tbuckley/cabot-search huggingface dataset:
Phase 2 study of gemcitabine, docetaxel, and doxorubicin in patients with advanced, unresectable, and/or metastatic sarcoma who have failed prior therapies.
Authors: Andrew Eugene Hendifar, Neal S Chawla, Kamalesh Kumar Sankhala, Xiao Zhang, Doris V. Quon, Victoria S Chua, Lita Fernandez, William E. Mendanha, Sant P. Chawla
Journal: Journal of Clinical Oncology (2015)

10573 Background: Gemcitabine and docetaxel chemotherapy protocols have proven efficacy in the treatment of metastatic soft tissue sarcomas. Doxorubicin is also a commonly used treatment both as a single agent and as a part of combination therapies. This phase 2 study was designed to assess the efficacy and safety of a combination regimen of gemcitabine, docetaxel , and doxorubicin. Methods: This is a single institution study of advanced sarcoma pateints who were refractory to 1st line chemotherapy. Adequate performance status, organ function, and measurable disease (RECIST v1.1) were required. Patients received Gemcitabine (400 mg/m2), Doxorubicin (20 mg/m2) and Docetaxel (20 mg/m2) on days 1 and 8 of a 21 day cycle, and must have completed 2 cycles in order to be evaluable. Disease assessment was completed using the RECIST 1.1 criteria and toxicity was evaluated using the NCI CTCAE version 4.2. Results: A total of 32 patients were enrolled from 08/2011 - 08/2014 and 31 patients received at least 2 cycles of therapy. Pts with leiomyosarcoma (n = 7) liposarcoma (7) synovial sarcoma (2), chondrosarcoma (2), bone tumors (6), and others (8). The majority of patients (n = 21, 66%) previously received doxorubicin and many (n = 8, 25%) had previously received gemcitabine and docetaxel in combination. The average number of previous regimens was 3 previous chemotherapies (range, 1 to 7). The median age was 49 (range, 21 – 69). A median of 5 cycles of gemcitabine, docetaxel and doxorubicin were given (range, 1-12). A partial response was seen in 16 % of patients (5/31), and stable disease > 3 months in 39% (12/31). Clinical benefit (CR+PR+SD > 3months) was 17/31 55% (95% CI .36 -0.7) Grade 3 and 4 hematologic toxicities were observed in 14 patients (thrombocytopenia 12 pts, and neutropenia 2 pts) however, no patients were discontinued for toxicity. Conclusions: The combination of gemcitabine, doxorubicin, and docetaxel is an active regimen with a manageable toxicity profile in patients with advanced and pre-treated soft tissue and bone sarcomas.
Syndromic congenital myelofibrosis associated with a loss-of-function variant in RBSN
Authors: Pilar L. Magoulas, Oleg A. Shchelochkov, Matthew N. Bainbridge, Shay Ben-Shachar, Svetlana Yatsenko, Lorraine Potocki, Richard A. Lewis, Charles Searby, Andrea N. Marcogliese, M. Tarek Elghetany, Gladys Zapata, Paula P. Hernández, Manasi Gadkari, Derek Einhaus, Donna M. Muzny, Richard A. Gibbs, Alison A. Bertuch, Daryl A. Scott, Silvia Corvera, Luis M. Franco
Journal: Blood (2018)
A donepezil/cyclodextrin complexation orodispersible film: Effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption
Authors: Tingting Liu, Xiaocao Wan, Zheng Luo, Chao Liu, Peng Quan, Dongmei Cun, Liang Fang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

The aim of this study was to develop a palatable donepezil (DP) orodispersible film (ODF) to facilitate the swallowing process and investigate the effect of cyclodextrin on taste-masking based on dynamic process and
Association of therapeutic management with a good prognosis in unresectable hepatocellular carcinoma patients undergoing sorafenib treatment: Dose adjustment and conversion therapy.
Authors: Takayoshi Oikawa, Hidekatsu Kuroda, Kei Endo, Kei Sawara, Yasuhiro Takikawa
Journal: Journal of Clinical Oncology (2018)

498 Background: When treating hepatocellular carcinoma (HCC) with sorafenib, it is important for the physician to evaluate the therapeutic effects because of the characteristic therapeutic response, the toxicity, and out of consideration for the liver function. We evaluated the relationship between changes in therapeutic management and the efficacy of sorafenib in the treatment of unresectable HCC. Methods: Out of a total of 118 patients who received sorafenib in our hospital between January 2010 and September 2017, 96 patients could be followed up and were included in the present study. We evaluated the profile of sorafenib treatment (etiology, cStage, initial dose, the percentage of cases in which the dose was changed), the clinical response by mRECIST, adverse events by CTCAE v.4.0, overall survival (OS), and the rate of patients continued sorafenib treatment or underwent conversion therapy after the development of progressive disease (PD) in two distinct periods of treatment: the former period (in which ordinary management was applied); and the latter period (in which management practices were strengthened in relation to the dose ). Results: Significant differences were observed in the rate (y/n) of change in the sorafenib dose and the rate of patients continued sorafenib treatment after the development of PD (the former/the latter, 13/42, 25/16, p = 0.005, 24/31,25/16, p = 0.045, respectively). A significant difference was observed in OS in the two periods (the former/ the latter, median OS 8.1/16.5 months, p = 0.019). In the latter period the percentage of dose escalation (400→800mg /day) was 60%. With regard to the clinical course after the development of PD, 15 patients (36.6%) in the latter received transarterial chemoembolization, and had a disease control rate of 60%. Conclusions: The prognosis of patients receiving sorafenib treatment for unresectable HCC can be extended when efforts are made to appropriately manage their medication based on their overall condition. After a sorafenib-treated patient develops PD, the continuation of sorafenib treatment or the addition of locoregional therapy may achieve a good response.
Neratinib: Inching Up on the Cure Rate of HER2+ Breast Cancer?
Authors: Nisha Unni, Dhivya R. Sudhan, Carlos L. Arteaga
Journal: Clinical Cancer Research (2018)

Neratinib was recently approved by the FDA for extended adjuvant treatment of HER2+ breast cancer. The ExteNET trial showed improvement in invasive disease-free survival (iDFS) in the neratinib arm compared with placebo. The benefit was more pronounced in patients with estrogen receptor-positive (ER+)/HER2+ tumors, suggesting bidirectional cross-talk between the ER and HER pathways. Clin Cancer Res; 24(15); 3483-5. ©2018 AACRSee related article by Singh et al., p. 3486.
3D heterogeneous islet organoid generation from human embryonic stem cells using a novel engineered hydrogel platform
Authors: Joseph Candiello, Taraka Sai Pavan Grandhi, Saik Kia Goh, Vimal Vaidya, Maya Lemmon-Kishi, Kiarash Rahmani Eliato, Robert Ros, Prashant N. Kumta, Kaushal Rege, Ipsita Banerjee
Journal: Biomaterials (2018)
Abstract 18758: Epigenetic Regulation of Acute Coronary Syndromes
Authors: Luigi M Biasucci, Mandolini Claudia, Maria Chiara Grimaldi, Giulio La Rosa, Filippo Crea
Journal: Circulation (2016)

Background: Long noncoding RNAs (lncRNA) are long transcripts of more than 200 nt of length not encoding for proteins; they represent a novel source of molecules with a regulatory function at trans...
A Bioreactor Technology for Modeling Fibrosis in Human and Rodent Precision‐Cut Liver Slices
Authors: Hannah L. Paish, Lee H. Reed, Helen Brown, Mark C. Bryan, Olivier Govaere, Jack Leslie, Ben S. Barksby, Marina Garcia Macia, Abigail Watson, Xin Xu, Marco Y.W. Zaki, Laura Greaves, Julia Whitehall, Jeremy French, Steven A. White, Derek M. Manas, Stuart M. Robinson, Gabriele Spoletini, Clive Griffiths, Derek A. Mann, Lee A. Borthwick, Michael J. Drinnan, Jelena Mann, Fiona Oakley
Journal: Hepatology (2019)

Precision cut liver slices (PCLSs) retain the structure and cellular composition of the native liver and represent an improved system to study liver fibrosis compared to two‐dimensional mono‐ or co‐cultures. The aim of this study was to develop a bioreactor system to increase the healthy life span of PCLSs and model fibrogenesis. PCLSs were generated from normal rat or human liver, or fibrotic rat liver, and cultured in our bioreactor. PCLS function was quantified by albumin enzyme‐linked immunosorbent assay (ELISA). Fibrosis was induced in PCLSs by transforming growth factor beta 1 (TGFβ1) and platelet‐derived growth factor (PDGFββ) stimulation ± therapy. Fibrosis was assessed by gene expression, picrosirius red, and α‐smooth muscle actin staining, hydroxyproline assay, and soluble ELISAs. Bioreactor‐cultured PCLSs are viable, maintaining tissue structure, metabolic activity, and stable albumin secretion for up to 6 days under normoxic culture conditions. Conversely, standard static transwell‐cultured PCLSs rapidly deteriorate, and albumin secretion is significantly impaired by 48 hours. TGFβ1/PDGFββ stimulation of rat or human PCLSs induced fibrogenic gene expression, release of extracellular matrix proteins, activation of hepatic myofibroblasts, and histological fibrosis. Fibrogenesis slowly progresses over 6 days in cultured fibrotic rat PCLSs without exogenous challenge. Activin receptor‐like kinase 5 (Alk5) inhibitor (Alk5i), nintedanib, and obeticholic acid therapy limited fibrogenesis in TGFβ1/PDGFββ‐stimulated PCLSs, and Alk5i blunted progression of fibrosis in fibrotic PCLS. Conclusion: We describe a bioreactor technology that maintains functional PCLS cultures for 6 days. Bioreactor‐cultured PCLSs can be successfully used to model fibrogenesis and demonstrate efficacy of antifibrotic therapies.
Abstract 16463: Rotor-Based Ventricular Fibrillation Exhibits Greater Surface Electrogram Voltage Variation Compared to Focal Source-Based VF Due to Complex Rotor Behavior: A Clinical and Computational Study
Authors: Gordon Ho, Christopher T Villongco, Omid Yousefian, Yonatan Faiwiszewski, Justin Hayase, Wouter-Jan Rappel, Andrew D McCulloch, David E Krummen
Journal: Circulation (2016)

Introduction:  Ventricular fibrillation is a common fatal arrhythmia. The ECG of VF appears chaotic but may be useful to non-invasively identify VF-sustaining mechanisms to guide therapy.   Hypothesis:  We hypothesized that rotors and focal sources manifest distinct features on the ECG. Computational modeling may identify the mechanistic basis of these features.   Methods:  VF was induced at EP study in 31 patients referred for ventricular arrhythmia ablation. Simultaneous ECG and intracardiac recordings were obtained using biventricular basket catheters. Endocardial phase maps mechanistically classified each VF cycle as rotor or focal source. ECGs of each VF mechanism were compared using 3D voltage variation criteria. To control for patient differences, ECGs were analyzed only from patients demonstrating both mechanisms. Biventricular computer simulations of VF driven by focal sources or rotors were created. The ECGs and activation patterns of each simulated VF mechanism were analyzed.   Results:  Eight patients had periods of both VF mechanisms. Rotor-based VF exhibited greater voltage variation than focal source-based VF (57±15% vs 25±17%, p=0.004, Fig 1A-B). Simulations revealed similar differences between rotors (Fig 1E) and focal sources (41±15% vs 21±4%, p=0.02, Fig 1C). Modeling revealed that greater voltage variation may be due to wavebreak and secondary rotor initiation often in the contralateral ventricle. Conversely, single stationary rotors had minimal voltage variation (25±11% vs 41±15%, p=0.03, Fig 1D).   Conclusions:  In conclusion, controlled clinical and computational studies reveal that quantitative criteria of ECG voltage variation differ significantly between VF-sustaining mechanisms. Wavebreak and secondary rotor initiation contributes to such variation. Future studies should prospectively evaluate if these criteria can separate VF mechanisms and guide therapy such as anti-arrhythmic medication choice or substrate ablation.
Hepatic CREBZF couples insulin to lipogenesis by inhibiting insig activity and contributes to hepatic steatosis in diet‐induced insulin‐resistant mice
Authors: Feifei Zhang, Zhimin Hu, Gaopeng Li, Shaofeng Huo, Fengguang Ma, Aoyuan Cui, Yaqian Xue, Yamei Han, Qi Gong, Jing Gao, Hua Bian, Zhuoxian Meng, Haifu Wu, Gang Long, Yi Tan, Yan Zhang, Xu Lin, Xin Gao, Aimin Xu, Yu Li
Journal: Hepatology (2018)

Insulin is critical for the regulation of de novo fatty acid synthesis, which converts glucose to lipid in the liver. However, how insulin signals are transduced into the cell and then regulate lipogenesis remains to be fully understood. Here, we identified CREB/ATF bZIP transcription factor (CREBZF) of the activating transcription factor/cAMP response element‐binding protein (ATF/CREB) gene family as a key regulator for lipogenesis through insulin‐Akt signaling. Insulin‐induced gene 2a (Insig‐2a) decreases during refeeding, allowing sterol regulatory element binding protein 1c to be processed to promote lipogenesis; but the mechanism of reduction is unknown. We show that Insig‐2a inhibition is mediated by insulin‐induced CREBZF. CREBZF directly inhibits transcription of Insig‐2a through association with activating transcription factor 4. Liver‐specific knockout of CREBZF causes an induction of Insig‐2a and Insig‐1 and resulted in repressed lipogenic program in the liver of mice during refeeding or upon treatment with streptozotocin and insulin. Moreover, hepatic CREBZF deficiency attenuates hepatic steatosis in high‐fat, high‐sucrose diet–fed mice. Importantly, expression levels of CREBZF are increased in livers of diet‐induced insulin resistance or genetically obese ob/ob mice and humans with hepatic steatosis, which may underscore the potential role of CREBZF in the development of sustained lipogenesis in the liver under selective insulin resistance conditions. Conclusion : These findings uncover an unexpected mechanism that couples changes in extracellular hormonal signals to hepatic lipid homeostasis; disrupting CREBZF function may have the therapeutic potential for treating fatty liver disease and insulin resistance. (H epatology 2018).
Understanding patients' perceptions of asthma control: a qualitative study
Authors: Natalie Bidad, Neil Barnes, Chris Griffiths, Rob Horne
Journal: European Respiratory Journal (2018)

Asthma control is suboptimal for many sufferers despite the existence of effective treatments. Patients' self-management is influenced by their perceptions of asthma and its treatment. This study explored sufferers' perceptions of asthma control and their influence on self-management behaviours. Participants (n=42) recruited from primary and secondary care asthma clinics in London in the UK each underwent a qualitative interview exploring perceptions and experiences of asthma control. Purposive sampling ensured variation in disease severity, degree of asthma control, age and socioeconomic status. Grounded theory was employed in thematic analysis of transcribed interviews. Five themes relating to perceptions of asthma control and self-management were identified: personal meaning of control, intermittent prevention, compromising control to avoid medication, pharmacological agents overemphasised in control and the role of asthma review in control. Within the first theme, some participants had an internal barometer of the level of symptoms that indicated their asthma was getting “out of control” that was set much higher than Asthma Control Test criteria. The findings provide new insights into patients’ perceptions of asthma control. Symptoms indicative of poor control were often tolerated as part of living with asthma. Identification of barriers and drivers to self-management highlight potential targets for strategies aimed at optimising asthma management.
A Single-Cell Transcriptome Atlas of the Mouse Glomerulus
Authors: Nikos Karaiskos, Mahdieh Rahmatollahi, Anastasiya Boltengagen, Haiyue Liu, Martin Hoehne, Markus Rinschen, Bernhard Schermer, Thomas Benzing, Nikolaus Rajewsky, Christine Kocks, Martin Kann, Roman-Ulrich Müller
Journal: Journal of the American Society of Nephrology (2018)

Background Three different cell types constitute the glomerular filter: mesangial cells, endothelial cells, and podocytes. However, to what extent cellular heterogeneity exists within healthy glomerular cell populations remains unknown. Methods We used nanodroplet-based highly parallel transcriptional profiling to characterize the cellular content of purified wild-type mouse glomeruli. Results Unsupervised clustering of nearly 13,000 single-cell transcriptomes identified the three known glomerular cell types. We provide a comprehensive online atlas of gene expression in glomerular cells that can be queried and visualized using an interactive and freely available database. Novel marker genes for all glomerular cell types were identified and supported by immunohistochemistry images obtained from the Human Protein Atlas. Subclustering of endothelial cells revealed a subset of endothelium that expressed marker genes related to endothelial proliferation. By comparison, the podocyte population appeared more homogeneous but contained three smaller, previously unknown subpopulations. Conclusions Our study comprehensively characterized gene expression in individual glomerular cells and sets the stage for the dissection of glomerular function at the single-cell level in health and disease.
Abstract A32: Sall2 transcription factor: A novel regulator of G1-S cyclins
Authors: Viviana E. Hermosilla, David E. Escobar, Matias I. Hepp, Elizabeth N. Riffo, Ginessa Salgado, Violeta Morin, Mario Galindo, Ariel F. Castro, Roxana Pincheira, Roxana Pincheira
Journal: Cancer Research (2018)

Abstract Spalt-like proteins are Zinc finger transcription factors present from C. elegans to vertebrates, with critical roles in development. In vertebrates, four paralogues have been identified (Sall1-4), with Sall2 being the most dissimilar member of the family. Sall2 has shown to be important for brain and eye development and–unlike its vertebrate paralogues–it has also been proposed as a tumor suppressor. Sall2 activity promotes cell cycle arrest and cell death and its expression is downregulated in several types of cancer. Despite this, very few Sall2 transcriptional targets have been identified until date. In agreement with previous reports, characterization of primary and immortalized mouse embryonic fibroblasts (MEFs) showed a proliferative advantage of isogenic Sall2-/- vs Sall2+/+ cells. In order to identify the molecular mechanisms underlying Sall2 function during cell cycle, iMEFs were synchronized at G2/M phase with nocodazole. Flow cytometry, Western blot, and qRT-PCR analyses were performed after nocodazole release. In accordance with the role of Sall2 in promoting cell cycle arrest, a more rapid progression from G2/M to G1/S was noticed in Sall2-deficient cells, which correlates with an increased expression of Cyclin D1 (Ccnd1) and Cyclin E1 (Ccne1). Similar results were obtained in HEK293 and SKOV3 human cell lines, suggesting that Sall2 controls cell cycle progression by downregulating G1-S cyclins. Sall2-mediated repression of CCND1 and CCNE1 was confirmed by luciferase reporter assays. In addition, bioinformatic analysis led to the identification of several putative Sall2 binding sites within CCND1 and CCNE1 promoters. Sall2 binding to CCND1 and CCNE1 promoters was demonstrated by chromatin immunoprecipitation. Analysis of tissues from Sall2+/+ and Sall2-/- mice confirmed the inverse correlation between expression of SALL2 and G1-S cyclins. Importantly, the same correlation was found in different types of tumor by analyzing publicly available databases, suggesting that Sall2-Cyclin D1-Cyclin E1 axis could be downregulated in cancer. Thus, we have identified two novel Sall2 transcriptional targets at G1-S transition. Altogether, our findings support the role of Sall2 as a tumor suppressor, by acting as a transcriptional repressor during cell cycle. Citation Format: Viviana E. Hermosilla, David E. Escobar, Matias I. Hepp, Elizabeth N. Riffo, Ginessa Salgado, Violeta Morin, Mario Galindo, Ariel F. Castro, Roxana Pincheira, Roxana Pincheira. Sall2 transcription factor: A novel regulator of G1-S cyclins [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A32.
Re: Lindén et al.: Normal-tension glaucoma has normal intracranial pressure: a prospective study of intracranial pressure and intraocular pressure in different body positions ( Ophthalmology . 2018;125:361–368)
Authors: Brandon Baartman, Ramu Sudhagoni, Russell Swan, Michael Greenwood, John Berdahl
Journal: Ophthalmology (2018)
The association of lifetime alcohol use with mortality and cancer risk in older adults: A cohort study
Authors: Andrew T. Kunzmann, Helen G. Coleman, Wen-Yi Huang, Sonja I. Berndt
Journal: PLoS Medicine (2018)

Background While current research is largely consistent as to the harms of heavy drinking in terms of both cancer incidence and mortality, there are disparate messages regarding the safety of light-moderate alcohol consumption, which may confuse public health messages. We aimed to evaluate the association between average lifetime alcohol intakes and risk of both cancer incidence and mortality. Methods and findings We report a population-based cohort study using data from 99,654 adults (68.7% female), aged 55–74 years, participating in the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards models assessed the risk of overall and cause-specific mortality, cancer incidence (excluding nonmelanoma skin cancer), and combined risk of cancer and death across categories of self-reported average lifetime alcohol intakes, with adjustment for potential confounders. During 836,740 person-years of follow-up (median 8.9 years), 9,599 deaths and 12,763 primary cancers occurred. Positive linear associations were observed between lifetime alcohol consumption and cancer-related mortality and total cancer incidence. J-shaped associations were observed between average lifetime alcohol consumption and overall mortality, cardiovascular-related mortality, and combined risk of death or cancer. In comparison to lifetime light alcohol drinkers (1–3 drinks per week), lifetime never or infrequent drinkers (<1 drink/week), as well as heavy (2–<3 drinks/day) and very heavy drinkers (3+ drinks/day) had increased overall mortality and combined risk of cancer or death. Corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for combined risk of cancer or death, respectively, were 1.09 (1.01–1.13) for never drinkers, 1.08 (1.03–1.13) for infrequent drinkers, 1.10 (1.02–1.18) for heavy drinkers, and 1.21 (1.13–1.30) for very heavy drinkers. This analysis is limited to older adults, and residual confounding by socioeconomic factors is possible. Conclusions The study supports a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk. The results indicate that intakes below 1 drink per day were associated with the lowest risk of death. Trial registration NCT00339495 (ClinicalTrials.gov).
A common TCN1 loss-of-function variant is associated with lower vitamin B12 concentration in African Americans
Authors: Yao Hu, Laura M. Raffield, Linda M. Polfus, Arden Moscati, Girish Nadkarni, Michael H. Preuss, Xue Zhong, Qiang Wei, Stephen S. Rich, Yun Li, James G. Wilson, Adolfo Correa, Ruth J. F. Loos, Bingshan Li, Paul L. Auer, Alex P. Reiner
Journal: Blood (2018)