tbuckley/cabot-search huggingface dataset:
Balancing Selection for Pathogen Resistance Reveals an Intercontinental Signature of Red Queen Coevolution
Authors: Yann Bourgeois, Peter D Fields, Gilberto Bento, Dieter Ebert
Journal: Molecular Biology and Evolution (2021)

The link between long-term host-parasite coevolution and genetic diversity is key to understanding genetic epidemiology and the evolution of resistance. The model of Red Queen host-parasite coevolution posits that high genetic diversity is maintained when rare host resistance variants have a selective advantage, which is believed to be the mechanistic basis for the extraordinarily high levels of diversity at disease-related genes such as the major histocompatibility complex in jawed vertebrates and R-genes in plants. The parasites that drive long-term coevolution are, however, often elusive. Here we present evidence for long-term balancing selection at the phenotypic (variation in resistance) and genomic (resistance locus) level in a particular host-parasite system: the planktonic crustacean Daphnia magna and the bacterium Pasteuria ramosa. The host shows widespread polymorphisms for pathogen resistance regardless of geographic distance, even though there is a clear genome-wide pattern of isolation by distance at other sites. In the genomic region of a previously identified resistance supergene, we observed consistent molecular signals of balancing selection, including higher genetic diversity, older coalescence times, and lower differentiation between populations, which set this region apart from the rest of the genome. We propose that specific long-term coevolution by negative-frequency-dependent selection drives this elevated diversity at the host's resistance loci on an intercontinental scale and provide an example of a direct link between the host's resistance to a virulent pathogen and the large-scale diversity of its underlying genes.
P-138 Margetuximab combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/- chemotherapy in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction or gastric cancer
Authors: D. Catenacci, M. Koshiji Rosales, H. Chung, H. Yoon, M. Moehler, Y. Kang, L. Shen
Journal: Annals of Oncology (2021)
Life expectancy: White people in England and Wales had worst outcomes before pandemic, data show
Authors: Gareth Iacobucci
Journal: BMJ (2021)

White men and women in England and Wales had lower life expectancy at birth than all other ethnic groups, show new data for 2011 to 2014 from the Office for National Statistics have shown.1

People in the black African ethnic group had statistically significant higher life expectancy than most groups, the data show (table 1).

View this table:

Table 1 
Life expectancy at birth by sex and ethnic group, England and Wales, 2011 to 2014



The analysis was the first in which the ONS has used linked 2011 census and death registration data to produce experimental national estimates of life expectancy and mortality …
WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape
Authors: Chunwan Lu, Zhuoqi Liu, John D Klement, Dafeng Yang, Alyssa D Merting, Dakota Poschel, Thomas Albers, Jennifer L Waller, Huidong Shi, Kebin Liu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Despite PD-L1 (Programmed death receptor ligand-1) expression on tumor cells and cytotoxic T lymphocytes tumor infiltration in the tumor microenvironment, human pancreatic cancer stands out as one of the human cancers that does not respond to immune checkpoint inhibitor (ICI) immunotherapy. Epigenome dysregulation has emerged as a major mechanism in T cell exhaustion and non-response to ICI immunotherapy, we, therefore, aimed at testing the hypothesis that an epigenetic mechanism compensates PD-L1 function to render pancreatic cancer non-response to ICI immunotherapy. Methods Two orthotopic pancreatic tumor mouse models were used for chromatin immunoprecipitation-Seq and RNA-Seq to identify genome-wide dysregulation of H3K4me3 and gene expression. Human pancreatic tumor and serum were analyzed for osteopontin (OPN) protein level and for correlation with patient prognosis. OPN and PD-L1 cellular location were determined in the tumors using flow cytometry. The function of WDR5-H3K4me3 axis in OPN expression were determined by Western blotting. The function of H3K4me3-OPN axis in pancreatic cancer immune escape and response to ICI immunotherapy was determined in an orthotopic pancreatic tumor mouse model. Results Mouse pancreatic tumors have a genome-wide increase in H3K4me3 deposition as compared with normal pancreas. OPN and its receptor CD44 were identified being upregulated in pancreatic tumors by their promoter H3K4me3 deposition. OPN protein is increased in both tumor cells and tumor-infiltrating immune cells in human pancreatic carcinoma and is inversely correlated with pancreatic cancer patient survival. OPN is primarily expressed in tumor cells and monocytic myeloid-derived suppressor cells (M-MDSCs), whereas PD-L1 is expressed in tumor cells, M-MDSCs, polymorphonuclear MDSCs and tumor-associated macrophages. WDR5 is essential for H3K4me3-specific histone methyltransferase activity that regulates OPN expression in tumor cells and MDSCs. Inhibition of WDR5 significantly decreased OPN protein level. Inhibition of WDR5 or knocking out of OPN suppressed orthotopic mouse pancreatic tumor growth. Inhibition of WDR5 also significantly increased efficacy of anti-PD-1 immunotherapy in suppression of mouse pancreatic tumor growth in vivo. Conclusions OPN compensates PD-L1 function to promote pancreatic cancer immune escape. Pharmacological inhibition of the WDR5-H3K4me3 epigenetic axis is effective in suppressing pancreatic tumor immune escape and in improving efficacy of anti-PD-1 immunotherapy in pancreatic cancer.
P3-1 The experience of nivolumab therapy in the patients with advanced and recurrence gastric cancer
Authors: Noriko Wada, Yusuke Akamaru, Takahiro Shimaoka, Soichiro Harada, Satoshi Eguchi, Ryo Ikeshima, Koji Munakata, Daisuke Takiuchi, Naoki Hama, Hirofumi Ota, Kunitaka Shibata
Journal: Annals of Oncology (2021)
P-48 Study of paclitaxel and ramucirumab as second-line therapy after failure of FOLFOX-6 regimen in metastatic stomach carcinoma patients
Authors: V. Goel, P. Jain, P. Goyal, N. Patnaik, S. Pasricha, V. Koyyala, V. Talwar
Journal: Annals of Oncology (2021)
Obesity and severe coronavirus disease 2019: molecular mechanisms, paths forward, and therapeutic opportunities
Authors: Tiantian Yan, Rong Xiao, Nannan Wang, Ruoyu Shang, Guoan Lin
Journal: Theranostics (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to have higher pathogenicity among patients with obesity.Obesity, termed as body mass index greater than 30 kg/m 2 , has now been demonstrated to be important comorbidity for disease severity during coronavirus disease 2019 (COVID-19) pandemic and associated with adverse events.Unraveling mechanisms behind this phenomenon can assist scientists, clinicians, and policymakers in responding appropriately to the COVID-19 pandemic.In this review, we systemically delineated the potential mechanistic links between obesity and worsening COVID-19 from altered physiology, underlying diseases, metabolism, immunity, cytokine storm, and thrombosis.Problematic ventilation caused by obesity and preexisting medical disorders exacerbate organ dysfunction for patients with obesity.Chronic metabolic disorders, including dyslipidemia, hyperglycemia, vitamin D deficiency, and polymorphisms of metabolism-related genes in obesity, probably aid SARS-CoV-2 intrusion and impair antiviral responses.Obesity-induced inadequate antiviral immunity (interferon, natural killer cells, invariant natural killer T cell, dendritic cell, T cells, B cell) at the early stage of SARS-CoV-2 infection leads to delayed viral elimination, increased viral load, and expedited viral mutation.Cytokine storm, with the defective antiviral immunity, probably contributes to tissue damage and pathological progression, resulting in severe symptoms and poor prognosis.The prothrombotic state, driven in large part by endothelial dysfunction, platelet hyperactivation, hypercoagulability, and impaired fibrinolysis in obesity, also increases the risk of severe COVID-19.These mechanisms in the susceptibility to severe condition also open the possibility for host-directed therapies in population with obesity.By bridging work done in these fields, researchers can gain a holistic view of the paths forward and therapeutic opportunities to break the vicious cycle of obesity and its devastating complications in the next emerging pandemic.
Low-Density Lipoprotein Cholesterol Trajectories and Prevalence of High Low-Density Lipoprotein Cholesterol Consistent With Heterozygous Familial Hypercholesterolemia in US Children
Authors: Yiyi Zhang, Jessica G. Woo, Elaine M. Urbina, David R. Jacobs, Andrew E. Moran, Sarah D. de Ferranti
Journal: JAMA Pediatrics (2021)

This cohort study aims to characterize age-related longitudinal low-density lipoprotein trajectories among US children.
若年家族性高コレステロール血症(FH)の頚動脈内膜・中膜厚さは非FH同腹兄弟より大きい
Authors: Takata Mutsuko, Kawashiri Masaaki, Nohara Atsushi, Noguchi Tohru, Tada Hayato, Nakanishi Chiaki, Tsuchida Masayuki, Inazu Akihiro, Kobayashi Junji, Mabuchi Hiroshi, Yamagishi Masakazu
Journal: Circulation (2009)
DNA Methylome Alterations Are Associated with Airway Macrophage Differentiation and Phenotype during Lung Fibrosis
Authors: Peter McErlean, Christopher G. Bell, Richard J. Hewitt, Zabreen Busharat, Patricia P. Ogger, Poonam Ghai, Gesa J. Albers, Emily Calamita, Shaun Kingston, Philip L. Molyneaux, Stephan Beck, Clare M. Lloyd, Toby M. Maher, Adam J. Byrne
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.
Abstract 1461: Stabilization of Extracellular Matrix Antagonizes Proinflammatory Signaling and Prevents Progression of Aortic Aneurysm In Vivo
Authors: Koichi Yoshimura, Hiroki Aoki, Masahiko Onoda, Yasuhiro Ikeda, Hidekazu Aoyama, Noriyasu Morikage, Akira Furutani, Kimikazu Hamano, Masunori Matsuzaki
Journal: Circulation (2006)

We and others reported that proinflammatory signaling in aortic wall enhances degradation of extracellular matrix (ECM) and, at the same time, impairs ECM biosynthesis, leading to the destabilizati...
A study evaluating outcomes of cirrhotic patients managed virtually in a specialist liver cirrhosis service due to the COVID crisis
Authors: A. Cole, M. Bashyam, R. Nathwani, D. Kockerling, S. Mukherjee, B. Mullish, L. Possamai, H. Lewis, M. Lemoine, N. Selvapatt, A. Dhar
Journal: Journal of Hepatology (2021)
Case 22-2021: A 64-Year-Old Woman with Cognitive Impairment, Headache, and Memory Loss
Authors: Shamik Bhattacharyya, R. Gilberto Gonzalez, Bart K. Chwalisz, Samantha N. Champion
Journal: New England Journal of Medicine (2021)

A 64-year-old woman was admitted with a 6-week history of cognitive impairment, headache, and memory loss. She had hyperreflexia and impaired attention and memory. MRI showed diffuse subarachnoid hyperintensities and leptomeningeal enhancement on FLAIR sequences. A diagnostic test was performed.
Abstract 15127: The Effect of Intracoronary Infusion of Mobilized Peripheral Blood Stem Cells on Left Ventricular Function after Myocardial Infarction
Authors: John Terrovitis, Argyrios Ntalianis, John Kanakakis, Christos Papadimitriou, Christos Pantsios, Evangelos Eleftherakis, Christos Kapelios, Elisavet Kaldara, Evangelos Repasos, Savvas Toumanidis, John Nanas
Journal: Circulation (2011)

Therapy with intracoronary infusion of stem cells after myocardial infarction is a safe procedure which may exert beneficial effects in patients with left ventricular dysfunction. Purpose: We inves...
Targeting KDM4B that coactivates c-Myc-regulated metabolism to suppress tumor growth in castration-resistant prostate cancer
Authors: Meng-Jen Wu, Chih-Jung Chen, Ting-Yu Lin, Ying-Yuan Liu, Lin-Lu Tseng, Mei-Ling Cheng, Chih-Pin Chuu, Huai-Kuang Tsai, Wen-Ling Kuo, Hsing-Jien Kung, Wen-Ching Wang
Journal: Theranostics (2021)

Rationale:The progression of prostate cancer (PCa) to castration-resistant PCa (CRPC) despite continuous androgen deprivation therapy is a major clinical challenge.Over 90% of patients with CRPC exhibit sustained androgen receptor (AR) signaling.KDM4B that removes the repressive mark H3K9me3/2 is a transcriptional activator of AR and has been implicated in the development of CRPC.However, the mechanisms of KDM4B involvement in CRPC remain largely unknown.Here, we sought to demonstrate the molecular pathway mediated by KDM4B in CRPC and to provide proof-of-concept evidence that KDM4B is a potential CRPC target.Methods: CRPC cells (C4-2B or CWR22Rv1) depleted with KDM4B followed by cell proliferation (in vitro and xenograft), microarray, qRT-PCR, Seahorse Flux, and metabolomic analyses were employed to identify the expression and metabolic profiles mediated by KDM4B.Immunoprecipitation was used to determine the KDM4B-c-Myc interaction region.Reporter activity assay and ChIP analysis were used to characterize the KDM4B-c-Myc complex-mediated mechanistic actions.The clinical relevance between KDM4B and c-Myc was determined using UCSC Xena analysis and immunohistochemistry. Results: We showed that KDM4B knockdown impaired CRPC proliferation, switched Warburg to OXPHOS metabolism, and suppressed gene expressions including those targeted by c-Myc.We further demonstrated that KDM4B physically interacted with c-Myc and they were co-recruited to the c-Myc-binding sequence on the promoters of metabolic genes (LDHA, ENO1, and PFK).Importantly, KDM4B and c-Myc synergistically promoted the transactivation of the LDHA promoter in a demethylase-dependent manner.We also provided evidence that KDM4B and c-Myc are co-expressed in PCa tissue and that high expression of both is associated with worse clinical outcome.Conclusions: KDM4B partners with c-Myc and serves as a coactivator of c-Myc to directly enhance c-Myc-mediated metabolism, hence promoting CRPC progression.Targeting KDM4B is thus an alternative therapeutic strategy for advanced prostate cancers driven by c-Myc and AR.
MO37-6 Longitudinal disease monitoring with ctDNA during osimertinib treatment in EGFR T790M positive NSCLC patients (WJOG8815L)
Authors: Terufumi Kato, Kazuko Sakai, Takayuki Takahama, Mototsugu Shimokawa, Koichi Azuma, Masayuki Takeda, Isamu Okamoto, Haruko Daga, Shunsuke Teraoka, Toshiaki Takahashi, Tatsuo Ohira, Toshihide Yokoyama, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Kazuto Nishio
Journal: Annals of Oncology (2021)
Effectiveness of Supportive Care Measurements to Reduce Infections during Induction for Children with Acute Myeloid Leukemia: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)
Authors: Daiichiro Hasegawa, Takako Miyamura, Kozo Nagai, Kazuko Kudo, Tawa Akio, Hirozumi Sano, Keitaro Fukushima, Shotaro Iwamoto, Akitoshi Kinoshita, Hiroyuki Takahashi, Kiminori Terui, Hideki Nakayama, Yuki Arakawa, Kentaro Nakashima, Shohei Yamamoto, Akiko Moriya Saito, Keizo Horibe, Daisuke Tomizawa, Takashi Taga, Souichi Adachi
Journal: Blood (2017)
P4-3 A reevaluation of adjuvant chemotherapy for colon cancer in our department
Authors: Kazuma Kobayashi, Takuro Fujita, Ayaka Sato, Shinichiro Ito, Yusuke Inoue, Satomi Okada, Sayaka Kuba, Michi Morita, Shinichiro Kobayashi, Yasuhiro Maruya, Masayuki Fukumoto, Taiichiro Kosaka, Akihiko Soyama, Minoru Fukuda, Takuya Honda, Tomohiko Adachi, Masaaki Hidaka, Kengo Kanetaka, Susumu Eguchi
Journal: Annals of Oncology (2021)
Microbes in gynecologic cancers: Causes or consequences and therapeutic potential
Authors: Mohd Wahid, Sajad A Dar, Arshad Jawed, Raju Kumar Mandal, Naseem Akhter, Saif Khan, Farah Khan, Sudisha Jogaiah, Ashutosh Kumar Rai, Ramandeep Rattan
Journal: Seminars in Cancer Biology (2021)
Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection
Authors: Faisal Kamal, Sacheen Kumar, Michael R. Edwards, Kirill Veselkov, Ilaria Belluomo, Tatiana Kebadze, Andrea Romano, Maria-Belen Trujillo-Torralbo, Tasnim Shahridan Faiez, Ross Walton, Andrew I. Ritchie, Dexter J. Wiseman, Ivan Laponogov, Gavin Donaldson, Jadwiga A. Wedzicha, Sebastian L. Johnston, Aran Singanayagam, George B. Hanna
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiology. Objectives: To determine whether volatile organic compound measurement could distinguish viral from bacterial infection in COPD. Methods: We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC production during acute respiratory viral infection. Highly sensitive gas chromatography-mass spectrometry techniques were used to measure VOC production from infected airway epithelial-cell cultures and in exhaled breath samples from healthy subjects experimentally challenged with rhinovirus (RV)-A16 and from subjects with COPD with naturally occurring exacerbations. Measurements and Main Results: We identified a novel VOC signature comprising decane and other long-chain alkane compounds that is induced during RV infection of cultured airway epithelial cells and is also increased in the exhaled breath from healthy subjects experimentally challenged with RV and from patients with COPD during naturally occurring viral exacerbations. These compounds correlated with the magnitude of antiviral immune responses, viral burden, and exacerbation severity but were not induced by bacterial infection, suggesting that they represent a specific virus-inducible signature. Conclusions: Our study highlights the potential for measurement of exhaled breath VOCs as rapid, noninvasive biomarkers of viral infection. Further studies are needed to determine whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.
The ROMANOV study found impaired humoral and cellular immune responses to SARS-CoV-2 mRNA vaccine in virus-unexposed patients receiving maintenance hemodialysis
Authors: Maxime Espi, Xavier Charmetant, Thomas Barba, Laetitia Koppe, Caroline Pelletier, Emilie Kalbacher, Elodie Chalencon, Virginie Mathias, Anne Ovize, Emmanuelle Cart-Tanneur, Christine Bouz, Laurence Pellegrina, Emmanuel Morelon, Denis Fouque, Laurent Juillard, Olivier Thaunat
Journal: Kidney International (2021)
Abstract 15719: Platelet Receptors GPIbα and GPIIb - Novel Mediators of Arteriogenesis?
Authors: Judith I Pagel, Marie L von Bruehl, Said Farschtschi, Wolfgang Schaper, Steffen Massberg, Elisabeth Deindl
Journal: Circulation (2011)

The growth of preexistent collateral arteries into functional bypasses (arteriogenesis) is the only natural mechanism to compensate for the occlusion of a major artery. Whereas the recruitment of l...
Association between serum tumor necrosis factor-α and sarcopenia in liver cirrhosis
Authors: Ji Won Han, Da In Kim, Hee Chul Nam, U Im Chang, Jin Mo Yang, Do Seon Song
Journal: Clinical and Molecular Hepatology (2021)

Sarcopenia is an independent prognostic factor of liver cirrhosis (LC). However, the association between LC-related systemic inflammation and sarcopenia is unclear.Sprague-Dawley rats were treated with thioacetamide (TAA) or saline as a control. Rifaximin was administered to TAA-induced LC rats. Enzyme-linked immunosorbent assay was performed to measure inflammatory mediators in rat serum. RT-PCR was performed to measure the molecular expression in tissues. Hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to investigate tissue pathology. Serum tumor necrosis factor-α levels, liver stiffness (LS), and the L3 skeletal muscle index (L3SMI) were measured in 60 patients with chronic liver disease.LC and sarcopenia were successfully induced by TAA. Serum TNF-α levels were increased in LC rats and correlated with myostatin expression, muscle weight, and myofiber diameter. The expression of intestinal occludin and zona occludens-1 was reduced in LC rats and associated with serum TNF-α levels and sarcopenia. In patients with LS ≥7 kPa or sarcopenia, serum TNF-α levels were significantly increased, which was also confirmed when we raised the LS cutoff to 10 kPa. The L3SMI was inversely correlated with serum TNF-α levels in patients with LS ≥7 kPa. TNF-α was reduced by rifaximin, which might have resulted in reduced expression of muscular MuRF1 and myostatin and improvements in myofiber diameters within muscle tissues.These results suggest that serum TNF-α is associated with LC-related sarcopenia. Rifaximin might be effective in reducing serum TNF-α levels and improving sarcopenia in LC, but these results need to be validated in future studies.
The Roles of Cytoplasmic Lipid Droplets in Modulating Intestinal Uptake of Dietary Fat
Authors: Alyssa S. Zembroski, Changting Xiao, Kimberly K. Buhman
Journal: Annual Review of Nutrition (2021)

Dietary fat absorption is required for health but also contributes to hyperlipidemia and metabolic disease when dysregulated. One step in the process of dietary fat absorption is the formation of cytoplasmic lipid droplets (CLDs) in small intestinal enterocytes; these CLDs serve as dynamic triacylglycerol storage organelles that influence the rate at which dietary fat is absorbed. Recent studies have uncovered novel factors regulating enterocyte CLD metabolism that in turn influence the absorption of dietary fat. These include peroxisome proliferator-activated receptor α activation, compartmentalization of different lipid pools, the gut microbiome, liver X receptor and farnesoid X receptor activation, obesity, and physiological factors stimulating CLD mobilization. Understanding how enterocyte CLD metabolism is regulated is key in modulating the absorption of dietary fat in the prevention of hyperlipidemia and its associated metabolic disorders.