tbuckley/cabot-search huggingface dataset:
Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions
Authors: Dror Kolodkin-Gal, Lior Roitman, Yossi Ovadya, Narmen Azazmeh, Benjamin Assouline, Yehuda Schlesinger, Rachel Kalifa, Shaul Horwitz, Yonatan Khalatnik, Anna Hochner-Ger, Ashraf Imam, Jonathan Abraham Demma, Eitan Winter, Hadar Benyamini, Sharona Elgavish, Areej AS Khatib, Karen Meir, Karine Atlan, Eli Pikarsky, Oren Parnas, Yuval Dor, Gideon Zamir, Ittai Ben-Porath, Valery Krizhanovsky
Journal: Gut (2021)

Objective Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. Design To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. Results We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. Conclusions These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.
Plumbing the Depths of Ethical Payment for Research Participation
Authors: Holly Fernandez Lynch, Thomas C. Darton, Jae Levy, Frank McCormick, Ubaka Ogbogu, Ruth O. Payne, Alvin E. Roth, Akilah Jefferson Shah, Thomas Smiley, Emily A. Largent
Journal: The American Journal of Bioethics (2021)

This article refers to:Promoting Ethical Payment in Human Infection Challenge StudiesPromoting Ethical Payments in Human Challenge Studies Conducted in LMICs: Are We Asking the Right Questions?A Call for Radical Transparency regarding Research PaymentsPaying for Fairness? Incentives and Fair Subject SelectionResearch Participants Should Be Rewarded Rather than "Compensated for Time and Burdens"Considering the Importance of Context for Ethical Practice on Reimbursement, Compensation and Incentives for Volunteers in Human Infection Controlled StudiesPaying the Right Amount to Challenge Trial Participants – We Need to Use Behavioral Science Insights to Sell What's RightWhat Fairness Demands: How We Can Promote Fair Compensation in Human Infection Challenge Studies and BeyondTime to Professionalize Service to Research? Pay Nothing or Full Wage for Labor
A CLINICAL STUDY OF THE END-RESULTS OF SOME FOCAL INFECTIONS
Journal: JAMA (1920)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Opioid-Associated Out-of-Hospital Cardiac Arrest: Distinctive Clinical Features and Implications for Health Care and Public Responses: A Scientific Statement From the American Heart Association
Authors: Cameron Dezfulian, Aaron M. Orkin, Bradley A. Maron, Jonathan Elmer, Saket Girotra, Mark T. Gladwin, Raina M. Merchant, Ashish R. Panchal, Sarah M. Perman, Monique Anderson Starks, Sean van Diepen, Eric J. Lavonas
Journal: Circulation (2021)

Opioid overdose is the leading cause of death for Americans 25 to 64 years of age, and opioid use disorder affects >2 million Americans. The epidemiology of opioid-associated out-of-hospital cardiac arrest in the United States is changing rapidly, with exponential increases in death resulting from synthetic opioids and linear increases in heroin deaths more than offsetting modest reductions in deaths from prescription opioids. The pathophysiology of polysubstance toxidromes involving opioids, asphyxial death, and prolonged hypoxemia leading to global ischemia (cardiac arrest) differs from that of sudden cardiac arrest. People who use opioids may also develop bacteremia, central nervous system vasculitis and leukoencephalopathy, torsades de pointes, pulmonary vasculopathy, and pulmonary edema. Emergency management of opioid poisoning requires recognition by the lay public or emergency dispatchers, prompt emergency response, and effective ventilation coupled to compressions in the setting of opioid-associated out-of-hospital cardiac arrest. Effective ventilation is challenging to teach, whereas naloxone, an opioid antagonist, can be administered by emergency medical personnel, trained laypeople, and the general public with dispatcher instruction to prevent cardiac arrest. Opioid education and naloxone distributions programs have been developed to teach people who are likely to encounter a person with opioid poisoning how to administer naloxone, deliver high-quality compressions, and perform rescue breathing. Current American Heart Association recommendations call for laypeople and others who cannot reliably establish the presence of a pulse to initiate cardiopulmonary resuscitation in any individual who is unconscious and not breathing normally; if opioid overdose is suspected, naloxone should also be administered. Secondary prevention, including counseling, opioid overdose education with take-home naloxone, and medication for opioid use disorder, is important to prevent recurrent opioid overdose.
Racial disparities in depression incidence, management, and mortality after prostate cancer diagnosis.
Authors: Ravi Bharat Parikh, Joseph J. Gallo, John Cashy, Kyle William Robinson, Vivek Narayan, Yu-Ning Wong, Ravishankar Jayadevappa, Sumedha Chhatre
Journal: Journal of Clinical Oncology (2021)

201 Background: Depressive disorder is a common cause of morbidity among men with prostate cancer (PC) and may contribute to known racial disparities in PC outcomes. We estimated the incidence, management, and impact of depressive disorder (depression) on overall mortality among African American (AA) and non-Hispanic White (W) Veterans with localized PC. Methods: In this retrospective cohort study, we used linked administrative, survey, and electronic health record data from the Veterans Health Administration (VA) Corporate Data Warehouse to identify AA and W Veterans with no preexisting depression who were diagnosed with localized PC between January 1, 2004 and December 31, 2013. Patients were followed through December 31, 2019. The primary outcomes were incident depression (defined from diagnosis codes and PHQ-2 and -9 screenings between six months to five years after PC diagnosis), receipt of anti-depressant therapy, and all-cause mortality. We used logistic and Cox regression models, adjusted for sociodemographic factors, PSA, Gleason score, and prostate cancer treatment, to estimate associations with all outcomes, using race-by-depression and race-by-treatment interaction terms to investigate racial disparities. Results: Among 32,194 Veterans diagnosed with localized prostate cancer (median age 67 years [interquartile range [IQR] 62 to 73 years], median follow-up 9.9 years [IQR 8.0 to 12.1 years]), 8,177 (25.4%) were AA. Overall, 8,285 (25.7%) Veterans were diagnosed with depression after PC diagnosis, and 2,525 (30.5%) of depressed Veterans received an antidepressant. Compared to Veterans without depression, Veterans with incident depression had higher all-cause mortality (adjusted hazard ratio [aHR] 1.30 [95% CI 1.25-1.35]). Race moderated all outcomes: AAs were more likely than Ws to be diagnosed with depression. However, among those with depression, AAs were less likely than Ws to receive an antidepressant. Interaction analyses showed that the HR of all-cause mortality associated with depression among AAs was significantly greater than that of Ws. Antidepressant receipt was not associated with improved mortality (aHR 1.05 [95% CI 0.97-1.13]); this finding was not moderated by race. Conclusions: Depression was common among men with prostate cancer within a large equal-access health care system, and African American men had more adverse depression-related outcomes than White men. Identifying and managing incident depression should be a key target of efforts to improve prostate cancer outcomes and disparities. [Table: see text]
Efficacy of Decitabine plus Anti-PD-1 Camrelizumab in Patients with Hodgkin Lymphoma Who Progressed or Relapsed after PD-1 Blockade Monotherapy
Authors: Chunmeng Wang, Yang Liu, Liang Dong, Xiang Li, Qingming Yang, Malcolm V. Brock, Qian Mei, Jiejie Liu, Meixia Chen, Fengxia Shi, Miao Liu, Jing Nie, Weidong Han
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up. Patients and Methods: We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1–5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962). Results: Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% [nine complete responses (CR); 36%] in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival. Conclusions: Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors.
Global, regional, and national mortality trends in youth aged 15–24 years between 1990 and 2019: a systematic analysis
Authors: Bruno Masquelier, Lucia Hug, David Sharrow, Danzhen You, Colin Mathers, Patrick Gerland, Leontine Alkema
Journal: The Lancet Global Health (2021)

The global health community is devoting considerable attention to adolescents and young people, but risk of death in this population is poorly measured. We aimed to reconstruct global, regional, and national mortality trends for youths aged 15-24 years between 1990 and 2019.In this systematic analysis, we used all publicly available data on mortality in the age group 15-24 years for 195 countries, as compiled by the UN Inter-agency Group for Child Mortality Estimation. We used nationally representative vital registration data, estimated the completeness of death registration, and extracted mortality rates from surveys with sibling histories, household deaths reported in censuses, and sample registration systems. We used a Bayesian B-spline bias-reduction model to generate trends in 10q15, the probability that an adolescent aged 15 years would die before reaching age 25 years. This model treats observations of the 10q15 probability as the product of the actual risk of death and an error multiplier that varies depending on the data source. The main outcome that we assessed was the levels of and trends in youth mortality and the global and regional mortality rates from 1990 to 2019.Globally, the probability of an individual dying between age 15 years and 24 years was 11·2 deaths (90% uncertainty interval [UI] 10·7-12·5) per 1000 youths aged 15 in 2019, which is about 2·5 times less than infant mortality (28·2 deaths [27·2-30·0] by age 1 year per 1000 live births) but is higher than the risk of dying from age 1 to 5 (9·7 deaths [9·1-11·1] per 1000 children aged 1 year). The probability of dying between age 15 years and 24 years declined by 1·4% per year (90% UI 1·1-1·8) between 1990 and 2019, from 17·1 deaths (16·5-18·9) per 1000 in 1990; by contrast with this total decrease of 34% (27-41), under-5 mortality declined by 59% (56-61) in this period. The annual number of deaths declined from 1·7 million (90% UI 1·7-1·9) in 1990 to 1·4 million (1·3-1·5) in 2019. In sub-Saharan Africa, the number of deaths increased by 20·8% from 1990 to 2019. Although 18·3% of the population aged 15-24 years were living in sub-Saharan Africa in 2019, the region accounted for 37·9% (90% UI 34·8-41·9) of all worldwide deaths in youth.It is urgent to accelerate progress in reducing youth mortality. Efforts are particularly needed in sub-Saharan Africa, where the burden of mortality is increasingly concentrated. In the future, a growing number of countries will see youth mortality exceeding under-5 mortality if current trends continue.UN Children's Fund, Bill & Melinda Gates Foundation, United States Agency for International Development.
Evolutionary action score identifies a subset of TP53 mutated myelodysplastic syndrome with favorable prognosis
Authors: Rashmi Kanagal-Shamanna, Guillermo Montalban-Bravo, Panagiotis Katsonis, Koji Sasaki, Caleb A. Class, Elias Jabbour, David Sallman, Anthony Michael Hunter, Christopher Benton, Kelly S. Chien, Rajyalakshmi Luthra, Carlos E. Bueso-Ramos, Tapan Kadia, Michael Andreeff, Rami S. Komrokji, Najla H Al Ali, Nicholas Short, Naval Daver, Mark J. Routbort, Joseph D. Khoury, Keyur Patel, Irene Ganan-Gomez, Yue Wei, Gautam Borthakur, Farhad Ravandi, Kim-Anh Do, Kelly A. Soltysiak, Olivier Lichtarge, L. Jeffrey Medeiros, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: Blood Cancer Journal (2021)
CD4 T Cell–Dependent Rejection of Beta-2 Microglobulin Null Mismatch Repair–Deficient Tumors
Authors: Giovanni Germano, Steve Lu, Giuseppe Rospo, Simona Lamba, Benoit Rousseau, Sonia Fanelli, Denise Stenech, Dung T. Le, John Hays, Maria Grazia Totaro, Vito Amodio, Rosaria Chilà, Anna Mondino, Luis A. Diaz, Federica Di Nicolantonio, Alberto Bardelli
Journal: Cancer Discovery (2021)

Abstract Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast, B2M loss does not appear to affect response to ICPis in mismatch repair–deficient (MMRd) colorectal tumors where biallelic inactivation of B2M is frequently observed. We inactivated B2m in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocompetent mice, MMRd B2m null cells were tumorigenic and regressed when treated with anti–PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd B2m null tumors did not require CD8+ T cells but relied on the presence of CD4+ T cells. Human tumors expressing low levels of B2M display increased intratumoral CD4+ T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors, and we identify a unique role for CD4+ T cells in tumor rejection. Significance: B2M alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers B2M loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4+ T-cell activation. This article is highlighted in the In This Issue feature, p. 1601
Wnt–β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression
Authors: Jasmin Quandt, Stephen Arnovitz, Leila Haghi, Janine Woehlk, Azam Mohsin, Michael Okoreeh, Priya S. Mathur, Akinola Olumide Emmanuel, Abu Osman, Manisha Krishnan, Samuel B. Morin, Alexander T. Pearson, Randy F. Sweis, Joel Pekow, Christopher R. Weber, Khashayarsha Khazaie, Fotini Gounari
Journal: Nature Immunology (2021)
Aggressiveness and Metastatic Potential of Breast Cancer Cells Co-Cultured with Preadipocytes and Exposed to an Environmental Pollutant Dioxin: An <i>in Vitro</i> and <i>in Vivo</i> Zebrafish Study
Authors: Meriem Koual, Céline Tomkiewicz, Ida Chiara Guerrera, David Sherr, Robert Barouki, Xavier Coumoul
Journal: Environmental Health Perspectives (2021)

Breast cancer (BC) is a major public health concern, and its prognosis is very poor once metastasis occurs. The tumor microenvironment and chemical pollution have been suggested recently to contribute, independently, to the development of metastatic cells. The BC microenvironment consists, in part, of adipocytes and preadipocytes in which persistent organic pollutants (POPs) can be stored.We aimed to test the hypothesis that these two factors (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an extensively studied, toxic POP and the microenvironment) may interact to increase tumor aggressiveness.We used a co-culture model using BC MCF-7 cells or MDA-MB-231 cells together with hMADS preadipocytes to investigate the contribution of the microenvironment and 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD on BC cells. Global differences were characterized using a high-throughput proteomic assay. Subsequently we measured the BC stem cell-like activity, analyzed the cell morphology, and used a zebrafish larvae model to study the metastatic potential of the BC cells.We found that coexposure to TCDD and preadipocytes modified BC cell properties; moreover, it induced the expression of ALDH1A3, a cancer stem cell marker, and the appearance of giant cancer cells with cell-in-cell structures (CICs), which are associated with malignant metastatic progression, that we demonstrated in vivo.The results of our study using BC cell lines co-cultured with preadipocytes and a POP and an in vivo zebrafish model of metastasis suggest that the interactions between BC cells and their microenvironment could affect their invasive or metastatic potential. https://doi.org/10.1289/EHP7102.
Abstract 3169: The therapeutically inflamed tumor microenvironment drives melanoma progression
Authors: Andrew M. Bradshaw, Erica Kuo, Jelena Grahovac, Kyle Sylakowski, Cindy Sander, Howard Edington, John M. Kirkwood, Alan Wells
Journal: Cancer Research (2021)

Abstract Even the most therapy responsive melanomas eventually evade immune checkpoint inhibition. Interestingly, initial responses seem to benefit from localized inflammation, but this can become prohibitive when treating advanced disease. Subsequently, there is an urgent need to elucidate how inflammation impacts the tumor microenvironment (TME). Here, inhibition of EGFR and Ras/Raf/MEK is shown to drive the release of a pro-inflammatory secretome that activates the TME to promote progression. This secretome was enriched with immune recruiting cytokines and members of the transforming growth factor beta (TGFβ) superfamily. Both healthy and cancer associated fibroblasts (CAFs) were hyperactivated in response to the inflamed secretome with induction of the inflammatory marker, alpha smooth muscle actin (αSMA). Pharmacologic inhibition of TGFβ receptor type I (TGFβRI) using SB431542 or clinically relevant TEW-7197, diminished CAF αSMA phenotype, disrupted TGFβ and phospo-SMAD2/3 signaling, and blunted CAF expression of tumor promoting extracellular matrix and adhesion molecules. Invasion of melanoma spheroids was enhanced ~2.5-fold in CAF coculture transwells. However, treatment with MEK inhibitor AZD6244 and TEW-7197 only limited invasion of mixed melanoma and CAF multi-cell spheroids in vitro. Prompted by this, the extracellular matrix of patient-derived and melanoma xenograft tumors was analyzed for inflammatory protein expression. Micrometastatic foci were flanked by peri-tumor αSMA+ CAFs and enriched for inflammatory Tenascin-C (TNC) at the invasive front. The analysis of human melanoma tissue microarrays corroborated the experimentally observed expression of αSMA CAFs and TNC which statistically increase with malignant tumor grade. Conversely, the anti-invasive Decorin (DCN), decreased in malignant melanoma while collagen-1 increased during late stage tumor fibrosis. These findings prompted the use of ex vivo human skin organ cultures (SOCs) to define how cell matrix impacted melanoma. Addition of DCN to the SOC eliminated melanoma vertical invasion whereas pathological TNC promoted progression. Thus, a BRAFV600E resistant patient-derived metastatic cell line was used to establish intrasplenic xenografts that were treated after one week using AZD6244 and TEW-7197. Both monotherapy and combination therapy were well tolerated and resulted in reduced splenic tumor burden, αSMA staining, and halted metastasis to the liver. Citation Format: Andrew M. Bradshaw, Erica Kuo, Jelena Grahovac, Kyle Sylakowski, Cindy Sander, Howard Edington, John M. Kirkwood, Alan Wells. The therapeutically inflamed tumor microenvironment drives melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3169.