancy and breast-feeding: There is not enough reliable information about the safety of taking cranberry for therapeutic reasons if you are pregnant or breast feeding. Stay on the safe side and avoid use.
β’ Children: Cranberry juice is LIKELY SAFE for children when taken by mouth as a food or drink.
β’ Aspirin allergy: Cranberries contain significant amounts of salicylic acid. Salicylic acid is similar to aspirin. Avoid drinking large quantities of cranberry juice if you are allergic to aspirin.
β’ Inflammation of the stomach lining (Atrophic gastritis): Cranberry juice might increase how much vitamin B12 the body absorbs for people with atrophic gastritis.Β
β’ Diabetes: Some cranberry juice products are sweetened with extra sugar. If you have diabetes, stick with cranberry products that are sweetened with artificial sweeteners.
β’ Low stomach acid (hypochlorhydria). Cranberry juice might increase how much vitamin B12 the body absorbs for people with low levels of stomach acid.
β’ Kidney stones: Cranberry juice and cranberry extracts contain a large amount of a chemical called oxalate. In fact, there is some evidence that some cranberry extract tablets can boost the level of oxalate in the urine by as much as 43%. Since kidney stones are made primarily from oxalate combined with calcium, healthcare providers worry that cranberry might increase the risk of kidney stones. To be on the safe side, avoid taking cranberry extract products or drinking a lot of cranberry juice if you have a history of kidney stones.
Β
The Takeaway
Cranberry juice can be a healthy part of your diet, and even help protect against certain health issues. But itβs not a substitute for treating a medical condition. If you think you have a UTI, go see your doctor.
Normal serving sizes of cranberry juice are safe and healthy, but overdoing it could cause side effects like upset stomach, diarrhea, or spikes in blood sugar.
Cranberry juice can also cause issues for people taking blood-thinning medications. Talk to your doctor about whether or not you should limit or avoid cranberry juice while taking your medication.
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3,450,643,204,740,642,300 | Book Review #4: The Body Keeps the Score.
book review Apr 26, 2020
βIT IS NOT THAT SOMETHING DIFFERENT IS SEEN, BUT THAT ONE SEES DIFFERENTLY." β CARL JUNG
The Body Keeps The Score: Brain, Mind,Β and Body in the Healing of Trauma. By Dr. Bessel van der Kolk.Β Penguin Books, New York, NY. (2014)
The most effective coaches are those that have the ability to connect with others, understand the importance of psychology, and value knowledge about human behavior. You cannot have physiology without psychology. There is information out there about coaching tactics for personality and temperament (Brett Bartholomew), neurological profiling for program design (Christian Thibaudeau) , and targeting neurotransmitters for adherence.
These can be important considerations for training and coaching, however humans are extremely complex and there is always a deeper level. When you interact with others, that deeper level may include understanding how trauma can manifest itself in the body.
We all interact with people who are in pain (not just physical). Trauma doesnβt have to be one event, it can be the inability to cope with a perceived threat at a young age, in which coping strategies become ingrained in our physiology and neurology. These strategies can be teeth clenching, breathe holding, curling toes, and tightening of abdominals (More Information).
Our current behavior and our response to stress is created by past experiences. Our behavior is based upon prediction, in which we will revert back to the behavior from past emotional or physical stressors. As coaches, we need to acknowledge feelings, create body awareness, appreciate the impact of our clients past experiences related to their current behaviors (this includes creating a referral network), and changing our own behaviors to best interact with that client.
As human beings we belong to an extremely resilient species.Β Since time immemorial we have rebounded from our relentless wars, countless disasters (both natural and man-made), and the violence and betrayal in our own lives. But traumatic experiencesΒ do leave traces, whether on a large scale (on our histories and cultures) or close to home, on our families, with dark secrets being imperceptibly passed down through generations. They also leave traces on our minds and emotions, on our capacity for joy and intimacy, and even our biology and immune systems.β
β Dr. Bessel van der Kolk (p.1)
THE BODY KEEPS THE SCORE
Dr. Bessel van der Kolk is the founder and medical director of the Trauma center in Brookline, Massachusetts. In his book, Dr. Bessel van der Kolk shares his years of clinical practice and scientific literature in relation to how trauma can reshape the body and brain (whole body response). He presents treatments such as meditation, sports, yoga, and self expression for recovery. Β
Traumatic experiences physically affects the brain and the body, causing anxiety, inability to concentrate, and the inability to feel sensation. Dr. Bessel van der Kolk explores the complexity of the mind, structure and function of the brainβs emotional pathways, the ways in which humans are connected and attached to each other, and how emotions/behavior are reflected in movement.
Trauma (which can be solely unconscious) can literally change the structure and function of the brain, increase stress hormones, create hypervigilance to threat (real or imagined), restrict movement, create sleep disturbances, oversensitivity to touch or sound, and increase the perception of pain. These experiences can occur as a baby and contribute to the emotional and perceptual map of the world in the developing brain.
βWE HAVE BEGUN TO UNDERSTAND HOW OVERWHELMING EXPERIENCES AFFECT OUR INNERMOST SENSATIONS AND Β OUR RELATIONSHIP TO OUR PHYSICAL REALITY-THE CORE OF WHO WE AREβ¦[TRAUMA] CHANGES NOT ONLY HOW WE THINK AND WHAT WE THINK ABOUT, BUT ALSO OUR VERY CAPACITY TO THINK.β
BIG HITTERS:
β’ βSocial environment interacts with brain chemistryβΒ What is the environment that you are trying to create as a coach? How are you making people feel?
β’ Emotions assign value to an experience.
β’ βIn many places drugs have displaced therapy and enabled patients to suppress their problems without addressing the underlying issues.β
β’ βThe brain-disease model takes control over peopleβs fate out of their own hands and puts doctors and insurance companies in charge of fixing their problems.β (p.37)
β’ βHalf a million children in the United States currently take antipsychotic drugs.β
β’ Can coaches and exercise have a greater impact than prescription medication?
β’ Do we care enough to find a different solution?
β’ Activities such as breathing, moving, and touching can be used to regulate our own physiology.
β’ βBeing able to move andΒ dosomething to protect oneselfΒ is a critical factor in determining whether or not a horrible experience will leave long-lasting scar.βΒ
β’ Physical movement and emotional expression are valuable for overall health and healing.
β’ βRealizing that other people can think and feel differently from usβ¦β
β’ WE ALL PERCEIVE THE WORLD DIFFERENTLY. You are coaching others with their own perceptions and constructed view of the world, not yours.
β’ βWithout flexible, active frontal lobes people become creatures of habit, and their relationships become superficial and routine.βΒ (p.60) Β
β’ βGroundingβ(related to treatment) means that you can feel you butt in your chair, see the light coming through the window, feel the tension in your calves, and hear the wind stirring the tree outside (p.70). This is sensation.
β’ Our physical shape (body language-nonverbal expression of emotion), tone of voice, and facial expressions feed our emotional pathways (and vice versa) and provide communication and intention to others.Β This is the body-brain connection.
β’ We can experience physical pain from emotions.
β’ The heart, guts, and brain are connected and communicate via the pneumogastric nerve. Mind and body are indistinguishable.
β’ Youβre inability to digest your food can be related to your emotional state (possibly due to exposure to stress).
β’ Sense of purpose involves both movement and emotions.Β Making things meaningful and providing others with a sense of purpose or importance is one of the most genuine things you can do as a coach. Β
β’ Social support.Β βOur culture teaches us to focus on personal uniqueness, but at a deeper level we barely exist as individual organisms. Our brain are built to help us function as members of a tribe. We are part of that tribe even when we are by ourselvesβ¦β (p.80)
β’ βBeing able to feel safe with other people is probably the single most important aspectβ¦safe connections are fundamental to meaningful and satisfying lives.β
β’ βMost traumatize people find themselves chronically out of sync with the people around them.β
β’ Exercise and movementΒ provides body awareness and increased capacity to manage stress.
β’ The βcore of our self-awareness rests on the physical sensations that convey the inner states of the body. β Physical self-awareness provides the ability to release the tyranny of the past and provides a sense of self.
β’ Practices such as movement therapy and yoga can be used as sensory experiences by exploring traumaβs deeper impact on the body (neuroscience of self-awareness). Simply noticing what you feel fosters emotional regulation. Sensory (and motor) experiences are importantβ¦
β’ The flip side is exercise addiction, which can be sensation seeking.
β’ βNobody grows up under ideal circumstancesβ¦every life is difficult in its own way.β (p.306)
βWHEN WE CANNOT RELY ON OUR BODY TO SIGNAL SAFETY OR WARNING AND INSTEAD FEEL CHRONICALLY OVERWHELMED BY PHYSICAL STIRRINGS, WE LOSE THE CAPACITY TO FEEL AT HOME IN OUR OWN SKIN, AND BY EXTENSION, IN THE WORLD.β (P.307)
OVERALLΒ SCORE: 8.6/10
When you are a coach, you have a responsibility for a position of influence. I often observe the dehumanization of athletes in relation to the avoidance of human connection. Today, we limit social interaction with the use of technology and often breed a superficial environment. Coaches have the ability to positively impact other individuals but there needs to be knowledge of human behavior (including the information presented in the book), communication skills, and acknowledgement.
We are all different. We all perceive the world differently from past experiences and temperaments. Remember this when you are dealing with others (position of influence).
Have compassion.
This book is dense and emotional at times, however ever since I read it a few years ago it has been in my list for top 3 favorite books. The information presented is invaluable in appreciating behavior, past experiences, pain, and relationships. It is close to a β10β because itβs an exploration of the complexity of the human species, and thatβs quality to me.
Related Recommended Resource:Β Seth Oberst, DPT, SCS, CSCS and his Stress, Movement & Pain course
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There is an overwhelmingΒ amount of information out there, so I put all the best resources from the most trusted professionals in the industry together in one place. Download this free resource guide,Β so you can save time searching and start learning from the most respected minds in the industry. | {
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4,927,777,015,434,544,000 | CBD Oil Strength Explained
Aug 17, 2021 | CBD Oils
If you browse our CBD oils, youβll find a range of strengths, from 300 mg CBD Tinctures to 1500 mg CBDA Tinctures. Before you begin a CBD regimen, make sure you understand what those strength numbers refer to.
Read the Labels Carefully
You need to know how much CBD is in the product and how much of the product you should take. CBD doses are expressed in milligrams (mg). Make sure to read the product labels carefully. In the case of cbdMDβs 300 mg CBD oil, the β300 mgβ refers to the entire tincture package. Look at the fine print and instructions to get the CBD concentration per serving.
CBDA Tincture Label
Another example. βcbdMDβsΒ CBD oil capsulesΒ come in 30-count and 60-count bottles. The highest number of milligrams for a 30-count bottle is 1500, while the highest for a 60-count bottle is 3000. However, if you look at the labelβs bottom, it says the same thing: β50 mg CBD per capsule.β The 60-count bottle has twice as many milligrams per bottle because it has twice as many capsules per bottle, not because itβs more potent per capsule.β cbdMD
Is it Milligrams of Pure CBD?
cbdMDβs βSuperior Broad Spectrumβ process uses precise measurements, so thereβs no guesswork involved, and the milligrams on the labels of their products represent the quantity of pure CBD; the other hemp-based ingredients are extras. There are exceptions. The 1500 mg CBD PM tinctures and soft gels have 40 mg of CBD and 10 mg of CBN. The best way to view precisely what is in a product, view its lab results (COA).
Healer CBDA Tinctures, using the βHealer Spectrumβ, also have a Certificate of Analysis that you can view to find out the exact concentrations of CBDA.
What CBD Strength Should You Use?
Unfortunately, there is not a one-size-fits-all answer to this question, even between people with similar body types. Healer recommends that βless is moreβ when starting a CBD regime, as you learn how your body reacts.
Potency Options
β’ Low-Potency CBD (150-300 mg) makes good options for those who are especially responsive to CBD products (perhaps their endocannabinoid system is more active) or who simply want to use CBD for wellness support.
β’ Mid-range CBDΒ (600-750 mg) may be more helpful for those who need a little extra support or who are not getting the benefits they need from the lower dosage.
β’ High-Strength CBD (1000 mg and up) is available for those with more cumbersome issues such as difficulty maintaining a healthy sleep pattern or more prone to stress responses.
It is advised to start with the lowest concentration and work your way up slowly, as needed.
CBD Results Do Take Time
Per cbdMD, βAnother thing we know is that CBD tends to accumulate in your body over time. While some people report dramatic results on first use, many others find that the reaction creeps up on them after a few weeks of daily consumption.Β
For that reason, we advise starting slow. As you may have noticed, a low-concentration CBD product is also a cheaper one, so if you can derive benefits from it, then it can be helpful for your pocketbook as well as your health. Try taking a modest CBD oil strength every morning and evening, monitor the responses, and gradually increase if necessary.Β
Give it about a month before adjusting the serving size up, if needed. But if you feel it is too much, you can decrease the serving size at any time. Just know as you adjust up, you need time for the product to work in your system adequately, and it takes a few weeks to assess this appropriately.β
cbd in the human body
Delivery Methods
βTo get CBD into your system, you can swallow, absorb under your tongue, inhale it or absorb through skin (topical). In each of these methods, the CBD gets broken down a little before it reaches your bloodstream β the percentage of CBD that makes it to the bloodstream determines the productβs bioavailability,β per cbdMD.
Keep in mind, your metabolism has a play in the precise bioavailability, as well.
Ingesting CBD
Whether through CBD capsules or edibles such as gummies, swallowing has the lowest bioavailability because it has to go through your digestive system before getting to your bloodstream. Swallowing can beΒ usefulΒ if you like your CBD slow and steady because it lasts for about seven hours.
CBD Through a Mucous Membrane
This is typically performed by dropping CBD oil under your tongue and holding it there for 30 to 60 seconds before swallowing. This is how CBD, and CBDA Tinctures, can be used for best results, as bioavailability through this method is higher.
CBD Drops in Food and Drink
You can add drops to your food or drink. But this may delay onset time and require more drops
Inhaled CBD
Vaping, generally. This yields a much higher bioavailability than oral methods since your lungs are full of tiny blood vessels designed to absorb the gasses found there. This method yields a faster, stronger, but shorter-lived impact, usually around three or four hours.
Topical CBD
Lotion rubbed on and the CBD is absorbed through the skin. This is not getting into your bloodstream, though since your skin also has an endocannabinoid receptors, you can still derive some benefit from them.
CBD Gummies
Building Your Own CBD Regimen
The first question to ask is, βWhy am I taking CBD exactly?β What benefits are you looking for? The answers will play a role in what product you choose to use. Starting out, you may need to establish a baseline, and to get that you may want to keep a daily CBD regime, try different products based on physical or mental needs,
Β
CBD Oil Benefits
Some desired CBD oil benefits could include:
β’ General improved wellness.
β’ Better rest.
β’ Help winding down at bedtime.
β’ A more balanced sense of calm.
β’ Help with managing daily stress.
β’ Help with common aches from, for example, βoverdoing it.β
β’ Workout recovery, such as some products designed with ingredients such as histamine dihydrochloride to help with pain and soreness.
β’ To soothe or moisturize the skin.
CBD Oil for Exercise Recovery
If youβre leading an active lifestyle or have a particularly strenuous project set up like a home repair or a hiking trip, you might want to take a more concentrated CBD oil to aid in exercise recovery. Joint and muscle strains can benefit from CBD Freeze or CBD Recover, thanks to added topical painkillers. The difference in CBD oil strengths is an important factor in how you use it.
Daily CBD Oil for Wellness
The easiest way to keep a daily CBD regimen is to fit it into your existing routine. For instance, if you take supplements every morning, you can add a low- or medium-strength CBD oil capsule to the set. Or, if youβre religious about your morning coffee, try adding a few drops of CBD oil to get you started on the right foot.
CBD Oil for Sleep
Times of physical or mental strain can also make it tough to maintain normal sleep patterns. On such occasions, a nightly dropper full ofΒ CBD oil with melatoninΒ could be just the thing. Melatonin enhances the relaxing powers of CBD and helps stabilize your circadian rhythms.
For a thorough rundown of the different product options, check outΒ How to Take CBD Oil.
Consult With Your Physician
This is a general guide. Your physician, who knows you and your body, can give you a good idea before starting a CBD regimen. Also, your physician can ensure that you are not taking any medications that might interact with CBD.
Β
These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.
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-747,280,241,509,980,800 | Are you a physician?
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The Symptoms of Basal Cell Carcinoma
The symptoms of basal cell carcinoma occasionally resemble the features of non-cancerous skin conditions like psoriasis or eczema. Only a trained physician or specialist can decide for sure if it is basal cell carcinoma. If you believe you may have a basal cell carcinoma, see a doctor right away.
The Symptoms of Basal Cell Carcinoma: 5 Warning Signs
1. Open Sores
Open sores that bleed, ooze, or crust repeatedly are a common sign of early stage basal cell carcinoma. For example, a wound or sore that remains open for a couple of weeks, heals, closes, and then a couple weeks later reopens.
2. Reddish, Irritated Skin
Patches of red, irritated skin can be a symptom of basal cell carcinoma. They frequently occur on the face, chest, shoulders, arms, and legs. In some cases, the area in question may cause pain or itchiness, in others, the skin remains red with no discomfort at all.
3. Shiny Bumps or Nodules
Raised areas of skin that are shiny or pearly are another warning sign of basal cell carcinoma. They can appear pink, red, or white, and tan, black, or brown on those with dark hair. Occasionally, these nodules can be confused with a normal mole.
4. Elevated Growths
Growths with a slightly raised border and crusted indentation in the center, often pink, are another symptom of basal cell carcinoma. As the growth grows in size, blood vessels may develop on its surface.
5. Apparent Scars
Waxy, yellow, or white areas on the skin that look similar to scars are an indicator of the presence of an invasive basal cell carcinoma that is actually larger than it appears to be on the surface. They generally have ill-defined borders, and the skin looks taut.
If you think you might have a basal cell carcinoma, contact your doctor immediately. If you are seeking treatment for basal cell or squamous cell carcinoma, consider the SRT-100β’ as an alternative to Mohs surgery.
The SRT-100β’ delivers precise bursts of Superficial RadiotherapyΒ to the affected area. The treatment is painless, and there is no downtime afterwards. Interested in learning more about the SRT-100β’? Contact Sensus Healthcare today or ask your doctor if the SRT-100β’ is the right treatment for you.
Start your journey to a happy & healthy recovery.
Or search for a treatment location:
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FIND A TREATMENT LOCATION
Β©Copyright 2022 - Sensus Healthcare - All Rights Reserved. | {
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Playing video games for long hours can cause vision-related problems in kids such as eye strain or computer vision syndrome. When your eyes are exposed to excessive screen time, you may experience symptoms such as eye fatigue, blurry vision, eye discomfort and headaches.
Kids get so addicted to video games, that they forget to take breaks in between. Continuous use of display screens can put your eye health at risk and may even cause focusing problems, especially in developing children.
Why is screen time bad for our eyes?
Keeping your head buried in a screen can cause problems with your eye health. Display screens emit blue light which inhabits short wavelengths that contain more energy. This light is harmful to our eyes and leads to ocular exhaustion. This is why opticians recommend you have a blue light coating on yourΒ prescription glassesΒ lenses to combat this problem.
When youβre staring at screens, you often think that your eyes are at rest and arenβt working hard. But, this is not true. In fact, the opposite of that is true.
Your eyes put more effort during screen time as compared to any other activity. Also, people tend to blink less when theyβre looking at display screens. When our mind is focused on something, we tend to blink our eyes less so we donβt miss anything. But, it only leads to dry and irritated eyes which can turn into a huge problem over time.
How do video games affect your vision?
Most video games are long and take hours to finish. This is a lengthy commitment and will require your eyes to focus on the screen for a long time. Long-term exposure to blue light leads to a few temporary visual symptoms like headaches, blurred vision or even nearsightedness.
Prolonged hours of using screens at close proximity can even lead to computer vision syndrome. This problem is also known as digital eye strain and has symptoms similar to the ones we talked about above.
So, if your kids are into video games, you need to make sure they are taking frequent breaks to give their eyes some rest. If they need vision correction, you can buyΒ prescription glasses onlineΒ or offlineΒ loaded with blue light filters so they donβt strain their eyes while playing.
Also, the positioning of the device and your posture matter if you donβt want to have bad back or neck and shoulder pain.
Focusing problems
The eyes focus differently when youβre looking at a screen than when youβre reading a book. When reading a book, newspaper or magazine, your eyes know exactly at what distance to focus to give you the clearest vision.
But, this is quite different with display screens. Since these screens shave blue light, the contrast is off due to which the eyes need to constantly change their focus and get tired in the process.
Also, when playing video games, people tend to focus their eyes on the screen for far too long than they should. This makes it a tough job for the eyes to focus on any other distance even long after you finish playing.
If youβre a professional player, then you need to protect your eyes while you play your favourite video games for hours. Invest in a good-quality pair of gaming glasses that not only block blue light but reduce screen glare and magnify your vision so you can see the images on the screen in a wide frame.
You can turn your normal glasses frames for menΒ or women into gaming glasses by replacing the lenses with the ones that have blue light filters in them. This process is called reglazing glasses where you only change the lens and save yourself the cost of buying a whole pair.
What should parents do?
If your kids enjoy playing video games, encourage them to limit the time and take frequent breaks. Donβt let them play continuously for more than 20 minutes. You can take them out to the park so they can indulge in some outdoor activities as well. It will take their minds off of gaming.
Make sure theyβre sitting at an appropriate distance from the screen. Using devices in close proximity makes you more likely to fall victim to digital eye strain.
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"code": "617.8",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "16",
"label": "Personal Blog"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | f177b5043c75ce8646dc8ec41dbca083 |
-6,488,302,194,022,573,000 | "If You Think You Get Resources, Then Read This\n\nImportant Information On Ketosis\n\nPeople who ar(...TRUNCATED) | {"url":"https://www.witchhunteronline.com/if-you-think-you-get-resources-then-read-this/","source_do(...TRUNCATED) | {"line_start_idx":[0,47,48,81,82,437,438,923,924,1502,1503,1857,1858,2325,2326,2599,2600,2640,2641],(...TRUNCATED) | {"red_pajama_v2":{"ccnet_original_length":2678.0,"ccnet_original_nlines":18.0,"rps_doc_curly_bracket(...TRUNCATED) | {"free_decimal_correspondence":{"primary":{"code":"613.2","labels":{"level_1":"Industrial arts, Tech(...TRUNCATED) | f177b5043c75ce8646dc8ec41dbca083 |
End of preview. Expand
in Data Studio
π₯ Taxonomy Med w/ DCLM
π Website | π₯οΈ Code | π Paper
A high-quality medical dataset curated from web data using taxonomy-based filtering, containing 205 billion tokens of medical content.
π― Dataset Overview
This dataset is part of the Essential-Web project, which introduces a new paradigm for dataset curation using expressive metadata and simple semantic filters. Unlike traditional medical datasets that require complex domain-specific pipelines, our approach leverages a 12-category taxonomy to efficiently identify and extract high-quality medical content.
π¬ EAI-Taxonomy Med w/ DCLM (205B tokens): Documents targeting scientific medical content that exhibit reasoning and are technically correct, combined with the DCLM classifier to filter for instruction-dense documents.
π Performance
Our taxonomy-based approach achieves superior results with significantly less curation effort:
| Dataset | CareQA-en | MedMCQA | MedQA-USMLE | PubMedQA | MMLU-Med | Curation Complexity |
|---|---|---|---|---|---|---|
| DCLM-baseline | 26.9% | 31.6% | 25.9% | 70.6% | 31.0% | General web filtering |
| TheBlueScrubs-v1 | 25.1% | 32.2% | 25.3% | 69.2% | 25.7% | Complex domain pipeline |
| EAI-Taxonomy Med | 27.7% | 32.5% | 28.1% | 67.0% | 29.5% | Simple semantic filter |
| EAI-Taxonomy Med w/ DCLM | 31.5% | 32.7% | 30.1% | 68.6% | 39.2% | + DCLM classifier |
π Key Findings
- Robust Performance: Achieves best or near-best performance across all medical evaluations
- Above Random Performance: Successfully performs above chance (~25%) on MedQA-USMLE where baseline methods fail
- Consistent Improvements: +13.8% average improvement over existing specialized medical datasets
- Efficiency: Strong medical knowledge without complex domain-specific curation pipelines
Dataset Schema Documentation
Overview
This dataset contains web-crawled text data with comprehensive metadata, quality signals, and taxonomic classifications. Each record represents a document extracted from web archives with detailed provenance tracking and quality assessment metrics.
Core Fields
| Field | Type | Description | Path |
|---|---|---|---|
id |
Int64 |
Unique identifier based on document hash | id |
text |
String |
The main textual content of the document | text |
EAI Taxonomy Classification
Comprehensive hierarchical classification system with primary and secondary labels - the most important feature of this dataset. The taxonomy is designed to provide detailed subject categorization, document type identification, content quality assessment, and extraction quality indicators.
Free Decimal Correspondence (FDC)
A Dewey Decimal-inspired classification system with 3-level hierarchical labels. The FDC provides nested categories where each successive level refines its parent category. It's designed to be compatible with the Dewey Decimal System for library cataloging.
Level Structure:
- Level 1: Top-level categories (0-9) covering broad subject areas like General works, Philosophy, Religion, Social Sciences, etc.
- Level 2: Sub-divisions (00-99) that refine Level 1 categories
- Level 3: Specific categories (000-999) that further refine Level 2 categories
| Component | Description | Path |
|---|---|---|
| Primary Code | Main classification code | eai_taxonomy.free_decimal_correspondence.primary.code |
| Primary Level 1 | Top-level category (0=General works, 1=Philosophy, 2=Religion, 3=Social Sciences, 4=Language, 5=Science, 6=Technology, 7=Arts, 8=Literature, 9=History/Geography) | eai_taxonomy.free_decimal_correspondence.primary.labels.level_1 |
| Primary Level 2 | Mid-level category | eai_taxonomy.free_decimal_correspondence.primary.labels.level_2 |
| Primary Level 3 | Specific category | eai_taxonomy.free_decimal_correspondence.primary.labels.level_3 |
| Secondary Code | Alternative classification code | eai_taxonomy.free_decimal_correspondence.secondary.code |
| Secondary Level 1 | Alternative top-level category | eai_taxonomy.free_decimal_correspondence.secondary.labels.level_1 |
| Secondary Level 2 | Alternative mid-level category | eai_taxonomy.free_decimal_correspondence.secondary.labels.level_2 |
| Secondary Level 3 | Alternative specific category | eai_taxonomy.free_decimal_correspondence.secondary.labels.level_3 |
We recommend this viewer for easily navigating the FDC categories when curating filters: https://www.librarything.com/mds
Bloom's Taxonomy Integration
Based on Anderson and Krathwohl's 2001 revision of Bloom's Taxonomy of Educational Objectives, providing two complementary categorization dimensions for educational content analysis.
Knowledge Domain
Categorizes the type of knowledge demonstrated in the document:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main knowledge domain code | eai_taxonomy.bloom_knowledge_domain.primary.code |
| Primary Label | Main knowledge domain label | eai_taxonomy.bloom_knowledge_domain.primary.label |
| Secondary Code | Alternative knowledge domain code | eai_taxonomy.bloom_knowledge_domain.secondary.code |
| Secondary Label | Alternative knowledge domain label | eai_taxonomy.bloom_knowledge_domain.secondary.label |
Possible Values:
| Code | Label | Description |
|---|---|---|
-1 |
Abstain | Unable to determine |
1 |
Factual | Basic elements to learn or solve problems |
2 |
Conceptual | Interrelationships between basic elements within larger context |
3 |
Procedural | Methods and techniques in the discipline |
4 |
Metacognitive | Awareness of how learning works in relation to oneself |
Cognitive Processing Level
Assesses the learning and thinking skill levels demonstrated by the document author:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main cognitive process code | eai_taxonomy.bloom_cognitive_process.primary.code |
| Primary Label | Main cognitive process label | eai_taxonomy.bloom_cognitive_process.primary.label |
| Secondary Code | Alternative cognitive process code | eai_taxonomy.bloom_cognitive_process.secondary.code |
| Secondary Label | Alternative cognitive process label | eai_taxonomy.bloom_cognitive_process.secondary.label |
Possible Values:
| Code | Label | Description |
|---|---|---|
-1 |
Abstain | Unable to determine |
1 |
Remember | Retrieve relevant knowledge from memory |
2 |
Understand | Determine meaning of instructional messages |
3 |
Apply | Use a procedure in a given situation |
4 |
Analyze | Break materials into components and determine relationships |
5 |
Evaluate | Make judgments based on criteria and standards |
6 |
Create | Create new or original work |
Document Characteristics
Document Type v1
In-house classification of common web document types and formats:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main document type code | eai_taxonomy.document_type_v1.primary.code |
| Primary Label | Main document type label | eai_taxonomy.document_type_v1.primary.label |
| Secondary Code | Alternative document type code | eai_taxonomy.document_type_v1.secondary.code |
| Secondary Label | Alternative document type label | eai_taxonomy.document_type_v1.secondary.label |
Possible Values:
| Code | Label | Examples |
|---|---|---|
-1 |
Abstain | Unable to classify |
1 |
News/Editorial | CNN articles, opinion columns |
2 |
Academic/Research | ArXiv papers, research articles |
3 |
Reference/Encyclopedic/Educational | FAQs, Wikipedia entries |
4 |
Code/Software | GitHub repos, code examples |
5 |
Social/Forum | Conversation threads, Q&A boards |
6 |
Promotional/Advertisement | Product pages, calls to action |
7 |
Search/Directory/Bibliography | Link pages, search results |
8 |
Adult/Pornographic | Adult content |
9 |
Personal/Misc | Blogs, user profiles |
10 |
Machine-Generated | Lorem ipsum, garbled text |
11 |
Legal/Regulatory | Contracts, terms of service |
12 |
Government/Political | Legislation, press releases |
13 |
Literary/Creative | Poems, short stories |
14 |
Reviews/Critiques | Film critiques, product reviews |
15 |
E-Commerce/Marketplace | eBay listings, Amazon pages |
16 |
Images/Videos/Audio | YouTube videos, Imgur pages |
17 |
Other/Unclassified | Documents that resist classification |
Document Type v2
Updated classification based on WebOrganizer taxonomy with refined categories for improved document classification accuracy:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main document type code (v2) | eai_taxonomy.document_type_v2.primary.code |
| Primary Label | Main document type label (v2) | eai_taxonomy.document_type_v2.primary.label |
| Secondary Code | Alternative document type code (v2) | eai_taxonomy.document_type_v2.secondary.code |
| Secondary Label | Alternative document type label (v2) | eai_taxonomy.document_type_v2.secondary.label |
Complete Value Mapping:
| Code | Label | Examples |
|---|---|---|
-1 |
Abstain | Documents requiring human review |
1 |
About (Org.) | Company about pages, mission statements |
2 |
About (Personal) | Personal bios, LinkedIn profiles |
3 |
Academic Writing | Research papers, abstracts, dissertations |
4 |
Audio Transcript | Interview transcripts, court records, captions |
5 |
Comment Section | Reddit threads, blog comments |
6 |
Content Listing | Site maps, product catalogs, directory listings |
7 |
Creative Writing | Song lyrics, novel excerpts, poetry |
8 |
Documentation | API docs, README files, user manuals |
9 |
FAQ | FAQ pages, Q&A lists |
10 |
Knowledge Article | Wikipedia articles, Britannica entries |
11 |
Legal Notices | Privacy policies, license agreements, terms of service |
12 |
Listicle | Buzzfeed-style articles, "Top 10" lists |
13 |
News (Org.) | Government blog posts, corporate announcements |
14 |
News Article | Newspaper articles, CNN content, breaking news |
15 |
Nonfiction Writing | Editorials, obituaries, memoirs, opinion pieces |
16 |
Personal Blog | Personal journals, diary entries, lifestyle blogs |
17 |
Product Page | Product descriptions, course offerings, sales pages |
18 |
Q&A Forum | Quora posts, Stack Exchange discussions |
19 |
Spam / Ads | SEO keyword stuffing, promotional spam |
20 |
Structured Data | Datasheets, glossaries, JSON files, databases |
21 |
Customer Support | Help articles, troubleshooting guides |
22 |
Truncated | Paywalled sites, image galleries, partial content |
23 |
Tutorial | Cooking recipes, WikiHow pages, step-by-step guides |
24 |
User Review | Yelp reviews, TripAdvisor feedback, product reviews |
25 |
Other/Unclassified | Miscellaneous documents not fitting other categories |
Extraction Artifacts
Assessment of technical extraction quality, identifying issues from HTML-to-text conversion:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main extraction artifact code | eai_taxonomy.extraction_artifacts.primary.code |
| Primary Label | Main extraction artifact label | eai_taxonomy.extraction_artifacts.primary.label |
| Secondary Code | Alternative extraction artifact code | eai_taxonomy.extraction_artifacts.secondary.code |
| Secondary Label | Alternative extraction artifact label | eai_taxonomy.extraction_artifacts.secondary.label |
Possible Values:
| Code | Label | Description |
|---|---|---|
-1 |
Abstain | Unable to determine |
0 |
No Artifacts | Clean text with no leftover HTML or irrelevant elements |
1 |
Leftover HTML | HTML/code artifacts remaining after extraction |
2 |
Text Extraction Errors | Broken math expressions, encoding errors, improperly parsed tables |
3 |
Irrelevant Content | Headers, footers, nav menus extracted by mistake |
4 |
Indeterminate | Insufficient content to judge |
Missing Content
Assessment of content completeness and extraction success:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main missing content code | eai_taxonomy.missing_content.primary.code |
| Primary Label | Main missing content label | eai_taxonomy.missing_content.primary.label |
| Secondary Code | Alternative missing content code | eai_taxonomy.missing_content.secondary.code |
| Secondary Label | Alternative missing content label | eai_taxonomy.missing_content.secondary.label |
Possible Values:
| Code | Label | Description |
|---|---|---|
-1 |
Abstain | Unable to determine |
0 |
No Missing Content | Complete and coherent text |
1 |
Truncated Snippets | Obvious "...", incomplete paragraphs, cut-off text |
2 |
Click Here References | "Download here", "Click here" without linked content |
3 |
Incoherent Flow | Unreadable or illogical flow due to missing context |
4 |
Missing Images or Figures | Placeholders or references to missing visual content |
5 |
Missing Referenced Data | References to absent tables/datasets (e.g., "See Table 3") |
6 |
Indeterminate | Insufficient content to judge |
Text Structure Information
| Field | Type | Description | Path |
|---|---|---|---|
| Line Start Indices | List[Int32] |
Starting indices of each line | line_start_n_end_idx.line_start_idx |
| Line End Indices | List[Int32] |
Ending indices of each line | line_start_n_end_idx.line_end_idx |
Content Quality Dimensions
Quality assessment inspired by NaturalReasoning and FineWeb efforts to categorize web data by information sophistication.
Reasoning Depth
Assesses the complexity and sophistication of logical reasoning in the document:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main reasoning depth code | eai_taxonomy.reasoning_depth.primary.code |
| Primary Label | Main reasoning depth label | eai_taxonomy.reasoning_depth.primary.label |
| Secondary Code | Alternative reasoning depth code | eai_taxonomy.reasoning_depth.secondary.code |
| Secondary Label | Alternative reasoning depth label | eai_taxonomy.reasoning_depth.secondary.label |
Possible Values:
| Code | Label | Description |
|---|---|---|
-1 |
Abstain | Unable to determine |
1 |
No Reasoning | Facts present but no evidence of reasoning |
2 |
Basic Reasoning | Basic analysis with minimal explanation and summarization |
3 |
Intermediate Reasoning | Some logical steps connecting ideas and structured thinking |
4 |
Advanced Reasoning | Multi-step reasoning and thorough analysis with well-developed explanations |
5 |
Exceptional Reasoning | Novel abstractions, theoretical frameworks, long chain-of-thought, original insights, or proofs |
6 |
Indeterminate | Insufficient context to judge |
Technical Correctness
Evaluates the accuracy and precision of technical information:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main technical correctness code | eai_taxonomy.technical_correctness.primary.code |
| Primary Label | Main technical correctness label | eai_taxonomy.technical_correctness.primary.label |
| Secondary Code | Alternative technical correctness code | eai_taxonomy.technical_correctness.secondary.code |
| Secondary Label | Alternative technical correctness label | eai_taxonomy.technical_correctness.secondary.label |
Possible Values:
| Code | Label | Description |
|---|---|---|
-1 |
Abstain | Unable to determine |
1 |
Technically Flawed | Significant errors undermining content validity |
2 |
Partially Correct | Some correctness but contains flaws, omissions, or errors |
3 |
Mostly Correct | Technical correctness with minor flaws or incomplete explanations |
4 |
Highly Correct | High technical correctness with precise definitions and clear explanations |
5 |
Exceptionally Correct | Exceptional technical correctness with formal proofs and flawless content |
6 |
Not Applicable/Indeterminate | No technical content or insufficient context |
Education Level
Assesses the appropriate educational background required to comprehend the content:
| Component | Description | Path |
|---|---|---|
| Primary Code | Main education level code | eai_taxonomy.education_level.primary.code |
| Primary Label | Main education level label | eai_taxonomy.education_level.primary.label |
| Secondary Code | Alternative education level code | eai_taxonomy.education_level.secondary.code |
| Secondary Label | Alternative education level label | eai_taxonomy.education_level.secondary.label |
Possible Values:
| Code | Label | Description |
|---|---|---|
-1 |
Abstain | Unable to determine |
1 |
General Audience | Accessible to anyone with basic literacy; simple terms |
2 |
High School Level | Requires high school education; specialized terminology explained for non-experts |
3 |
Undergraduate Level | Requires college education; uses specialized terminology and assumes background knowledge |
4 |
Graduate/Expert Level | Requires graduate education or domain expertise; assumes deep background knowledge |
5 |
Indeterminate | Insufficient content to judge educational level |
Metadata
Metadata Structure
The metadata field contains a nested structure with web archive information:
| Field | Type | Description | Path |
|---|---|---|---|
| URL Information | |||
| URL | String |
Original URL of the document | metadata.url |
| Source Domain | String |
Domain name of the source | metadata.source_domain |
| Snapshot ID | String |
Identifier for the web archive snapshot | metadata.snapshot_id |
| WARC Metadata | WARC (Web ARChive) format metadata | ||
| Content Length | String |
Size of the content | metadata.warc_metadata.Content-Length |
| Content Type | String |
MIME type of the content | metadata.warc_metadata.Content-Type |
| Block Digest | String |
Checksum of the WARC block | metadata.warc_metadata.WARC-Block-Digest |
| Concurrent To | String |
Related WARC records | metadata.warc_metadata.WARC-Concurrent-To |
| Date | String |
Timestamp of the crawl | metadata.warc_metadata.WARC-Date |
| IP Address | String |
Source server IP address | metadata.warc_metadata.WARC-IP-Address |
| Payload Type | String |
Identified content type | metadata.warc_metadata.WARC-Identified-Payload-Type |
| Payload Digest | String |
Checksum of the payload | metadata.warc_metadata.WARC-Payload-Digest |
| Record ID | String |
Unique WARC record identifier | metadata.warc_metadata.WARC-Record-ID |
| Target URI | String |
Original target URL | metadata.warc_metadata.WARC-Target-URI |
| Truncated | String |
Truncation status | metadata.warc_metadata.WARC-Truncated |
| Type | String |
WARC record type | metadata.warc_metadata.WARC-Type |
| Warcinfo ID | String |
Associated warcinfo record | metadata.warc_metadata.WARC-Warcinfo-ID |
| Additional Info | |||
| WARC Info | String |
Additional WARC information | metadata.warc_info |
Quality Signals
The dataset includes two comprehensive quality assessment frameworks:
Red Pajama v2 Quality Metrics
Text quality indicators derived from the Red Pajama v2 filtering pipeline:
Content Structure Metrics
| Metric | Description | Path |
|---|---|---|
| Original Length | Original document length | quality_signals.red_pajama_v2.ccnet_original_length |
| Original Lines | Number of lines in original document | quality_signals.red_pajama_v2.ccnet_original_nlines |
| Sentence Count | Total sentence count | quality_signals.red_pajama_v2.rps_doc_num_sentences |
| Word Count | Total word count | quality_signals.red_pajama_v2.rps_doc_word_count |
| Mean Word Length | Average word length | quality_signals.red_pajama_v2.rps_doc_mean_word_length |
Language Quality Metrics
| Metric | Description | Path |
|---|---|---|
| Stop Word Fraction | Proportion of stop words | quality_signals.red_pajama_v2.rps_doc_stop_word_fraction |
| Unique Words Fraction | Fraction of unique words | quality_signals.red_pajama_v2.rps_doc_frac_unique_words |
| All Caps Words | Fraction of words in all capitals | quality_signals.red_pajama_v2.rps_doc_frac_all_caps_words |
| Non-Alphabetic Words | Fraction of non-alphabetic words | quality_signals.red_pajama_v2.rps_doc_frac_no_alph_words |
| Unigram Entropy | Entropy measure of word distribution | quality_signals.red_pajama_v2.rps_doc_unigram_entropy |
Content Pattern Analysis
| Metric | Description | Path |
|---|---|---|
| Curly Bracket Density | Curly bracket density (code indicator) | quality_signals.red_pajama_v2.rps_doc_curly_bracket |
| Symbol-to-Word Ratio | Symbol-to-word ratio | quality_signals.red_pajama_v2.rps_doc_symbol_to_word_ratio |
| Ellipsis Line Endings | Lines ending with ellipsis | quality_signals.red_pajama_v2.rps_doc_frac_lines_end_with_ellipsis |
| Lorem Ipsum Detection | Lorem ipsum text detection | quality_signals.red_pajama_v2.rps_doc_lorem_ipsum |
| Offensive Content | Potentially offensive content detection | quality_signals.red_pajama_v2.rps_doc_ldnoobw_words |
| UT1 Blacklist | UT1 blacklist filtering score | quality_signals.red_pajama_v2.rps_doc_ut1_blacklist |
Duplication Detection
| Metric | Description | Path |
|---|---|---|
| 5-gram Duplication | Character-level duplication for 5-grams | quality_signals.red_pajama_v2.rps_doc_frac_chars_dupe_5grams |
| 6-gram Duplication | Character-level duplication for 6-grams | quality_signals.red_pajama_v2.rps_doc_frac_chars_dupe_6grams |
| 7-gram Duplication | Character-level duplication for 7-grams | quality_signals.red_pajama_v2.rps_doc_frac_chars_dupe_7grams |
| 8-gram Duplication | Character-level duplication for 8-grams | quality_signals.red_pajama_v2.rps_doc_frac_chars_dupe_8grams |
| 9-gram Duplication | Character-level duplication for 9-grams | quality_signals.red_pajama_v2.rps_doc_frac_chars_dupe_9grams |
| 10-gram Duplication | Character-level duplication for 10-grams | quality_signals.red_pajama_v2.rps_doc_frac_chars_dupe_10grams |
| Top 2-gram Coverage | Most frequent 2-gram coverage | quality_signals.red_pajama_v2.rps_doc_frac_chars_top_2gram |
| Top 3-gram Coverage | Most frequent 3-gram coverage | quality_signals.red_pajama_v2.rps_doc_frac_chars_top_3gram |
| Top 4-gram Coverage | Most frequent 4-gram coverage | quality_signals.red_pajama_v2.rps_doc_frac_chars_top_4gram |
Domain Importance Scores
| Metric | Description | Path |
|---|---|---|
| Books Importance | Similarity to book content | quality_signals.red_pajama_v2.rps_doc_books_importance |
| Books Importance (Length Corrected) | Length-corrected books similarity | quality_signals.red_pajama_v2.rps_doc_books_importance_length_correction |
| OpenWebText Importance | Similarity to OpenWebText | quality_signals.red_pajama_v2.rps_doc_openwebtext_importance |
| OpenWebText Importance (Length Corrected) | Length-corrected OpenWebText similarity | quality_signals.red_pajama_v2.rps_doc_openwebtext_importance_length_correction |
| Wikipedia Importance | Similarity to Wikipedia | quality_signals.red_pajama_v2.rps_doc_wikipedia_importance |
| Wikipedia Importance (Length Corrected) | Length-corrected Wikipedia similarity | quality_signals.red_pajama_v2.rps_doc_wikipedia_importance_length_correction |
FastText Classification Scores
Domain and content type classification probabilities:
| Metric | Description | Path |
|---|---|---|
| DCLM Score | DataComp-LM classifier score | quality_signals.fasttext.dclm |
| English Confidence | English language confidence | quality_signals.fasttext.english |
| Educational Content | Educational content approximation | quality_signals.fasttext.fineweb_edu_approx |
| General Math | General mathematics content | quality_signals.fasttext.eai_general_math |
| Web Math | OWM Web-based mathematics content | quality_signals.fasttext.eai_open_web_math |
| Code Content | Code content detection | quality_signals.fasttext.eai_web_code |
How to Load the Dataset
This section provides examples of how to load the EssentialAI/eai-taxonomy-med-w-dclm dataset using different Python libraries and frameworks.
Using Hugging Face Datasets (Standard Method)
The simplest way to load the dataset is using the Hugging Face datasets library:
from datasets import load_dataset
# Load the entire dataset
dataset = load_dataset("EssentialAI/eai-taxonomy-med-w-dclm")
# View dataset structure
print(dataset)
print(f"Number of examples: {len(dataset['train'])}")
You can also load the dataset in streaming mode to avoid downloading the entire dataset at once:
from datasets import load_dataset
# Load in streaming mode
dataset = load_dataset("EssentialAI/eai-taxonomy-med-w-dclm", streaming=True)
data_stream = dataset["train"]
# Iterate through examples
for example in data_stream.take(5):
print(example)
Using PySpark
For large-scale distributed processing, you can load the dataset using PySpark with the pyspark_huggingface library:
# First install the required library:
# pip install pyspark_huggingface
import pyspark_huggingface
from pyspark.sql import SparkSession
# Initialize Spark session
spark = SparkSession.builder.appName("EAI-Taxonomy-Med-w-DCLM").getOrCreate()
# Load the dataset using the "huggingface" data source
df = spark.read.format("huggingface").load("EssentialAI/eai-taxonomy-med-w-dclm")
# Basic dataset exploration
print(f"Dataset shape: {df.count()} rows, {len(df.columns)} columns")
df.show(10)
df.printSchema()
# Load only specific columns for efficiency
df_subset = (
spark.read.format("huggingface")
.option("columns", '["column1", "column2"]') # Replace with actual column names
.load("EssentialAI/eai-taxonomy-med-w-dclm")
)
# Run SQL queries on the dataset
df.createOrReplaceTempView("eai_taxonomy_med_w_dclm_dataset")
result = spark.sql("""
SELECT COUNT(*) as total_examples
FROM eai_taxonomy_med_w_dclm_dataset
""")
result.show()
Using Daft
Daft provides a modern DataFrame library optimized for machine learning workloads. You can load the dataset directly from Hugging Face:
import daft
# Load the entire dataset
df = daft.read_parquet("hf://datasets/EssentialAI/eai-taxonomy-med-w-dclm")
# Basic exploration
print("Dataset schema:")
df.schema()
print("First 5 rows:")
df.show(5)
If you need to access private datasets or use authentication:
import daft
from daft.io import IOConfig, HTTPConfig
io_config = IOConfig(http=HTTPConfig(bearer_token="your_token"))
df = daft.read_parquet("hf://datasets/EssentialAI/eai-taxonomy-med-w-dclm", io_config=io_config)
Installation Requirements
Make sure you have the required libraries installed:
# For Hugging Face datasets
pip install datasets
# For PySpark with Hugging Face integration
pip install pyspark_huggingface
# For Daft
pip install daft
π Citation
@misc{ai2025essentialwebv1024ttokens,
title={Essential-Web v1.0: 24T tokens of organized web data},
author={Essential AI and : and Andrew Hojel and Michael Pust and Tim Romanski and Yash Vanjani and Ritvik Kapila and Mohit Parmar and Adarsh Chaluvaraju and Alok Tripathy and Anil Thomas and Ashish Tanwer and Darsh J Shah and Ishaan Shah and Karl Stratos and Khoi Nguyen and Kurt Smith and Michael Callahan and Peter Rushton and Philip Monk and Platon Mazarakis and Saad Jamal and Saurabh Srivastava and Somanshu Singla and Ashish Vaswani},
year={2025},
eprint={2506.14111},
archivePrefix={arXiv},
primaryClass={cs.CL},
url={https://arxiv.org/abs/2506.14111},
}
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Size of downloaded dataset files:
572 GB
Size of the auto-converted Parquet files:
572 GB
Number of rows:
81,231,104