tbuckley/cabot-search huggingface dataset:
A physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PD) model of docetaxel (Doc) and neutropenia in humans
Authors: J. A. Florian, M. J. Egorin, W. C. Zamboni, J. L. Eiseman, T. F. Lagattuta, C. P. Belani, G. S. Chatta, H. I. Scher, D. B. Solit, R. S. Parker
Journal: Journal of Clinical Oncology (2007)

2567 Background: We have scaled our previously described murine Doc PBPK model (Florian et. al, Proc. AACR, 2006) to humans to determine if it predicts human plasma Doc concentration. The resulting human plasma Doc predictions were then coupled to a low- order neutrophil model from the literature (Karlsson et. al, Clin. Cancer Res., 2006), and individual patient absolute neutrophil count (ANC) predictions were compared with actual ANC data. Methods: Plasma Doc concentration vs. time data were obtained from 75 patients given 1-h Doc infusions and sampled out to 48 h. 67 patients received 50–75 mg/m 2 q3wk, and 8 patients received 35 mg/m 2 weekly. Plasma Doc concentrations were determined by LC-MS, &amp; ANC were measured weekly during cycle 1. Human organ volumes &amp; blood flow rates for humans were obtained from the literature and scaled based on individual patient weight. Intra-tissue exchange rates &amp; liver clearance rate from the mouse PBPK model were used unchanged as parameters in the scaled model. The PBPK model was used to drive the ANC model, which had been developed with data from patients treated on a q3wk schedule. Simulations were performed using MATLAB, and model predictions were compared with actual data based on a weighted sum squared error metric. Results: The initial, scaled PBPK model performed well in describing actual plasma Doc concentrations during the infusion &amp; at times after 5 h, but not at the intermediate time points. Consequently, transition rates for the “other” compartment were estimated for the human population. The updated model was more accurate in predicting human plasma Doc concentrations (mean improvement 17%; range -3 to 70%). When the scaled PBPK model was coupled with the neutrophil model, the resulting predicted neutrophil profiles agreed with those from patients dosed on a q3w regimen, but not with those dosed weekly. Conclusions: This unique PBPK/PD model allows the prediction of human plasma Doc concentrations provided the patient weight &amp; dose are known. Further validation of the coupled PBPK/PD model, including predicted tumor concentrations, is ongoing. No significant financial relationships to disclose.
Annals Graphic Medicine - Dr. Mom: Types of Rounds
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2020)

Web Exclusives3 March 2020Annals Graphic Medicine - Dr. Mom: Types of RoundsFREEGrace E. Farris, MDGrace E. Farris, MDMount Sinai School of Medicine, New York, New York (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0004 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Mount Sinai School of Medicine, New York, New York (G.E.F.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G18-0042.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Icahn School of Medicine at Mount Sinai and chief of hospital medicine at Mount Sinai West hospital in New York, New York. You can view her work at her Web site: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 3 March 2020Volume 172, Issue 5Page: W69-W70KeywordsConflicts of interestDisclosureHospital medicineHospitalists ePublished: 3 March 2020 Issue Published: 3 March 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract P335: Using Cardiovascular Disease Risk Versus Blood Pressure To Guide The Initiation Of Antihypertensive Medication Among Us Adults
Authors: Swati Sakhuja, Shakia T Hardy, Philip Akinyelure, Byron C Jaeger, Daichi Shimbo, Adam P Bress, Paul Muntner
Journal: Circulation (2020)

Introduction: The primary goal of initiating antihypertensive medication is to prevent cardiovascular disease (CVD). It has been hypothesized that using CVD risk to guide the decision to initiate antihypertensive medication may prevent more CVD events than treatment guided by blood pressure (BP) alone. Methods: We estimated the number of CVD and all-cause deaths that could be prevented among US adults through the initiation of antihypertensive medication based on high CVD risk versus high BP. CVD and all-cause mortality rates were calculated using data from 4,390 participants 40 to 79 years of age not taking antihypertensive medication from the 1999 to 2004 National Health and Nutrition Examination Survey (NHANES) mortality follow-up study. High BP was defined by systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg. High CVD risk was defined by 10-year predicted CVD risk ≥10% using the Pooled Cohort risk equations or a history of CVD. Relative risks and 95% confidence limits for CVD and all-cause mortality with antihypertensive medication of 0.75 (0.57-0.98) and 0.76 (0.63-0.91), respectively, were obtained from the Blood Pressure Lowering Treatment Trialists Collaboration. Results: Among US adults not taking antihypertensive medication, 19.4% (23.5 million) had high BP and 25.5% (30.9 million) had high CVD risk. CVD mortality rates were 5.3 and 3.9 per 1,000 person-years among US adults with high CVD risk versus high BP, respectively (Table). Using high CVD risk to guide antihypertensive medication initiation is projected to prevent 403,093 deaths from CVD over 10 years compared with 224,312 deaths from CVD projected to be prevented using a BP-guided treatment approach. More all-cause deaths are projected to be prevented by using high CVD risk (2.2 million deaths) rather than high BP (1.1 million deaths) to guide the decision to initiate antihypertensive medication. Conclusions: Using predicted CVD risk instead of BP alone to guide antihypertensive medication initiation is projected to prevent more CVD and all-cause deaths.
Ultrasensitive Genetically Encoded Indicator for Hydrogen Peroxide Identifies Roles for the Oxidant in Cell Migration and Mitochondrial Function
Authors: Valeriy V. Pak, Daria Ezeriņa, Olga G. Lyublinskaya, Brandán Pedre, Pyotr A. Tyurin-Kuzmin, Natalie M. Mishina, Marion Thauvin, David Young, Khadija Wahni, Santiago Agustín Martínez Gache, Alexandra D. Demidovich, Yulia G. Ermakova, Yulia D. Maslova, Arina G. Shokhina, Emrah Eroglu, Dmitry S. Bilan, Ivan Bogeski, Thomas Michel, Sophie Vriz, Joris Messens, Vsevolod V. Belousov
Journal: Cell Metabolism (2020)
Chronic exposure to excess iron promotes EMT and cancer via p53 loss in pancreatic cancer
Authors: Yangzom D. Bhutia, Jiro Ogura, Paul J. Grippo, Carolina Torres, Toshihiro Sato, Mitchell Wachtel, Sabarish Ramachandran, Ellappan Babu, Sathish Sivaprakasam, Devaraja Rajasekaran, Bradley Schniers, Nhu On, Logan Smoot, Muthusamy Thangaraju, Jaya P. Gnana-Prakasam, Vadivel Ganapathy
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Based on the evidence that hemochromatosis, an iron-overload disease, drives hepatocellular carcinoma, we hypothesized that chronic exposure to excess iron, either due to genetic or environmental causes, predisposes an individual to cancer. Using pancreatic cancer as our primary focus, we employed cell culture studies to interrogate the connection between excess iron and cancer, and combined in vitro and in vivo studies to explore the connection further. Ferric ammonium citrate was used as an exogenous iron source. Chronic exposure to excess iron induced epithelial-mesenchymal transition (EMT) in normal and cancer cell lines, loss of p53, and suppression of p53 transcriptional activity evidenced from decreased expression of p53 target genes (p21, cyclin D1, Bax, SLC7A11). To further extrapolate our cell culture data, we generated EL-KrasG12D (EL-Kras) mouse (pancreatic neoplastic mouse model) expressing Hfe+/+and Hfe−/− genetic background. p53 target gene expression decreased in EL-Kras/Hfe−/− mouse pancreas compared to EL-Kras/Hfe+/+ mouse pancreas. Interestingly, the incidence of acinar-to-ductal metaplasia and cystic pancreatic neoplasms (CPN) decreased in EL-Kras/Hfe−/− mice, but the CPNs that did develop were larger in these mice than in EL-Kras/Hfe+/+ mice. In conclusion, these in vitro and in vivo studies support a potential role for chronic exposure to excess iron as a promoter of more aggressive disease via p53 loss and SLC7A11 upregulation within pancreatic epithelial cells.
Convergent Losses of TLR5 Suggest Altered Extracellular Flagellin Detection in Four Mammalian Lineages
Authors: Virag Sharma, Nikolai Hecker, Felix Walther, Heiko Stuckas, Michael Hiller
Journal: Molecular Biology and Evolution (2020)

Toll-like receptors (TLRs) play an important role for the innate immune system by detecting pathogen-associated molecular patterns. TLR5 encodes the major extracellular receptor for bacterial flagellin and frequently evolves under positive selection, consistent with coevolutionary arms races between the host and pathogens. Furthermore, TLR5 is inactivated in several vertebrates and a TLR5 stop codon polymorphism is widespread in human populations. Here, we analyzed the genomes of 120 mammals and discovered that TLR5 is convergently lost in four independent lineages, comprising guinea pigs, Yangtze river dolphin, pinnipeds, and pangolins. Validated inactivating mutations, absence of protein-coding transcript expression, and relaxed selection on the TLR5 remnants confirm these losses. PCR analysis further confirmed the loss of TLR5 in the pinniped stem lineage. Finally, we show that TLR11, encoding a second extracellular flagellin receptor, is also absent in these four lineages. Independent losses of TLR5 and TLR11 suggest that a major pathway for detecting flagellated bacteria is not essential for different mammals and predicts an impaired capacity to sense extracellular flagellin.
Abstract P323: HIV- and Subclinical Cardiovascular Disease-specific Transcriptomes in Nonclassical Monocytes: The Women’s Interagency HIV Study
Authors: Juan Lin, David B Hanna, Qibin Qi, tao wang, Karin A Mueller, Yanal Ghosheh, Kathryn Anastos, Jason M LAZAR, Wendy MacK, Phyllis Tien, MARDGE COHEN, ofotokun igho, Stephen Gange, SONIA HEATH, Russell P Tracy, Howard N Hodis, ALAN LANDAY, Robert Kaplan, Klaus F Ley
Journal: Circulation (2020)

Objectives: Nonclassical monocytes (NCM) have patrolling functions relevant to atherosclerosis. While NCM have low surface CXCR4 expression in people with concurrent HIV and CVD (Mueller Cardiovasc Res 2019), the extent of CVD-related gene expression and the pathways involved are unknown. We described the gene transcription signature of NCM to provide insight into potential mechanisms of HIV-associated CVD. Methods: We identified transcriptomic changes in circulating NCM among women with and without chronic HIV infection. CVD was defined by plaques found on B-mode carotid artery ultrasound. The study included 23 HIV - CVD - , 21 HIV + CVD - , 20 HIV - CVD + , and 21 HIV + CVD + women, with these four groups matched by age (median = 45), race (95% minority) and smoking (86% ever-smokers). Using cryopreserved cells, we flow-sorted NCM (CD14 dim CD16+) and deep-sequenced their mRNA (average depth &gt;40 million reads) to identify differentially expressed genes (DEG) contrasting HIV alone, CVD alone, and concurrent HIV + CVD + groups, versus HIV - CVD - , based on FDR-adjusted P&lt;0.05. Results: After filtering to genes with raw counts &gt;10 in &gt;60% of participants, 11,343 protein coding genes were analyzed. HIV alone was associated with 10 DEGs on NCM (Figure). Women affected by both HIV and CVD had 93 DEGs, only six of which were shared by the HIV alone DEG signal. CVD alone was associated only with upregulated CDK18, which was also identified as a DEG in the HIV + CVD + group. Conclusion: Concurrent HIV and CVD (HIV + CVD + ) is associated with altered gene expression in NCMs relative to HIV - CVD - , generating responses that involve interleukins (IL32, IL4R), immune checkpoint inhibition (LAG3), chemokines (CCL4, CCL5) and lipid homeostasis (ABCD2).
Covid-19: a digital epidemic
Authors: Arnaud Chiolero
Journal: BMJ (2020)

The covid-19 epidemic is not only viral-it is also digital. 1 Information spread through social and traditional media, as well as through governmental or health agencies, has reached a huge scale, certainly unprecedented in human history.The death count is followed closely as it rises-at least for the moment.Images and stories of quarantine are everywhere.As a result, the health risk of this epidemic is framed as scary and uncontrollable, which contributes to an epidemic of fear.Too much information, not balanced or filtered, is harmful and blurs sound health related decisions. 2 Measures taken to prevent the spread have opportunity costs; they have a huge impact on trade and can have important economic costs.The spread of infectious disease is considered a "top global economic risk." 3 Digital spread could increase this risk.
Risk SNP-Mediated Enhancer–Promoter Interaction Drives Colorectal Cancer through Both <i>FADS2</i> and <i>AP002754.2</i>
Authors: Jianbo Tian, Jiao Lou, Yimin Cai, Meilin Rao, Zequn Lu, Ying Zhu, Danyi Zou, Xiating Peng, Haoxue Wang, Ming Zhang, Siyuan Niu, Yue Li, Rong Zhong, Jiang Chang, Xiaoping Miao
Journal: Cancer Research (2020)

Abstract Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C&amp;gt;G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17–1.36; P = 2.57 × 10–9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer–promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology. Significance: This study provides an oncogenic regulatory circuit among several oncogenes including E2F1, FADS2, and AP002754.2 underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer–promoter interaction loops.
Significant fibrosis predicts new-onset diabetes mellitus and arterial hypertension in patients with NASH
Authors: Javier Ampuero, Rocío Aller, Rocío Gallego-Durán, Javier Crespo, José Luis Calleja, Carmelo García-Monzón, Judith Gómez-Camarero, Joan Caballería, Oreste Lo Iacono, Luis Ibañez, Javier García-Samaniego, Agustín Albillos, Rubén Francés, Conrado Fernández-Rodríguez, Moisés Diago, Germán Soriano, Raúl J. Andrade, Raquel Latorre, Francisco Jorquera, Rosa María Morillas, Desamparados Escudero, Pamela Estévez, Manuel Hernández Guerra, Salvador Augustín, Jesús M. Banales, Patricia Aspichueta, Salvador Benlloch, José Miguel Rosales, Javier Salmerón, Juan Turnes, Manuel Romero Gómez
Journal: Journal of Hepatology (2020)
Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A
Authors: Bin Teng, Chen Huang, Chuan-Li Cheng, Anjaneyulu Udduttula, Xiang-Fang Yu, Chang Liu, Jian Li, Zhen-Yu Yao, Jing Long, Li-Fu Miao, Chao Zou, Jun Chu, Jian V. Zhang, Pei-Gen Ren
Journal: Journal of Hepatology (2020)
Abstract P393: Current and Future Perceptions of Well-being are Associated With General Health Status in Adults: Results From the Gallup National Health and Well-being Index, 2018
Authors: Christina M Shay, Remy Poudel, Kimberly Stitzel, Yosef Khan
Journal: Circulation (2020)

Background: Growing evidence exists indicate that subjective perceptions of well-being (i.e. life satisfaction) are favorably associated with overall health status. Few reports are available that explore this association in nationally representative samples of US adults. Methods: Data from were collected from 115,929 US adults (18+ y) from all 50 states via dual mail and web-based sampling through the 2018 Gallup National Health and Well-Being Survey. Well-being was assessed by asking individuals to place themselves on a 10-step ladder with ‘worst possible life’ representing the lowest rung and ‘best possible life’ the top rung; ratings were collected for both their current life and their life in 5 years. Based on both current and future life ratings, individuals were categorized as thriving, struggling, or suffering. General health status was assessed based 5 options (excellent to poor). Results: Significant positive trends were observed between current and future levels of life satisfaction with ratings of general health status after accounting for age, sex, education, an income (p&lt;0.001 and p&lt;0.001, respectively) (Figure 1). Similarly, the proportion of adults categorized as “Thriving” was higher across more favorable levels of general health status. Conclusions: Level of well-being assessed by subjective rating of life satisfaction is strongly, positively, and independently associated with perception of general health status in a large sample of US adults. These results may demonstrate the strong influence of well-being on the preservation of health, however, further prospective examination of these associations are warranted.
Neonatal Early-Onset Sepsis Calculator and Antibiotic Therapy
Authors: Zubair H. Aghai
Journal: JAMA Pediatrics (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 Pediatrics 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 Pediatrics journal
Abstract P232: Poor Lower Extremity Physical Function Increases Risk For Heart Failure In Older Women: The OPACH Study
Authors: John Bellettiere, Andrea Z LaCroix, Chongzhi Di, Charles Eaton, Michael J Lamonte
Journal: Circulation (2020)

Background: A hallmark of clinically manifest heart failure (HF) is reduced levels of exercise tolerance and physical function. It is unclear, however, whether an association exists between poor physical function and future development of HF, particularly at older ages. Methods: Women (n=5327; mean±SD age = 79±7) with no history of HF completed the Short Physical Performance Battery (SPPB) to measure physical function. The SPPB consists of three timed tasks that assess standing balance (with 3 progressively difficult balance tests), strength (with 5 unassisted chair stands), and gait (with a 4m usual-pace walk), and is scored 0 (worst) to 12 (best). Four previously-defined categories were used: very low (SPPB 0-3; n=237); low (4-6; n=900), moderate (7-9; n=2139), and high (10-12; n=1767; referent group). Women were followed for up to 8 years for incident physician-adjudicated HF hospitalization. Cox proportional hazards regression models were adjusted for age, race-ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, and accelerometer-measured moderate to vigorous physical activity (MVPA) and sedentary time. Results: The number of HF cases (crude rate/1000 person-years) across the above SPPB categories (very low to high) were 41 (33.5), 78 (15.5), 96 (7.8), and 41 (4.0). Covariate-adjusted HRs (95% CIs) were 3.39 (2.05-5.84), 2.20 (1.47-3.31), 1.74 (1.20-2.51) and 1.00 (ref), trend P&lt;.001. After additional adjustment for MVPA and sedentary time, the fully-adjusted HRs (95% CIs) were 2.85 (1.71-4.75), 1.94 (1.29-2.93), 1.61 (1.10, 2.32) and 1.00 (ref), trend P&lt;.001. When modeled continuously (per 3-unit decrement in SPPB score), fully-adjusted associations were consistent over stratum of age (&lt;80: HR=1.72; ≥80: HR=1.56; interaction P=.05), race-ethnicity (white: HR=1.59; black: HR=1.59; Hispanic: HR=1.18; P=.57), and accelerometer-measured total physical activity (&lt;5.6 hr/d: HR=1.54; ≥5.6 hr/d: HR=1.51; P=.81). Conclusions: A significant inverse association between SPPB score and HF incidence was observed in ambulatory older women, independent of age, physical activity levels, and other HF predictors. Physical function is a modifiable factor that may be important for HF prevention in later life.
術後肺塞栓症に対し緊急手術で救命し得た一例 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: 松尾晴海, 清水陽一, 浅見光一, 塩月雄士, 香山大輔, 中村香織, 吉田成彦, 吉田浩紹, 森井健
Journal: Circulation (2002)
Abstract 13177: Epidemiology of Neonatal Cardiac Surgery Induced Acute Kidney Injury From the Neonatal and Pediatric Heart and Renal Outcomes Network
Authors: Jeffrey Alten, David S Cooper, Katja M Gist, David Selewski, Garrett Reichle, Sarah Tabbutt, Rebecca Bertrandt, Andrew Smith, Jun Sasaki, Kristal M Hock, Michael G Gaies, Santiago Borasino
Journal: Circulation (2019)

Introduction: Neonatal and Pediatric Heart and Renal Outcomes Network (NEPHRON) is a multicenter collaborative created to better understand cardiac surgery induced acute kidney injury (CS-AKI). NEP...