tbuckley/cabot-search huggingface dataset:
A phase 1b/2 study of VS-6766 in combination cetuximab in patients (pts) with advanced KRAS mt colorectal cancer (CRC).
Authors: Ardaman Shergill, Chih-Yi Liao, Hedy L. Kindler, Blase N. Polite, Daniel V.T. Catenacci
Journal: Journal of Clinical Oncology (2022)

TPS219 Background: KRAS mutations (mts) are present in about 45% of CRC and predict lack of response to anti-EGFR therapy like cetuximab. Limited therapy options exist for pts after prior 5-FU based regimens. Regorafenib or TAS-102 is commonly used however, the modest clinical benefit, and toxicity limit their use. Novel therapies are needed for pts at this point in their disease course. KRAS G12D and G12V mts occur in 11-12% and 9-10% of CRC, respectively, whereas G12C mts occur in 3-4% of CRCs . KRAS G12C mts occur in 3-4% of CRCs. Recently, results of phase 1/2 KRYSTAL-1 study were reported. Adagrasib (a KRAS G12C inhibitor) was used with/without cetuximab in heavily pretreated CRC pts harboring KRAS G12C mts. The objective response rate (ORR) and disease control rate (DCR) was 43% and 100% (resp.) in pts receiving cetuximab and adagrasib (28 evaluable pts), and 22% and 87%, resp., in those receiving adagrasib alone (42 evaluable pts). Phase 1b CodeBreaK101 study evaluating sotorasib ( KRAS G12C inhibitor) and panitumumab (anti-EGFR) combination in KRAS G12C mt CRC showed 15.4% confirmed ORR and 26.9% unconfirmed ORR. These data are encouraging, suggesting EGFR inhibition in combination with downstream KRAS inhibition may represent important therapeutic strategy for this disease. KRAS mts lead to constitutive activation of the MAPK pathway signaling and cell activation. VS-6766 is a novel dual RAF/MEK inhibitor which has shown activity in KRAS mutated tumors. Combination of EGFR inhibition and VS-6766 may overcome resistance of KRAS mt CRC cancers to EGFR inhibition alone. Preclinically, VS-6766 and EGFR inhibition showed synergy in KRAS mt CRC cell lines, including cell lines harboring KRAS G12D and G12V mts, and CRC PDX of KRAS G12V mt CRC showed tumor regression with this combination. These data support the development of VS-6766 with anti-EGFR therapy in KRAS mt CRC warranting this phase 1 study to evaluate safety and efficacy of this combination in clinical settings. Methods: This is an open label, single arm study evaluating VS-6766 with cetuximab in pts with KRAS mt advanced CRC. Phase 1b primary endpoints include safety and tolerability, and maximum tolerated dose and recommended phase 2 dose determination. ORR is the primary endpoint of the Phase 2 study. Secondary endpoints include OS and PFS. There will be upto 4 dose levels tested. Three de-escalation doses to find the optimal cetuximab dose, and one dose escalation of VS-6766, are planned. Eligible pts include those with metastatic CRC and progression after 5-FU, oxaliplatin, irinotecan and VEGFi therapy. Based on prior studies, dermatologic, gastrointestinal, ocular and CPK elevation have been the main toxicities noted with VS-6766. The study is funded by research grants from Verastem Oncology. Cetuximab will be supplied by Eli Lilly.
Opioid use in rheumatic diseases: preventing another pandemic
Authors: None The Lancet Rheumatology
Journal: The Lancet Rheumatology (2020)

As the COVID-19 pandemic continues to surge in many countries worldwide, the indirect effects of the pandemic are starting to come to the fore. One of these effects is a rebound of the epidemic of opioid overuse in the USA, undoing much of the recent progress that had been made in reducing harm and drug overdoses. Even before the COVID-19 crisis, 130 Americans were dying from opioid overdoses every day. In some states, drug overdoses have increased up to 50% compared with the same time last year, with some reporting more deaths than for COVID-19.
Mac Cheever (1944–2021): a tribute to a life of achievement and service
Authors: Philip D Greenberg, Mary L Disis, Kim A Margolin, Lynn M Matrisian, Paul M Sondel
Journal: Journal for ImmunoTherapy of Cancer (2022)

Mac Cheever left this world way too soon on September 23, 2021, and, while he will be greatly missed both personally and professionally, his contributions and imprint, especially in the field of immunotherapy of cancer, will certainly be enduring. He was also a devoted and loving friend, husband,
Systemic Inflammation Induces Release of Cell-Free DNA from Hematopoietic and Parenchymal Cells in Mice and Human
Authors: Anna Kroeze, Anne Jan van der Meer, Arie J Hoogendijk, Aicha Ait Soussan, C. Ellen van der Schoot, Walter A Wuillemin, Carlijn Voermans, Tom van der Poll, Sacha S Zeerleder
Journal: Blood (2018)
Association Between Change in Accelerometer-Measured and Self-Reported Physical Activity and Cardiovascular Disease in the Look AHEAD Trial
Journal: Diabetes Care (2022)

OBJECTIVE To conduct post hoc secondary analysis examining the association between change in physical activity. Measured with self-report and accelerometry, from baseline to 1 and 4 years and cardiovascular disease (CVD) outcomes in the Look AHEAD Trial. RESEARCH DESIGN AND METHODS Participants were adults with overweight/obesity and type 2 diabetes with physical activity. Data at baseline and year 1 or 4 (n = 1,978). Participants were randomized to diabetes support and education or intensive lifestyle intervention. Measures included accelerometry-measured moderate-to-vigorous physical activity (MVPA), self-reported physical activity, and composite (morbidity and mortality) CVD outcomes. RESULTS In pooled analyses of all participants, using Cox proportional hazards models, each 100 MET-min/week increase in accelerometry-measured MVPA from baseline to 4 years was associated with decreased risk of the subsequent primary composite outcome of CVD. Results were consistent for changes in total MVPA (hazard ratio 0.97 [95% CI 0.95, 0.99]) and MVPA accumulated in ≥10-min bouts (hazard ratio 0.95 [95% CI 0.91, 0.98]), with a similar pattern for secondary CVD outcomes. Change in accelerometry-measured MVPA at 1 year and self-reported change in physical activity at 1 and 4 years were not associated with CVD outcomes. CONCLUSIONS Increased accelerometry-measured MVPA from baseline to year 4 is associated with decreased risk of CVD outcomes. This suggests the need for long-term engagement in MVPA to reduce the risk of CVD in adults with overweight/obesity and type 2 diabetes.
Preface
Journal: Annual Review of Nutrition (2006)

The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved health outcomes.A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing."Modified fasting regimens appear to promote weight loss and may improve metabolic health.Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health.Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep.If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.
Cerebrovascular Disorders
Authors: William H. Olson
Journal: JAMA (1991)

In his preface, Dr Toole states that his book was written for clinicians with a limited knowledge of the cerebral circulation and that the major emphasis would be on the diagnosis and management of cerebrovascular disease. Thus, the book would be particularly helpful to internists, family practitioners, and neurology residents. The initial chapters concentrate on providing the reader with a sound background in anatomy, physiology, and biochemistry. Many of these issues are addressed again further on in the text when the specific problems are discussed. In this era of technological advances, the chapter on the neurovascular examination at the bedside is particularly helpful. It includes a section on how to listen for bruits and what to look for in an ophthalmologic examination. In general, each chapter is clearly divided into sections on etiology and pathogenesis, pathophysiology, pathological findings, clinical features, examination of the patient, and management. Throughout the text are
Options beyond BRAF targeted therapy in second-line treatment of patients with BRAFV600E mutant (BRAFmt) metastatic colorectal cancer (mCRC).
Authors: Vanessa Wong, Wei Hong, Sumitra Ananda, Catherine Dunn, Rachel Wong, Yat Hang To, Matthew E. Burge, Louise M. Nott, Jeanne Tie, Jeremy David Shapiro, Ross Jennens, Muhammad Adnan Khattak, Aflah Roohullah, Peter Gibbs
Journal: Journal of Clinical Oncology (2022)

47 Background: BRAFmt is a negative prognostic factor in mCRC but also identifies a patient population that may benefit from BRAF targeted therapy. Results from recent trials (BEACON and SWOG1406) demonstrate improved survival outcomes in second- and third-line settings when combining a BRAF inhibitor, an EGFR inhibitor (EGFRi) +/- a MEK inhibitor. In both trials, irinotecan and cetuximab was the control arm with a dismal response rate of 2-4% and progression free survival (PFS) of only 2 months. This suggests chemotherapy plus an EGFRi may not be the optimal approach where BRAF-targeted therapies are not available or have failed. Methods: Data from July 2009 to September 2021 was analysed from TRACC, a multi-site Australian mCRC comprehensive prospective registry enrolling consecutive patients. Patient characteristics, treatment and survival outcomes were examined for patients treated with chemotherapy (CT) alone, with bevacizumab (BEV) or with an EGFRi. Results: Of 2046 registry patients, 256 (13%) harboured a BRAFmt. 72 BRAFmt patients had received second-line (28%) treatment, including CT alone (n = 28), CT plus BEV (n = 26), and CT plus EGFRi (n = 18). Baseline characteristics are shown in the table. Median second-line PFS was 3.3, 4.7 and 1.8 months, for CT alone, CT plus BEV and CT plus EGFRi respectively. Median overall survival (OS) was 8.7, 7.9 and 2.5 months respectively. In multivariate analysis, PFS when treated with CT plus EGFRi trended inferior to CT alone (p = 0.054) and CT plus BEV (p = 0.061), whereas for OS, treatment with CT plus EGFRi was inferior to CT alone (p = 0.038) and CT plus BEV (p = 0.015). Poor PFS was associated with age ≥ 65 years (HR 3.03, p &lt; 0.001) and ECOG ≥ 2 (HR 2.62, p = 0.004), but not associated with a right side primary (p = 0.17), mismatch repair (MMR) status (p = 0.86), or ≥ 3 organs with metastases (p = 0.32). Poor OS was associated with age ≥ 65 years (HR 3.11, p &lt; 0.001), ECOG ≥ 2 (HR 7.32, p &lt; 0.001), right side primary (HR 3.03, p = 0.002) and proficient MMR status (HR 3.57, p = 0.018), but not associated with ≥ 3 organs with metastases (p = 0.17). Conclusions: Less than one-third of BRAFmt mCRC patients received second-line therapy in a real-world setting, indicating an urgency to explore activity of BRAF targeted therapy in the first line setting. Treated patients received limited benefit, with CT plus EGFRi PFS outcomes comparable to BEACON control arm (1.8 vs 2.0 months) and trending inferior to other options. The best OS outcomes were achieved with CT alone or CT plus BEV.[Table: see text]
MicroRNAs as Indicators into the Causes and Consequences of Whole-Genome Duplication Events
Authors: Kevin J Peterson, Alan Beavan, Peter J Chabot, Mark A McPeek, Davide Pisani, Bastian Fromm, Oleg Simakov
Journal: Molecular Biology and Evolution (2021)

Whole-genome duplications (WGDs) have long been considered the causal mechanism underlying dramatic increases to morphological complexity due to the neo-functionalization of paralogs generated during these events. Nonetheless, an alternative hypothesis suggests that behind the retention of most paralogs is not neo-functionalization, but instead the degree of the inter-connectivity of the intended gene product, as well as the mode of the WGD itself. Here, we explore both the causes and consequences of WGD by examining the distribution, expression, and molecular evolution of microRNAs (miRNAs) in both gnathostome vertebrates as well as chelicerate arthropods. We find that although the number of miRNA paralogs tracks the number of WGDs experienced within the lineage, few of these paralogs experienced changes to the seed sequence, and thus are functionally equivalent relative to their mRNA targets. Nonetheless, in gnathostomes, although the retention of paralogs following the 1R autotetraploidization event is similar across the two subgenomes, the paralogs generated by the gnathostome 2R allotetraploidization event are retained in higher numbers on one subgenome relative to the second, with the miRNAs found on the preferred subgenome showing both higher expression of mature miRNA transcripts and slower molecular evolution of the precursor miRNA sequences. Importantly, WGDs do not result in the creation of miRNA novelty, nor do WGDs correlate to increases in complexity. Instead, it is the number of miRNA seed sequences in the genome itself that not only better correlate to instances in complexification, but also mechanistically explain why complexity increases when new miRNA families are established.
Abstract P298: Associations Between Time-varying Physical Activity and Physical Performance Measures in Postmenopausal Women: the Women’s Health Initiative
Authors: Deepika Laddu, Betsy C Wertheim, David O Garcia, Robert Brunner, Aladdin H Shadyab, Erik Groessl, Scott B Going, Michael J LaMonte, Brad Cannell, Meryl LeBoff, Jane A Cauley, Cynthia A Thomson, Marcia L Stefanick
Journal: Circulation (2017)

Introduction: Maintaining regular physical activity (PA) may delay the onset of functional disability and preserve mobility later in life. Whereas many population-based studies have reported the prospective relationship of initial PA levels to later-life functional status, few studies have examined the longitudinal relationships between changes in PA to changes in physical functioning. This study examined associations between changes in PA and changes in standard physical performance measures (PPM) over 6-years in older women. Methods: Recreational PA was reported using the WHI questionnaire; gait speed, timed chair stand, and grip strength were assessed in clinic using standardized protocols. Exposures were assessed at baseline, years 1, 3 and 6 of the Women’s Health Initiative Clinical Trials (n=5092 women; mean age = 69.8 y). Mixed effects linear regression models were used to evaluate the association between time-varying PA and change in each PPM. Potential interactions between time-varying PA and race and age (&lt;70 y; ≥70 y) were also tested. Results: At baseline, 23.0% women were categorized as sedentary (SED; &lt;100 MET-min/wk), 30.4% as light PA level (100- &lt;500 MET-min/wk), 27.5% as moderate (500- &lt;1200 MET-min/wk); and 19.1% as high PA (≥ 1200 MET-min/wk). Significant, dose-response associations between PA and improvements in all PPMs were observed over the 6 y follow-up after adjusting for demographic, lifestyle, and clinical factors. Compared to SED, women in the high PA groups showed better grip strength (0.48 kg higher; P &lt;0.01), more chair stands (0.35 more; P &lt;0.001), and faster gait speeds (0.06 m/s faster ; P &lt;0.001). Older women (≥70 y) benefited more from higher levels of PA than the younger women (P interaction for age =0.014), as reflected by their greater increase in chair stands ( P &lt;0.001); however, interactions between PA and race were not significant. Conclusions: These findings provide evidence that, in post-menopausal women, maintaining higher PA levels over time is associated with benefits in lower extremity function, as compared to being sedentary. These data are consistent with the view that regular PA plays an important role in maintaining functional status during aging, particularly in older women.
Paced Tachycardia
Authors: Miguel A. Arias, Irene Narváez, Marta Pachón
Journal: Circulation (2020)

ECG CHALLENGEA 72-year-old man was implanted with a biventricular implantable cardioverter defibrillator 6 years ago for ischemic dilated cardiomyopathy with a healed myocardial infarction associated with severe left ventricular systolic dysfunction, complete left bundle-branch block, and New York Heart Association Class II heart failure.He underwent ventricular tachycardia (VT) ablation for recurrent implantable cardioverter defibrillator shocks for fast VT episodes despite amiodarone treatment.Seven months later, while still on amiodarone treatment, he was admitted to the emergency department complaining of chest pain and dyspnea.The ECG in Figure 1 was recorded on admission.What type of tachycardia does the patient present?How should the patient be managed?Please turn the page to read the diagnosis.
<i>QuickStats:</i> Death Rates* from Septicemia<sup>†</sup> Among Persons Aged ≥65 Years, by Age Group — National Vital Statistics System, United States, 2000–2018
Authors: Ellen Kramarow, Julie Weeks, Cynthia Reuben
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

≥85 yrs 65-74 yrs 75-84 yrs ≥65 yrs * Deaths per 100,000 population in each age group.† Deaths attributed to septicemia were identified using International Classification of Diseases, Tenth Revision underlying cause of death codes A40-A41.During 2000-2018, the death rate from septicemia among persons aged ≥65 years generally decreased from 70.8 to 58.7 deaths per 100,000 population.The death rate was lower in 2018 than in 2000 among persons aged 75-84 years (80.4 compared with 69.4) and among persons aged ≥85 years (215.7 compared with 167.4).The death rate for persons aged 65-74 was similar in 2000 (31.0) and 2018 (30.0).In each year during 2000-2018, the death rate was highest among persons aged ≥85 years and lowest among persons aged 65-74 years.
Leads from the MMWR. Antigenic variation of recent influenza A(H3N2) viruses
Journal: JAMA (1988)

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The landscape of human tissue and cell type specific expression and co-regulation of senescence genes
Authors: Peng Xu, Minghui Wang, Won-min Song, Qian Wang, Guo-Cheng Yuan, Peter H. Sudmant, Habil Zare, Zhidong Tu, Miranda E. Orr, Bin Zhang
Journal: Molecular Neurodegeneration (2022)

Abstract Background Cellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. However, the prevalence of senescent cells in healthy human tissues and the global SnG expression signature in different cell types are poorly understood. Methods This study performed an integrative gene network analysis of bulk and single-cell RNA-seq data in non-diseased human tissues to investigate SnG co-expression signatures and their cell-type specificity. Results Through a comprehensive transcriptomic network analysis of 50 human tissues in the Genotype-Tissue Expression Project (GTEx) cohort, we identified SnG-enriched gene modules, characterized SnG co-expression patterns, and constructed aggregated SnG networks across primary tissues of the human body. Our network approaches identified 51 SnGs highly conserved across the human tissues, including CDKN1A ( p21 )-centered regulators that control cell cycle progression and the senescence-associated secretory phenotype (SASP). The SnG-enriched modules showed remarkable cell-type specificity, especially in fibroblasts, endothelial cells, and immune cells. Further analyses of single-cell RNA-seq and spatial transcriptomic data independently validated the cell-type specific SnG signatures predicted by the network analysis. Conclusions This study systematically revealed the co-regulated organizations and cell type specificity of SnGs in major human tissues, which can serve as a blueprint for future studies to map senescent cells and their cellular interactions in human tissues.
Corrections
Authors: Gary Davis
Journal: Hepatology (2008)

the sentence that reads "In conclusion, MRI is a useful tool for identifying the two major subtypes of HCA (HNF-1␣ and ␤-catenin mutations), which have distinctly different patterns on MRI" should be corrected to "In conclusion, MRI is a useful tool for identifying the two major subtypes of HCA (HNF-1␣ mutated and inflammatory HCAs), which have distinctly different patterns on MRI."
Reintervention and Survival After Transcatheter Pulmonary Valve Replacement
Authors: Doff B. McElhinney, Yulin Zhang, Daniel S. Levi, Stanimir Georgiev, Elżbieta Katarzyna Biernacka, Bryan H. Goldstein, Shabana Shahanavaz, Athar M. Qureshi, Allison K. Cabalka, Holly Bauser-Heaton, Alejandro J. Torres, Brian H. Morray, Aimee K. Armstrong, Oscar Millan-Iturbe, Lynn F. Peng, Jamil A. Aboulhosn, Witold Rużyłło, Felix Berger, Lars Sondergaard, Dietmar Schranz, John P. Cheatham, Thomas K. Jones, Peter Ewert, Stephan Schubert
Journal: Journal of the American College of Cardiology (2022)
Left ventricular ejection fraction remains a strong predictor of long-term but not short-term all-cause, cardiac and arrhythmic mortality after myocardial infarction: An analysis of 2828 patients Yee Guan Yap, Trinh Duong, Martin Bland, Christian Torp-Pederson, Lars Kober, Stuart Connolly, Robin Roberts, Bradley Marchant, Marek Malik, A. John Camm. St. George's Hospital Medical School, London, United Kingdom
Journal: Journal of the American College of Cardiology (2001)