tbuckley/cabot-search huggingface dataset:
Delving into Early-onset Pancreatic Ductal Adenocarcinoma: How Does Age Fit In?
Authors: Erica S. Tsang, James T. Topham, Joanna M. Karasinska, Michael K.C. Lee, Laura M. Williamson, Shehara Mendis, Robert E. Denroche, Gun Ho Jang, Steve E. Kalloger, Richard A. Moore, Andrew J. Mungall, Oliver F. Bathe, Patricia A. Tang, Faiyaz Notta, Julie M. Wilson, Janessa Laskin, Grainne M. O'Kane, Jennifer J. Knox, Rachel A. Goodwin, Jonathan M. Loree, Steven J.M. Jones, Marco A. Marra, Steven Gallinger, David F. Schaeffer, Daniel J. Renouf
Journal: Clinical Cancer Research (2020)

With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood.We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor samples. Patient samples were stratified into EOPC (age of onset ≤55 years; n = 117), intermediate (age of onset 55-70 years; n = 264), and average (age of onset ≥70 years; n = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups.EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in CDKN2A (P = 0.0017), and were more likely to achieve biallelic mutation of CDKN2A through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset (P = 1.5e-4). Transcription factor forkhead box protein C2 (FOXC2) was significantly upregulated in EOPC tumors (P = 0.032). Genes significantly correlated with FOXC2 in PDAC samples were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included VIM (P = 1.8e-8), CDH11 (P = 6.5e-5), and CDH2 (P = 2.4e-2).Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient samples highlights a distinctive pattern of biallelic CDKN2A mutation in EOPC tumors. Increased expression of FOXC2 in EOPC, with the correlation between FOXC2 and EMT pathways, represents novel molecular characteristics of EOPC.See related commentary by Lou, p. 8.
Convalescent plasma therapy for B-cell–depleted patients with protracted COVID-19
Authors: Thomas Hueso, Cécile Pouderoux, Hélène Péré, Anne-Lise Beaumont, Laure-Anne Raillon, Florence Ader, Lucienne Chatenoud, Déborah Eshagh, Tali-Anne Szwebel, Martin Martinot, Fabrice Camou, Etienne Crickx, Marc Michel, Matthieu Mahevas, David Boutboul, Elie Azoulay, Adrien Joseph, Olivier Hermine, Claire Rouzaud, Stanislas Faguer, Philippe Petua, Fanny Pommeret, Sébastien Clerc, Benjamin Planquette, Fatiha Merabet, Jonathan London, Valérie Zeller, David Ghez, David Veyer, Amani Ouedrani, Pierre Gallian, Jérôme Pacanowski, Arsène Mékinian, Marc Garnier, France Pirenne, Pierre Tiberghien, Karine Lacombe
Journal: Blood (2020)
A Report by the Editor-in-Chief for Molecular Biology and Evolution (MBE), Volume 36
Authors: Sudhir Kumar
Journal: Molecular Biology and Evolution (2020)

MBE provides society members an opportunity for active participation in the creation of a journal supporting our community's needs and interests.During the 2019 calendar year, MBE received 1,208 new manuscripts and 405 revised submissions.A vast majority of MBE submissions originated in Europe (35%), North America (29%; 27% from the USA), and Asia (28%; 21% from China).Articles account for almost 87% of original submissions, followed by Letters (8%).MBE continues to publish Brief Communications (usually to communicate software and resource updates), Perspectives, and Reviews in smaller numbers, as well as Protocols by invitation.In Volume 36, we experimented with the publication of paired "Comment and Response," in which we allowed researchers to submit a 500-word comment about a previously published MBE manuscript.We then allowed the authors of the original manuscript to provide an equivalent length response.Although, in principle, we would like to support scientific dialogue, we did find this experiment to be time-consuming, given to contention, and not likely to be particularly useful for our general readership.We are, therefore, not actively pursuing the continuation of this format, but will continue to explore ways to enable community discussion of research.MBE's impact factor for 2019 (citations during 2019 of manuscripts published in 2017 and 2018) is 11.06.Trends in citation thus far in 2020 suggest that next year's Impact Factor will continue to be high.We feel strongly that our focus should remain on serving our research community, rather than the pursuit of singular metrics, mainly as MBE's impact factor is currently heavily influenced by a few highly cited manuscripts.Society-owned journals such as MBE face increasing competition for high-impact manuscripts from a proliferation of "Nature" and "Science"-branded journals.Our best hope for maintaining the quality and quantity of submissions to MBE will be to draw on our journal's unique strengths and reputation within our research community.MBE's rejection rate for original submissions in 2019 was 72%, with 46% of these rejected at the editorial level, without soliciting external review.This procedure has helped us to keep the average time until the first decision to 25 days.
Hardwiring Heart Transplant Volume Growth
Authors: Jason Bjelkengren, Todd F. Dardas
Journal: JAMA Network Open (2020)

Makoto Mori, MD; Lynn Wilson, RN; Ayyaz Ali, MD, PhD; Tariq Ahmad, MD, MPH; Muhammad Anwer, MD; Daniel Jacoby, MD; Arnar Geirsson, MD; Harlan M. Krumholz, MD, SM
Bone marrow regeneration requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma
Authors: Karin Golan, Abhishek K. Singh, Orit Kollet, Mayla Bertagna, Mark J. Althoff, Eman Khatib-Massalha, Ekaterina Petrovich-Kopitman, Ashley M. Wellendorf, Hassan Massalha, Smadar Levin-Zaidman, Tali Dadosh, Breanna Bohan, Mruniya V. Gawali, Biplab Dasgupta, Tsvee Lapidot, Jose A. Cancelas
Journal: Blood (2020)
Gut microbiota, NLR proteins, and intestinal homeostasis
Authors: Hao Guo, Sara A. Gibson, Jenny P.Y. Ting
Journal: The Journal of Experimental Medicine (2020)

The gastrointestinal tract harbors a highly complex microbial community, which is referred to as gut microbiota. With increasing evidence suggesting that the imbalance of gut microbiota plays a significant role in the pathogenesis of multiple diseases, interactions between the host immune system and the gut microbiota are now attracting emerging interest. Nucleotide-binding and leucine-rich repeat-containing receptors (NLRs) encompass a large number of innate immune sensors and receptors, which mediate the activation of Caspase-1 and the subsequent release of mature interleukin-1β and interleukin-18. Several family members have been found to restrain rather than activate inflammatory cytokines and immune signaling. NLR family members are central regulators of pathogen recognition, host immunity, and inflammation with utmost importance in human diseases. In this review, we focus on the potential roles played by NLRs in controlling and shaping the microbiota community and discuss how the functional axes interconnecting gut microbiota with NLRs impact the modulation of colitis, inflammatory bowel diseases, and colorectal cancer.
Corrigendum to: “Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis” [J Hepatol (2020) 241-251]
Authors: Constantinos A. Parisinos, Henry R. Wilman, E. Louise Thomas, Matt Kelly, Rowan C. Nicholls, John McGonigle, Stefan Neubauer, Aroon D. Hingorani, Riyaz S. Patel, Harry Hemingway, Jimmy D. Bell, Rajarshi Banerjee, Hanieh Yaghootkar
Journal: Journal of Hepatology (2020)

It has come to our attention that there are errors in the Table 2 of the original manuscript "Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis".Table 2The association between 6 independent genetic variants and liver cT1. A linear mixed model was used for genetic associations (levels of significance: p <5 × 10-8).SNPCHRBase pairsEAOAEAFGeneVariant typeAmino acid changeBETAStandard errorp valueVariance explained (%)rs7593592811220,100,497CCA0.06SLC30A10Intron0.1370.0262.8 × 10-80.23rs131073254103,188,709TC0.07SLC39A8MissenseA391T0.5440.0221.2 × 10-1333.95rs1117238341424,572,932AG0.02PCK2Missense, IntronR561Q0.2910.0463.0 × 10-110.27rs585429261919,379,549TC0.07TM6SF2MissenseE167K0.1240.0221.4 × 10-80.22rs4820268∗rs4820268 is in LD (r2 = 0.77) with rs855791 (V736A).2237,469,591GA0.46TMPRSS6SynonymousD521D0.0660.0121.6 × 10-90.2rs7384092244,324,727GC0.21PNPLA3MissenseI148M0.0950.0149.6 × 10-130.29The coordinates and SNP IDs are in build 37. Effects are in SD. Beta represents effects in standard deviation (SD). CHR, chromosome; EA, effect allele; EAF, effect allele frequency; OA, other allele.∗ rs4820268 is in LD (r2 = 0.77) with rs855791 (V736A). Open table in a new tab The coordinates and SNP IDs are in build 37. Effects are in SD. Beta represents effects in standard deviation (SD). CHR, chromosome; EA, effect allele; EAF, effect allele frequency; OA, other allele. The Variance Explained for SNP rs738409 has been incorrectly reported as 0.9. The correct value is 0.29. The amino acid changes for SNPs rs111723834, rs58542926 and rs738409 have been incorrectly reported as A561G, I148M and E167K, respectively. The correct amino acid changes are R561Q, E167K and I148M, respectively. SNP rs4820268 variant type (synonymous) and amino acid change (D521D) have also been corrected. Please see the corrected Table 2 below. These errors have occured during manual editing of the table and do not affect the results and conclusions of this article. The authors would like to apologise for any inconvenience caused. Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitisJournal of HepatologyVol. 73Issue 2PreviewMRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases. Full-Text PDF Open Access
Response to Anti-PD-1 in Microsatellite-Stable Colorectal Cancer: A STAT Need
Authors: Maliha Nusrat
Journal: Clinical Cancer Research (2020)

Abstract Most colorectal cancers are microsatellite-stable with no response to anti-PD-1 therapy, necessitating the development of new immunomodulatory treatment strategies. Coinhibition of anti-PD-1 and STAT3 can elicit an effective antitumor response in a small subset of patients with microsatellite-stable colorectal cancer, and biomarkers predictive of response are under investigation. See related article by Kawazoe et al., p. 5887
Unraveling the Genetic Basis for the Rapid Diversification of Male Genitalia between <i>Drosophila</i> Species
Authors: Joanna F D Hagen, Cláudia C Mendes, Shamma R Booth, Javier Figueras Jimenez, Kentaro M Tanaka, Franziska A Franke, Luis Baudouin-Gonzalez, Amber M Ridgway, Saad Arif, Maria D S Nunes, Alistair P McGregor
Journal: Molecular Biology and Evolution (2020)

Abstract In the last 240,000 years, males of the Drosophila simulans species clade have evolved striking differences in the morphology of their epandrial posterior lobes and claspers (surstyli). These appendages are used for grasping the female during mating and so their divergence is most likely driven by sexual selection. Mapping studies indicate a highly polygenic and generally additive genetic basis for these morphological differences. However, we have limited understanding of the gene regulatory networks that control the development of genital structures and how they evolved to result in this rapid phenotypic diversification. Here, we used new D. simulans/D. mauritiana introgression lines on chromosome arm 3L to generate higher resolution maps of posterior lobe and clasper differences between these species. We then carried out RNA-seq on the developing genitalia of both species to identify the expressed genes and those that are differentially expressed between the two species. This allowed us to test the function of expressed positional candidates during genital development in D. melanogaster. We identified several new genes involved in the development and possibly the evolution of these genital structures, including the transcription factors Hairy and Grunge. Furthermore, we discovered that during clasper development Hairy negatively regulates tartan (trn), a gene known to contribute to divergence in clasper morphology. Taken together, our results provide new insights into the regulation of genital development and how this has evolved between species.
Association of Survival With Adjuvant Chemotherapy Among Patients With Early-Stage Non–Small Cell Lung Cancer With vs Without High-Risk Clinicopathologic Features
Authors: Ranjan Pathak, Sarah B. Goldberg, Maureen Canavan, Jeph Herrin, Jessica R. Hoag, Michelle C. Salazar, Marianna Papageorge, Theresa Ermer, Daniel J. Boffa
Journal: JAMA Oncology (2020)

Tumor size larger than 4 cm is accepted as an indication for adjuvant chemotherapy in patients with node-negative non-small cell lung cancer (NSCLC). Treatment guidelines suggest that high-risk features are also associated with the efficacy of adjuvant chemotherapy among patients with early-stage NSCLC, yet this association is understudied.To assess the association between adjuvant chemotherapy and survival in the presence and absence of high-risk pathologic features in patients with node-negative early-stage NSCLC.This retrospective cohort study using data from the National Cancer Database included 50 814 treatment-naive patients with a completely resected node-negative NSCLC diagnosed between January 1, 2010, and December 31, 2015. The study was limited to patients who survived at least 6 weeks after surgery (ie, estimated median time to initiate adjuvant chemotherapy after surgery) to mitigate immortal time bias. Statistical analysis was performed from December 1, 2018, to February 29, 2020.Adjuvant chemotherapy use vs observation, stratified according to the presence or absence of high-risk pathologic features (visceral pleural invasion, lymphovascular invasion, and high-grade histologic findings), sublobar surgery, and tumor size.The association of high-risk pathologic features with survival after adjuvant chemotherapy vs observation was evaluated using Cox proportional hazards regression models.Overall, 50 814 eligible patients with NSCLC (27 365 women [53.9%]; mean [SD] age, 67.4 [9.5] years]) were identified, including 4220 (8.3%) who received adjuvant chemotherapy and 46 594 (91.7%) who did not receive adjuvant chemotherapy. Among patients with tumors 3 cm or smaller, chemotherapy was not associated with improved survival (hazard ratio [HR], 1.10; 95% CI, 0.96-1.26; P = .17). For patients with tumors larger than 3 cm to 4 cm, adjuvant chemotherapy was associated with a survival benefit among patients who underwent sublobar surgery (HR, 0.72; 95% CI, 0.56-0.93; P = .004). For tumors larger than 4 cm to 5 cm, a survival benefit was associated with adjuvant chemotherapy only in patients with at least 1 high-risk pathologic feature (HR, 0.67; 95% CI, 0.56-0.80; P = .02). For tumors larger than 5 cm, adjuvant chemotherapy was associated with a survival benefit irrespective of the presence of high-risk pathologic features (HR, 0.75; 95% CI, 0.61-0.91; P = .004).In this cohort study, tumor size alone was not associated with improved efficacy of adjuvant chemotherapy in patients with early-stage (node-negative) NSCLC. High-risk clinicopathologic features and tumor size should be considered simultaneously when evaluating patients with early-stage NSCLC for adjuvant chemotherapy.
Lineage-specific regulation of inducible and constitutive mast cells in allergic airway inflammation
Authors: Tahereh Derakhshan, Sachin K. Samuchiwal, Nils Hallen, Lora G. Bankova, Joshua A. Boyce, Nora A. Barrett, K. Frank Austen, Daniel F. Dwyer
Journal: The Journal of Experimental Medicine (2020)

Murine mast cells (MCs) contain two lineages: inducible bone marrow–derived mucosal MCs (MMCs) and constitutive embryonic-derived connective tissue MCs (CTMCs). Here, we use RNA sequencing, flow cytometry, and genetic deletion in two allergic lung inflammation models to define these two lineages. We found that inducible MCs, marked by β7 integrin expression, are highly distinct from airway CTMCs at rest and during inflammation and unaffected by targeted CTMC deletion. β7High MCs expand and mature during lung inflammation as part of a TGF-β–inducible transcriptional program that includes the MMC-associated proteases Mcpt1 and Mcpt2, the basophil-associated protease Mcpt8, granule components, and the epithelial-binding αE integrin. In vitro studies using bone marrow–derived MCs (BMMCs) identified a requirement for SCF in this TGF-β–mediated development and found that epithelial cells directly elicit TGF-β–dependent BMMC up-regulation of mMCP-1 and αE integrin. Thus, our findings characterize the expansion of a distinct inducible MC subset in C57BL/6 mice and highlight the potential for epithelium to direct MMC development.
Different Sources of Allelic Variation Drove Repeated Color Pattern Divergence in Cichlid Fishes
Authors: Sabine Urban, Alexander Nater, Axel Meyer, Claudius F Kratochwil
Journal: Molecular Biology and Evolution (2020)

The adaptive radiations of East African cichlid fish in the Great Lakes Victoria, Malawi, and Tanganyika are well known for their diversity and repeatedly evolved phenotypes. Convergent evolution of melanic horizontal stripes has been linked to a single locus harboring the gene agouti-related peptide 2 (agrp2). However, where and when the causal variants underlying this trait evolved and how they drove phenotypic divergence remained unknown. To test the alternative hypotheses of standing genetic variation versus de novo mutations (independently originating in each radiation), we searched for shared signals of genomic divergence at the agrp2 locus. Although we discovered similar signatures of differentiation at the locus level, the haplotypes associated with stripe patterns are surprisingly different. In Lake Malawi, the highest associated alleles are located within and close to the 5' untranslated region of agrp2 and likely evolved through recent de novo mutations. In the younger Lake Victoria radiation, stripes are associated with two intronic regions overlapping with a previously reported cis-regulatory interval. The origin of these segregating haplotypes predates the Lake Victoria radiation because they are also found in more basal riverine and Lake Kivu species. This suggests that both segregating haplotypes were present as standing genetic variation at the onset of the Lake Victoria adaptive radiation with its more than 500 species and drove phenotypic divergence within the species flock. Therefore, both new (Lake Malawi) and ancient (Lake Victoria) allelic variation at the same locus fueled rapid and convergent phenotypic evolution.
Avelumab for advanced Merkel cell carcinoma in the Netherlands: a real-world cohort
Authors: Sonja Levy, Maureen J B Aarts, Ferry A L M Eskens, Kristien B M I Keymeulen, Lukas B Been, Dirk Grünhagen, Alexander van Akkooi, Mathilde Jalving, Margot E T Tesselaar
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Merkel cell carcinoma (MCC) is associated with high recurrence rates and poor survival when metastatic disease is present. The immune checkpoint inhibitor avelumab has shown high response rates (RRs) and durable responses in patients with advanced MCC (aMCC) in clinical trials. To date, only results from clinical trials, patients treated in an expanded access program and very small numbers of patients have been reported. In this study, detailed real-world efficacy and toxicity data of avelumab in patients with aMCC are reported. Methods Patients with aMCC treated in four dedicated referral centers in the Netherlands were analyzed from February 2017 until December 2019. Patients were included if they had received at least one administration of avelumab, regardless of previous lines of therapy. Patient data were collected retrospectively from patient records. Primary endpoints were response rate (RR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Results Fifty-four patients received avelumab. Eight (15%) patients had locally advanced disease (laMCC). In 40 (74%) patients, avelumab was first-line treatment, these included all patients with laMCC. The median follow-up was 8.9 (range 0.5–35.9) months. RR was 57% (n=31) with 24% (n=13) of patients achieving a complete response. The median DOR was 8.4 (range 1.3–22.1) months and 23 (43%) patients had an ongoing response at the end of the study. The median PFS was 8.6 (95% CI 1.6–15.5) months, and the median OS was 25.8 (95% CI 9.1–42.4) months. Six (11%) patients experienced grade 3 toxicity. No grade 4–5 toxicity was seen. Conclusions In this real-world cohort, clinical efficacy and toxicity outcomes in clinical practice were in line with results from clinical trials and showed relatively high RRs and durable responses in patients with aMCC.
Factors limiting the utility of bronchoalveolar lavage in the diagnosis of COVID-19
Authors: Francesco Salton, Pietro Geri, Marco Confalonieri
Journal: European Respiratory Journal (2020)

<b>Given the strong agreement between negative upper respiratory tract swabs and BAL, it should be emphasised that BAL has a limited role in excluding COVID-19 if swabs and chest CT are concordantly negative</b>https://bit.ly/3m8rjHL
The Use of Peptide Receptor Radionuclide Therapy in Patients With Neuroendocrine Tumor Cardiac Metastases
Authors: Irene S. Yu, Gayle Funk, Eugene Lin, Hagen F. Kennecke
Journal: Clinical Nuclear Medicine (2020)

Cardiac metastases are an infrequent site of metastasis in neuroendocrine tumors, and the treatment implications in the era of peptide receptor radionuclide therapy (PRRT) are unclear. Potential safety concerns exist regarding cardiac integrity and function in response to PRRT. We describe our institutional experience with 4 patients with well-differentiated, midgut neuroendocrine tumors with cardiac involvement detected on Ga-DOTATATE PET/CT scans who were treated with PRRT.
Clinical Risk Score to Predict Early Left Ventricular Thrombus After ST-Segment Elevation Myocardial Infarction
Authors: Magdalena Holzknecht, Martin Reindl, Christina Tiller, Ivan Lechner, Rafael Perez Cabrera, Agnes Mayr, Christoph Brenner, Gert Klug, Axel Bauer, Bernhard Metzler, Sebastian Johannes Reinstadler
Journal: JACC. Cardiovascular imaging (2020)
The Mechanism of Kidney Disease Due to APOL1 Risk Variants
Authors: Etienne Pays
Journal: Journal of the American Society of Nephrology (2020)

The apoL1 C-terminal variants G1 and G2 are linked to CKD.[1][1] Expression of these variants induces effacement of podocyte foot processes, leading to the loss of these cells from glomeruli and impairment of the blood filtration activity of the kidney. A characteristic of G1/G2-linked disease is