tbuckley/cabot-search huggingface dataset:
KAML: improving genomic prediction accuracy of complex traits using machine learning determined parameters
Authors: Lilin Yin, Haohao Zhang, Xiang Zhou, Xiaohui Yuan, Shuhong Zhao, Xinyun Li, Xiaolei Liu
Journal: Genome biology (2020)

Advances in high-throughput sequencing technologies have reduced the cost of genotyping dramatically and led to genomic prediction being widely used in animal and plant breeding, and increasingly in human genetics. Inspired by the efficient computing of linear mixed model and the accurate prediction of Bayesian methods, we propose a machine learning-based method incorporating cross-validation, multiple regression, grid search, and bisection algorithms named KAML that aims to combine the advantages of prediction accuracy with computing efficiency. KAML exhibits higher prediction accuracy than existing methods, and it is available at https://github.com/YinLiLin/KAML.
Abstract B06: Proteomic biomarker for detection of ovarian cancer using gynecologic liquid biopsy
Authors: Georgina D. Barnabas, Keren Bahar-Shany, Stav Sapoznik, Jacob Korach, Tamar Perri, Eitan Friedman, David Stockheim, Ariella Jakobson-Setton, Ram Eitan, Limor Helpman, Yfat Kadan, Sarit Aviel-Ronen, Michal Harel, Tamar Geiger, Keren Levanon
Journal: Clinical Cancer Research (2020)

Abstract The vast majority of high-grade ovarian cancer (HGOC) patients are diagnosed at a metastatic stage, resulting in exceptionally low cure rates. Current screening options fail to improve mortality due to the absence of early-stage-specific biomarkers and the poor systemic representation of early-stage tumors. We postulated that a gynecologic liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Furthermore, while mutation-based assays are challenged by the rarity of tumor DNA within nonmutated DNA, analyzing the proteomic profile may potentially enable earlier detection, as it reveals perturbations in both the tumor compartment as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we isolated microvesicles and performed mass spectrometric proteomic analysis of the UtL samples. Liquid biopsies from HGOC patients (n=85), controls (n=183), and healthy BRCA mutation carriers (n=37), were divided into discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8,578 UtL proteins in total, and on average ~3,000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 63% sensitivity and 73% specificity. The signature correctly identified all Stage I lesions and highlighted increased risk in healthy BRCA carriers. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis but require integration with other biomarker types for improved prediction. Citation Format: Georgina D. Barnabas, Keren Bahar-Shany, Stav Sapoznik, Jacob Korach, Tamar Perri, Eitan Friedman, David Stockheim, Ariella Jakobson-Setton, Ram Eitan, Limor Helpman, Yfat Kadan, Sarit Aviel-Ronen, Michal Harel, Tamar Geiger, Keren Levanon. Proteomic biomarker for detection of ovarian cancer using gynecologic liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B06.
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled Study of PF-04447943 in Patients with Stable Sickle Cell Disease: Changes in Exploratory Biomarkers
Authors: Robert J Charnigo, Jo Howard, David Beidler, Denis Rybin, Beesan Tan, Alan D Michelson, Andrew L Frelinger, Nicholas Clarke
Journal: Blood (2017)
Endocuff combined with buffer-traction: a method to make endoscopic submucosal dissection in proximal colon easy
Authors: Xiaotian Sun, Zheng Lu
Journal: Endoscopy (2020)

We have successfully combined an endocuff and buffer-traction for endoscopic submucosal dissection (ESD) in the proximal colon ([Video 1]). This patient had a severe adhesion in the abdominal cavity from previous abdominal surgery. A 3-cm laterally spreading neoplasm was found at 5 cm from the anastomosis.
Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes
Authors: Pier Vitale Nuzzo, Jacob E. Berchuck, Keegan Korthauer, Sandor Spisak, Amin H. Nassar, Sarah Abou Alaiwi, Ankur Chakravarthy, Shu Yi Shen, Ziad Bakouny, Francesco Boccardo, John Steinharter, Gabrielle Bouchard, Catherine R. Curran, Wenting Pan, Sylvan C. Baca, Ji-Heui Seo, Gwo-Shu Mary Lee, M. Dror Michaelson, Steven L. Chang, Sushrut S. Waikar, Guru Sonpavde, Rafael A. Irizarry, Mark Pomerantz, Daniel D. De Carvalho, Toni K. Choueiri, Matthew L. Freedman
Journal: Nature Medicine (2020)
Engraftment kinetics after transplantation of double unit cord blood grafts combined with haplo-identical CD34+ cells without antithymocyte globulin
Authors: Ioannis Politikos, Sean M. Devlin, Maria E. Arcila, Jonathan C. Barone, Molly A. Maloy, Kristine A. Naputo, Josel D. Ruiz, Christopher M. Mazis, Andromachi Scaradavou, Scott T. Avecilla, Parastoo B. Dahi, Sergio A. Giralt, Katherine C. Hsu, Ann A. Jakubowski, Esperanza B. Papadopoulos, Miguel A. Perales, Craig S. Sauter, Roni Tamari, Doris M. Ponce, Richard J. O’Reilly, Juliet N. Barker
Journal: Leukemia (2020)
Deletion of the myeloid endothelin-B receptor confers long-term protection from angiotensin II-mediated kidney, eye and vessel injury
Authors: Léa Guyonnet, Alicja Czopek, Tariq E. Farrah, Véronique Baudrie, Philippe Bonnin, Anna Chipont, Olivia Lenoir, Florian Sennlaub, Christophe Roubeix, David J. Webb, David C. Kluth, Matthew A. Bailey, Pierre-Louis Tharaux, Neeraj Dhaun
Journal: Kidney International (2020)

The endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ETB) receptors (LysM-CreEdnrblox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-CreEdnrblox/lox and littermate controls (Ednrblox/lox) for six weeks. Unexpectedly, LysM-CreEdnrblox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-CreEdnrblox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-CreEdnrblox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-CreEdnrblox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ETB signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-CreEdnrblox/lox mice than in controls. At six weeks, macrophages from LysM-CreEdnrblox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrblox/lox mice. Thus, myeloid cell ETB receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages.
Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high-risk mutational patterns
Authors: Carolina Schinke, Eileen M. Boyle, Cody Ashby, Yan Wang, Valeriy Lyzogubov, Christopher Wardell, Pingping Qu, Antje Hoering, Shayu Deshpande, Katie Ryan, Sharmilan Thanendrarajan, Meera Mohan, Naveen Yarlagadda, Maliha Khan, Samrat Roy Choudhury, Maurizio Zangari, Frits van Rhee, Faith Davies, Bart Barlogie, Gareth Morgan, Brian A. Walker
Journal: Blood Cancer Journal (2020)

Abstract Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by the presence of ≥20% circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood and, given the rarity of the disease, are challenging to study. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype, we performed whole-exome sequencing and gene expression analysis in 23 and 41 patients with newly diagnosed pPCL, respectively. The results reveal an enrichment of complex structural changes and high-risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular, pPCL patients with traditional low-risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group. Furthermore, gene expression profiling showed upregulation of adverse risk modifiers in pPCL compared to non-pPCL MM, while adhesion molecules and extracellular matrix proteins became increasingly downregulated. In conclusion, this is one of the largest studies to dissect pPCL on a genomic and molecular level.
Combination vaccine based on citrullinated vimentin and enolase peptides induces potent CD4-mediated anti-tumor responses
Authors: Victoria A Brentville, Rachael L Metheringham, Ian Daniels, Suha Atabani, Peter Symonds, Katherine W Cook, Mireille Vankemmelbeke, Ruhul Choudhury, Poonam Vaghela, Mohamed Gijon, Ghislaine Meiners, Willem-Jan Krebber, Cornelis J M Melief, Lindy G Durrant
Journal: Journal for ImmunoTherapy of Cancer (2020)

Stress-induced post-translational modifications occur during autophagy and can result in generation of new epitopes and immune recognition. One such modification is the conversion of arginine to citrulline by peptidylarginine deiminase enzymes.We used Human leukocyte antigen (HLA) transgenic mouse models to assess the immunogenicity of citrullinated peptide vaccine by cytokine Enzyme linked immunosorbant spot (ELISpot) assay. Vaccine efficacy was assessed in tumor therapy studies using HLA-matched B16 melanoma and ID8 ovarian models expressing either constitutive or interferon-gamma (IFNγ) inducible Major Histocompatibility Complex (MHC) class II (MHC-II) as represented by most human tumors. To determine the importance of CD4 T cells in tumor therapy, we analyzed the immune cell infiltrate into murine tumors using flow cytometry and performed therapy studies in the presence of CD4 and CD8 T cell depletion. We assessed the T cell repertoire to citrullinated peptides in ovarian cancer patients and healthy donors using flow cytometry.The combination of citrullinated vimentin and enolase peptides (Modi-1) stimulated strong CD4 T cell responses in mice. Responses resulted in a potent anti-tumor therapy against established tumors and generated immunological memory which protected against tumor rechallenge. Depletion of CD4, but not CD8 T cells, abrogated the primary anti-tumor response as well as the memory response to tumor rechallenge. This was further reinforced by successful tumor regression being associated with an increase in tumor-infiltrating CD4 T cells and a reduction in tumor-associated myeloid suppressor cells. The anti-tumor response also relied on direct CD4 T cell recognition as only tumors expressing MHC-II were rejected. A comparison of different Toll-like receptor (TLR)-stimulating adjuvants showed that Modi-1 induced strong Th1 responses when combined with granulocyte-macrophage colony-stimulating factor (GMCSF), TLR9/TLR4, TLR9, TLR3, TLR1/2 and TLR7 agonists. Direct linkage of the TLR1/2 agonist to the peptides allowed the vaccine dose to be reduced by 10-fold to 100-fold without loss of anti-tumor activity. Furthermore, a CD4 Th1 response to the citrullinated peptides was seen in ovarian cancer patients.Modi-1 citrullinated peptide vaccine induces potent CD4-mediated anti-tumor responses in mouse models and a CD4 T cell repertoire is present in ovarian cancer patients to the citrullinated peptides suggesting that Modi-1 could be an effective vaccine for ovarian cancer patients.
The renin–angiotensin system: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications
Authors: Betty Diamond
Journal: The Journal of Experimental Medicine (2020)

The renin–angiotensin system (RAS) has long been appreciated as a major regulator of blood pressure, but has more recently been recognized as a mechanism for modulating inflammation as well. While there has been concern in COVID-19 patients over the use of drugs that target this system, the RAS has not been explored fully as a druggable target. The abbreviated description of the RAS suggests that its dysregulation may be at the center of COVID-19.
An Endoplasmic Reticulum Stress–MicroRNA‐26a Feedback Circuit in NAFLD
Authors: Haixia Xu, Yan Tian, Dongmei Tang, Sailan Zou, Geng Liu, Jiulin Song, Guixiang Zhang, Xiao Du, Wei Huang, Bin He, Weiqiang Lin, Liang Jin, Wendong Huang, Jiayin Yang, Xianghui Fu
Journal: Hepatology (2020)

Background and Aims Endoplasmic reticulum (ER) stress is an adaptive response to excessive ER demand and contributes to the development of numerous diseases, including nonalcoholic fatty liver disease (NAFLD), which is hallmarked by the accumulation of lipid within hepatocytes. However, the underlying mechanisms remain elusive. MicroRNAs (miRNAs) play an indispensable role in various stress responses, but their implications in ER stress have not yet been systemically investigated. In this study, we identify a negative feedback loop consisting of hepatic ER stress and miR‐26a in NAFLD pathogenesis. Approach and Results Combining miRNA dot blot array and quantitative PCR, we find that miR‐26a is specifically induced by ER stress in liver cells. This induction of miR‐26a is critical for cells to cope with ER stress. In human hepatoma cells and murine primary hepatocytes, overexpression of miR‐26a markedly alleviates chemical‐induced ER stress, as well as palmitate‐triggered ER stress and lipid accumulation. Conversely, deficiency of miR‐26a exhibits opposite effects. Mechanistically, miR‐26a directly targets the eukaryotic initiation factor 2α, a core ER stress effector controlling cellular translation. Intriguingly, miR‐26a is reduced in the livers of patients with NAFLD. Hepatocyte‐specific restoration of miR‐26a in mice significantly mitigates high‐fat diet–induced ER stress and hepatic steatosis. In contrast, deficiency of miR‐26a in mice exacerbates high‐fat diet–induced ER stress, lipid accumulation, inflammation and hepatic steatosis. Conclusions Our findings suggest ER stress–induced miR‐26a up‐regulation as a regulator for hepatic ER stress resolution, and highlight the ER stress/miR‐26a/eukaryotic initiation factor 2α cascade as a promising therapeutic strategy for NAFLD.
CAD Severity on Cardiac CTA Identifies Patients With Most Benefit of Treating LDL-Cholesterol to ACC/AHA and ESC/EAS Targets
Authors: Martin Bødtker Mortensen, Flemming Hald Steffensen, Hans Erik Bøtker, Jesper Møller Jensen, Niels Peter Rønnow Sand, Kristian Hay Kragholm, Helle Kanstrup, Henrik Toft Sørensen, Jonathon Leipsic, Michael J. Blaha, Bjarne Linde Nørgaard
Journal: JACC. Cardiovascular imaging (2020)
Complete resolution of a hamstring intramuscular tendon injury on MRI is not necessary for a clinically successful return to play
Authors: Robin Vermeulen, Emad Almusa, Stan Buckens, Willem Six, Rod Whiteley, Guus Reurink, Adam Weir, Maarten Moen, Gino M M J Kerkhoffs, Johannes L Tol
Journal: British Journal of Sports Medicine (2020)

Clinical decision-making around intramuscular tendon injuries of the hamstrings is a controversial topic in sports medicine. For this injury, MRI at return to play (RTP) might improve RTP decision-making; however, no studies have investigated this.
Use of convalescent plasma in hospitalized patients with COVID-19: case series
Authors: Livia Hegerova, Ted A. Gooley, Kelly A. Sweerus, Cynthia Maree, Neil Bailey, Megumi Bailey, Vanessa Dunleavy, Krish Patel, Kirsten Alcorn, Rebecca Haley, Jill M. Johnsen, Barbara A. Konkle, Annamarie C. Lahti, Morgan L. Alexander, Jason D. Goldman, Anne Lipke, Sun-jung Lim, Mark D. Sullivan, John S. Pauk, John M. Pagel
Journal: Blood (2020)
Slowing the Opioid Epidemic by Controlling a Source
Authors: Steven A. Farmer, Michelle Schreiber, Keith A. Horvath
Journal: JAMA Cardiology (2020)

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 Cardiology 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 Cardiology journal
Variable Spontaneous Mutation and Loss of Heterozygosity among Heterozygous Genomes in Yeast
Authors: Duong T Nguyen, Baojun Wu, Hongan Long, Nan Zhang, Caitlyn Patterson, Stephen Simpson, Krystalynne Morris, W Kelley Thomas, Michael Lynch, Weilong Hao
Journal: Molecular Biology and Evolution (2020)

Abstract Mutation and recombination are the primary sources of genetic variation. To better understand the evolution of genetic variation, it is crucial to comprehensively investigate the processes involving mutation accumulation and recombination. In this study, we performed mutation accumulation experiments on four heterozygous diploid yeast species in the Saccharomycodaceae family to determine spontaneous mutation rates, mutation spectra, and losses of heterozygosity (LOH). We observed substantial variation in mutation rates and mutation spectra. We also observed high LOH rates (1.65–11.07×10−6 events per heterozygous site per cell division). Biases in spontaneous mutation and LOH together with selection ultimately shape the variable genome-wide nucleotide landscape in yeast species.
Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug
Authors: Alexandre J. Debacker, Jon Voutila, Matthew Catley, David Blakey, Nagy Habib
Journal: Molecular Therapy (2020)

Targeted delivery of oligonucleotides to liver hepatocytes using N-acetylgalactosamine (GalNAc) conjugates that bind to the asialoglycoprotein receptor has become a breakthrough approach in the therapeutic oligonucleotide field. This technology has led to the approval of givosiran for the treatment of acute hepatic porphyria, and there are another seven conjugates in registrational review or phase 3 trials and at least another 21 conjugates at earlier stages of clinical development. This review highlights some of the recent chemical and preclinical advances in this space, leading to a large number of clinical candidates against a diverse range of targets in liver hepatocytes. The review focuses on the use of this delivery system for small interfering RNAs (siRNAs) and antisense molecules that cause downregulation of target mRNA and protein. A number of other approaches such as anti-microRNAs and small activating RNAs are starting to exploit the technology, broadening the potential of this approach for therapeutic oligonucleotide intervention.
COVID-19: Playing away the pandemic
Authors: Vijay Shankar Balakrishnan
Journal: The Lancet Infectious Diseases (2020)

Markus Geiger is a mechanical engineer based in Munich, Germany, whose night job is to create board games. Father of two, the 39-year old Geiger owns a company where he churns out games using 3D printers and CO2 laser cutters. His latest release is Corona Battle Against COVID-19, which he touts to kill the lockdown boredom. "This game is not about being a virus or the disease, rather to use logic and strategies to solve complex tasks and win the virus, while also keeping the world running [in the game]," said Geiger.
Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia
Authors: Arnold Kloos, Konstantinos Mintzas, Lina Winckler, Razif Gabdoulline, Yasmine Alwie, Nidhi Jyotsana, Nadine Kattre, Renate Schottmann, Michaela Scherr, Charu Gupta, Felix F. Adams, Adrian Schwarzer, Dirk Heckl, Axel Schambach, Suzan Imren, R. Keith Humphries, Arnold Ganser, Felicitas Thol, Michael Heuser
Journal: Leukemia (2020)

Abstract To establish novel and effective treatment combinations for chronic myelomonocytic leukemia (CMML) preclinically, we hypothesized that supplementation of CMML cells with the human oncogene Meningioma 1 (MN1) promotes expansion and serial transplantability in mice, while maintaining the functional dependencies of these cells on their original genetic profile. Using lentiviral expression of MN1 for oncogenic supplementation and transplanting transduced primary mononuclear CMML cells into immunocompromised mice, we established three serially transplantable CMML-PDX models with disease-related gene mutations that recapitulate the disease in vivo. Ectopic MN1 expression was confirmed to enhance the proliferation of CMML cells, which otherwise did not engraft upon secondary transplantation. Furthermore, MN1-supplemented CMML cells were serially transplantable into recipient mice up to 5 generations. This robust engraftment enabled an in vivo RNA interference screening targeting CMML-related mutated genes including NRAS , confirming that their functional relevance is preserved in the presence of MN1. The novel combination treatment with azacitidine and the MEK-inhibitor trametinib additively inhibited ERK-phosphorylation and thus depleted the signal from mutated NRAS. The combination treatment significantly prolonged survival of CMML mice compared to single-agent treatment. Thus, we identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and propose its clinical development.
抗IL-6受容体抗体(トシリズマブ)を用いた長期治療の結果として生じるヘプシジンの下方制御は,多中心性キャッスルマン病における炎症の貧血を改善する
Authors: J Song Soken-Nakazawa, Tomosugi Naohisa, Kawabata Hiroshi, Ishikawa Takayuki, Nishikawa Teppei, Yoshizaki Kazuyuki
Journal: Blood (2010)