tbuckley/cabot-search huggingface dataset:
Abstract 385: Cardiac Myosin Binding Protein-C Mutants Disrupt Ubiquitin Proteasome System and Hsc70 Functions
Authors: Amelia A Glazier, Adam Helms, Neha Hafeez, Srisha Kotlo, Jaime Yob, Vi Tang, Sharlene Day
Journal: Circulation Research (2017)

The most commonly mutated gene in hypertrophic cardiomyopathy (HCM) is cardiac myosin binding protein C (MYBPC3). Over 90% of MYBPC3 mutations are nonsense, but whether these mutations manifest in loss- or gain-of-function is unresolved. Evidence suggests MYBPC3 mutants impact protein quality control mechanisms. The objective of this study was to evaluate interactions of MYBPC3 with proteostatic systems and test the hypothesis that these interactions affect protein homeostasis in cardiomyocytes. WT and mutant MYBPC3 constructs were expressed in neonatal rat ventricular myocytes (NRVMs) via adenovirus. Mutant MYBPC3 induced ubiquitin proteasome system reporter GFPu accumulation (fold increase in GFPu-positive cells vs control: WT 138±14.0%, mutant 198±27.2%, mean±SEM, p&lt;0.05 vs control and WT), indicating proteasome dysfunction. Affinity purification/mass spectrometry identified molecular chaperones Hsp70 and Hsc70 as prominent interactors with MYBPC3. We observed MYBPC3 degradation by cycloheximide chase in response to Hsc70 siRNA knockdown or pharmacological treatment with Hsp70 activator YM-1. Hsc70 knockdown slowed degradation of WT and mutant MYBPC3 (WT control t ½ =5.47±0.70 hr, WT Hsc70 knockdown t ½ =13.5±1.62 hr; mutant control t ½ =3.42±0.61 hr, mutant Hsc70 knockdown t ½ =9.87±0.95 hr), while YM-1 treatment accelerated degradation (WT DMSO t ½ =10.2±3.28 hr, WT YM-1 t ½ =3.16±0.61 hr; mutant DMSO t ½ =11.7±2.67 hr, mutant YM-1 t ½ =1.37±0.16 hr). We then evaluated whether transferrin uptake via clathrin mediated endocytosis, a critical Hsc70-dependent activity, was affected by mutant MYBPC3. Transferrin uptake was significantly decreased in NRVMs expressing mutant MYBPC3 compared to WT and untreated controls (transferrin-positive cells: control 22.93±3.34%, WT 17.47±0.70%, mutant 9.30±1.63%, mean±SEM, p&lt;0.05 vs control and WT). In conclusion, we have demonstrated that Hsp70 chaperones interact with MYBPC3 in cardiomyocytes and affect MYBPC3 degradation, suggesting MYBPC3 is a client of Hsp70 and Hsc70. Additionally, expression of mutant MYBPC3 causes ubiquitin proteasome impairment and interferes with normal Hsc70 function. These results support our hypothesis that mutant MYBPC3 affects protein homeostasis in HCM.
Research brief
Authors: Jane Bradbury
Journal: The Lancet Infectious Diseases (2013)

Two studies provide new information about the HIV-1 envelope glycoprotein (env) trimer—the molecule that contains the receptor binding sites and membrane fusion machinery that HIV requires to enter its host cells. The first study uses x-ray crystallography to identify the structure of an antigenically near-native, cleaved, stabilised env trimer in complex with a broadly neutralising antibody. The second study uses cryoelectron microscopy to build a structural model of the same trimer in complex with a different antibody.
Molecular profiling to identify potential therapeutic targets in hepatocellular carcinoma.
Authors: Madappa N. Kundranda, Josh Routh, Ariane C. Kemkes, Michelle Turner, Nishitha Therala, David W. Hall, Cynthia A. Flannery, Mark C. Evans, Jean-Paul De La O, Snehal Govind Thakkar
Journal: Journal of Clinical Oncology (2022)

471 Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is often diagnosed at an advanced stage with limited effective therapies. The advent of comprehensive genomic molecular profiling has the potential to identify novel therapeutic options in the treatment of HCC. In this descriptive clinical utility study, we evaluated the utility of the Oncotype MAP Pan-Cancer Tissue (MAP) test to identify potential therapeutic options, including clinical trials. Methods: Between October 2018 and October 2020, we identified 41 samples from patients with HCC submitted for MAP testing. The MAP test uses tumor tissue to identify single nucleotide variants, indels, copy number alterations, and select structural variants and fusions by next-generation sequencing (NGS) of a 257 gene panel. Tumor mutational burden and microsatellite instability are also determined. A custom immunohistochemical (IHC) panel is also performed. Results from NGS and IHC are run against a proprietary knowledgebase of genomic and proteomic data that includes FDA approvals, NCCN Recommendations and published biomarker data on potentially targetable alterations. Eligibility for ongoing clinical trials is determined using the NCI database. Results: Of the 41 samples, 37 (90%) met minimum tissue requirements (3mm 2 and 15% tumor cellularity) for DNA sequencing. Of these 37 samples, 36 (97%) were successfully sequenced for NGS testing. Median turnaround time from the date of accessioning to the date of laboratory report was 5 days (interquartile range (IQR) 4-6 days). The most frequently identified genomic variants characterized as pathogenic, or unknown significance, were TP53, CTNNB1 and FAT1 genes. Thirty-two samples (86%) had a genomic alteration that could potentially direct treatment. Six samples (16%) had findings directing to an approved treatment for HCC, 4 (11%) had findings for an approved treatment of a different tumor type, and 22 (59%) had findings for one or more clinical trials. Conclusions: The Oncotype MAP Pan-Cancer Tissue test identified molecular variants that could be used to inform treatment decisions in 86% of HCC samples, including 16% to an approved HCC therapy. The Oncotype MAP test may be considered as another tool in the management of advanced HCC patients.
An Easy Conundrum.—What He Should do with It.
Authors: None J. W. X.
Journal: JAMA (1893)

Detroit, Mich., Nov. 25, 1893. <h3>To the Editor:</h3> —In my mail, the other day, I received a blank application for membership. I am already a member and have been for years. What do you expect<i>me</i>to do with this blank? Yours truly, <h3>Ans.</h3> —Get a new member with it, please.
Modeling Metastatic Colonization in a Decellularized Organ Scaffold‐Based Perfusion Bioreactor (Adv. Healthcare Mater. 1/2022)
Authors: Maria Rafaeva, Edward R. Horton, Adina R.D. Jensen, Chris D. Madsen, Raphael Reuten, Oliver Willacy, Christian B. Brøchner, Thomas H. Jensen, Kamilla Westarp Zornhagen, Marina Crespo, Dina S. Grønseth, Sebastian R. Nielsen, Manja Idorn, Per thor Straten, Kristoffer Rohrberg, Iben Spanggaard, Martin Højgaard, Ulrik Lassen, Janine T. Erler, Alejandro E. Mayorca‐Guiliani
Journal: Advanced Healthcare Materials (2022)

Cancer Metastasis Highlighting article number 2100684 by Janine T. Erler, Alejandro E. Mayorca-Guiliani and co-workers, this cover represents cancer cells extravasating out of a vessel into a decellularized extracellular matrix (ECM) organ scaffold. Upon arriving in the capillary bed, the cells adhere to the ECM and use it to migrate into the organ. The authors' metastasis model system is based on a bioreactor where ECM organ scaffolds are provided with the conditions necessary to sustain cell life. Cell-ECM interactions coerce cells into behaving as they would in a living organism.
Machine learning based on routine laboratory indicators promoting the discrimination between active tuberculosis and latent tuberculosis infection
Authors: Ying Luo, Ying Xue, Huijuan Song, Guoxing Tang, Wei Liu, Huan Bai, Xu Yuan, Shutao Tong, Feng Wang, Yimin Cai, Ziyong Sun
Journal: Journal of Infection (2022)

BackgroundDiscriminating active tuberculosis (ATB) from latent tuberculosis infection (LTBI) remains challenging. The present study aims to evaluate the performance of diagnostic models established using machine learning based on routine laboratory indicators in differentiating ATB from LTBI.MethodsParticipants were respectively enrolled at Tongji Hospital (discovery cohort) and Sino-French New City Hospital (validation cohort). Diagnostic models were established based on routine laboratory indicators using machine learning.ResultsA total of 2619 participants (1025 ATB and 1594 LTBI) were enrolled in discovery cohort and another 942 subjects (388 ATB and 554 LTBI) were recruited in validation cohort. ATB patients had significantly higher levels of tuberculosis-specific antigen/phytohemagglutinin ratio and coefficient variation of red blood cell volume distribution width, and lower levels of albumin and lymphocyte count than those of LTBI individuals. Six models were built and the optimal performance was obtained from GBM model. GBM model derived from training set (n = 1965) differentiated ATB from LTBI in the test set (n = 654) with a sensitivity of 84.38% (95% CI, 79.42%-88.31%) and a specificity of 92.71% (95% CI, 89.73%-94.88%). Further validation by an independent cohort confirmed its encouraging value with a sensitivity of 87.63% (95% CI, 83.98%-90.54%) and specificity of 91.34% (95% CI, 88.70%-93.40%), respectively.ConclusionsWe successfully developed a model with promising diagnostic value based on machine learning for the first time. Our study proposed that GBM model may be of great benefit served as a tool for the accurate identification of ATB.
Cardioprotection by an adenosine A2A receptor agonist in a canine model of myocardial stunning produced by multiple episodes of transient ischemia David K. Glover, Mirta Ruiz, Kazuya Takehana, Frank D. Petruzella, Jayson M. Rieger, Timothy L. Macdonald, Denny D. Watson, Joel Linden, George A. Beller. University of Virginia, Charlottesville, VA
Journal: Journal of the American College of Cardiology (2001)
Correction: Influence of past reproductive performance on risk of spontaneous abortion
Authors: B Marc, O Diamant-Berger, R Gherardi, F Baud, M Garnier, Diamant -Berger
Journal: BMJ (1989)

Drugs that are concealed by dealers or "body packers" in the gastrointestinal tract for smuggling can be detected by several methods."'3Analysis of urine,2 radiography of the abdomen,' 3 and natural clearanceh ave been reported.Little has been reported on managing dealers who quickly swallow packets of drugs at the time of arrest3'5 apart from an occasional fatal overdose.5Unlike those swallowed by body packers, the drugs ingested by "quick swallowers" are not in wrappings designed for ingestion.We evaluated the usual methods of drug detection in 50 subjects who were suspected of quick swallowing of drugs and we also gave them an emetic.
Abnormal repolarization dynamics in patients with hypertrophic cardiomyopathy: A new risk factor for sudden death? Christopher C. E. Lang, Saidi A. Mohiddin, Andrew D. Flapan, Lameh Fananapazir. University of Edinburgh, Edinburgh, United Kingdom, National Heart, Lung and Blood Institute, Bethesda, MD
Journal: Journal of the American College of Cardiology (2001)
Deep learning analysis of the adipose tissue and the prediction of prognosis in colorectal cancer.
Authors: Anqi Lin, Jian Zhang, Peng Luo
Journal: Journal of Clinical Oncology (2022)

139 Background: Colorectal cancer (CRC) is the third most common type of cancer and has a poor prognosis and high recurrence rate. Research has shown that the lipid microenvironment surrounding tumors is closely associated with the occurrence, development, and metastasis of CRC. Recently, advances in artificial intelligence have greatly improved the accuracy of models for CRC prognosis and survival analysis. Methods: According to pathological images from the National Center for Tumor diseases(NCT), the University Medical Center Mannheim(UMM) database and the ImageNet data set, a model called VGG19 was pre-trained. A deep convolutional neural network(CNN), VGG19 CRC, was trained by the migration learning method. According to the VGG19 CRC model, adipose tissue scores were calculated for TCGA-CRC hematoxylin and eosin(H&amp;E) images and images from patients at Zhujiang Hospital of Southern Medical University and First People’s Hospital of Chenzhou. Kaplan-Meier(KM) analysis was used to compare the overall survival(OS) of patients. The XCell and MCP-Counter algorithms were used to evaluate the immune cell scores of the patients. Gene set enrichment analysis(GSEA) and single-sample GSEA(ssGSEA) were used to analyze upregulated and downregulated pathways. Results: In TCGA-CRC, patients with high-adipocytes(high-ADI) CRC had significantly shorter OS times than those with low-ADI CRC. In a validation queue from Zhujiang Hospital of Southern Medical University(Local-CRC1), patients with high-ADI had worse OS than CRC patients with low-ADI. In another validation queue from First People's Hospital of Chenzhou(Local-CRC2), patients with low-ADI CRC had significantly longer OS than patients with high-ADI CRC. In subgroup analysis, ADI could be used as a prognostic marker for patients with colon adenocarcinoma(COAD) and rectum adenocarcinoma(READ), as well as male and female CRC patients. Among these subgroups, patients with lower ADI also had significantly improved OS. Compared with the low-ADI group, high-ADI patients had significantly decreased CD8+ T cells, T cells,and monocytes in the tumor immune microenvironment(TIME), while M2 macrophages were significantly increased. According to the GSEA and ssGSEA analyses, pathways mediating anti-tumor immunity were significantly downregulated in the high-ADI group, while some oncogenic signaling pathways were significantly upregulated. Conclusions: We developed a deep convolution network to segment various tissues from pathological H&amp;E images of CRC and automatically quantify ADI. This allowed us to further analyze and predict the survival of CRC patients according to information from their segmented pathological tissue images, such as tissue components and the tumor microenvironment. Furthermore, we found that ADI may also predict OS in CRC patients and among the subgroups.
Methanethiol Poisoning
Authors: William T. Shults
Journal: JAMA (1970)

A 53-year-old man was hospitalized because of coma appearing shortly after exposure to methanethiol. Acute, severe hemolytic anemia and methemoglobinemia developed: both were brief in duration. The likely mechanism of the hemolysis was an oxidant effect of methanethiol in a person deficient in erythrocytic glucose-6-phosphate dehydrogenase (G-6-PD). Deep coma persisted until death 28 days after exposure to the chemical agent.
Vasoconstrictor effect of the angiotensin converting enzyme resistant chymase substrate 6Pro11 D-Ala129 angiotensin I in human dorsal hand veins: in vivo demonstration of non ACE conversion of angiotensin II in humans John E. McDonald, Neal Padmanabahn, Mark C. Petrie, Chris Hillier, John M. C. Connell, John J. V. McMurray. GLASGOW UNIVERSITY, GLASGOW, United Kingdom, CALEDONIAN UNIVERSITY, GLASGOW, United Kingdom
Journal: Journal of the American College of Cardiology (2001)
Heberden Society: Annual Report, 1953
Authors: Mervyn Gordon, Mr Gray, George Hamblen-Thomas, Dr Crosby, M Desmarais, Drs Glyn, B Cruick- Shank, Ronald Harris, R Lovell, K Latter, M Jacobs, J Joule, G Dawson, P Storey, H Ball, D Slack, Hugh Burt, Hon Librarian, W Copeman, Anon Dawson, T Beaume, M Cheyne, G Ellwanger, G Falconer, W Palmer
Journal: Annals of the Rheumatic Diseases (1954)

papers presented, maintained as high a standard as in the previous year.It is with deep regret that the death is recorded of Dr.
The preference for sugar over sweetener depends on a gut sensor cell
Authors: Kelly L. Buchanan, Laura E. Rupprecht, M. Maya Kaelberer, Atharva Sahasrabudhe, Marguerita E. Klein, Jorge A. Villalobos, Winston W. Liu, Annabelle Yang, Justin Gelman, Seongjun Park, Polina Anikeeva, Diego V. Bohórquez
Journal: Nature Neuroscience (2022)

Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.
Abstract 17190: Dual Hit of HIV-1 and Opioids Promote Oxidative Stress Mediated Pulmonary Endothelial Dysfunction
Authors: Himanshu Sharma, Stuti Agarwal, Ling Chen, Navneet K Dhillon
Journal: Circulation (2018)

Introduction: HIV related pulmonary hypertension is one of the serious non-infectious cardiovascular complications in HIV infected individuals, especially among intravenous drug users. We previously demonstrated that opioids in combination with viral protein(s) result in reactive oxygen species (ROS) mediated induction of autophagy in pulmonary endothelial cells leading to shift in the cells from apoptosis to apoptosis resistant proliferative status associated with angio-proliferative remodeling observed in PAH. Here, we delineate the major sources of HIV-1 and morphine induced oxidative burst and its role in development of PAH using in-vivo model. Methods: Human pulmonary microvascular endothelial cells (HPMECs) were treated with morphine and HIV-Tat in the presence or absence of ROS scavengers followed by measurement of ROS. Mitochondrial specific superoxide radicals were measured with MitoSOX dye and ratio of mitochondrial DNA to nuclear DNA was determined by real-time PCR. To assess the in-vivo effect of HIV-1 and morphine on pulmonary vascular dysfunction, male HIV-Tg/WT Fischer rats (n=7-13per group) were subcutaneously administered 10 mg/kg body wt. morphine or saline daily IP for 21 days. Right ventricle systolic pressure (RVSP) and fulton Index were measured along with immunohistochemistry analysis of lungs. Result: Increased oxidative stress in HPMECs in response to combined treatment of morphine and tat (M+T) was noted to be contributed by mitochondria, NADPH oxidase and xanthine oxidase as observed by the decrease in ROS production of M+T treated cells on pre-treatment with ROS scavenger viz., Mitotempo (mitochondria), VAS3947 (NADPH oxidase) and allopurinol (Xanthine oxidase). However, M+T mediated early apoptosis and late hyperproliferation of HPMECs was prevented in presence of NADPH oxidase inhibitor. In parallel we observed elevated mitochondrial specific ROS at 2 hr and increased mitophagy at 3h followed by increase in total mitochondrial mass at 4-6h of MT treatment. Further, we observed significant increase in RVSP and RV hypertrophy in HIV-Tg rats exposed to morphine compared to WT rats. Immunohistochemical analysis also showed significant pulmonary vascular remodelling including endothelial proliferation in lung sections from HIV+morphine rats. Conclusion: Our findings suggest NADPH oxidase specific ROS role in autophagy-dependent increased proliferation of M+T treated HPMECs. Further our in-vivo findings provide evidence of potentiation of PAH development with the dual hit HIV-1 and opioids.
Experimental medical ecology: the tasks ahead
Authors: H. A. Schneider
Journal: JAMA (1965)

Ecology is defined as that branch of biology concerned with the mutual relations between organisms and their environment. Medical ecology, then, concerns itself with man, with his mutual relations within his species, with all other species, and finally, with all of these phenomena as they are related to the environment. The word "medical" conveys further a value judgment, that all of what has just been said is to be viewed as opening a path to measures implementing the preservation and restoration of health. It is a large undertaking, indeed, and with all of its myriad aspects it is a staggering one. Considering that the classical mechanics of physics, even today, has not solved the problem posed by the mutual relations involving the position and momentum of only three single bodies, there is good reason to be humble about medical ecology. But, if we should be humble, there is no need
COVID-19 puts societies to the test
Authors: None The Lancet Public Health
Journal: The Lancet Public Health (2020)

As of April 21, the coronavirus outbreak has infected more than 2·3 million people and taken 162 956 lives—35 884 in the USA, 24 114 in Italy, 20 852 in Spain, 20 233 in France, 16 509 in the UK, 5209 in Iran, 4642 in China—all underestimates most probably. Beyond these numbers are people, families, communities, societies that have been affected in unprecedented ways. The coronavirus pandemic puts societies to the test: it is a test of political leadership, of national health systems, of social care services, of solidarity, of the social contract—a test of our very own fabric.
Long term prognostic value of cardiac troponin T levels following percutaneous coronary angioplasty Manoj R. Muttreja, William H. Matthai, Jorge R. Kizer, Joseph McConnell, Heather Nardone, Ali Sonel, Martin G. Keane, Robert L. Wilensky. Hospital of the University of Pennsylvania, Philadelphia, PA
Journal: Journal of the American College of Cardiology (2001)