tbuckley/cabot-search huggingface dataset:
FAK in the nucleus prevents VSMC proliferation by promoting p27 and p21 expression via Skp2 degradation
Authors: Kyuho Jeong, James M Murphy, Eun-Young Erin Ahn, Ssang-Taek Steve Lim
Journal: Cardiovascular Research (2021)

Vascular smooth muscle cells (VSMCs) normally exhibit a very low proliferative rate. Vessel injury triggers VSMC proliferation, in part, through focal adhesion kinase (FAK) activation, which increases transcription of cyclin D1, a key activator for cell cycle-dependent kinases (CDKs). At the same time, we also observe that FAK regulates the expression of the CDK inhibitors (CDKIs) p27 and p21. However, the mechanism of how FAK controls CDKIs in cell cycle progression is not fully understood.We found that pharmacological and genetic FAK inhibition increased p27 and p21 by reducing stability of S-phase kinase-associated protein 2 (Skp2), which targets theCDKIs for degradation. FAK N-terminal domain interacts with Skp2 and an APC/C E3 ligase activator fizzy-related 1 (Fzr1) in the nucleus, which promote ubiquitination and degradation of both Skp2 and Fzr1. Notably, overexpression of cyclin D1 alone failed to promote proliferation of genetic FAK kinase-dead (KD) VSMCs, suggesting that the FAK-Skp2-CDKI signalling axis is distinct from the FAK-cyclin D1 pathway. However, overexpression of both cyclin D1 and Skp2 enabled proliferation of FAK-KD VSMCs, implicating that FAK ought to control both activating and inhibitory switches for CDKs. In vivo, wire injury activated FAK in the cytosol, which increased Skp2 and decreased p27 and p21 levels.Both pharmacological FAK and genetic FAK inhibition reduced Skp2 expression in VSMCs upon injury, which significantly reduced intimal hyperplasia through elevated expression of p27 and p21. This study revealed that nuclear FAK-Skp2-CDKI signalling negatively regulates CDK activity in VSMC proliferation.
Life in Deserts: The Genetic Basis of Mammalian Desert Adaptation
Authors: Joana L. Rocha, Raquel Godinho, José C. Brito, Rasmus Nielsen
Journal: Trends in Ecology & Evolution (2021)

Deserts are among the harshest environments on Earth. The multiple ages of different deserts and their global distribution provide a unique opportunity to study repeated adaptation at different timescales. Here, we summarize recent genomic research on the genetic mechanisms underlying desert adaptations in mammals. Several studies on different desert mammals show large overlap in functional classes of genes and pathways, consistent with the complexity and variety of phenotypes associated with desert adaptation to water and food scarcity and extreme temperatures. However, studies of desert adaptation are also challenged by a lack of accurate genotype-phenotype-environment maps. We encourage development of systems that facilitate functional analyses, but also acknowledge the need for more studies on a wider variety of desert mammals.
Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology
Authors: Margaret A. Tempero, Mokenge P. Malafa, Mahmoud Al-Hawary, Stephen W. Behrman, Al B. Benson, Dana B. Cardin, E. Gabriela Chiorean, Vincent Chung, Brian Czito, Marco Del Chiaro, Mary Dillhoff, Timothy R. Donahue, Efrat Dotan, Cristina R. Ferrone, Christos Fountzilas, Jeffrey Hardacre, William G. Hawkins, Kelsey Klute, Andrew H. Ko, John W. Kunstman, Noelle LoConte, Andrew M. Lowy, Cassadie Moravek, Eric K. Nakakura, Amol K. Narang, Jorge Obando, Patricio M. Polanco, Sushanth Reddy, Marsha Reyngold, Courtney Scaife, Jeanne Shen, Charles Vollmer, Robert A. Wolff, Brian M. Wolpin, Beth Lynn, Giby V. George
Journal: Journal of the National Comprehensive Cancer Network (2021)

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.
Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer
Authors: Antao Chang, Liang Liu, Justin M. Ashby, Dan Wu, Yanan Chen, Stacey S. O'Neill, Shan Huang, Juan Wang, Guanwen Wang, Dongmei Cheng, Xiaoming Tan, W.J. Petty, Boris C. Pasche, Rong Xiang, Wei Zhang, Peiqing Sun
Journal: Cancer Research (2021)

Abstract When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here, we report that KMT2 mutations occur frequently in non–small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)–mediated DNA repair, KMT2C/D mutations sensitized NSCLC to Poly(ADP-ribose) polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low BRCA1/2 mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency KMT2C/D mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent BRCA1/2 mutations. Significance: This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency KMT2C/D mutations as biomarkers for response to PARP inhibition in cancer.
Association between the renin–angiotensin system and chronic lung allograft dysfunction
Authors: Gregory Berra, Sofia Farkona, Zahraa Mohammed-Ali, Max Kotlyar, Liran Levy, Sergi Clotet-Freixas, Phillip Ly, Benjamin Renaud-Picard, Guan Zehong, Tina Daigneault, Allen Duong, Ihor Batruch, Igor Jurisica, Ana Konvalinka, Tereza Martinu
Journal: European Respiratory Journal (2021)

Chronic lung allograft dysfunction (CLAD) is the major cause of death after lung transplantation. Angiotensin II (AngII), the main effector of the renin–angiotensin system, elicits fibrosis in both kidney and lung. We identified six AngII-regulated proteins (Ras homolog family member B (RHOB), bone marrow stromal cell antigen 1 (BST1), lysophospholipase 1 (LYPA1), glutamine synthetase (GLNA), thrombospondin 1 (TSP1) and laminin subunit β2 (LAMB2)) that were increased in urine of patients with kidney allograft fibrosis. We hypothesised that the renin–angiotensin system is active in CLAD and that AngII-regulated proteins are increased in bronchoalveolar lavage fluid (BAL) of CLAD patients. We performed immunostaining of AngII receptors (AGTR1 and AGTR2), TSP1 and GLNA in 10 CLAD lungs and five controls. Using mass spectrometry, we quantified peptides corresponding to AngII-regulated proteins in BAL of 40 lung transplant recipients (stable, acute lung allograft dysfunction (ALAD) and CLAD). Machine learning algorithms were developed to predict CLAD based on BAL peptide concentrations. Immunostaining demonstrated significantly more AGTR1 + cells in CLAD versus control lungs (p=0.02). TSP1 and GLNA immunostaining positively correlated with the degree of lung fibrosis (R 2 =0.42 and 0.57, respectively). In BAL, we noted a trend towards higher concentrations of AngII-regulated peptides in patients with CLAD at the time of bronchoscopy, and significantly higher concentrations of BST1, GLNA and RHOB peptides in patients that developed CLAD at follow-up (p&lt;0.05). The support vector machine classifier discriminated CLAD from stable and ALAD patients at the time of bronchoscopy (area under the curve (AUC) 0.86) and accurately predicted subsequent CLAD development (AUC 0.97). Proteins involved in the renin–angiotensin system are increased in CLAD lungs and BAL. AngII-regulated peptides measured in BAL may accurately identify patients with CLAD and predict subsequent CLAD development.
Buprenorphine Opioid Treatment During the COVID-19 Pandemic
Authors: Mimosa Luigi, Michael Luo, Etienne J. P. Maes
Journal: JAMA Internal Medicine (2021)

Thuy D. Nguyen, PhD; Sumedha Gupta, PhD; Engy Ziedan, PhD; Kosali I. Simon, PhD; G. Caleb Alexander, MD, MS; Brendan Saloner, PhD; Bradley D. Stein, MD, PhD
COVID-19: from hospitals to courts – Author's reply
Authors: Michele Usuelli
Journal: The Lancet (2021)

I thank Nicola Magnavita and colleagues for raising important points regarding my Correspondence.1Usuelli M The Lombardy region of Italy launches the first investigative COVID-19 commission.Lancet. 2020; 396: e86-e87Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar I agree that the process of analysing the pandemic through a commission is slow, but citizens deserve to know the results of an audit. Some structural problems within health management existed before this pandemic; COVID-19 only emphasised them. Citizens now also fully understand that their regional vote affects their lives. Criticising decentralisation is valid, but the implementation of any law should be analysed before changing the law. Within decentralisation, Italy foresaw central and regional quinquennial sociosanitary plans. The plans define and prospectively update the organisation of the health system. The most recent national plan was produced in 2006 and the regional plan for Lombardy, Italy, was produced in 2010. Plans for pandemic preparedness are out of date and have not been implemented. Stress, grievance, and suffering can lead to conflict at every level. In Lombardy, hospital managers have penalised some doctors who stood up and spoke openly about mismanagements. Accountability, ownership, transparency, humility, and admission of mistakes by politicians and managers can powerfully de-escalate conflicts and are the first steps towards improvement. I am regional councillor of Lombardy, president of +Europa/Radicali, and a member of the Regional Council of Lombardy's COVID-19 investigative commission. The Lombardy region of Italy launches the first investigative COVID-19 commissionDuring the first months of 2020, Italy had the highest number of cases of COVID-19 in Europe and in the world. Lombardy, with a population of 10 million people, was the region of Italy hit the hardest by the pandemic. According to the Italian Ministry of Health's COVID-19 dashboard Lombardy had 114 800 cases and 16 994 deaths as of Oct 13, 2020, which is one third of all cases and half of all deaths in Italy. Full-Text PDF COVID-19: from hospitals to courtsMichele Usuelli1 raised two questions to the international scientific community. First, whether there were errors in the management of the COVID-19 health emergency in Lombardy, Italy. Second, whether having 20 regional health services across Italy is useful in controlling a pandemic. Full-Text PDF
Abstract 12995: Sex and Race Differences in Ventricular-Arterial Coupling in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Xuan Ding, Vivek Patel, Meng Xu, Evan Brittain, Sanjiv J Shah, Norrina B Allen, Joao Ac Lima, Satoru Kishi, James G Terry, Jeffrey Carr, Deepak K Gupta
Journal: Circulation (2020)

Background: Coupling between the left ventricle and arterial system can be quantified as the ventricular-arterial coupling (VAC) ratio with 1.00 reflecting optimal physiology. VAC has been most studied in heart failure, with higher values associating with worse prognosis, but its correlates among individuals without heart failure are less characterized. Thus, in the Coronary Artery Risk Development in Young Adults (CARDIA) study we tested the hypothesis that VAC ratio differs by sex and race. Methods: We studied VAC in 2,812 (42% male, 47% black, median age 50 years) CARDIA year 25 exam participants with transthoracic echocardiogram data available and no history of heart failure, myocardial infarction, peripheral vascular disease, or valvular disease. VAC was calculated as arterial elastance (Ea) divided by LV end systolic elastance (Ees). Ea and Ees were calculated as end systolic pressure/stroke volume and by the modified Chen single beat method, respectively. Associations between sex and race with VAC were tested in multivariable-adjusted linear regression. Results: VAC ratio differed by both sex and race with higher unadjusted values in men (median 1.14 [25 th -75 th percentile 1.08-1.20]) compared with women (1.11 [1.05-1.17]), p &lt; 0.001, and white (1.12 [1.07-1.18]) compared with black (1.11 [1.06-1.18]) individuals, p = 0.004. In adjusted models, male sex (beta 0.027 [95% CI 0.021 to 0.037], p &lt;0.001) and white race (0.007 [0.002 to 0.012], p = 0.009) remained associated with higher VAC ratio (Figure 1). Sex, LV ejection fraction (beta -0.096 [95% CI -0.099 to -0.093], and total arterial compliance (-0.045 [-0.049 to -0.041]) were the most strongly associated correlates of VAC. Systolic blood pressure, creatinine, heart rate, LDL, and triglycerides inversely associated with VAC. Age and LV remodeling index positively associated with VAC. Conclusions: In community dwelling middle-aged adults, male sex and white race independently associated with higher VAC.
Call for a pan-European COVID-19 response must be comprehensive – Authors' reply
Authors: Viola Priesemann, Melanie M Brinkmann, Sandra Ciesek, Sarah Cuschieri, Thomas Czypionka, Giulia Giordano, Claudia Hanson, Niel Hens, Emil Iftekhar, Peter Klimek, Mirjam Kretzschmar, Andreas Peichl, Matjaž Perc, Francesco Sannino, Eva Schernhammer, Alexander Schmidt, Anthony Staines, Ewa Szczurek
Journal: The Lancet (2021)
Questionable Conceptualizations of Nonmedical Use Can Contribute to Needless Distress
Authors: Michael E. Schatman, Hannah Shapiro, Erica L. Wegrzyn
Journal: JAMA Oncology (2021)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Modeling metastasis biology and therapy in real time in the mouse lung
Authors: Arnulfo Mendoza, Sung-Hyeok Hong, Tanasa Osborne, Mohammed A. Khan, Kirk Campbell, Joseph Briggs, Ananth Eleswarapu, Lauren Buquo, Ling Ren, Stephen M. Hewitt, EL Habib Dakir, Susan Garfield, Renard Walker, Glenn Merlino, Jeffrey E. Green, Kent W. Hunter, Lalage M. Wakefield, Chand Khanna
Journal: Journal of Clinical Investigation (2010)
Unearthing LTR Retrotransposon <i>gag</i> Genes Co-opted in the Deep Evolution of Eukaryotes
Authors: Jianhua Wang, Guan-Zhu Han
Journal: Molecular Biology and Evolution (2021)

LTR retrotransposons comprise a major component of the genomes of eukaryotes. On occasion, retrotransposon genes can be recruited by their hosts for diverse functions, a process formally referred to as co-option. However, a comprehensive picture of LTR retrotransposon gag gene co-option in eukaryotes is still lacking, with several documented cases exclusively involving Ty3/Gypsy retrotransposons in animals. Here, we use a phylogenomic approach to systemically unearth co-option of retrotransposon gag genes above the family level of taxonomy in 2,011 eukaryotes, namely co-option occurring during the deep evolution of eukaryotes. We identify a total of 14 independent gag gene co-option events across more than 740 eukaryote families, eight of which have not been reported previously. Among these retrotransposon gag gene co-option events, nine, four, and one involve gag genes of Ty3/Gypsy, Ty1/Copia, and Bel-Pao retrotransposons, respectively. Seven, four, and three co-option events occurred in animals, plants, and fungi, respectively. Interestingly, two co-option events took place in the early evolution of angiosperms. Both selective pressure and gene expression analyses further support that these co-opted gag genes might perform diverse cellular functions in their hosts, and several co-opted gag genes might be subject to positive selection. Taken together, our results provide a comprehensive picture of LTR retrotransposon gag gene co-option events that occurred during the deep evolution of eukaryotes and suggest paucity of LTR retrotransposon gag gene co-option during the deep evolution of eukaryotes.
An Evolutionary Approach to Clonally Complex Hematologic Disorders
Authors: Emily Schwenger, Ulrich Steidl
Journal: Blood Cancer Discovery (2021)

Emerging clonal complexity has brought into question the way in which we perceive and, in turn, treat disorders of the hematopoietic system. Former models of cell-intrinsic clonal dominance driven by acquisition of driver genes in a stereotypic sequence are often insufficient in explaining observations such as clonal hematopoiesis, and new paradigms are in order. Here, we review the evidence both within the hematologic malignancy field and also borrow from perspectives rooted in evolutionary biology to reframe pathogenesis of hematologic disorders as dynamic processes involving complex interplays of genetic and non-genetic subclones and the tissue microenvironment in which they reside.
Covid-19: Vaccine woes highlight vital role of traditional public health
Authors: Fiona Godlee
Journal: BMJ (2021)

Covid-19 still dominates the global consciousness and therefore The BMJ's coverage.This is unlikely soon to change, with the pandemic still growing exponentially. 1 This year has already seen over 50% more deaths worldwide than the whole of 2020, 2 and, while lockdown and vaccines have cut deaths and illness in the UK, the government's advisers warn that plans for easing restrictions risk a serious summer resurgence. 3 Vaccination remains a source of great hope, and in the UK the programme has showcased what the NHS can do when given the remit and resources. 4 But, despite its early promise, the Oxford University-AstraZeneca vaccine is now mired in confusion, conflict, and doubt.Explanations range from the company's inexperience as a vaccine producer and its poor communication to toxic geopolitics and even a profit motivated attack on this not-for-profit venture. 5Whatever the cause, the real concern is the effect of increased vaccine hesitancy on the wider vaccination programme.Gardner T, Fraser C. Longer waits, missing patients and catching up.Health Foundation.13 Apr 2021.
Primary and secondary non-response: in need of operational definitions in observational studies
Authors: Enriqueta Vallejo-Yagüe, Edward C Keystone, Sreemanjari Kandhasamy, Raphael Micheroli, Axel Finckh, Andrea Michelle Burden
Journal: Annals of the Rheumatic Diseases (2021)

Treatment response to biologics and targeted synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis (RA) patients can be classified as primary or secondary non-response, based on evidence of an initial response. Conceptually, primary non-response is generally considered if the drug was ineffective, with no clinical response within the initial treatment period, while secondary non-response would be considered if, after an initial response, the effectiveness is lost over time.1–4 Despite these generally accepted definitions, there is no consensus on how to operationalise these concepts. Consequently, the current observational evidence is highly heterogeneous and the prevalence of primary versus secondary failure remains largely unknown.

The underlying mechanisms for primary and secondary non-response may differ,3 5 thus, we believe that defining the type of non-response is key to improving patient care. While primary non-response may be due to a mechanistic failure, secondary non-response may be driven by immunogenicity. Previous studies have shown that both the type of non-response and the development of antidrug antibodies (ADAbs) are important factors when predicting the success of the second biologic.6 7 Thus, developing clear definitions of how to operationalise primary and secondary non-response is essential to accelerate research that aims to predict the optimal therapy for a given patient,5 which will, in turn, improve clinical practice recommendations. For example, if a patient is a primary non-responder to a tumour necrosis factor inhibitor (anti-TNF), the best practice would likely be to switch to a biologic with different mechanism of action. However, if the patient was able to achieve clinical response prior to failure (secondary non-responder), it would be reasonable to proceed with another anti-TNF. Additionally, following the growing postmarketing research targeting comparative effectiveness of treatments in RA, agreement on operational definitions would improve cross-study comparisons. Thus, we believe that unifying this terminology would benefit the …