tbuckley/cabot-search huggingface dataset:
Abstract 17245: Deficiency of Tet Methylcytosine Dioxygenase 2 (tet2),A Key Enzyme in Cytosine Demethylation,Is an Epigenetic Driver of Inflammation and Disease Progression in Pulmonary Arterial Hypertension
Authors: Francois Potus, Elina K cook, Lian Tian, Charles C Hindmarch, Patricia Lima, Rauh J Michael, Stephen L Archer
Journal: Circulation (2018)

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by remodelling of distal pulmonary arteries associated with inflammation, endothelial cells (EC) dysfunction and a pro-proliferative/anti-apoptotic phenotype in pulmonary arterial smooth muscle cells (PASMC). Tet methylcytosine dioxygenase 2 (Tet2) is a key enzyme in cytosine demethylation that is crucial for epigenetic control of gene expression. Deficiency of Tet2 expression in myeloid cellsresults in increased inflammatory cytokine levels. Moreover, impaired Tet2 expression in EC has also been associated with decreased autophagy, as well as EC dysfunction. In addition, Tet2 silencing contributes to pro-proliferative phenotype of SMC. Thus, we hypothesized that Tet2 deletion would contribute to PAH by upregulation of inflammation and induction of PASMC proliferation and EC dysfunction. Methods and Results: To assess the ability of Tet2 deficiency to induce PAH we assessed cardiopulmonary hemodynamics in a conditional hematopoietic and endothelial cells Tet2 -/- mouse model. Tet2 -/- mice developed PAH associated with significant increases of right ventricular systolic pressure (RVSP), elevation of total pulmonary resistance (TPR) and increased vascular wall thickness of distal pulmonary arteries. Tet2 -/- lung tissue as well as macrophages and EC sorted from the lung displayed aberrant inflammatory cytokine signalling with robust overexpression of IL1βnoted on a Nanostring immune gene expression panel. In vitro IL1βincreased PASMC proliferation measured using EDU. Downregulation of TET2 in PASMC using siRNA resulted in a similar PAH-like phenotype. Moreover, lung from Tet2 -/- mice exhibited an alteration of vasoactive mediator gene expression (increased endothelin-1 (ET1), Arginase 2 (Arg2) and decreased eNOS). Finally we showed that downregulation of Tet2 (achieved by nebulization of si-Tet2) in rats with monocrotaline-induced PAH exacerbated disease severity (increasing TPR adverse pulmonary vascular remodelling).This phenotype was independent of the sex, was associated with a moderate decrease in RV function but had no significant effect on LV hemodynamic parameters. Conclusions: Tet2 is a protective epigenetic regulator that when conditionally downregulated in hematopoietic and endothelial cells leads toPAH by inducing a state of inflammation that contributes to PASMC proliferation and EC dysfunction which drives adverse pulmonary vascular remodelling.
Characteristics of prostate cancer patients captured by facility-based versus geography-based cancer registries.
Authors: Christopher Paul Filson, Parth K. Modi, Kevin C. Ward
Journal: Journal of Clinical Oncology (2022)

237 Background: Cancer registries provide valuable information related to cancer epidemiology, treatment, and outcomes. However, the sampling for inclusion can impact generalizability of findings to other settings. We use a population-based cancer registry to evaluate demographics, cancer factors, and treatment patterns based on eligibility for a facility-based cancer registry. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify men diagnosed with prostate cancer (site = C61.9) in 2018. Exposure was whether data were reported from a facility accredited by American College of Surgeons’ Commission on Cancer (CoC), providing eligibility for the National Cancer Database (NCDB) (i.e., NCDB-eligible). Outcomes of interest included demographics, tumor factors (e.g., biopsy grade), and treatment. Bivariate testing and multivariable regression analyses tested for significant associations between exposure and outcomes of interest. Results: We identified 57,713 men diagnosed with prostate cancer in 2018, of which 32,384 (61.9%) were eligible for inclusion in NCDB. NCDB-eligible men were younger (66.6 vs 67.8 years, p &lt; 0.001), less likely to be Hispanic/Latino (8.0% vs 14.4%, p &lt; 0.001), and more likely to reside in a county with median income over $75,000 (39.7% vs 33.3%, p &lt; 0.001). NCDB eligibility varied widely by registry, from 96.1% in Connecticut to 44.7% in Utah. The proportion of localized cancer patients with Grade Group 1 cancer on biopsy was higher among men ineligible for NCDB (41.4% vs 26.9%, p &lt; 0.001). The proportion of patients with more advanced disease at presentation was higher among NCDB-eligible patients (metastatic: 9.4% vs 6.8%; regional: 18.7% vs 8.7%; p &lt; 0.001). For patients with localized or regional cancer, treatment was identified more frequently among NCDB-eligible patients for both low-risk (38.5% vs 22.7%, p &lt; 0.001) and high-risk tumors (84.9% vs 64.2%). Among treated patients, use of radical prostatectomy was more common among NCDB-eligible patients (low risk: 58.9% vs 43.1%; high risk: 53.7% vs 43.4%, p &lt; 0.001). Conclusions: Prostate cancer patients eligible for inclusion in the facility based NCDB have important differences in demographics, severity of cancer risk, and treatment patterns compared to those who are not eligible. Generalizations related to epidemiologic trends, practice patterns, and outcomes for prostate cancer patients in the NCDB should be interpreted with caution.
Triplet therapy in metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis.
Authors: Syed Arsalan Ahmed Naqvi, Zaryab Bin Riaz, Anum Riaz, Mahnoor Islam, Rabbia Siddiqi, Waleed Ikram, Muhammad Ali Jafar, Parminder Singh, Praful Kumar Ravi, Irbaz Bin Riaz, Alan Haruo Bryce
Journal: Journal of Clinical Oncology (2022)

136 Background: Intensification of initial treatment of in patients with metastatic castration-sensitive prostate cancer (mCSPC) with androgen pathway inhibition (API) in addition to docetaxel (DOC) and androgen deprivation therapy (ADT) has shown promise to improve clinical outcomes. Thus, we synthesize the data from modern clinical trials to estimate overall estimates of progression and survival outcomes. Methods: A systematic search of electronic databases (MEDLINE and EMBASE) was conducted to include phase III randomized controlled trials (RCTs) evaluating triplet therapy (API+DOC+ADT) against doublet therapy (DOC+ADT) in mCSPC. Outcomes of interest included overall survival (OS) and radiographic progression-free survival (rPFS). A DerSimonian-Laird random-effects meta-analysis was performed to pool precomputed hazard ratios (HRs) and confidence intervals (CIs) after logarithmic transformation using inverse-variance weighting approach. Cochran’s Q statistical test was used to assess statistically significant heterogeneity not explained by chance, while I 2 statistical test was used to quantify the total observed variability, due to between-study heterogeneity. I 2 values &gt;50% indicated substantial heterogeneity. A summary of findings table was constructed to translate relative estimates to absolute risks. Results: A total of 1,531 patients in four RCTs with direct comparative data between triplet and doublet therapies, were included in this meta-analysis. PEACE-1 was the only RCT directly assessing this question (AAP+DOC+ADT). ENZA+DOC+ADT was evaluated as a subgroup in two RCTs (ENZAMET; ARCHES), APA+DOC+ADT was evaluated as a subgroup in one (TITAN). To be able to pool studies, the relative efficacy of control arm in ENZAMET (first generation bicalutamide + ADT) was considered equivalent to ADT based on prior literature. A total of 672 rPFS events were observed (34%; 261 events in triplet therapy, 54%; 411 events in doublet therapy). The difference was statistically significant (HR: 0.49; 95% CI: 0.42-0.58; I 2 : 0%). Similarly, 469 OS events were observed (28%; 217 events in triplet therapy, 33%; 252 events in doublet therapy). The difference was statistically significant (HR: 0.80; 95% CI: 0.67-0.96; I 2 : 0%). The summary of findings is outlined in the table. Conclusions: The results of this meta-analysis support an improvement in rPFS and OS in favor of triplet therapy over doublet therapy for mCRPC. However, comparative effectiveness of different triplet regimens may be different and needs further exploration.[Table: see text]
Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study
Authors: L. Gianni, C.S. Huang, D. Egle, B. Bermejo, C. Zamagni, M. Thill, A. Anton, S. Zambelli, G. Bianchini, S. Russo, E.M. Ciruelos, R. Greil, V. Semiglazov, M. Colleoni, C. Kelly, G. Mariani, L. Del Mastro, I. Maffeis, P. Valagussa, G. Viale
Journal: Annals of Oncology (2022)
Abstract 17348: Privileged or Not?: Immunologic Properties of Allogenic Endothelial Progenitor Cell-Derived Extracellular Vesicles
Authors: Jennifer J Chung, Samir Zaman, Jonathan Gordon, Maria F Arisi, Elizabeth Li, Carol W Chen, Ann C Gaffey, Pavan Atluri
Journal: Circulation (2018)

Introduction: Extracellular vesicles (EV) from allogeneic progenitor cells are considered safe for treatment of ischemic myocardium based on the assumption of immune-privilege. However no studies have rigorously examined the local immune response following pooled-donor EV therapy. Understanding the specific immune reaction to endothelial progenitor cell-derived EVs (EEVs) has critical implications for clinical translation to treatment of acute myocardial infarction (MI). Aim: We aim to characterize the immune cells that respond acutely to injected intramyocardial delivery of pooled donor EEVs using in-depth flow cytometric (FCM) analysis. Methods: EEVs were isolated from pooled, primary bone-marrow EPCs from male Wistar rats. Uptake of DiI labeled EEVs by rat endothelial cells, cardiac fibroblasts, and myoblasts was assessed in vitro . In vivo immune response to EEVs in rats was studied after intramyocardial injection of PBS and PBS-EV. Left ventricular (LV) tissue digested at D1 and D6 was analyzed by 9-Color FCM for detection and differentiation of T, B, and NK cells, neutrophils, and monocytes. Local immune cell infiltration was assessed by H&amp;E staining at D5 post-injection. Results: All cells tested had robust EEV internalization of DiI stain. H&amp;E showed immune cell infiltration near the injection site, but no gross difference in EEV vs. PBS at D5. In-depth FCM of the LV at D1 and D6 post injection showed marked decrease in lymphocyte infiltration, but increased percentage of NK, B and CD8+ T cells from D1 to D6. EEVs did not significantly change the percentage of lymphocyte infiltration vs. PBS at D1 or D6. Conclusions: FCM can be successfully used for in-depth characterization of cardiac immune cell-types in rat models of allogeneic myocardial therapy. Allogeneic EEV therapy demonstrates robust, rapid internalization into the major cardiac cell types and elicit minimal additional innate or acquired immune response compared to saline injection.
Circulating tumor DNA responses to high-dose testosterone injections in CRPC patients.
Authors: Sydney Caputo, Ellen B. Jaeger, William Fleming, Charlotte Manogue, Minqi Huang, Alex Lieberman, Malcolm Light, Isabelle P. Sussman, Patrick Miller, Pedro C. Barata, Brian E. Lewis, Jodi Lyn Layton, Elisa M. Ledet, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2022)

173 Background: Some proportion of men with CRPC have favorable responses to high doses of testosterone (HDT) and some do not. Genomic determinants of these responders and non-responders are poorly understood. Herein ctDNA predictors of response are assessed using a responder/non-responder analysis. Methods: All men with CRPC had been pretreated with abiraterone, enzalutamide, or both. A ctDNA test was obtained prior to high doses of testosterone (administered as a dose of 400 mg IM testosterone cypionate every 3-4 weeks). Guardant 360 was used to analyze ctDNA (with an allelic fraction cut-off of &gt; 0.5%) to ascertain the presence or absence of pathogenic mutations. Lower allelic fractions were not analyzed. Responders had a PSA decline of 50% or more (N = 16), non-responders received at least two doses of testosterone but never had any PSA decline at all (N = 20). All patients were treated at Tulane Cancer Center. Results: AR amplifications were more commonly detected (p = 0.036) pre-treatment in the ctDNA of responders (5/16) as compared to non-responders (1/20). No differences were found in those with common AR mutations; T878A was detected in 2/16 responders and 2/20 non-responders, L702H was detected in 1/16 responders and 2/20 non-responders. No differences were seen with regard to TP53 mutations, 6/20 non-responders and 7/16 responders. Non- AR/non- TP53 mutations were not distinct in the two groups but trended (P = 0.15) toward being more common in non-responders (5/16 in responders versus 11/20 non-responders). Pre- and post- ctDNA analyses were conducted in 5/6 patients for those with AR amplification at baseline. In all 5 of these patients, the degree of AR amplification diminished after testosterone injections. Conclusions: In this analysis of CRPC patients who were responders and non-responders to 400 mg testosterone cypionate q 3-4 weeks (post-abiraterone and/or enzalutamide), only AR amplifications in ctDNA were predictive of response. In all measured patients, the degree of AR amplification in the ctDNA diminished after testosterone injections.
Enteric Fever
Authors: J. Ritchie
Journal: BMJ (1937)

INFECTIONMEDAL JOURNIAL at a subsequent operation.In women and such men as desire it the finger may be conserved, but for the subject employed in manLual labour better function may be obtained by amputatkrn.Summary 1.This paper is based on the experience gained in the study of 183 cases of infections of the hand, of which fifty-one cases were pulp-space infections.2. Aching followed by throbbing and inability to sleep, associated with induration of the pulp, should be the established indications for immediate operation in pulpspace infection.3. With adequate drainage inflammation in the pulp readily subsides.If resolution is delayed it is uirged that the transfixion operation should be carried out.4. Complications in pulp-space infection can be pre- vented by providing adequate drainage in the early stages.5. In a chronic case it is essential to employ radio- logical examination before proceeding to treatment.6.In the treatment of sequestrum formation and the prevention of tenosynovitis it is necessary to employ care in operation, and if possible to conserve the base of the distal phalanx.
13. Children and Adolescents: <i>Standards of Medical Care in Diabetes—2019</i>
Journal: Diabetes Care (2018)

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Medical News
Journal: JAMA (1974)

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
A systematic review of immune checkpoint inhibitors (ICI) in non-clear cell renal cell cancer (nccRCC) subtypes.
Authors: Ana Filipa Reis, Thomas A Odeny, Diana Simão, Mario Fontes-Sousa, Ysel Chiara Vina Rodrigues, Channing Judith Paller, Pedro C. Barata
Journal: Journal of Clinical Oncology (2022)

353 Background: ICI were approved for advanced RCC treatment either alone or combined with another ICI or a tyrosine kinase inhibitor. While most trial data derive from clear cell (cc) histology, the differential activity of ICI in nccRCC subtypes is not entirely known. The aim of this analysis is to summarize the reported activity of ICI-based therapies in ncc-subtypes or in tumors with sarcomatoid/rhabdoid features. Methods: A systematic literature search following PRISMA guidelines was performed. PubMed, GoogleScholars and ASCO Database were searched for the key-words “renal cell cancer” and “immune check point inhibitors” and equivalents. Publications between July 2016 - July 2021 were considered. All original articles reporting outcomes of ICI in at least 5 patients with an advanced nccRCC were eligible. Case reports, reviews, out of scope publications and articles with no full text available were excluded. Results: This study included a total of 14 publications, mostly case series except one phase II and one phase IIIb/IV trial. The table below summarizes the different histological subtypes included in these studies, more frequently papillary (10-88%), chromophobe (0-34%) and unclassified (4-27.5%) RCC. As for first line (L), ICI monotherapy elicited an overall response ratio (ORR) of 5-26.7%, a median progression free survival (mPFS) of 2.2-4.2 months (m) and a median overall survival (mOS) of 16.3-28.9m. ICI combination therapy associated with a higher ORR of 14.2-33%, a mPFS of 2.4-8.3m and a mOS not reached (NR). In ≥2 nd L, ICI alone elicited an ORR of 9.4-22.6%, a mPFS of 3.5-7.1m and a mOS of 11.6m-NR. ICI combination therapy was superior, with a reported ORR of 31-44.4%, a mPFS of 4.3-5.6m and a mOS NR. Overall, ICI therapy elicited a higher ORR in papillary tumors (5-50%). Unclassified RCC response was more variable (0-66.7%). Chromophobe tumors had a lower ORR of 0-20%. ICI therapy outcomes among nccRCC with sarcomatoid/rhabdoid features were of an ORR of 0-42.1%, a mPFS of 2.3-6.9m and a mOS of 25.5m–NR. Nonetheless, outcomes were inferior in ncc comparing to cc tumors. Conclusions: The observed activity of ICI-based therapies was heterogenous among nccRCC subtypes. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.[Table: see text]
The role of schools in driving SARS-CoV-2 transmission: Not just an open-and-shut case
Authors: Laura F. White, Eleanor J. Murray, Arijit Chakravarty
Journal: Cell Reports Medicine (2022)

Keeping schools open without permitting COVID-19 spread has been complicated by conflicting messages around the role of children and schools in fueling the pandemic. Here, we describe methodological limitations of research minimizing SARS-CoV-2 transmission in schools, and we review evidence for safely operating schools while reducing overall SARS-CoV-2 transmission.
A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.
Authors: Matthew R. Zibelman, Michael Anthony Carducci, Yasser Ged, Ana M. Molina, Rahul Ravilla, David R. Shaffer, Courtney Lambert, Mahvish Tafseer, Rachel Basiura, Danielle Weismann, Rutika Kokate, Karthik Devarajan, Karen Ruth, R. Katherine Alpaugh, Fern Anari, Pooja Ghatalia, Daniel M. Geynisman, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2022)

291 Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab (nivo). Methods: This phase I/II study investigated the combination of axi and nivo in an initial dose finding phase I portion with a 3+3 design to determine the recommended phase 2 dose (RP2D) of axi. The phase II portion included 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs alone or IO/IO combination (NCT03172754). We are presenting results from the treatment naïve arm only. Included patients had to have histology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The RP2D of axi was 5 mg BID from the phase I portion and patients could be treated for up to 2 years. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Forty-four patients were accrued to the treatment naïve arm. One withdrew consent and was replaced but is included in the safety analysis, while 42 patients are evaluable for efficacy. The median age was 65 yrs (range: 42-84 yrs) and the group was predominantly male (83.7%) and white (95.3%). Using the IMDC risk group grading, 18 patients (41.9%) were favorable risk, 22 patients (51.2%) were intermediate risk and 3 patients (7 %) were poor risk. Median follow-up was 11.5 months. Best response data is shown in the table and is notable for an ORR of 69.0%, with only 1 patient (2.4%) experiencing primary progressive disease, for a disease control rate of 97.6%. Median progression free survival was 16.4 months (95% CI: 10.6 - 21.9 mo), and median overall survival (OS) was not reached. OS at 12 months was 86.7%. Adverse event (AE) data was similar to published data for IO/TKI combinations, with no grade 4-5 AEs. Twenty-nine patients experienced a grade 3 AE (70.7%), the most common of which was hypertension, and 14.0% discontinued the study due to treatment-related toxicity. Conclusions: The combination of axi/nivo for treatment naïve patients with mRCC demonstrated efficacy comparable to available IO/TKI combinations with a similar safety profile. Clinical trial information: NCT03172754. [Table: see text]
Infant Consultations.
Authors: T. H. Evans
Journal: JAMA (1905)

Philadelphia, Dec. 1, 1905. <h3>To the Editor:</h3> —Reading your notice of the Congress of "Gouttes de Lait," I would like to call your attention to the fact that there has been started in Philadelphia within the last two months a little hospital under the name of The Christ's Hospital, whose work is the same as those European stations. The purpose of the clinics is to allow mothers to bring their babies to have their diet, hygiene and general care supervised by competent medical men. The question of milk supply is a vital one, and advice to the mothers on milk mixtures is very important. You note on p. 1747 that some of these stations do not survive; it requires an infinite patience to deal with some of the more ignorant mothers. Many of them have been brought up in a mill, and have faint ideas about housekeeping. They do not