tbuckley/cabot-search huggingface dataset:
Heterogeneity and excitability of <i>BRAF</i> <i>V600E</i>-induced tumors is determined by Akt/mTOR-signaling state and <i>Trp53</i>-loss
Authors: Silvia Cases-Cunillera, Karen M J van Loo, Julika Pitsch, Anne Quatraccioni, Sugirthan Sivalingam, Paolo Salomoni, Valeri Borger, Dirk Dietrich, Susanne Schoch, Albert J Becker
Journal: Neuro-Oncology (2021)

Developmental brain tumors harboring BRAFV600E somatic mutation are diverse. Here, we describe molecular factors that determine BRAFV600E-induced tumor biology and function.Intraventricular in utero electroporation in combination with the piggyBac transposon system was utilized to generate developmental brain neoplasms, which were comprehensively analyzed with regard to growth using near-infrared in-vivo imaging, transcript signatures by RNA sequencing, and neuronal activity by multielectrode arrays.BRAF V600E expression in murine neural progenitors elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG) only in concert with active Akt/mTOR-signaling. Purely glial tumors resembling aspects of polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAFV600E alone. Additional somatic Trp53-loss is sufficient to generate anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAFV600E/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter.mTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAFV600E-induced tumors.
Industry involvement in rheumatology consensus-based recommendations: a systematic review
Authors: Dominique Feterman Jimenez, Garret Duron, Joshua Hendin, Eduardo Mantovani Cardoso, Maria O Valenzuela-Almada, Sebastian Vallejo, Ali Duarte-Garcia, Paul Sufka, Samuel L Whittle, Philip C Robinson, Larry J Prokop, Michael S Putman
Journal: The Lancet Rheumatology (2021)
Reply: The effectiveness of singing <i>versus</i> exercise training
Authors: Anders Løkke, Mette Kaasgaard, Karen Hjerrild Andreasson, Daniel Bech Rasmussen, Ole Hilberg, Peter Vuust, Uffe Bodtger
Journal: European Respiratory Journal (2021)

<b>This paper reports a proof-of-concept study, clarifying that singing actually affects 6MWD, and this finding is promising when offering PR to patients who for some reason cannot or will not participate in conventional exercise training</b>https://bit.ly/3276d7b
Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

Targeted Therapy Induces Cross-Resistance to ImmunotherapyPatients with metastatic melanoma are currently treated with both targeted therapy and immunotherapy in an effort to increase response, but it is unclear how first-line treatment with targeted therapy impacts the tumor microenvironment and how this could influence the subsequent response to immunotherapy.Haas and colleagues utilize mouse models and clinical data to demonstrate melanoma tumors that become resistant to MAPK pathway inhibitors and relapse subsequently develop cross-resistance to immunotherapy.Cross-resistance was achieved by reactivation of MAPK signaling in targeted therapy-resistant tumors, which included increased transcription of known MAPK target genes in addition to regulation of new genes by MAPK.Resistance to targeted therapy was associated with decreases in both the number and function of cytotoxic T cells and CD103 þ dendritic cells in the tumor microenvironment, and restoration of dendritic cell function and treatment with MAPK inhibitors resensitized tumors to immunotherapy.
Evaluating covid-19 vaccine efficacy and safety in the post-authorisation phase
Authors: Christof Prugger, Angela Spelsberg, Ulrich Keil, Juan Erviti, Peter Doshi
Journal: BMJ (2021)

When covid-19 vaccines were first authorised, regulators required post-authorisation studies to tackle important uncertainties about efficacy and safety. But these studies may have little practical value unless there is greater engagement and scrutiny from the wider scientific community, argue <b>Christof Prugger and colleagues</b>
Abstract 17250: Novel Association Of Left Ventricular Outflow Tract Obstructions With Chromosome 5p Deletions
Authors: Kira Mascho, Svetlana Yatsenko, Jiuann-huey I Lin
Journal: Circulation (2021)

Case Presentation: Patient 1: Female infant diagnosed with Cri du Chat Syndrome (CdCS) (Fig. 1A), hypoplastic left heart syndrome variant (Fig. 1 B), duodenal atresia (Fig. 1 E, F), IUGR. Chromosomal microarray (CMA) showed a 4.3 Mb deletion at 5p15.33 (Fig. 1A) and a 32.2 Mb duplication of 5q32. Dysmorphisms including hypertelorism, low set ears, and micrognathia were noted. Echocardiogram showed a hypoplastic left ventricle, mitral valve dysplasia (Fig. 1B), dysplastic aortic valve (Fig. 1C), interrupted aortic arch (Fig. 1D). Patient 2: Male infant prenatally diagnosed with aortic valve stenosis, aortic arch hypoplasia (Fig. 1H, I), and IUGR. Multiple dysmorphic features including microcephaly, hypertelorism, down slanting palpebral fissures, and abnormal distal extremities. CMA revealed a large deletion at 5p13.33-p13.2 (Fig 1G). He underwent aortic valvuloplasty complicated by development of a posterior left ventricular wall pseudoaneurysm (Fig. 1J). He later underwent arch reconstruction. At 2 months of age, he was diagnosed with obstructive jaundice requiring a biliary drain (Fig.1K, L). He had been gaining weight and height steadily (Fig.1M, N). We identified 5 more patients with 5p deletions and left outflow tract obstructions (LVOTO) from the Cytogenomics of Cardiovascular Malformations Consortium (Table 1). Discussion: CdCS is the most common 5p deletion syndrome and is associated with mild congenital heart defects in 15-30% of individuals. There is no reported association between LVOTO and 5p deletions. These 7 patients did not all share the same deletions and had high mortality. Further studies are needed to better understand possible genetic etiologies.
JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice
Authors: Cristina Rivellini, Emanuela Porrello, Giorgia Dina, Simona Mrakic-Sposta, Alessandra Vezzoli, Marco Bacigaluppi, Giorgia Serena Gullotta, Linda Chaabane, Letizia Leocani, Silvia Marenna, Emanuela Colombo, Cinthia Farina, Jia Newcombe, Klaus-Armin Nave, Ruggero Pardi, Angelo Quattrini, Stefano C. Previtali
Journal: Journal of Clinical Investigation (2021)

Oligodendrocytes are the primary target of demyelinating disorders, and progressive neurodegenerative changes may evolve in the CNS. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, animal models do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell-autonomous deletion of the nuclear COP9 signalosome component CSN5 (JAB1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking JAB1 expression underwent a senescence-like phenotype that fostered chronic inflammation and oxidative stress. These mutants developed progressive CNS demyelination, microglia inflammation, and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration, whereas the deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and may be considered a potential therapeutic target.
Error in Figure
Authors: Manyoo Agarwal, Gregg Fonarow, Boback Ziaeian
Journal: JAMA Cardiology (2021)

Liv Tybjærg Nordestgaard, MD; Mette Christoffersen, MScPharm, PhD; Bo Kobberø Lauridsen, MD, PhD; Shoaib Afzal, MD, DMSc; Børge Grønne Nordestgaard, MD, DMSc; Ruth Frikke-Schmidt, MD, DMSc; Anne Tybjærg-Hansen, MD, DMSc
Tumor antigens and immune subtypes guided mRNA vaccine development for kidney renal clear cell carcinoma
Authors: Hang Xu, Xiaonan Zheng, Shiyu Zhang, Xianyanling Yi, Tianyi Zhang, Qiang Wei, Hong Li, Jianzhong Ai
Journal: Molecular Cancer (2021)

Abstract Current treatment strategy for kidney renal clear cell carcinoma (KIRC) is limited. Tumor-associated antigens, especially neoantigen-based personalized mRNA vaccines represent new strategies and manifest clinical benefits in solid tumors, but only a small proportion of patients could benefit from them, which prompts us to identify effective antigens and suitable populations to facilitate mRNA vaccines application in cancer therapy. Through performing expression, mutation, survival and correlation analyses in TCGA-KIRC dataset, we identified four genes including DNA topoisomerase II alpha (TOP2A), neutrophil cytosol factor 4 (NCF4), formin-like protein 1 (FMNL1) and docking protein 3 (DOK3) as potential KIRC-specific neoantigen candidates. These four genes were upregulated, mutated and positively associated with survival and antigen-presenting cells in TCGA-KIRC. Furthermore, we identified two immune subtypes, named renal cell carcinoma immune subtype 1 (RIS1) and RIS2, of KIRC. Distinct clinical, molecular and immune-related signatures were observed between RIS1 and RIS2. Patients of RIS2 had better survival outcomes than those of RIS1. Further comprehensive immune-related analyses indicated that RIS1 is immunologically “hot” and represent an immunosuppressive phenotype, whereas RIS2 represents an immunologically “cold” phenotype. RIS1 and RIS2 also showed differential features with regard to tumor infiltrating immune cells and immune checkpoint-related genes. Moreover, the immune landscape construction identified the immune cell components of each KIRC patient, predicted their survival outcomes, and assisted the development of personalized mRNA vaccines. In summary, our study identified TOP2A, NCF4, FMNL1 and DOK3 as potential effective neoantigens for KIRC mRNA vaccine development, and patients with RIS2 tumor might benefit more from mRNA vaccination.
The Toll of Racism on African American Mothers and Their Infants
Authors: Benard P. Dreyer
Journal: JAMA Network Open (2021)

Rachel R. Hardeman, PhD, MPH; Tongtan Chantarat, PhD, MPH; Morrison Luke Smith, MPH; J'Mag Karbeah, MPH; David C. Van Riper, MA; Dara D. Mendez, PhD, MPH
Screening and Interventions to Prevent Dental Caries in Children Younger Than 5 Years
Authors: Karina W. Davidson, Michael J. Barry, Carol M. Mangione, Michael Cabana, Aaron B. Caughey, Esa M. Davis, Katrina E. Donahue, Chyke A. Doubeni, Martha Kubik, Li Li, Gbenga Ogedegbe, Lori Pbert, Michael Silverstein, James Stevermer, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2021)

<h3>Importance</h3> Dental caries is the most common chronic disease in children in the US. According to the 2011-2016 National Health and Nutrition Examination Survey, approximately 23% of children aged 2 to 5 years had dental caries in their primary teeth. Prevalence is higher in Mexican American children (33%) and non-Hispanic Black children (28%) than in non-Hispanic White children (18%). Dental caries in early childhood is associated with pain, loss of teeth, impaired growth, decreased weight gain, negative effects on quality of life, poor school performance, and future dental caries. <h3>Objective</h3> To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening and interventions to prevent dental caries in children younger than 5 years. <h3>Population</h3> Asymptomatic children younger than 5 years. <h3>Evidence Assessment</h3> The USPSTF concludes with moderate certainty that there is a moderate net benefit of preventing future dental caries with oral fluoride supplementation at recommended doses in children 6 months or older whose water supply is deficient in fluoride. The USPSTF concludes with moderate certainty that there is a moderate net benefit of preventing future dental caries with fluoride varnish application in all children younger than 5 years. The USPSTF concludes that the evidence is insufficient on performing routine oral screening examinations for dental caries by primary care clinicians in children younger than 5 years and that the balance of benefits and harms of screening cannot be determined. <h3>Recommendation</h3> The USPSTF recommends that primary care clinicians prescribe oral fluoride supplementation starting at age 6 months for children whose water supply is deficient in fluoride. (B recommendation) The USPSTF recommends that primary care clinicians apply fluoride varnish to the primary teeth of all infants and children starting at the age of primary tooth eruption. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of routine screening examinations for dental caries performed by primary care clinicians in children younger than 5 years. (I statement)
COVID-19 Vaccine Is Effective in Inflammatory Bowel Disease Patients and Is Not Associated With Disease Exacerbation
Authors: Raffi Lev-Tzion, Gili Focht, Rona Lujan, Adi Mendelovici, Chagit Friss, Shira Greenfeld, Revital Kariv, Amir Ben-Tov, Eran Matz, Daniel Nevo, Yuval Barak-Corren, Iris Dotan, Dan Turner
Journal: Clinical Gastroenterology and Hepatology (2021)
Functional precision oncology: Testing tumors with drugs to identify vulnerabilities and novel combinations
Authors: Anthony Letai, Patrick Bhola, Alana L. Welm
Journal: Cancer Cell (2021)

Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information to guide therapy. The heterogeneity of human cancer has led to the realization that personalized approaches are needed to improve treatment outcomes. Precision oncology has traditionally used static features of the tumor to dictate which therapies should be used. Static features can include expression of key targets or genomic analysis of mutations to identify therapeutically targetable "drivers." Although a surprisingly small proportion of individuals derive clinical benefit from the static approach, functional precision medicine can provide additional information regarding tumor vulnerabilities. We discuss emerging technologies for functional precision medicine as well as limitations and challenges in using these assays in the clinical trials that will be necessary to determine whether functional precision medicine can improve outcomes and eventually become a standard tool in clinical oncology.
Deciphering metformin action in obese mice: A critical re-evaluation of established protocols
Authors: Mairam Kaplanian, Cecile Philippe, Sameer Abu Eid, Martina T. Hackl, Matthäus Metz, Marianna Beghini, Andreea C. Luca, Alexandra Kautzky-Willer, Thomas Scherer, Clemens Fürnsinn
Journal: Metabolism (2021)
Compelling Interaction of Cigarette Smoking and Polygenetic Risk Emerges for Lung Function and COPD
Authors: Dana B. Hancock
Journal: JAMA Network Open (2021)

Woori Kim, PhD; Matthew Moll, MD; Dandi Qiao, PhD; Brian D. Hobbs, MD, MMSc; Nick Shrine, PhD; Phuwanat Sakornsakolpat, MD; Martin D. Tobin, PhD; Frank Dudbridge, PhD; Louise V. Wain, PhD; Christine Ladd-Acosta, PhD; Nilanjan Chatterjee, PhD; Edwin K. Silverman, MD, PhD; Michael H. Cho, MD, MPH; Terri H. Beaty, PhD
Ultrasensitive and affordable assay for early detection of primary liver cancer using plasma cell‐free DNA fragmentomics
Authors: Xiangyu Zhang, Zheng Wang, Wanxiangfu Tang, Xinyu Wang, Rui Liu, Hua Bao, Xin Chen, Yulin Wei, Shuyu Wu, Hairong Bao, Xue Wu, Yang Shao, Jia Fan, Jian Zhou
Journal: Hepatology (2021)

Early detection of primary liver cancer (PLC), including HCC, intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC (cHCC-ICC), is essential for patients' survival. This study aims to develop an accurate and affordable method for PLC early detection and differentiating ICC from HCC using plasma cell-free DNA (cfDNA) fragmentomic profiles.Whole-genome sequencings (WGS) were performed using plasma cfDNA samples from 192 patients with PLC (159 HCC, 26 ICC, 7 cHCC-ICC) and 170 noncancer controls (including 53 liver cirrhosis [LC] or HBV-positive) enrolled in the training cohort. An ensembled stacked model for PLC detection was constructed using the training cohort. The model performance was assessed in an independent test cohort (189 patients with PLC [157 HCC, 26 ICC, 6 cHCC-ICC], 164 noncancer controls [including 51 LC/HBV]). Our model showed excellent performance for cancer detection in the test cohort (AUC: 0.995, 96.8% sensitivity at 98.8% specificity). It showed excellent sensitivities in detecting early-stage PLC (I: 95.9%, II: 97.9%), small tumors (≤3 cm: 98.2%), and HCC (96.2%) or ICC (100%). The AUC for distinguishing PLC from LC/HBV reached 0.985 (96.8% specificity at 96.1% specificity). Promisingly, our model maintained consistent performances during the downsampling process, even using 1X coverage data (AUC: 0.994, 93.7% sensitivity at 98.8% specificity). A separate model showed potential for distinguishing ICC from HCC (AUC: 0.776).Our model, outperforming previous reports at a lower cost by solely using low-coverage WGS data, exhibits excellent clinical potential for ultrasensitive and affordable detection of PLC and its subtypes.
Errors in Table and Figure
Journal: JAMA Network Open (2021)

Errors in Table and FigureIn the Original Investigation "The Association Between School Closures and Child Mental Health During COVID-19," 1 published September 3, 2021, there were errors in Table 1 andFigure 2. In Table 1, the SDs for household income should have been 54.6 for participants attending in-person school, 53.4 for participants attending remote school, and 58.1 for participants attending hybrid school.In Figure 2A, the labels should have read "In-person school" and "Remote school."This article has been corrected.
What are we doing when we perceive numbers?
Authors: Max Jones, Karim Zahidi, Daniel D Hutto
Journal: Behavioral and Brain Sciences (2021)

Abstract Clarke and Beck rightly contend that the number sense allows us to directly perceive number. However, they unnecessarily assume a representationalist approach and incur a heavy theoretical cost by invoking “modes of presentation.” We suggest that the relevant evidence is better explained by adopting a radical enactivist approach that avoids characterizing the approximate number system (ANS) as a system for representing number.
Perceptions of Telehealth vs In-Person Visits Among Older Adults With Advanced Kidney Disease, Care Partners, and Clinicians
Authors: Keren Ladin, Thalia Porteny, Julia M. Perugini, Kristina M. Gonzales, Kate E. Aufort, Sarah K. Levine, John B. Wong, Tamara Isakova, Dena Rifkin, Elisa J. Gordon, Ana Rossi, Susan Koch-Weser, Daniel E. Weiner
Journal: JAMA Network Open (2021)

Telehealth has been posited as a cost-effective means for improving access to care for persons with chronic conditions, including kidney disease. Perceptions of telehealth among older patients with chronic illness, their care partners, and clinicians are largely unknown but are critical to successful telehealth use and expansion efforts.To identify patient, care partner, and nephrologists' perceptions of the patient-centeredness, benefits, drawbacks of telehealth compared to in-person visits.This qualitative study used semistructured interviews conducted from August to December 2020 with purposively sampled patients (aged 70 years or older, chronic kidney disease stages 4 to 5), care partners, and clinicians in Boston, Massachusetts; Chicago, Illinois; Portland, Maine; and San Diego, California.Participants described telehealth experiences, including factors contributing to and impeding engagement, satisfaction, and quality of care. Thematic analysis was used to analyze data.Of 60 interviews, 19 (32%) were with clinicians, 30 (50%) with patients, and 11 (18%) with care partners; 16 clinicians (84%) were nephrologists; 17 patient participants (43%) were non-Hispanic Black, and 38 (67%) were women. Four overarching themes characterized telehealth's benefits and drawbacks for patient-centered care among older, chronically ill adults: inconsistent quality of care, patient experience and engagement, loss of connection and mistrust (eg, challenges discussing bad news), and disparities with accessing telehealth. Although telehealth improved convenience and care partner engagement, participants expressed concerns about clinical effectiveness and limitations of virtual physical examinations and potentially widening disparities in access. Many participants shared concerns about harms to the patient-clinician relationship, limited ability to comfort patients in virtual settings, and reduced patient trust.Older patients, care partners, and kidney clinicians (ie, nephrologists and physician assistants) shared divergent views of patient-centered telehealth care, especially its clinical effectiveness, patient experience, access to care, and clinician-patient relationship. Understanding older patients' and kidney clinicians' perceptions of telehealth elucidate barriers that should be addressed to promote high-quality care and telehealth use.
Cobolt: integrative analysis of multimodal single-cell sequencing data
Authors: Boying Gong, Yun Zhou, Elizabeth Purdom
Journal: Genome biology (2021)

Abstract A growing number of single-cell sequencing platforms enable joint profiling of multiple omics from the same cells. We present , a novel method that not only allows for analyzing the data from joint-modality platforms, but provides a coherent framework for the integration of multiple datasets measured on different modalities. We demonstrate its performance on multi-modality data of gene expression and chromatin accessibility and illustrate the integration abilities of by jointly analyzing this multi-modality data with single-cell RNA-seq and ATAC-seq datasets.
The authors reply:
Authors: M. Luiza Caramori, Katherine R. Tuttle, Nikhil Tandon, David J. Tunnicliffe, Ian H. de Boer, Peter Rossing, Juliana C.N. Chan, Hiddo J.L. Heerspink, Clint Hurst, Kamlesh Khunti, Adrian Liew, Erin D. Michos, Sankar D. Navaneethan, Wasiu A. Olowu, Tami Sadusky, Christoph Wanner, Katy G. Wilkens, Sophia Zoungas, Lyubov Lytvyn, Jonathan C. Craig, Martin Howell, Marcello Tonelli, Michael Cheung, Amy Earley
Journal: Kidney International (2021)