tbuckley/cabot-search huggingface dataset:
Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study).
Authors: Robert J. Motzer, Camillo Porta, Masatoshi Eto, Thomas Powles, Viktor Grünwald, Thomas E. Hutson, Boris Alekseev, Sun Young Rha, Evgeny Kopyltsov, María José Méndez Vidal, Sung-Hoo Hong, Anil Kapoor, Teresa Alonso Gordoa, Jeffrey C. Goh, Jaime R. Merchan, Alan D. Smith, Kalgi Mody, Rodolfo F. Perini, Dongyuan Xing, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2021)

269 Background: In pts with advanced RCC, second-line treatment with LEN + EVE prolonged progression-free survival (PFS) compared with EVE alone. LEN + PEMBRO, also showed preliminary efficacious evidence in a phase 1/2 RCC study. Here, we describe the investigational study results of first-line LEN + PEMBRO or LEN + EVE versus SUN in pts with advanced RCC. Methods: Pts were randomized (1:1:1) to receive LEN 20 mg orally once daily + PEMBRO 200 mg IV every 3 weeks (wks); or LEN 18 mg + EVE 5 mg orally once daily; or SUN 50 mg orally once daily (4 wks on/2 wks off). Eligible pts had advanced RCC with no prior systemic therapy. Randomization was stratified by geographic region and MSKCC prognostic group. The primary endpoint was PFS by Independent Review Committee per RECIST v1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. A sequential approach was used to test PFS first, then OS and ORR. PFS and OS were compared across arms by a stratified log-rank test; hazard ratios (HRs) were estimated by a stratified Cox regression model. Results: 1069 pts were randomized (Table). After a median follow-up of 27 months (data cutoff August 28, 2020), PFS was significantly improved with LEN + PEMBRO (median 24 months [mos]) vs SUN (median 9 mos; HR 0.39, 95% CI 0.32–0.49) and LEN + EVE (median 15 mos) vs SUN (HR 0.65, 95% CI 0.53–0.80). OS was significantly longer with LEN + PEMBRO vs SUN (HR 0.66, 95% CI 0.49–0.88), whereas OS with LEN + EVE vs SUN was not statistically different (HR 1.15, 95% CI 0.88–1.50). ORR was significantly greater with LEN + PEMBRO (ORR 71%; complete response [CR] 16%) vs SUN (ORR 36%; CR 4%; odds ratio 4.35, 95% CI 3.16–5.97) and LEN + EVE (ORR 54%; CR 10%) vs SUN (odds ratio 2.15, 95% CI 1.57–2.93). Grade ≥3 treatment-related adverse events occurred in 72% of pts in the LEN + PEMBRO arm and 73% of pts in the LEN + EVE arm compared with 59% of pts in the SUN arm. Conclusions: LEN + PEMBRO demonstrated significant improvements in PFS, OS and ORR vs SUN. LEN + EVE demonstrated significant improvements in PFS and ORR vs SUN. Safety was manageable and consistent with the known single-agent profiles. Clinical trial information: NCT02811861 . [Table: see text]
Males That Silence Their Father’s Genes: Genomic Imprinting of a Complete Haploid Genome
Authors: Andrés G de la Filia, Andrew J Mongue, Jennifer Dorrens, Hannah Lemon, Dominik R Laetsch, Laura Ross
Journal: Molecular Biology and Evolution (2021)

Abstract Genetic conflict is considered a key driver in the evolution of reproductive systems with non-Mendelian inheritance, where parents do not contribute equally to the genetic makeup of their offspring. One of the most extraordinary examples of non-Mendelian inheritance is paternal genome elimination (PGE), a form of haplodiploidy which has evolved repeatedly across arthropods. Under PGE, males are diploid but only transmit maternally inherited chromosomes, while the paternally inherited homologues are excluded from sperm. This asymmetric inheritance is thought to have evolved through an evolutionary arms race between the paternal and maternal genomes over transmission to future generations. In several PGE clades, such as the mealybugs (Hemiptera: Pseudococcidae), paternal chromosomes are not only eliminated from sperm, but also heterochromatinized early in development and thought to remain inactive, which could result from genetic conflict between parental genomes. Here, we present a parent-of-origin allele-specific transcriptome analysis in male mealybugs showing that expression is globally biased toward the maternal genome. However, up to 70% of somatically expressed genes are to some degree paternally expressed, while paternal genome expression is much more restricted in the male reproductive tract, with only 20% of genes showing paternal contribution. We also show that parent-of-origin-specific gene expression patterns are remarkably similar across genotypes, and that genes with completely biparental expression show elevated rates of molecular evolution. Our results provide the clearest example yet of genome-wide genomic imprinting in insects and enhance our understanding of PGE, which will aid future empirical tests of evolutionary theory regarding the origin of this unusual reproductive strategy.
In a global pandemic, sport and exercise medicine can mean so much more
Authors: Jane S Thornton, Karim M Khan
Journal: British Journal of Sports Medicine (2021)

The COVID-19 pandemic has been challenging, if not overwhelming, for many patients and healthcare providers in our field. Consultants-turned-frontline healthcare workers, athletes losing access to their raison-d’etre and even livelihood, researchers losing access to their labs. Competitive sport was hit hard, while physical activity levels soared for some as it provided escape from the land of lockdown. For people facing pre-existing socioeconomic and health inequities like women, Indigenous People, marginalised and racialised groups, patients in long-term care facilities and those with disabilities, the pandemic revealed the true magnitude of the physical inactivity crisis.

As sport and exercise clinicians and researchers, our advocacy on public health issues and unequal access to physical activity highlighted by the pandemic is critical. We have new opportunities to speak out and act on important policy issues as they arise. For example, we can champion for more walkable cities, broadcast the value of time being active outdoors, and remind the world of the positive effects of exercise on the immune system. We must also ensure proper screening and rehabilitation for our SARS-CoV-2 positive patients.

What have we learnt this year? This CASEM issue (see cover image) highlights three major …
Abstract 11580: Calmodulin-Dependent Protein Kinase Type 2 Upregulates Mitochondrial Calcium Uniporter to Maintain Bioenergetics in Chronically Stressed Heart
Authors: Pei Wang, Huiliang Zhang, Wang Wang
Journal: Circulation (2018)

Introduction: Mitochondrial calcium (Ca2+) plays a pivotal role in cardiac bioenergetics. Deranged mitochondrial Ca2+ underlies cardiomyocyte death and heart hypertrophy. Genetic ablation of mitoch...
Bone marrow NG2+/Nestin+ mesenchymal stem cells drive DTC dormancy via TGF-β2
Authors: Ana Rita Nobre, Emma Risson, Deepak K. Singh, Julie S. Di Martino, Julie F. Cheung, Jiapeng Wang, John Johnson, Hege G. Russnes, Jose Javier Bravo-Cordero, Alexander Birbrair, Bjorn Naume, Mohamad Azhar, Paul S. Frenette, Julio A. Aguirre-Ghiso
Journal: Nature Cancer (2021)
Time for Action on Drug Safety—Reply
Authors: Thomas J. Moore, Bruce M. Psaty, Curt D. Furberg
Journal: JAMA (1999)

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
The Role of Alcohol and Social Stress in Russia's Mortality Rate—Reply
Authors: David A. Leon, Vladimir M. Shkolnikov
Journal: JAMA (1999)

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
Racial differences in aneuploidy in high-grade muscle-invasive bladder cancer.
Authors: Adeel M Khan, Sarah C Markt, Lorelei A Mucci, Konrad H. Stopsack
Journal: Journal of Clinical Oncology (2021)

400 Background: Bladder cancer is marked by racial disparities in stage at presentation, treatment, and survival. It is unknown how somatic tumor genomes differ by race. Tumor aneuploidy, defined as aberrant counts of chromosome arms, is pervasive in tumors including bladder cancer. Its associations with race are incompletely understood. We sought here to characterize the relation of race with aneuploidy in high-grade muscle-invasive bladder cancer. Methods: To quantify how aneuploidy differs by race, we leveraged the cohort of patients with high-grade, muscle-invasive bladder cancer from The Cancer Genome Atlas. Chromosome arm gains and losses were identified based on Affymetrix SNP 6.0 arrays (Taylor 2018). We focused on aneuploidy burden defined as the count of chromosome arms altered by gains and losses per tumor, which was based on both p and q chromosome arms of all autosomes except for acrocentric autosomes (q arms only) and ranged from 0 to 34 altered chromosome arms. We used multivariable linear regression to obtain mean differences and 95% confidence intervals (CIs) in the number of altered chromosome arms between self-reported racial groups, adjusting for demographics (sex, age at diagnosis, smoking status) and tumor characteristics (grade, histology). We also evaluated associations between race and number of altered chromosome arms stratified by papillary/non-papillary histology and sex. Results: Of 362 participants, 315 self-identified as White (87%), 25 as Asian (7%), and 22 as Black (6%). 73% were men, 21% were current smokers, and 52% former smokers. Median age at diagnosis was 69 years (interquartile range [IQR]: 61 to 76). Asians and Blacks tended to be younger at diagnosis than Whites, with more never-smokers among Asians. More profiled tumors were of papillary histology among Asians (44%), and fewer among Blacks (18%), than among Whites (30%). Aneuploidy burden was high overall (median, 14 altered chromosome arms; IQR: 8 to 19); only 17% of tumors had five or fewer altered chromosome arms. Compared to Whites, aneuploidy burden overall was similar in tumors from Asians (adjusted mean difference, –2.3 fewer altered chromosome arms; 95% CI: –5.4 to 0.9) and Blacks (–1.7; 95% CI: –5.1 to 1.7). Asian race appeared more strongly associated with lower aneuploidy burden in non-papillary tumors (–3.9 altered chromosome arms; 95% CI: –7.7 to –0.1) than in papillary tumors (–0.3; 95% CI: –5.6 to 5.0), and in men (–3.5; 95% CI: –7.0 to 0.1) than in women (–0.8; 95% CI: –6.8 to 5.2). Conclusions: These findings suggest potential differences in aneuploidy burden between Asians and Whites among high-grade muscle-invasive bladder cancers. They also highlight a need for validation in cohorts that are more racially diverse and have a well-defined source population (study base) with detailed data on cancer risk factors and histopathology.
Replication of DNA Methylation Variation Reported in Cord Blood Samples From GDM-Affected Pregnancies in Preadolescent and Adolescent Offspring of Women With GDM
Authors: Line Hjort, Louise Groth Grunnet, Richard Saffery, Sjurdur Olsen, Allan Vaag
Journal: Diabetes Care (2021)

Offspring of women with gestational diabetes mellitus (GDM) exhibit a high risk of developing type 2 diabetes later in life, potentially as a result of developmental programming by epigenetic mechanisms (1,2). We read with great interest the meta-analysis by Howe et al. (3) integrating results of differential cord blood DNA methylation changes from seven epigenome-wide association studies (EWAS) including in total 3,677 mother-newborn pairs. Pregnancies complicated with GDM were associated with significantly lower cord blood methylation levels within the promoter region of the OR2L13 gene, as well as within the gene body of the CYP2E1 gene (3). At single CpG site levels, the authors reported GDM to be associated with differential methylations at six distinct CpG sites (3). As pointed out by Howe et al., replication of EWAS analyses is extremely important due to 1 ) high risk of confounders; 2 ) in general, small absolute methylation differences; and 3 ) analytical uncertainties related to multiple comparisons and adjustment for cell …
A pilot clinical trial of genomic-based therapy assignment with co-expression extrapolation (COXEN) in advanced/metastatic urothelial carcinoma.
Authors: Scot Anthony Niglio, Rosa Maria Nadal, Lisa M. Cordes, Seth M. Steinberg, Nicole N. Davarpanah, Rene Costello, Marissa Mallek, Daniel da Motta Girardi, Maria Merino, Yonghong Wang, Joshua Mannheimer, Daniel Edelman, Jennifer Walling, Paul S. Meltzer, Dan Theodorescu, Daniel Gustafson, Andrea B. Apolo
Journal: Journal of Clinical Oncology (2021)

452 Background: We investigated the Co-eXpression ExtrapolatioN (COXEN) algorithm to select “next best therapy” for patients with advanced/metastatic urothelial cancer based on gene expression profiles. Methods: This is a single-arm, open label pilot study, that investigates the COXEN algorithm’s ability to use patients’ tumor gene expression models to predict sensitivities to 75 FDA-approved anticancer agents. The COXEN results were reviewed and discussed in a multi-disciplinary molecular tumor board. From that a treatment plan was chosen based on monotherapy clinical efficacy data in urothelial carcinoma, combination safety data (combinations of agents were allowed provided phase I data were available), side effect profile/tolerability, response or resistance to prior therapies, therapy contraindications, and feasibility of therapy. The objective of this study was to determine the feasibility of using COXEN as a clinical decision algorithm to make a real-time treatment decision within 21 days of specimen collection in patients with advanced/metastatic urothelial carcinoma. Results: A total of 8 patients enrolled and underwent tumor biopsy for COXEN analysis. Five out of 8 patients received COXEN therapy within 21 days of biopsy with various regimens including: vorinostat and etoposide; doxorubicin; sunitinib; doxorubicin and paclitaxel; erlotinib and nab-paclitaxel. There were no objective responses. The 5 patients treated with COXEN therapy had a median potential follow up of 36 months, median overall survival of 8.4 months (95% CI: 5.2 months – not estimable), and median progression free survival of 2.2 months (95% CI: 1.4 – 3.9 months). Grade 3 or 4 adverse events included: febrile neutropenia (n=2), hypophosphatemia (n=1) and hyponatremia (n=1). This trial was terminated early due to a lack of treatment responses. Conclusions: The COXEN algorithm is a unique personalized method for selecting therapy for patients with advanced urothelial carcinoma. Although the COXEN method was feasible, it did not demonstrate clinical efficacy in this small cohort of patients. Clinical trial information: NCT02788201.
INTERNATIONAL CONGRESS.
Journal: JAMA (1890)

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
Consolidating the Circuit Model for Addiction
Authors: Christian Lüscher, Patricia H. Janak
Journal: Annual Review of Neuroscience (2021)

Addiction is a disease characterized by compulsive drug seeking and consumption observed in 20–30% of users. An addicted individual will favor drug reward over natural rewards, despite major negative consequences. Mechanistic research on rodents modeling core components of the disease has identified altered synaptic transmission as the functional substrate of pathological behavior. While the initial version of a circuit model for addiction focused on early drug adaptive behaviors observed in all individuals, it fell short of accounting for the stochastic nature of the transition to compulsion. The model builds on the initial pharmacological effect common to all addictive drugs—an increase in dopamine levels in the mesolimbic system. Here, we consolidate this early model by integrating circuits underlying compulsion and negative reinforcement. We discuss the genetic and epigenetic correlates of individual vulnerability. Many recent data converge on a gain-of-function explanation for circuit remodeling, revealing blueprints for novel addiction therapies.
Hypothermia Effectively Treats Tumors with Temperature-Sensitive p53 Mutations
Authors: Junhao Lu, Lihong Chen, Zheng Song, Mousumi Das, Jiandong Chen
Journal: Cancer Research (2021)

Abstract The p53 tumor suppressor is frequently inactivated by mutations in cancer. Most p53 mutations are located in the DNA-binding domain, causing local disruption of DNA-binding surface or global misfolding. Rescuing the structural defect of mutant p53 is an attractive therapeutic strategy, but its potential remains unproven due to a lack of drugs capable of efficiently rescuing misfolded p53. Although mutant p53 in tumors is inactive at 37°C, approximately 15% are temperature sensitive (ts) and regain DNA-binding activity at 32°C to 34°C (ts mutants). This temperature is achievable using a therapeutic hypothermia procedure established for resuscitated cardiac arrest patients. To test whether hypothermia can be used to target tumors with ts p53 mutations, the core temperature of tumor-bearing mice was lowered to 32°C using the adenosine A1 receptor agonist N6-cyclohexyladenoxine that suppresses brain-regulated thermogenesis. Hypothermia treatment (32 hours at 32°C × 5 cycles) activated endogenous ts mutant p53 in xenograft tumors and inhibited tumor growth in a p53-dependent fashion. Tumor regression and durable remission in a ts p53 lymphoma model was achieved by combining hypothermia with chemotherapy. The results raise the possibility of treating tumors expressing ts p53 mutations with hypothermia. Significance: Pharmacologic inhibition of brain-regulated thermogenesis and induction of 32°C whole-body hypothermia specifically targets tumors with temperature-sensitive p53 mutations, rescuing p53 transcriptional activity and inducing tumor regression. See related commentary by Hu and Feng, p. 3762
Abstract 12253: Prognostic Impact of Peak Oxygen Uptake and Heart Rate Reserve in Patients After Off-pump Coronary Artery Bypass Grafting
Authors: Abidan Abulimiti, Kazunori Shimada, Miho Yokoyama, Mitsuhiro Kunimoto, Tomomi Matsubara, Kei Fujiwara, Tatsuro Aikawa, Shohei Ouchi, Megumi Shimizu, Kosuke Fukao, Tomoyasu Kadoguchi, Tetsuro Miyazaki, Akie Shimada, Taira Yamamoto, Tetsuya Takahashi, Toshiyuki Fujiwara, Atsushi Amano, Hiruyuki Daida
Journal: Circulation (2019)

Background: The benefits of off-pump coronary artery bypass grafting (OP-CABG) are still controversial. Previous studies have demonstrated that peak oxygen uptake (peak VO2) and heart rate reserve ...
Global effect of the COVID-19 pandemic on paediatric cancer care: a cross-sectional study
Authors: Dylan Graetz, Asya Agulnik, Radhikesh Ranadive, Yuvanesh Vedaraju, Yichen Chen, Guillermo Chantada, Monika L Metzger, Sheena Mukkada, Lisa M Force, Paola Friedrich, Catherine Lam, Elizabeth Sniderman, Nickhill Bhakta, Laila Hessissen, Rashmi Dalvi, Meenakshi Devidas, Kathy Pritchard-Jones, Carlos Rodriguez-Galindo, Daniel C Moreira
Journal: The Lancet Child & Adolescent Health (2021)
Body Mass Index and Risk for COVID-19–Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death — United States, March–December 2020
Authors: Lyudmyla Kompaniyets, Alyson B. Goodman, Brook Belay, David S. Freedman, Marissa S. Sucosky, Samantha J. Lange, Adi V. Gundlapalli, Tegan K. Boehmer, Heidi M. Blanck
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Obesity (body mass index ≥30 kg/m 2 ) is frequently categorized into three categories: class 1 (30.0-34.9kg/m 2 ), class 2 (35.0-39.9kg/m 2 ), and class 3 (≥40 kg/m 2 ).Class 3 obesity is sometimes referred to as "extreme" or "severe" obesity.