tbuckley/cabot-search huggingface dataset:
Preclinical safety profile of tanespimycin (KOS-953) - a heat shock protein 90 (Hsp90) inhibitor
Authors: Wai Choy, Kathryn Kersey, Ziyang Zhong, Sara Eng, Lee-Juian Lin, Jason Roper, Delwin Bokelman, Mike Sherrill, Pieter Timmermans, Robert Johnson
Journal: Cancer Research (2007)

1568  Tanespimycin (KOS-953, 17-AAG, 17-allylamino-17-demethoxygeldanamycin) is a potent Hsp90 inhibitor that inhibits the binding of Hsp 90 to its “client proteins” (e.g. oncoproteins, nuclear hormone receptors and protein kinases) leading to their proteasomal degradation and cancer cell death. The anticancer activity of tanespimycin is being evaluated in Phase I and II clinical trials in multiple myeloma and breast cancer, both as a single agent and in combinations with bortezomib or trastuzumab. In single dose one-hour IV infusion studies, tanespimycin was well tolerated to 40 mg/kg in Sprague Dawley rats and to 36 mg/kg in cynomolgus monkeys. In 2-cycle one-hour IV infusion studies that mirror the clinical cycle regimen (each cycle is 4 doses/2 wks then 10-day recovery period, then repeat; 2-cycle = 7 weeks), adverse effects of tanespimycin were seen in the rat at doses of 40 mg/kg and above. These included mortality, inappetance, decreases in body weight, renal tubular degeneration, cecum/colon necrosis, bile duct hyperplasia, spleen/thymus necrosis, uterine atrophy and ovary necrosis. Hematology showed increases of reticulocytes and WBC; serum chemistry showed decreases of A/G ratios, increases of triglyceride and cholesterol. No statistically significant changes in AST/ALT were observed. This is in contrast to previous studies that showed increases of AST/ALT and liver necrosis in Fischer 344 rats after five daily bolus IV injections at doses of 15 mg/kg and above using a tanespimycin formulation containing egg phospholipid and dextrose in water. In the 2-cycle monkey study, tanespimycin was better tolerated than in rats. No mortality was observed up to 50 mg/kg, the highest dose administered. At doses above 30 mg/kg, adverse effects observed were inappetance, soft feces/diarrhea, emesis and decreases in thyroid/parathyroid weight. Hematology showed increases of platelets and lymphocytes; serum chemistry showed changes of AST/ALT. No histopathological changes were observed in the liver or in any major organs examined. A cardiovascular safety pharmacology study in dogs and in vitro/in vivo genetic toxicology studies did not show adverse effects. Importantly, no adverse effects on QTc interval were observed. As compared to the recommended Phase II clinical dose of 340 mg/m2, given twice weekly, the dose multiples of the 2-cycle studies, based on surface area, are 0.7 for the dose of 40 mg/kg in rats and 1.8 for the 50 mg/kg in monkeys. Chronic toxicology studies (6-months) are on-going in these two species.
Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case–control study
Authors: Michael J Abramson, Tsitsi Murambadoro, Sheikh M Alif, Geza P Benke, Shyamali C Dharmage, Ian Glaspole, Peter Hopkins, Ryan F Hoy, Sonja Klebe, Yuben Moodley, Shuli Rawson, Paul N Reynolds, Rory Wolfe, Tamera J Corte, E Haydn Walters
Journal: Thorax (2020)

Idiopathic pulmonary fibrosis (IPF) is a lung disease of unknown cause characterised by progressive scarring, with limited effective treatment and a median survival of only 2-3 years. Our aim was to identify potential occupational and environmental exposures associated with IPF in Australia.Cases were recruited by the Australian IPF registry. Population-based controls were recruited by random digit dialling, frequency matched on age, sex and state. Participants completed a questionnaire on demographics, smoking, family history, environmental and occupational exposures. Occupational exposure assessment was undertaken with the Finnish Job Exposure Matrix and Australian asbestos JEM. Multivariable logistic regression was used to describe associations with IPF as ORs and 95% CIs, adjusted for age, sex, state and smoking.We recruited 503 cases (mean±SD age 71±9 years, 69% male) and 902 controls (71±8 years, 69% male). Ever smoking tobacco was associated with increased risk of IPF: OR 2.20 (95% CI 1.74 to 2.79), but ever using marijuana with reduced risk after adjusting for tobacco: 0.51 (0.33 to 0.78). A family history of pulmonary fibrosis was associated with 12.6-fold (6.52 to 24.2) increased risk of IPF. Occupational exposures to secondhand smoke (OR 2.1; 1.2 to 3.7), respirable dust (OR 1.38; 1.04 to 1.82) and asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF. However occupational exposures to other specific organic, mineral or metal dusts were not associated with IPF.The burden of IPF could be reduced by intensified tobacco control, occupational dust control measures and elimination of asbestos at work.
Bone-Targeted Pharmacological Inhibition of Notch Signaling As a Novel Approach to Inhibit Myeloma Growth and Bone Destruction
Authors: Jesus Delgado-Calle, Gerald Wu, Jessica Nelson, Emily G Atkinson, Kevin McAndrews, Lifeng Xiao, Frank H Ebetino, Robert K Boeckman, David David Roodman, Teresita Bellido
Journal: Blood (2017)
Class I HLA Peptide Epitope Binding Efficiency Has No Impact on Graft Vs. Host Disease Incidence Following Allogeneic Hematopoietic Cell Transplantation
Authors: Charlotte McIlwaine Story, Jefferson L. Lansford, Dominic T. Moore, Chang Xu, Benjamin G. Vincent, Paul M. Armistead, Marcie L. Riches
Journal: Blood (2017)
Response to: ‘Emergency arising from patients’ fear of taking antimalarials during these COVID-19 times: are antimalarials as unsafe for cardiovascular health as recent reports suggest?’ by Santos-Moreno<i>et al</i>
Authors: Jean W Liew, Elizabeth R Graef, Jeffrey A Sparks, Alfred Hyoungju Kim
Journal: Annals of the Rheumatic Diseases (2020)

Response to: 'Emergency arising from patients' fear of taking antimalarials during these COVID-19 times: are antimalarials as unsafe for cardiovascular health as recent reports suggest?' by Santos-Moreno et alWe thank Santos-Moreno et al for their response to our commentary. 1 2The authors provide data on cardiovascular adverse events associated with maintenance antimalarial use for patients with rheumatoid arthritis (RA).In addition to our previous correspondence response 3 from Erre et al, 4 these additional data are reassuring to patients with rheumatic diseases on chronic doses of antimalarials regarding the continued safety of these medications.However, as we have also addressed in a previous response, the safety profile of antimalarials in patients with COVID-19 infection compared with patients with rheumatic disease may differ widely.][7] Lane et al recently used combined electronic health record and administrative data from five countries and a new user, active comparator cohort design to address two scientific questions among adults with RA 8 : (1) the risk of serious adverse events, particularly cardiovascular events, among individuals with RA initiating therapy with HCQ versus sulfasalazine; (2) the risk of these outcomes when azithromycin is started (compared with starting amoxicillin) among prevalent HCQ users with RA.The cardiovascular outcomes assessed in that study included cardiovascular mortality, cardiac arrhythmia, and heart failure, and were identified using ICD codes. 8However, there was no statistically significant association between HCQ use and cardiac arrhythmia, compared with sulfasalazine use (calibrated HR 0.89, 95% CI 0.77 to 1.04) among individuals with RA. 8 Although a similarly designed study using population-level data could be conceived to assess the study question presented by Santos-Moreno et al, the surrogate outcome of QTc prolongation would be more difficult to ascertain using administrative/ claims data.In summary, we agree that these data offer additional support that the possible cardiotoxicity of antimalarials for treatment of COVID-19 should not be extrapolated to patients with rheumatic disease where its safety and efficacy is well established.
Distinguishing Felsenstein Zone from Farris Zone Using Neural Networks
Authors: Alina F Leuchtenberger, Stephen M Crotty, Tamara Drucks, Heiko A Schmidt, Sebastian Burgstaller-Muehlbacher, Arndt von Haeseler
Journal: Molecular Biology and Evolution (2020)

Abstract Maximum likelihood and maximum parsimony are two key methods for phylogenetic tree reconstruction. Under certain conditions, each of these two methods can perform more or less efficiently, resulting in unresolved or disputed phylogenies. We show that a neural network can distinguish between four-taxon alignments that were evolved under conditions susceptible to either long-branch attraction or long-branch repulsion. When likelihood and parsimony methods are discordant, the neural network can provide insight as to which tree reconstruction method is best suited to the alignment. When applied to the contentious case of Strepsiptera evolution, our method shows robust support for the current scientific view, that is, it places Strepsiptera with beetles, distant from flies.
A Model of Care Optimized for Marginalized Remote Population Unravels Migration Pattern in India
Authors: Ameer Abutaleb, Mousumi Khatun, Jean Clement, Ayana Baidya, Pratibha Singh, Simanti Datta, Sk Mahiuddin Ahammed, Koshy George, ParthaSarathi Mukherjee, Amal Santra, Suvadip Neogi, Sachin Parikh, Vivek Pillai, Shyam Kottilil, Abhijit Chowdhury
Journal: Hepatology (2020)

Background and Aims Access to basic health needs remains a challenge for most of world’s population. In this study, we developed a care model for preventive and disease‐specific health care for an extremely remote and marginalized population in Arunachal Pradesh, the northeasternmost state of India. Approach and Results We performed patient screenings, performed interviews, and obtained blood samples in remote villages of Arunachal Pradesh through a tablet‐based data collection application, which was later synced to a cloud database for storage. Positive cases of hepatitis B virus (HBV) were confirmed and genotyped in our central laboratory. The blood tests performed included liver function tests, HBV serologies, and HBV genotyping. HBV vaccination was provided as appropriate. A total of 11,818 participants were interviewed, 11,572 samples collected, and 5,176 participants vaccinated from the 5 westernmost districts in Arunachal Pradesh. The overall hepatitis B surface antigen (HBsAg) prevalence was found to be 3.6% (n = 419). In total, 34.6% were hepatitis B e antigen positive (n = 145) and 25.5% had HBV DNA levels greater than 20,000 IU/mL (n = 107). Genotypic analysis showed that many patients were infected with HBV C/D recombinants. Certain tribes showed high seroprevalence, with rates of 9.8% and 6.3% in the Miji and Nishi tribes, respectively. The prevalence of HBsAg in individuals who reported medical injections was 3.5%, lower than the overall prevalence of HBV. Conclusions Our unique, simplistic model of care was able to link a highly resource‐limited population to screening, preventive vaccination, follow‐up therapeutic care, and molecular epidemiology to define the migratory nature of the population and disease using an electronic platform. This model of care can be applied to other similar settings globally.
O-18 Tumor mutational load, microsatellite instability, BRCAness, and actionable alterations in metastatic colorectal cancer: Results from the TRIBE2 study
Authors: C. Antoniotti, D. Rossini, F. Marmorino, S. Lonardi, F. Corti, R. Moretto, C. Ugolini, T. Latiano, M. Giordano, E. Tamburini, A. Passardi, D. Santini, A. Zaniboni, G. Aprile, R. Bordonaro, G. Zucchelli, V. Conca, G. Fontanini, H. Lenz, A. Falcone, M. Korn, C. Cremolini
Journal: Annals of Oncology (2020)
Population-based surveys of antibodies against SARS-CoV-2 in Southern Brazil
Authors: Mariângela F. Silveira, Aluísio J. D. Barros, Bernardo L. Horta, Lúcia C. Pellanda, Gabriel D. Victora, Odir A. Dellagostin, Claudio J. Struchiner, Marcelo N. Burattini, Andréia R. M. Valim, Evelise M. Berlezi, Jeovany M. Mesa, Maria Letícia R. Ikeda, Marilia A. Mesenburg, Marina Mantesso, Marinel M. Dall’Agnol, Raqueli A. Bittencourt, Fernando P. Hartwig, Ana M. B. Menezes, Fernando C. Barros, Pedro C. Hallal, Cesar G. Victora
Journal: Nature Medicine (2020)

Population-based data on COVID-19 are urgently needed. We report on three rounds of probability sample household surveys in the state of Rio Grande do Sul (Brazil), carried out in nine large municipalities using the Wondfo lateral flow point-of-care test for immunoglobulin M and G antibodies against SARS-CoV-2 (https://en.wondfo.com.cn/product/wondfo-sars-cov-2-antibody-test-lateral-flow-method-2/). Before survey use, the assay underwent four validation studies with pooled estimates of sensitivity (84.8%; 95% confidence interval (CI) = 81.4–87.8%) and specificity (99.0%; 95% CI = 97.8–99.7%). We calculated that the seroprevalence was 0.048% (2/4,151; 95% CI = 0.006–0.174) on 11–13 April (round 1), 0.135% (6/4,460; 95% CI = 0.049–0.293%) on 25–27 April (round 2) and 0.222% (10/4,500; 95% CI = 0.107–0.408) on 9–11 May (round 3), with a significant upward trend over the course of the surveys. Of 37 family members of positive individuals, 17 (35%) were also positive. The epidemic is at an early stage in the state, and there is high compliance with social distancing, unlike in other parts of Brazil. Periodic survey rounds will continue to monitor trends until at least the end of September, and our population-based data will inform decisions on preventive policies and health system preparedness at the state level. Three separate rounds of serological surveys in the state of Rio Grande do Sul in Brazil from mid-April to mid-May 2020 show an increase in antibodies specific for SARS-CoV-2 over time.
PD-5 Impact of biliary drainage for unresectable pancreatic cancer treated with FOLFIRINOX or gemcitabine plus nab-paclitaxel: Results from the NAPOLEON study
Authors: T. Honda, O. Takayuki, M. Shimokawa, F. Koga, Y. Ueda, J. Nakazawa, A. Komori, S. Arima, M. Fukahori, A. Makiyama, H. Taguchi, T. Shibuki, K. Nio, Y. Ide, N. Ureshino, K. Mitsugi, T. Otsuka, T. Shirakawa
Journal: Annals of Oncology (2020)
Abstract 16527: Kinetic of High-Sensitivity Cardiac Troponin T in Patients With Non ST-Segment Elevation Myocardial Infarction
Authors: Roberto Spoladore, Giulio Falasconi, Antonio Boccellino, Massimo Slavich, Alberto Maria Cappelletti, Gabriele Fragasso, Alberto Margonato
Journal: Circulation (2019)

Introduction: cardiac biomarkers including troponins are the cornerstone of the biological definition of acute myocardial infarction. In previous literature it was shown that hs-Troponin T blood as...
P-252 Serial cytokines as potential predictive/prognosis biomarkers in potentially resectable pancreatic adenocarcinoma
Authors: I. González Borja, J. Fernández Irigoyen, S. Goñi, I. Ghanem, I. Amat, V. Arrazubi, J. Pérez Sanz, I. Hernandez-Garcia, R. Vera, J. Feliu, A. Viudez
Journal: Annals of Oncology (2020)
P-334 Perioperative chemotherapy in the treatment of resectable and locally advanced gastric and junctional esophagogastric adenocarcinoma: Experience of a Portuguese central hospital
Authors: E. Neto, J. Marinho, I. Leão, H. Guedes, S. Silva, T. Costa, S. Custódio, A. Capela
Journal: Annals of Oncology (2020)
Once-daily, single-inhaler mometasone–indacaterol–glycopyrronium versus mometasone–indacaterol or twice-daily fluticasone–salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study
Authors: Huib A M Kerstjens, Jorge Maspero, Kenneth R Chapman, Richard N van Zyl-Smit, Motoi Hosoe, Ana-Maria Tanase, Catherine Lavecchia, Abhijit Pethe, Xu Shu, Peter D'Andrea
Journal: The Lancet Respiratory Medicine (2020)
Drug-drug cocrystals: Opportunities and challenges
Authors: Xiaojuan Wang, Shuzhang Du, Rui Zhang, Xuedong Jia, Ting Yang, Xiaojian Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Recently, drug-drug cocrystal attracts more and more attention. It offers a low risk, low-cost but high reward route to new and better medicines and could improve the physiochemical and biopharmaceutical properties of a medicine by addition of a suitable therapeutically effective component without any chemical modification. Having so many advantages, to date, the reported drug-drug cocrystals are rare. Here we review the drug-drug cocrystals that reported in last decade and shed light on the opportunities and challenges for the development of drug-drug cocrystals.
Covid-19: Doctors in France report case of baby infected in utero
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

French doctors have reported the case of a 23 year old woman in the last weeks of her first pregnancy who was hospitalised with covid-19 in March and gave birth by caesarean section to a baby boy found to have the infection in what appears to be the first documented case of transplacental transmission of the virus.
Genomic Binding Patterns of Forkhead Box Protein O1 Reveal Its Unique Role in Cardiac Hypertrophy
Authors: Jessica Pfleger, Ryan C. Coleman, Jessica Ibetti, Rajika Roy, Ioannis D. Kyriazis, Erhe Gao, Konstantinos Drosatos, Walter J. Koch
Journal: Circulation (2020)

Cardiac hypertrophic growth is mediated by robust changes in gene expression and changes that underlie the increase in cardiomyocyte size. The former is regulated by RNA polymerase II (pol II) de novo recruitment or loss; the latter involves incremental increases in the transcriptional elongation activity of pol II that is preassembled at the transcription start site. The differential regulation of these distinct processes by transcription factors remains unknown. Forkhead box protein O1 (FoxO1) is an insulin-sensitive transcription factor that is also regulated by hypertrophic stimuli in the heart. However, the scope of its gene regulation remains unexplored.To address this, we performed FoxO1 chromatin immunoprecipitation-deep sequencing in mouse hearts after 7 days of isoproterenol injections (3 mg·kg-1·mg-1), transverse aortic constriction, or vehicle injection/sham surgery.Our data demonstrate increases in FoxO1 chromatin binding during cardiac hypertrophic growth, which positively correlate with extent of hypertrophy. To assess the role of FoxO1 on pol II dynamics and gene expression, the FoxO1 chromatin immunoprecipitation-deep sequencing results were aligned with those of pol II chromatin immunoprecipitation-deep sequencing across the chromosomal coordinates of sham- or transverse aortic constriction-operated mouse hearts. This uncovered that FoxO1 binds to the promoters of 60% of cardiac-expressed genes at baseline and 91% after transverse aortic constriction. FoxO1 binding is increased in genes regulated by pol II de novo recruitment, loss, or pause-release. In vitro, endothelin-1- and, in vivo, pressure overload-induced cardiomyocyte hypertrophic growth is prevented with FoxO1 knockdown or deletion, which was accompanied by reductions in inducible genes, including Comtd1 in vitro and Fstl1 and Uck2 in vivo.Together, our data suggest that FoxO1 may mediate cardiac hypertrophic growth via regulation of pol II de novo recruitment and pause-release; the latter represents the majority (59%) of FoxO1-bound, pol II-regulated genes after pressure overload. These findings demonstrate the breadth of transcriptional regulation by FoxO1 during cardiac hypertrophy, information that is essential for its therapeutic targeting.
Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study
Authors: Danying Liao, Fen Zhou, Lili Luo, Min Xu, Hongbo Wang, Jiahong Xia, Yong Gao, Liqiong Cai, Zhihui Wang, Ping Yin, Yadan Wang, Lu Tang, Jun Deng, Heng Mei, Yu Hu
Journal: The Lancet Haematology (2020)

COVID-19 is an ongoing global pandemic. Changes in haematological characteristics in patients with COVID-19 are emerging as important features of the disease. We aimed to explore the haematological characteristics and related risk factors in patients with COVID-19.
P-59 High blood levels of soluble OX40 (CD134), an immune costimulatory molecule, indicate reduced survival in patients with advanced colorectal cancer
Authors: R. Sawada, Y. Arai, Y. Nagata, T. Nishimura, M. Noguchi, K. Amano, S. Homma, M. Saruta
Journal: Annals of Oncology (2020)
SW620ヒト結腸癌細胞におけるG2‐M停止からのスタウロスポリンで誘導されるアポトーシスの分離 アポトーシスカスケードの開始はミトコンドリア膜電位(Δψm)の上昇と関連する
Authors: Heerdt B G, Houston M A, Mariadason J M, Augenlicht L H
Journal: Cancer Research (2000)
Dysregulated skin barrier function in Tmem79 mutant mice promotes IL‐17A‐dependent spontaneous skin and lung inflammation
Authors: Sean P. Saunders, Achilleas Floudas, Tara Moran, Ciara M. Byrne, Michael D. Rooney, Caoimhe M. R. Fahy, Joan A. Geoghegan, Yoichiro Iwakura, Padraic G. Fallon, Christian Schwartz
Journal: Allergy (2020)

Atopic dermatitis (AD) is associated with a dysregulation of the skin barrier and may predispose to the development of secondary allergic conditions, such as asthma. Tmem79ma/ma mice harbor a mutation in the gene encoding Transmembrane Protein 79 (or Mattrin), which has previously been associated with AD. As a result of the Tmem79 gene mutation, these mice have a defective skin barrier and develop spontaneous skin inflammation. In this study, Tmem79ma/ma mice were assessed for the underlying immunological response in the development of spontaneous skin and lung inflammation.Development of spontaneous skin and lung inflammation in Tmem79ma/ma mice was analyzed. We further investigated susceptibility to cutaneous Staphylococcus aureus infection. Tmem79ma/ma were crossed to IL-17A-deficient mice to address the contribution of IL-17A to spontaneous skin and lung disease.Tmem79ma/ma mice developed IL-17A-dependent spontaneous AD-like inflammation and were refractory to S aureus infection. Mutant mice progressed to airway inflammation subsequent to the occurrence of dermatitis. The progression from skin to lung disease is dependent on adaptive immunity and is facilitated by cutaneous expansion of Th17 and TCRγδ T cells.Mice lacking Tmem79/Mattrin expression have a defective skin barrier. In adulthood, these mice develop dermatitis with secondary progression to lung inflammation. The development of skin and lung inflammation is IL-17A-dependent and mediated by TCRγδ T cells.
Genomic Profiling of Prostate Cancers from Men with African and European Ancestry
Authors: Yusuke Koga, Hanbing Song, Zachary R. Chalmers, Justin Newberg, Eejung Kim, Jian Carrot-Zhang, Daphnee Piou, Paz Polak, Sarki A. Abdulkadir, Elad Ziv, Matthew Meyerson, Garrett M. Frampton, Joshua D. Campbell, Franklin W. Huang
Journal: Clinical Cancer Research (2020)

African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic studies.