tbuckley/cabot-search huggingface dataset:
Exploiting B-cell Receptor Stereotypy to Design Tailored Immunotherapy in Chronic Lymphocytic Leukemia
Authors: Alessandra Rovida, Cristina Maccalli, Lydia Scarfò, Paolo Dellabona, Kostas Stamatopoulos, Paolo Ghia
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Approximately 30% of patients with chronic lymphocytic leukemia (CLL) can be grouped into subsets with stereotyped B-cell receptor immunoglobulin (BcR IG) displaying remarkable similarity in the heavy complementarity-determining region 3 (VH CDR3). Here, we investigated whether the consensus VH CDR3 sequences from CLL stereotyped subsets can be exploited for immunotherapy approaches. Experimental Design: Immunogenic epitopes from the consensus VH CDR3 sequence of the clinically aggressive subsets #1 and #2 and from Eμ-TCL1 mice, which spontaneously develop CLL with BcR IG stereotypy, were identified and used to generate specific HLA class I– and II–restricted T cells in vitro. T-cell reactivity was assayed in vitro as IFNγ production. Bone marrow–derived dendritic cells loaded with the peptides were used as vaccination strategy to restrain leukemia development in the Eμ-TCL1 mouse model. Results: These stereotyped epitopes were naturally processed and presented by CLL cells to the VH CDR3–specific T cells. Furthermore, we validated the efficacy of VH CDR3 peptide–based immunotherapy in the Eμ-TCL1 transplantable mouse model. Immunization of mice against defined VH CDR3 peptide epitopes, prior to the challenge with the corresponding leukemia cells, resulted in the control of CLL development in a significant fraction of mice, and increased overall survival. Conclusions: Our data highlight the immunogenicity of stereotyped VH CDR3 sequences and support the feasibility and efficacy of their use for novel cancer vaccine in CLL. Such approach has the advantage to generate “off-the-shelf” therapeutic vaccines for relevant groups of patients belonging to stereotyped subsets. See related commentary by Seiffert, p. 659
Impact of immune assessment on patterns of care in stage II colon cancer.
Authors: Afsaneh Barzi, Graham M. Poage, Aurelie Catteau, Dewi Vernerey
Journal: Journal of Clinical Oncology (2020)

295 Background: Approximately 25% of patients with colon cancer are diagnosed at stage II. Recommendations for adjuvant chemotherapy and follow-up for these patients are risk-based, however the benefit of therapy is not supported by consistent, robust evidence and there are physical and financial harms associated with adjuvant treatments. Immunoscore is a novel paradigm for risk refinement through measurement of the immune response to the tumor. However, the impact of this tool on physician recommendations for clinical management has yet to be defined. Methods: Medical oncologists were presented with 10 patient profiles (real-life, de-identified stage II cases submitted for clinical Immunoscore testing) and queried for their recommendations (adjuvant chemotherapy and frequency of surveillance) via an online survey. Next, they took part in a live meeting where the Immunoscore data were introduced and completed the same patient survey, but this time with the Immunoscore classification (High or Low) assigned. A physician was counted as influenced by immune response assessment when there was at least one therapeutic modification (chemotherapy decision or surveillance de-intensification) after an Immunoscore test result was provided. We hypothesized that a rate of practice change of 30% (H1) would be considered an impactful result, while 10% would not be impactful (H0). According to A’Hern’s design with a one-sided alpha of 5% and 80% power, 25 physicians needed to be included to test the hypothesis. If 6 or more practice changes (≥ 24%) were observed, the study would be considered positive. Results: Twenty-five physicians were enrolled, representing a range of practice settings from academic medical centers, to high-volume hospital networks, to private community practices; all physicians had experience in treating stage II colon cancer. On average, physicians elected to change their chemotherapy and/or surveillance recommendations 56% of the time, therefore the objective of the study was reached. All but one physician (96%) changed their recommendations for at least one case, while 92% (23/25) changed their preference for chemotherapy in at least 1 case. The rate of change for chemotherapy prescription was 36% per patient case (range: 7-13 changes). Altered surveillance strategies were infrequently observed when chemotherapy recommendations changed. Conclusions: In this physician survey of real-world stage II colon cancer cases, Immunoscore classification significantly impacted decision-making. This impact can translate into a significant reduction in non-value care.
Barriers and facilitators to implementation of serial point-of-care hearing tests using a novel iPad-based audiometry in platinum chemotherapy-treated cancer patients (pts).
Authors: Spencer Soberano, Khaleeq Khan, Katrina Hueniken, Elyon Diekoloreoluwa Famoriyo, Joelle Soriano, Sarfraz Gill, Luna Jia Zhan, Frances A. Shepherd, Adrian G. Sacher, Penelope Ann Bradbury, Natasha B. Leighl, Philippe L. Bedard, Aaron Richard Hansen, Anna Spreafico, Wei Xu, Catherine Brown, Geoffrey Liu
Journal: Journal of Clinical Oncology (2020)

223 Background: Platinum-based chemotherapy agents cause significant hearing loss in 40-80% of treated cancer pts. Lack of follow-up serial testing has created gaps in knowledge regarding hearing loss onset, progression, and possible recovery between treatment cycles. This study aims to determine barriers and facilitators to implementation of a tablet-based point-of-care hearing test, as a serial screening tool to address these knowledge gaps. Methods: From Jul 2019 to Mar 2020, 53 pts receiving high dose platinum agents were recruited from three clinics (Thoracic, head and neck, and testicular cancer) at a comprehensive cancer centre, to undergo serial audiometry testing. Baseline hearing tests, mid cycles (3,6, and 9 weeks), and post treatment tests (3,6,9,12, 19 and 24 months) were completed during the pts’ clinic appointments. Clinical research coordinators (CRCs) collected feedback from physicians, nurses, and pts to identify barriers and facilitators of implementing serial point-of-care hearing tests in these clinics. An inductive and iterative approach was used to identify themes. Implementation was tailored and mapped to the CIHR Knowledge to Action Framework (KTA). Results: Barriers: Logistical barriers included: locating quiet and accessible rooms to administer the test; pts being distracted or interrupted while completing the test; presence of family members adding to noise levels; concerns over the serial testing during treatment; length of each test; and clinic staff burden. Facilitators: User-friendly self-administered tests; increasing healthcare staff education and pt management. Adapting to the local context: Logistical barriers were resolved by CRCs designating quiet spaces for the study to occur, and meeting pts upon arrival to utilize their wait time. A ‘hearing test in progress’ sign put on exam room doors prevented interruptions. CRCs utilized the test’s ‘assisted mode’ feature to keep pts attentive and/or accelerate the process. Low noise level was emphasized to obtain accurate test results. Pt engagement in their test results facilitated retention in the study. Test length may be shortened in the future by omitting low frequency testing. Conclusions: Participants and stakeholders expressed support for in-clinic hearing tests and identified personal and systemic barriers to implementation. These findings suggest that implementation should focus on addressing concerns related to accessible rooms, pt time investment and overall clinic flow.
Author Correction: Glis1 facilitates induction of pluripotency via an epigenome–metabolome–epigenome signalling cascade
Authors: Linpeng Li, Keshi Chen, Tianyu Wang, Yi Wu, Guangsuo Xing, Mengqi Chen, Zhihong Hao, Cheng Zhang, Jinye Zhang, Bochao Ma, Zihuang Liu, Hao Yuan, Zijian Liu, Qi Long, Yanshuang Zhou, Juntao Qi, Danyun Zhao, Mi Gao, Duanqing Pei, Jinfu Nie, Dan Ye, Guangjin Pan, Xingguo Liu
Journal: Nature Metabolism (2020)
Development of self-management tip sheets for medical oncology and surgical patients electronically reporting symptoms in the home-care recovery setting.
Authors: Deborah Schrag, Raymond U. Osarogiagbon, Sandra L. Wong, Hannah Hazard, Jessica J Bian, Don S. Dizon, Christine Cronin, Michael J. Hassett
Journal: Journal of Clinical Oncology (2020)

299 Background: Patients receiving cancer treatments, including chemotherapy and surgery, often face immense morbidities. Poor symptom control frequently leads to decreased quality of life and an increased need for acute care services. For patients undergoing chemo, adverse side effects can deter them from receiving life-saving therapies. Similarly, poorly managed postoperative symptoms can delay recovery and timely receipt of adjuvant therapies. Empowering patients to proactively monitor, electronically report, and effectively treat symptoms in the home-care setting is critical to improving clinical outcomes. Methods: Through the NCI’s Moonshot-funded IMPACT consortium, 6 health systems developed a library of 70 open source symptom management tip sheets for medical oncology and surgical patients. The study team went through an iterative process with medical oncologists, surgeons, practice nurses, health educators, and patient advocates. Careful attention was paid to minimize the usage of regional dialects or idioms to ensure scalability and acceptability. The tip sheets achieved passing scores on two validated healthy literacy and readability tools. Results: Tip sheets were accessible to patients participating in the novel eSyM (electronic symptom management) program, a fully EHR-integrated ePRO model.eSyM and the incorporated tips were deployed at four health systems between fall 2019 and spring 2020 (Baptist Cancer Center, West Virginia University, Dartmouth-Hitchcock Medical Center, and Maine Medical Center). Patients enrolled in eSyM had access to the tip sheet library through their patient portal and could view them at any time. In addition, after completing an ePRO questionnaire, patients were given dedicated links to the tips for symptoms they reported. Each developed tip sheet included 4 sections: 1) things you can do on your own, 2) with over-the-counter medications, 3) with the help of your care team, 4) when to call your care team for help. This simplified structure allowed patients to determine how to manage symptoms on their own and when to seek out assistance. Conclusions: Presenting self-management tip sheets in response to patient-reported symptoms through a fully integrated patient portal platform is a novel approach to symptom management. Future efforts will include deploying the library and platform at two additional health institutions and evaluating the adoption, acceptability, and utilization of the tip sheets and their impact on clinical care outcomes.
COVID-19 in critical care: epidemiology of the first epidemic wave across England, Wales and Northern Ireland
Authors: Alvin Richards-Belle, Izabella Orzechowska, Doug W. Gould, Karen Thomas, James C. Doidge, Paul R. Mouncey, Michael D. Christian, Manu Shankar-Hari, David A. Harrison, Kathryn M. Rowan, Yemi Banjo, Kasia Borowczak, Tom Cousins, Peter Cummins, Keji Dalemo, Robert Darnell, Hanna Demissie, Laura Drikite, Andrew Fleming, Ditte Frederiksen, Sarah Furnell, Abdo Hussein, Abby Koelewyn, Tim Matthews, Sam Peters, Tyrone Samuels, Michelle Saull
Journal: Intensive Care Medicine (2020)

To describe critical care patients with COVID-19 across England, Wales and Northern Ireland and compare them with a historic cohort of patients with other viral pneumonias (non-COVID-19) and with international cohorts of COVID-19.Extracted data on patient characteristics, acute illness severity, organ support and outcomes from the Case Mix Programme, the national clinical audit for adult critical care, for a prospective cohort of patients with COVID-19 (February to August 2020) are compared with a recent retrospective cohort of patients with other viral pneumonias (non-COVID-19) (2017-2019) and with other international cohorts of critical care patients with COVID-19, the latter identified from published reports.10,834 patients with COVID-19 (70.1% male, median age 60 years, 32.6% non-white ethnicity, 39.4% obese, 8.2% at least one serious comorbidity) were admitted across 289 critical care units. Of these, 36.9% had a PaO2/FiO2 ratio of ≤ 13.3 kPa (≤ 100 mmHg) consistent with severe ARDS and 72% received invasive ventilation. Acute hospital mortality was 42%, higher than for 5782 critical care patients with other viral pneumonias (non-COVID-19) (24.7%), and most COVID-19 deaths (88.7%) occurred before 30 days. Meaningful international comparisons were limited due to lack of standardised reporting.Critical care patients with COVID-19 were disproportionately non-white, from more deprived areas and more likely to be male and obese. Conventional severity scoring appeared not to adequately reflect their acute severity, with the distribution across PaO2/FiO2 ratio categories indicating acutely severe respiratory disease. Critical care patients with COVID-19 experience high mortality and place a great burden on critical care services.
Operation Moonshot: is it time to rein in the public health experts?
Authors: Stewart Forsyth
Journal: BMJ (2020)

As covid-19 begins to fight back there is increasing concern that the general public are beginning to not only lose faith in politicians but also have concerns about the conflicting scientific and medical evidence that is being espoused by a proliferation of “public health experts.” 

The advice that “policy should follow the scientific evidence” is difficult …
Natural Selection on the Phase-Separation Properties of FUS during 160 My of Mammalian Evolution
Authors: Pouria Dasmeh, Andreas Wagner
Journal: Molecular Biology and Evolution (2020)

Protein phase separation can help explain the formation of many nonmembranous organelles. However, we know little about its ability to change in evolution. Here we studied the evolution of the mammalian RNA-binding protein Fused in Sarcoma (FUS), a protein whose prion-like domain (PLD) contributes to the formation of stress granules through liquid-liquid phase separation. Although the PLD evolves three times as rapidly as the remainder of FUS, it harbors absolutely conserved tyrosine residues that are crucial for phase separation. Ancestral reconstruction shows that the phosphorylation sites within the PLD are subject to stabilizing selection. They toggle among a small number of amino acid states. One exception to this pattern is primates, where the number of such phosphosites has increased through positive selection. In addition, we find frequent glutamine to proline changes that help maintain the unstructured state of FUS that is necessary for phase separation. Our work provides evidence that natural selection has stabilized the liquid forming potential of FUS and minimized the propensity of cytotoxic liquid-to-solid phase transitions during 160 My of mammalian evolution.
Child Abuse and Neglect Contributing to Youth Suicide
Authors: Jeoffry B. Gordon
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Use of CARG toxicity tool to predict chemotherapy toxicity in older veterans to facilitate better treatment outcomes.
Authors: Srinivasu Chamarthy, Geetika Kumar
Journal: Journal of Clinical Oncology (2020)

244 Background: Traditionally the Eastern Cooperative Oncology Group (ECOG) performance status has been used to assess objective patient well- being and to determine whether geriatric patients can tolerate chemotherapy. Hurria and colleagues from The Cancer and Aging Research Group (CARG) developed a validated geriatric assessment model for adults &gt; 65 yrs. to predict the risk of grade 3-5 chemotherapy toxicity in the treatment of solid tumors. The CARG score, ranging from scores of 0 to 19, incorporates measures of functional status such as fall history, hearing problems, physical capabilities, performance status as well as objective measures including age, gender, height, weight, cancer type, type and dose of chemotherapy, hemoglobin, and creatinine clearance. Methods: At the Dayton VA Medical Center, the utility of the CARG tool was studied in patients to predict chemotherapy tolerance for treatment naïve veterans age &gt; 65 yrs. who were diagnosed with solid tumor malignancies excluding leukemias. CARG scores were stratified as low (score 0-5), intermediate (score 6-9) and high risk (score 10-19). The CARG toxicity score was compared with standard use of ECOG performance status alone to predict chemotherapy toxicity. Subsequent changes in chemotherapy dosage, treatment delays due to adverse effects as well as mortality rate after treatment were also monitored. Results: The study, which enrolled 20 patients over 1 year, revealed that out of 18 patients with ECOG 0-2, 94% had at least an intermediate CARG risk for chemotherapy toxicity and 50% were shown to have high CARG risk for chemotherapy toxicity. Of the 11 high-risk CARG patients in the study, 45% had chemotherapy intolerance. Of the 17 treated patients with calculated CARG toxicity risk 50% or higher, there was a 41% mortality rate. Conclusions: Geriatric assessment modalities are integral to predict chemotherapy toxicity in geriatric patients. These modalities should be part of routine assessment of geriatric cancer patients in order to adequately incorporate their functional status when calculating chemotherapy dosage as the solitary use of ECOG performance status appears to be inadequate for this purpose. The calculated CARG risk percentage may be a better predictor of mortality rate than the ECOG score.
Efficacy and Safety of E6011, an Anti‐Fractalkine Monoclonal Antibody, in Patients With Active Rheumatoid Arthritis With Inadequate Response to Methotrexate: Results of a Randomized, Double‐Blind, Placebo‐Controlled Phase II Study
Authors: Yoshiya Tanaka, Tsutomu Takeuchi, Hisashi Yamanaka, Toshihiro Nanki, Hisanori Umehara, Nobuyuki Yasuda, Fumitoshi Tago, Yasumi Kitahara, Makoto Kawakubo, Kentaro Torii, Seiichiro Hojo, Tetsu Kawano, Toshio Imai
Journal: Arthritis & Rheumatology (2020)

To evaluate the efficacy and safety of E6011, a humanized IgG2 monoclonal antibody against human fractalkine (FKN), in a phase II, double-blind, placebo-controlled study in rheumatoid arthritis (RA) patients.Patients with moderate-to-severe RA who had an inadequate response to methotrexate were randomly assigned to a placebo group or to E6011 100-mg, 200-mg, or 400/200-mg groups at a 2:1:2:2 ratio. During the 24-week period, patients received the study drug subcutaneously at weeks 0, 1, and 2 and then once every 2 weeks. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.Study drugs were administered to 190 patients (placebo, n = 54; E6011 100 mg, n = 28; E6011 200 mg, n = 54; E6011 400/200 mg, n = 54), and 169 patients completed treatment. A significant difference from placebo was not found in ACR20 response rates at week 12 (37.0% [placebo], 39.3% [100 mg], 48.1% [200 mg], and 46.3% [400/200 mg], using nonresponder imputation). As a secondary end point, ACR20 response rate in the 200-mg and 400/200-mg groups attained statistical significance at week 24 (35.2% [placebo], 39.3% [100 mg], 53.7% [200 mg], and 57.4% [400/200 mg]). Subsequent exploratory subgroup analysis revealed greater efficacy of E6011, particularly in patients with a higher baseline proportion of CD16+ monocytes; ACR20 response rates in this patient subgroup at week 24 were 30.0% (placebo), 46.7% (100 mg), 57.7% (200 mg), and 69.6% (400/200 mg). E6011 administered for 24 weeks was well tolerated.This is the first evidence that E6011, a novel cell trafficking inhibitor targeting the FKN-CX3 CR1 interaction, is modestly effective with 24 weeks of treatment in RA patients, although the primary end point was not met.
Nonalcoholic fatty liver disease and alcohol-related liver disease: From clinical aspects to pathophysiological insights
Authors: Kenichi Ikejima, Kazuyoshi Kon, Shunhei Yamashina
Journal: Clinical and Molecular Hepatology (2020)

Two major causes of steatohepatitis are alcohol and metabolic syndrome. Although the underlying causes of alcoholrelated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) differ, there are certain similarities in terms of the mode of disease progression and underlying pathophysiological mechanisms. Further, excessive alcohol consumption is often seen in patients with metabolic syndrome, and alcoholic hepatitis exacerbation by comorbidity with metabolic syndrome is an emerging clinical problem. There are certain ethnic differences in the development of both NAFLD and ALD. Especially, Asian populations tend to be more susceptible to NAFLD, and genetic polymorphisms in patatin-like phospholipase domain-containing 3 (PNPLA3) play a key role in both NAFLD and ALD. From the viewpoint of pathophysiology, cellular stress responses, including autophagy and endoplasmic reticulum (ER) stress, are involved in the development of cellular injury in steatohepatitis. Further, gutderived bacterial products and innate immune responses in the liver most likely play a profound role in the pathogenesis of both ALD and NASH. Though the recent progress in the treatment of viral hepatitis has reduced the prevalence of viral-related development of hepatocellular carcinoma (HCC), non-viral HCC is increasing. Alcohol and metabolic syndrome synergistically exacerbate progression of steatohepatitis, resulting in carcinogenesis. The gut-liver axis is a potential therapeutic and prophylactic target for steatohepatitis and subsequent carcinogenesis.
Mas-related G protein–coupled receptor X2 and its activators in dermatologic allergies
Authors: Helen Kühn, Pavel Kolkhir, Magda Babina, Miriam Düll, Stefan Frischbutter, Jie Shen Fok, Qingqing Jiao, Martin Metz, Jörg Scheffel, Katharina Wolf, Andreas E. Kremer, Marcus Maurer
Journal: Journal of Allergy and Clinical Immunology (2020)