tbuckley/cabot-search huggingface dataset:
Zinc Finger E‐Box Binding Homeobox 1 Promotes Cholangiocarcinoma Progression Through Tumor Dedifferentiation and Tumor–Stroma Paracrine Signaling
Authors: Cindy Lobe, Marie Vallette, Ander Arbelaiz, Ester Gonzalez‐Sanchez, Laura Izquierdo, Anna Pellat, Nathalie Guedj, Corentin Louis, Valérie Paradis, Jesus M Banales, Cédric Coulouarn, Chantal Housset, Javier Vaquero, Laura Fouassier
Journal: Hepatology (2021)

Background and aims Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor that promotes metastatic and stem cell features, which has been associated with poor prognosis in cholangiocarcinoma (CCA), a desmoplastic cancer enriched in cancer-associated fibroblasts (CAFs). We aimed to define ZEB1 regulatory functions in malignant and stromal compartments of CCA. Approach and Results Bioinformatic and immunohistochemical analyses were performed to determine correlations between ZEB1 and markers of progressiveness in human intrahepatic CCA (iCCA). Gain-of-function and loss-of-function models were generated in CCA cells and liver myofibroblasts as a model of CAFs. Conditioned media (CM) was used to unravel tumor–stroma interplay. In vivo experiments were performed using a xenograft CCA model. ZEB1 expression in tumor cells of human iCCA was associated with undifferentiated tumor and vascular invasion. In vitro, ZEB1 promoted epithelial–mesenchymal transition and stemness in tumor cells, leading to cell migration and spheroid formation. In vivo, ZEB1-overexpressing CCA cells formed larger tumors with more abundant stroma. Expression of cellular communication network factor 2 (CCN2, encoding connective tissue growth factor [CTGF]) was increased in tumor cells from ZEB1-overexpressing xenografts and correlated with ZEB1 expression in human tumors. In vitro, CM from ZEB1-overexpressing tumor cells or recombinant CTGF induced myofibroblast proliferation. ZEB1 was also expressed by CAFs in human CCA, and its expression correlated with CCN2 in myofibroblasts and CCA stroma. In mice, cotransplantation of CCA cells with ZEB1-depleted myofibroblasts reduced CCA progressiveness compared to CCA cells/ZEB1-expressing myofibroblasts. Furthermore, ZEB1 controls the expression of paracrine signals (i.e., HGF and IL6) in tumor cells and myofibroblasts. Conclusions ZEB1 plays a key role in CCA progression by regulating tumor cell–CAF crosstalk, leading to tumor dedifferentiation and CAF activation.
Reconfiguring the Cardiovascular Clinical Trial Enterprise in the United States
Authors: Deepak L. Bhatt
Journal: JAMA Network Open (2021)

Akash Goyal, MD; Tony Schibler, MPA; Brooke Alhanti, PhD; Karen L. Hannan, BA; Christopher B. Granger, MD; Michael A. Blazing, MD; Renato D. Lopes, MD, PhD; John H. Alexander, MD; Eric D. Peterson, MD; Sunil V. Rao, MD; Jennifer B. Green, MD; Matthew T. Roe, MD; Tyrus Rorick, RN; Lisa G. Berdan, PA-C, MHS; Craig Reist, PhD; Kenneth W. Mahaffey, MD; Robert A. Harrington, MD; Robert M. Califf, MD; Manesh R. Patel, MD; Adrian F. Hernandez, MD; W. Schuyler Jones, MD
Determining PD-L1 Status in Patients With Triple-Negative Breast Cancer: Lessons Learned From IMpassion130
Authors: Sunil S Badve, Frédérique Penault-Llorca, Jorge S Reis-Filho, Regula Deurloo, Kalliopi P Siziopikou, Corrado D’Arrigo, Giuseppe Viale
Journal: JNCI Journal of the National Cancer Institute (2021)

Triple-negative breast cancer (TNBC) accounts for approximately 12% to 17% of all breast cancers and has an aggressive clinical behavior. Increased tumor-infiltrating lymphocyte counts are prognostic for survival in TNBC, making this disease a potential target for cancer immunotherapy. Research on immunophenotyping of tumor-infiltrating lymphocytes is revealing molecular and structural organization in the tumor microenvironment that may predict patient prognosis. The anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab plus nab-paclitaxel was the first cancer immunotherapy combination to demonstrate progression-free survival benefit and clinically meaningful overall survival benefit in the first-line treatment of metastatic TNBC (mTNBC) in patients with PD-L1-expressing tumor-infiltrating immune cells in 1% or more of the tumor area. This led to its United States and European Union approval for mTNBC and US approval of the VENTANA PD-L1 (SP142) assay as a companion diagnostic immunohistochemistry assay. Subsequently, the anti-programmed death-1 (PD-1 ) antibody pembrolizumab plus chemotherapy was approved by the US Food and Drug Administration for mTNBC based on progression-free survival benefit in patients with a combined positive score of at least 10 by its concurrently approved 22C3 companion diagnostic assay. Treatment guidelines now recommend PD-L1 testing for patients with mTNBC, and the testing landscape will likely become increasingly complex as new anti-PD-L1 and anti-PD-1 agents and diagnostics are approved for TNBC. Integrating PD-L1 testing into current diagnostic workflows for mTNBC may provide more treatment options for these patients. Therefore, it is critical for medical oncologists and pathologists to understand the available assays and their relevance to therapeutic options to develop an appropriate workflow for immunohistochemistry testing.
Microenvironment Activatable Nanoprodrug Based on Gripper-like Cyclic Phenylboronic Acid to Precisely and Effectively Alleviate Drug-induced Hepatitis
Authors: Qixiong Zhang, Shanshan Li, Lulu Cai, Yuxuan Zhu, Xingmei Duan, Peidu Jiang, Lei Zhong, Kun Guo, Rongsheng Tong
Journal: Theranostics (2021)

Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance.Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application.Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects.Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE).The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated.The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated.Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core.In HepaRG cells, cPBA-BE showed stronger cellular uptake.Due to the H2O2-and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells.Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice.cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver.Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H2O2 and pH-responsive properties by coupling a wide range of drugs containing o-diol.In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.
MO38-2 Metallothionein-3: Potential therapeutic target for sorafenib resistance in hepatocellular carcinoma
Authors: Miguel A. Merlos Rodrigo, Hana Michalkova, Veronika Smidova, Berta Casar, Vivian de los Rios, Jose I. Casal, Marina Serrano Macia, David Fernandez Ramos, Maria L. Martinez Chantar, Vojtech Adam, Zbynek Heger
Journal: Annals of Oncology (2021)
Abstract 2185: Ventilatory Efficiency Correlates with Exercise Pulmonary Hemodynamics in Chronic Heart Failure due to LV Systolic Dysfunction
Authors: Ravi V Shah, Gregory D Lewis, Marc J Semigran
Journal: Circulation (2007)

Introduction : Ventilatory efficiency (V E /V CO2 ) is a prognostic marker in heart failure (HF). The relationship between V E /V CO2 and cardiovascular function in systolic HF remains unclear. We used cardiopulmonary exercise testing with continuous hemodynamic monitoring to clarify the relationship between V E /V CO2 and rest and exercise hemodynamics in patients with HF due to LV systolic dysfunction. Methods : Breath-by-breath ventilation, pulmonary gas exchange, and right heart hemodynamics were measured during incremental cycle ergometry in 15 subjects (62±11 years old, 14 male, 53% ischemic HF, LVEF 0.28±0.05) with NYHA class II-IV HF at baseline and after 12 weeks. Ventilatory efficiency was determined by linear regression of V E versus V CO2 throughout exercise with R 2 &gt;0.95 in all cases. Pearson correlation and paired Student’s t -test (for baseline versus 12 week testing) were used for analysis. Results : Baseline V E /V CO2 was 40.6±10.5. Higher V E /V CO2 (reduced ventilatory efficiency) trended with higher resting mean pulmonary arterial (PA) pressure (r=0.49, p=0.06) and had a positive correlation with exercise PA pressure (r=0.57, p=0.03). Although pulmonary vascular resistance (PVR) at rest was not significantly related to V E /V CO2 (r=0.30, p=0.28), exercise PVR correlated with V E /V CO2 (r=0.62, p=0.01). There was no significant correlation between V E /V CO2 and rest (r=0.29) or exercise (r=0.27) pulmonary capillary wedge pressure; rest (r=−0.15) or exercise (r=−0.27) cardiac index; and rest (r=−0.17) or exercise (r=0.05) right atrial pressure. At 12 weeks, repeat exercise testing revealed no significant change in V E /V CO2 relative to baseline (41.4±15.4, p=0.70) or in any other measured hemodynamic parameters at rest or exercise. Conclusions : V E /V CO2 can be measured reproducibly in HF patients with LV systolic dysfunction. Impaired ventilatory efficiency is associated with higher exercise PA pressure and PVR, and is not related to rest or exercise ventricular filling pressures in this small patient cohort. In systolic HF, ventilatory efficiency may be intrinsically related to dynamic changes in pulmonary vasomotor tone occurring with exercise.
Mobile health strategies for blood pressure self-management in urban populations with digital barriers: systematic review and meta-analyses
Authors: Elaine C. Khoong, Kristan Olazo, Natalie A. Rivadeneira, Sneha Thatipelli, Jill Barr-Walker, Valy Fontil, Courtney R. Lyles, Urmimala Sarkar
Journal: npj Digital Medicine (2021)

Abstract Mobile health (mHealth) technologies improve hypertension outcomes, but it is unknown if this benefit applies to all populations. This review aimed to describe the impact of mHealth interventions on blood pressure outcomes in populations with disparities in digital health use. We conducted a systematic search to identify studies with systolic blood pressure (SBP) outcomes located in urban settings in high-income countries that included a digital health disparity population, defined as mean age ≥65 years; lower educational attainment (≥60% ≤high school education); and/or racial/ethnic minority (&lt;50% non-Hispanic White for US studies). Interventions were categorized using an established self-management taxonomy. We conducted a narrative synthesis; among randomized clinical trials (RCTs) with a six-month SBP outcome, we conducted random-effects meta-analyses. Twenty-nine articles (representing 25 studies) were included, of which 15 were RCTs. Fifteen studies used text messaging; twelve used mobile applications. Studies were included based on race/ethnicity (14), education (10), and/or age (6). Common intervention components were: lifestyle advice (20); provision of self-monitoring equipment (17); and training on digital device use (15). In the meta-analyses of seven RCTs, SBP reduction at 6-months in the intervention group (mean SBP difference = −4.10, 95% CI: [−6.38, −1.83]) was significant, but there was no significant difference in SBP change between the intervention and control groups ( p = 0.48). The use of mHealth tools has shown promise for chronic disease management but few studies have included older, limited educational attainment, or minority populations. Additional robust studies with these populations are needed to determine what interventions work best for diverse hypertensive patients.
Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity
Authors: Won Jin Ho, Qingfeng Zhu, Jennifer Durham, Aleksandra Popovic, Stephanie Xavier, James Leatherman, Aditya Mohan, Guanglan Mo, Shu Zhang, Nicole Gross, Soren Charmsaz, Dongxia Lin, Derek Quong, Brad Wilt, Ihab R. Kamel, Matthew Weiss, Benjamin Philosophe, Richard Burkhart, William R. Burns, Chris Shubert, Aslam Ejaz, Jin He, Atul Deshpande, Ludmila Danilova, Genevieve Stein-O’Brien, Elizabeth A. Sugar, Daniel A. Laheru, Robert A. Anders, Elana J. Fertig, Elizabeth M. Jaffee, Mark Yarchoan
Journal: Nature Cancer (2021)
<i>Pseudomonas aeruginosa</i> eradication after lung transplantation: is it the tip of the iceberg?
Authors: Jonathan Messika, Vincent Bunel, Gaelle Weisenburger, Cendrine Godet, Hervé Mal
Journal: European Respiratory Journal (2021)

<b>Is respiratory <i>Pseudomonas aeruginosa</i> infection or persistence in lung transplant recipients an early marker of an emerging chronic lung organ dysfunction? Or its by-product?</b>https://bit.ly/3nyPHlW
A robust vasculogenic microfluidic model using human immortalized endothelial cells and Thy1 positive fibroblasts
Authors: Zhengpeng Wan, Shun Zhang, Amy X Zhong, Sarah E Shelton, Marco Campisi, Shriram K Sundararaman, Giovanni S Offeddu, Eunkyung Ko, Lina Ibrahim, Mark F Coughlin, Tiankun Liu, Jing Bai, David A Barbie, Roger D Kamm
Journal: Biomaterials (2021)
Health effects of exposure to chlorination by‐products in swimming pools
Authors: Mariana Couto, Alfred Bernard, Luís Delgado, Franchek Drobnic, Marcin Kurowski, André Moreira, Rodrigo Rodrigues‐Alves, Maia Rukhadze, Sven Seys, Marta Wiszniewska, Santiago Quirce
Journal: Allergy (2021)

Concerns have been raised regarding the potential negative effects on human health of water disinfectants used in swimming pools. Among the disinfection options, the approaches using chlorine-based products have been typically preferred. Chlorine readily reacts with natural organic matter that are introduced in the water mainly through the bathers, leading to the formation of potentially harmful chlorination by-products (CBPs). The formation of CBPs is of particular concern since some have been epidemiologically associated with the development of various clinical manifestations. The higher the concentration of volatile CBPs in the water, the higher their concentration in the air above the pool, and different routes of exposure to chemicals in swimming pools (water ingestion, skin absorption, and inhalation) contribute to the individual exposome. Some CBPs may affect the respiratory and skin health of those who stay indoor for long periods, such as swimming instructors, pool staff, and competitive swimmers. Whether those who use chlorinated pools as customers, particularly children, may also be affected has been a matter of debate. In this article, we discuss the current evidence regarding the health effects of both acute and chronic exposures in different populations (work-related exposures, intensive sports, and recreational attendance) and identify the main recommendations and unmet needs for research in this area.
ACC/AHA Guidelines for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Executive Summary
Authors: Gabriel Gregoratos, Melvin D. Cheitlin, Alicia Conill, Andrew E. Epstein, Christopher Fellows, T. Bruce Ferguson, Roger A. Freedman, Mark A. Hlatky, Gerald V. Naccarelli, Sanjeev Saksena, Robert C. Schlant, Michael J. Silka
Journal: Circulation (1998)

HomeCirculationVol. 97, No. 13ACC/AHA Guidelines for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Executive Summary
Abstract 13251: Malnutrition and Low Omega 6 Pufa Levels on Admission Affect the Development of Delirium in Patients With Acute Cardiovascular Disease Admitted to Coronary Care Unit
Authors: Yurina Sugita, Tetsuro Miyazaki, Kazunori Shimada, Megumi Shimizu, Mitsuhiro Kunimoto, Tatsuro Aikawa, Shohei Ouchi, Tomoyasu Kadoguchi, Yuko Kawaguchi, Tomoyuki Shiozawa, Kiyoshi Takasu, Masaru Hiki, Shuhei Takahashi, Miho Yokoyama, Hiroshi Iwata, Hiroyuki Daida
Journal: Circulation (2018)

Background: Delirium frequently occurs in patients admitted to intensive care unit and is associated with poor clinical outcome. Although the brain is an organ with high metabolic activity and nutr...
Enhanced uptake and anti-maturation effect of celastrol-loaded mannosylated liposomes on dendritic cells for psoriasis treatment
Authors: Long Xi, Zibei Lin, Fen Qiu, Shaokui Chen, Ping Li, Xin Chen, Zhenping Wang, Ying Zheng
Journal: Acta Pharmaceutica Sinica B (2021)

Psoriasis is an autoimmune skin disease in which dendritic cells (DCs) trigger the progression of psoriasis by complex interactions with keratinocytes and other immune cells. In the present study, we aimed to load celastrol, an anti-inflammatory ingredient isolated from Chinese herbs, on mannosylated liposomes to enhance DC uptake as well as to induce DC tolerance in an imiquimod-induced psoriasis-like mouse model. Mannose was grafted onto liposomes to target mannose receptors on DCs. The results demonstrated that compared with unmodified liposomes, DCs preferred to take up more fluorescence-labeled mannosylated liposomes. After loading celastrol into mannose-modified liposomes, they effectively inhibited the expression of maturation markers, including CD80, CD86 and MHC-II, on DCs both in vitro and in vivo. Additionally, after intradermal injection with a microneedle, celastrol-loaded mannose-modified liposomes (CEL-MAN-LPs) achieved a superior therapeutic effect compared with free drug and celastrol-loaded unmodified liposomes in the psoriasis mouse model in terms of the psoriasis area and severity index, histology evaluation, spleen weight, and expression of inflammatory cytokines. In conclusion, our results clearly revealed that CEL-MAN-LPs was an effective formulation for psoriasis treatment and suggested that this treatment has the potential to be applied to other inflammatory diseases triggered by activated DCs.
Abstract 9653: Crucial Role of SmgGDS in the Molecular Mechanisms of the Pleiotropic Effects of HMG-CoA Reductase Inhibitors
Authors: Shin-ichi Tanaka, Kotaro Nochioka, Yoshihiro Fukumoto, Nobuyuki Shiba, Jun Miyoshi, Carol L Williams, James K Liao, Hiroaki Shimokawa
Journal: Circulation (2011)

Background: The pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. We have previously demonstrated that the pleiotropic effects of low-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway. However, the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by low-dose statins remain to be elucidated. Methods and Results: We tested our hypothesis that the small GTP-binding protein dissociation stimulator (SmgGDS) plays an important role in this mechanism. In cultured human umbilical venous endothelial cells (HUVEC), statins (atorvastatin, 10 to 30 μ mol/L and pitavastatin, 1 to 10 μ mol/L) concentration-dependently increased SmgGDS expression and decreased nuclear Rac1 after 24h treatment (both P&lt;0.05, n=3 each). Intranuclear degradation of Rac1 was reduced by the proteasome inhibitor, MG-132 (P&lt;0.01, n=3). When SmgGDS was knockdown by its siRNA in HUVEC, statins were no longer able to induce Rac1 degradation (P&lt;0.01, n=3) or to inhibit angiotensin II-induced production of reactive oxygen species (ROS) (P&lt;0.01, n=8). In littermate mice, the protective effects of statins (atorvastatin, 10 mg/kg/day for 2 weeks and pravastatin, 50 mg/kg/day for 2 weeks) against AngII-induced cardiovascular hypertrophy and diastolic dysfunction were noted (AngII group vs. statin groups, P&lt;0.01, n=10), whereas in SmgGDS-deficient mice, the protective effects of statins were absent (n=10). Finally, in normal healthy volunteers, a low-dose statin (pravastatin; 10 mg/day for 4 weeks) significantly increased SmgGDS expression (P&lt;0.01, n=19). A significant negative correlation was noted between the extent of SmgGDS expression and oxidative stress markers (MDA-LDL-cholesterol, R=0.45; 8-OHdG, R=0.40), whereas no significant correlation was noted with total or LDL-cholesterol. Conclusions: These results provide the first direct evidence that SmgGDS plays a crucial role in the molecular mechanisms of the pleiotropic effects of statins through enhancement of intranuclear Rac1 degradation in animals and humans.
Epidermal Growth Factor Receptor Mutation-PositiveNon-Small-Cell Lung Cancer in the Real-World Setting in CentralEurope The INSIGHT Study
Authors: Rodryg Ramlau, Tanja Cufer, Peter Berzinec, Rafal Dziadziuszko, Wlodzimier Oslzewski, Helmut Popper, Paolo Bajcic, Ladislav Dušek, Zuzana Zbožínková, Robert Pirker
Journal: Journal of Thoracic Oncology (2015)
GPs and emergency department doctors need more training to manage head injuries in amateur sportspeople, MPs say
Authors: Ingrid Torjesen
Journal: BMJ (2021)

Doctors in general practice and emergency departments need more training in managing patients with head trauma, an inquiry by MPs into concussion in sport has concluded.1

The report, from the House of Commons Digital, Culture, Media, and Sport Committee, concluded that the government needs to do more to protect people participating in sport at all levels from the long term health consequences of head injuries, including increasing awareness of the NHS frontline.

Richard Sylvester, a consultant neurologist at the Institute of Sport, Exercise, and Health, told the committee he was more concerned about the management of head injuries in grassroots sports than those at professional level who would have good access to medical specialists. “I see adolescents who cannot do their …
Corrigendum to: Progress in aorta and peripheral cardiovascular disease research
Authors: Lucia Mazzolai, Adriano Alatri, Alessandra Bura Rivière, Marco De Carlo, Christian Heiss, Christine Espinola-Klein, Oliver Schlager, Henrik Sillesen, Daniel Staub, José F Rodriguez-Palomares, Aline Verstraeten, Victor Aboyans
Journal: Cardiovascular Research (2021)