tbuckley/cabot-search huggingface dataset:
Program of Integrated Care for Patients with Chronic Obstructive Pulmonary Disease and Multiple Comorbidities (PIC COPD<sup>+</sup>): a randomised controlled trial
Authors: Louise Rose, Laura Istanboulian, Lise Carriere, Anna Thomas, Han-Byul Lee, Shaghayegh Rezaie, Roshan Shafai, Ian Fraser
Journal: European Respiratory Journal (2018)

We sought to evaluate the effectiveness of a multi-component, case manager-led exacerbation prevention/management model for reducing emergency department visits. Secondary outcomes included hospitalisation, mortality, health-related quality of life, chronic obstructive pulmonary disease (COPD) severity, COPD self-efficacy, anxiety and depression. Two-centre randomised controlled trial recruiting patients with ≥2 prognostically important COPD-associated comorbidities. We compared our multi-component intervention including individualised care/action plans and telephone consults (12-weekly then 9-monthly) with usual care (both groups). We used zero-inflated Poisson models to examine emergency department visits and hospitalisation; Cox proportional hazard model for mortality. We randomised 470 participants (236 intervention, 234 control). There were no differences in number of emergency department visits or hospital admissions between groups. We detected difference in emergency department visit risk, for those that visited the emergency department, favouring the intervention (RR 0.74, 95% CI 0.63–0.86). Similarly, risk of hospital admission was lower in the intervention group for those requiring hospital admission (RR 0.69, 95% CI 0.54–0.88). Fewer intervention patients died (21 versus 36) (HR 0.56, 95% CI 0.32–0.95). No differences were detected in other secondary outcomes. Our multi-component, case manager-led exacerbation prevention/management model resulted in no difference in emergency department visits, hospital admissions and other secondary outcomes. Estimated risk of death (intervention) was nearly half that of the control.
Effect of inhibition of protein kinase C delta (PKCδ) on pancreatic cancer cells.
Authors: George P. Sorescu, Lora W. Forman, Douglas V. Faller
Journal: Journal of Clinical Oncology (2012)

e14591 Background: 93% of pancreatic cancers have activating mutations in the K-Ras gene. We have previously shown that mutated, constitutively-activated Ras is lethal to cells if an essential Ras-driven survival pathway is disrupted by suppression of PKCδ. PKCδ has various cellular functions, but is not required for the survival of normal cells and its inhibition in vitro or in vivo has no known adverse effects. Signal transducer and activator of transcription 3 (STAT3) is constitutive driver of many solid cancers, including pancreatic cancers. STAT3 requires phosphorylation of Tyr 705 for activation and, once activated translocates to the nucleus, where it controls genes involved in cell survival or death. Methods: Human pancreatic cancer cell lines PancI, MIAPACA and primary human pancreatic cancer stem cells were studied. shRNA-mediated knockdown of PKCδ, with scrambled shRNA as a control, was used to validate PKCδ as a target. Rottlerin and KAM1 were used as relatively specific PKCδ inhibitors. For inhibition of STAT3, specific shRNA against STAT3 versus scrambled shRNA were employed for knock-downs. For cytotoxicity analyses, MTS assays were used to assess cell growth. Z-vad-FMK was used as a pan-caspase inhibitor. Immunoblotting was used to verify knock-down of PKCδ or STAT3 and to quantify the phosphorylation status of STAT3 phospho-Tyr 705. Results: PKCδ inhibition by either shRNA knock-down or inhibitor led to dephosphorylation of STAT3 at Tyr 705, extensive cytotoxicity of pancreatic cancer cells and dramatic reductions in tumor clonogenic capacity. Knock down of STAT3 was equally cytotoxic to pancreatic cancer cells. Cytotoxicity following PKCδ inhibition was not prevented by a pan-caspase inhibitor. Conclusions: Activated STAT3 and survival in pancreatic cancer cells requires PKCδ. Inhibition of PKCδ, and subsequent suppression of STAT3 activation, is cytotoxic for pancreatic cancer cells through a mechanism independent of caspase activation or apoptosis. Small molecule inhibitors of PKCδ have potential as targeted therapeutic agents against pancreatic tumors, pancreatic cancer stem cells, and other human tumors with mutational activation of Ras.
Long-term Outcomes Following Bariatric Surgery
Authors: Sarah Shubeck, Justin B. Dimick, Dana A. Telem
Journal: JAMA (2018)

This commentary discusses a study published in JAMA Surgery reporting 7-year weight and health outcomes for patients in the Longitudinal Assessment of Bariatric Surgery (LABS) Study who underwent Roux-en-Y gastric bypass or laparoscopic adjustable gastric banding.
Cancer immunotherapy beyond immune checkpoint inhibitors
Authors: Julian A. Marin-Acevedo, Aixa E. Soyano, Bhagirathbhai Dholaria, Keith L. Knutson, Yanyan Lou
Journal: Journal of Hematology & Oncology (2018)

Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.
Embers
Authors: Carol Snyder Halberstadt
Journal: JAMA (2018)

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Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10
Authors: Adrien Nougarede, Nikolay Popgeorgiev, Loay Kassem, Soleilmane Omarjee, Stephane Borel, Ivan Mikaelian, Jonathan Lopez, Rudy Gadet, Olivier Marcillat, Isabelle Treilleux, Bruno O. Villoutreix, Ruth Rimokh, Germain Gillet
Journal: Cancer Research (2018)

Abstract Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in &amp;gt;45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain–dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh. Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404–17. ©2018 AACR.
Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance)
Authors: Mark Jesus M. Magbanua, Hope S. Rugo, Denise M. Wolf, Louai Hauranieh, Ritu Roy, Praveen Pendyala, Eduardo V. Sosa, Janet H. Scott, Jin Sun Lee, Brandelyn Pitcher, Terry Hyslop, William T. Barry, Steven J. Isakoff, Maura Dickler, Laura van't Veer, John W. Park
Journal: Clinical Cancer Research (2018)

We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).
Abstract 07: Associations of Weight Gain From Early to Middle Adulthood With Major Health Outcomes in Later Life
Authors: Yan Zheng, JoAnn Manson, Changzheng Yuan, Matthew Liang, Francine Grodstein, Meir Stampfer, Walter Willett, Frank Hu
Journal: Circulation (2017)

Background: The association of weight gain from early to middle adulthood with a wide range of health outcomes later in life has not been systematically examined. Methods: We included 93,873 women from the Nurses’ Health Study and 25,374 men from the Health Professionals Follow-up Study who recalled weight at early adulthood (18 years in women, 21 years in men) and reported current weight in middle adulthood (55 years). Beginning from 55 years old, we prospectively followed them for incident cases of type 2 diabetes, hypertension, cardiovascular disease, cancer, three other medical conditions, and all-cause mortality. Among 51,185 women and 17,694 men who were at least 64 years of age in 2010, we also considered “healthy aging”, defined as no diagnosis of 11 major chronic diseases and no major cognitive impairment, physical impairment, or mental health limitations. Results: On average, female participants gained 12.55 kg (interquartile range: 14.36 kg) of body weight and males gained 9.68 kg (interquartile range: 11.19 kg) from early to middle adulthood. During a median follow-up of 18 years in women and 14 years in men, we documented 9360 incident cases of type 2 diabetes, 37,298 of hypertension, 9220 of cardiovascular disease, 20,222 of cancer (including 9458 of obesity-related cancers), 7438 of symptomatic cholelithiasis, 2702 of severe osteoarthritis, 31,960 of cataract extraction, and 27,250 deaths. In multivariate models, compared to those maintained stable weight (weight change &lt;2.5kg), participants who gained 20+ kg had increased risks of: diabetes (hazard ratio [HR, 95%CI], 10.93[9.65–12.39] in women, 8.19[6.41–10.46] in men), hypertension (2.24[2.15–2.34] in women, 2.11[1.91–2.33] in men), cardiovascular disease (1.87[1.72–2.04] in women, 1.72[1.40–2.11] in men), obesity-related cancers (1.53[1.41–1.66] in women, 1.27[0.95–1.69] in men), and mortality (1.43[1.37–1.50] in women, 1.34[1.18–1.51] in men); they had decreased odds of healthy aging (odds ratio [OR, 95%CI], 0.36[0.32–0.40] in women and 0.50[0.43–0.57] in men). In a meta-analysis combing both sexes, the increase in risk associated with each 10 kg weight gain was 71% for type 2 diabetes, 27% for hypertension, 17% for cardiovascular disease, 31% for symptomatic cholelithiasis, 15% for obesity-related cancers, 9% for severe osteoarthritis, 5% for cataract extraction, and 9% for mortality; for the same weight gain the odds of healthy aging was 28% lower. Conclusions: Our data provide strong evidence that weight gain from early to middle adulthood is associated with substantially increased risk of major chronic diseases and mortality, and overall decreased odds of aging with good health and well-being among women and men.
Clinical Translation of Pluripotent Cell-Derived Off-the-Shelf Natural Killer Cell Cancer Immunotherapy
Authors: Frank Cichocki, Ryan Bjordahl, Svetlana Gaidarova, Paul Rogers, Raedun Clarke, Brian Groff, Stacey Moreno, Ramzey Abujarour, Megan Robinson, Greg Bonello, Tom Lee, Weijie Lan, Betsy Rezner, Stewart Abbot, Darin Sumstad, Bruce Blazar, Daniel Shoemaker, Scott Wolchko, Dan Kaufman, David H. McKenna, Bahram Valamehr, Sarah Cooley, Jeffrey S. Miller
Journal: Blood (2017)
Arsenic trioxide in patients with hepatocellular carcinoma: A phase II trial
Authors: C. Lin, C. Hsu, C. Hsu, W. Hsu, A. Cheng, C. Yang
Journal: Journal of Clinical Oncology (2006)

14129 Background: Arsenic trioxide induces growth inhibition and apoptosis in human hepatocellular carcinoma (HCC) cell lines. A phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with HCC. Methods: Inclusion criteria included advanced HCC patients to whom no standard palliative treatment can be offered, good organ function and liver function reserve. Patients received arsenic trioxide 0.16–0.24 mg/kg/day for 5–6 days per week for 3–4 weeks followed by one-week rest. Tumor response was accessed every 2 months. Primary endpoint was percentage of patients with 6-month disease stabilization. Results: Twenty-nine patients (M/F = 24:5; median age: 59) with locally advanced or metastatic HCC received a total of 61 cycles (median, 2; range, 1–6). One patient had partial remission. Three patients had disease stabilization for at least six months. The 6-month tumor stabilization rate was 14% (95% CI, 1–27). The median overall survival was 4.8 months (95% CI, 1.4–8.2) and one-year survival estimated by Kaplan-Meier methodology was 30%. Conclusions: Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC patients. No significant financial relationships to disclose.
Flexible Modulation of CO‐Release Using Various Nuclearity of Metal Carbonyl Clusters on Graphene Oxide for Stroke Remediation
Authors: Mein Jin Tan, Han‐Chi Pan, Hui Ru Tan, Jian Wei Chai, Qi Feng Lim, Ten It Wong, Xiaodong Zhou, Zi‐Yao Hong, Lun‐De Liao, Kien Voon Kong
Journal: Advanced Healthcare Materials (2018)

Abstract Utilizing the size‐dependent adsorption properties of ruthenium carbonyl clusters (Ru–carbon monoxide (CO)) onto graphene oxide (GO), a facile CO‐release platform for in situ vasodilation as a treatment for stroke‐related vascular diseases is developed. The rate and amount of formation of the CO‐release‐active Ru II (CO) 2 species can be modulated by a simple mixing procedure at room temperature. The subsequent thermally induced oxidation of Ru II (CO) 2 to RuO 2 on the GO surface results in the release of CO. Further modulation of thermal and CO‐release properties can be achieved via a hybridization of medium‐ and high‐nuclearity of Ru–CO clusters that produces a RuO 2 /Ru II (CO) 2 / 6 Ru–CO–GO composite, where 6 Ru–CO–GO provides a photothermally activated reservoir of Ru II (CO) 2 species and the combined infrared absorption properties of GO and RuO 2 provides photothermal response for in situ CO‐release. The RuO 2 /Ru II (CO) 2 / 6 Ru–CO–GO composite does not produce any cytotoxicity and the efficacy of the composite is further demonstrated in a cortical photothrombotic ischemia rat model.
Genetic and Mechanistic Diversity in Hemophagocytic Lymphohistiocytosis
Authors: Ivan K. Chinn, Olive S. Eckstein, Erin C. Peckham-Gregory, Baruch R. Goldberg, Lisa R. Forbes, Sarah K. Nicholas, Emily M. Mace, Tiphanie P. Vogel, Harshal A. Abhyankar, Maria I. Diaz, Helen E. Heslop, Robert A. Krance, Caridad A. Martinez, Trung C. Nguyen, Dalia A. Bashir, Jordana R. Goldman, Asbjorg Stray-Pedersen, Luis A. Pedroza, M. Cecilia Poli, Juan Carlos Aldave Becerra, Sean A. McGhee, Zeynep H. Coban-Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Tram N. Cao, Diana N. Hong, Richard A. Gibbs, James R. Lupski, Jordan S. Orange, Kenneth L. McClain, Carl E. Allen
Journal: Journal of Allergy and Clinical Immunology (2018)
Fibrinogen and Clot Structure Is Affected By Eculizumab in Patients with Paroxysmal Nocturnal Haemoglobinuria
Authors: Fraser Macrae, Polly Bowman, Emma Linton, Barnaby Peacock-Young, Deborah Clarke, Darren J Newton, Claire E McKinley, Kathryn Riley, Nicola Copeland, Louise Arnold, Morag Griffin, Talha Munir, Peter Hillmen, Stephen John Richards, Robert Ariens, Anita Hill
Journal: Blood (2017)
Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration
Authors: Tobias Wertheimer, Enrico Velardi, Jennifer Tsai, Kirsten Cooper, Shiyun Xiao, Christopher C. Kloss, Katja J. Ottmüller, Zeinab Mokhtari, Christian Brede, Paul deRoos, Sinéad Kinsella, Brisa Palikuqi, Michael Ginsberg, Lauren F. Young, Fabiana Kreines, Sophia R. Lieberman, Amina Lazrak, Peipei Guo, Florent Malard, Odette M. Smith, Yusuke Shono, Robert R. Jenq, Alan M. Hanash, Daniel J. Nolan, Jason M. Butler, Andreas Beilhack, Nancy R. Manley, Shahin Rafii, Jarrod A. Dudakov, Marcel R. M. van den Brink
Journal: Science Immunology (2018)

BMP4 produced by endothelial cells promotes thymic regeneration after acute damage by activating FOXN1 and its downstream targets.
A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment
Authors: Marc L Hyer, Michael A Milhollen, Jeff Ciavarri, Paul Fleming, Tary Traore, Darshan Sappal, Jessica Huck, Judy Shi, James Gavin, Jim Brownell, Yu Yang, Bradley Stringer, Robert Griffin, Frank Bruzzese, Teresa Soucy, Jennifer Duffy, Claudia Rabino, Jessica Riceberg, Kara Hoar, Anya Lublinsky, Saurabh Menon, Michael Sintchak, Nancy Bump, Sai M Pulukuri, Steve Langston, Stephen Tirrell, Mike Kuranda, Petter Veiby, John Newcomb, Ping Li, Jing Tao Wu, Josh Powe, Lawrence R Dick, Paul Greenspan, Katherine Galvin, Mark Manfredi, Chris Claiborne, Benjamin S Amidon, Neil F Bence
Journal: Nature Medicine (2018)
Intrabiliary argon plasma coagulation hemostasis by direct cholangioscopy for a tricky post-ERCP bleeding
Authors: Andrea Anderloni, Francesco Auriemma, Alessandro Fugazza, Roberta Maselli, Alessandro Repici
Journal: Endoscopy (2018)

An 80-year-old man was admitted to the emergency department with fever, jaundice, and abdominal pain due to common bile duct (CBD) lithiasis. His past medical history revealed chronic renal failure and atrial fibrillation, which was treated with warfarin. Therapy with antibiotics and phytomenadione was promptly started, and international normalized ratio values returned to normal.
Serologic responses and effectiveness of hepatitis A vaccination among human immunodeficiency virus–positive individuals during the outbreak of acute hepatitis A
Authors: Kuan‐Yin Lin, Szu‐Min Hsieh, Hsin‐Yun Sun, Yi‐Chun Lo, Wang‐Huei Sheng, Yu‐Chung Chuang, Aristine Cheng, Sung‐Ching Pan, Guan‐Jhou Chen, Chien‐Ching Hung, Shan‐Chwen Chang
Journal: Hepatology (2018)

Outbreaks of hepatitis A virus (HAV) infection have been occurring among men who have sex with men in the Asia-Pacific region, the United States, and several European countries since June 2015 and recently among persons who are homeless and use illicit drugs in the United States. We evaluated the serologic responses and effectiveness of HAV vaccination in human immunodeficiency virus (HIV)-positive individuals during the outbreak in Taiwan. From June 1, 2015, to September 30, 2016, anti-HAV immunoglobulin G was prospectively determined among all HIV-positive individuals. We prospectively observed 1,533 HAV-seronegative, HIV-positive individuals (94.1% being men who have sex with men with a median cluster of differentiation 4 (CD4) count of 550 cells/μL) who were advised to receive two doses of HAV vaccine administered 6 months apart. Of them, 1,001 individuals (65.3%) received at least one dose of HAV vaccine during the study period and 532 (34.7%) declined to receive vaccine. The primary endpoints were serologic response at weeks 28-36 and acquisition of HAV infection during follow-up. The incidence rate of acute HAV infection was 3.7 and 99.3 per 1,000 person-years of follow-up in the vaccinated and unvaccinated groups, respectively, resulting in a vaccine effectiveness of 96.3%. At weeks 28-36, the seroconversion rates were 63.8% and 93.7% in the intention-to-treat and per-protocol analyses, respectively. The factors associated with seroconversion at weeks 28-36 were younger age (per 1-year decrease, adjusted odds ratio, 1.08; 95% confidence interval, 1.02-1.12) and undetectable plasma HIV RNA load (adjusted odds ratio, 3.19; 95% confidence interval, 1.32-7.68).During the outbreak of acute hepatitis A, two-dose HAV vaccination is effective at preventing HAV infection among HIV-positive individuals receiving combination antiretroviral therapy; our data highlight the importance of HAV serologic screening and vaccination to prevent outbreaks of acute hepatitis A in at-risk populations. (Hepatology 2018;68:22-31).
Membrane perturbation by bile acids causes signal transduction
Authors: Samira Jean-Louis, Jesse D. Martinez
Journal: Cancer Research (2004)

2743   Bile acids have been implicated as tumor promoters that may be involved in colon tumorigenesis. We have demonstrated that bile acids are cytotoxic to the colonic epithelium and activate several signaling pathways in colon cancer-derived cell lines. We have examined the genesis of bile acid signaling and found that signaling may be activated by perturbing the plasma membrane. Here we examined the effect of bile acids on the membranes of HCT116 cells. Examination of caveolae, specialized membrane domains known to contain a variety of signaling molecules by density sucrose gradients revealed that deoxycholic acid (DCA) depleted the membrane of caveolin-1. In addition, β-actin a protein known to be localized in caveolae was also displaced upon treatment with DCA. In contrast, treating with ursodeoxycholic acid (UDCA), a chemopreventive bile acid, resulted in a slight increase of caveolin-1. Cholesterol, a major constituent of caveolae was also examined since an intermolecular interaction exists between cholesterol and caveolin-1, the coat protein of caveolae. A role for cholesterol was also suggested in DCA-induced signaling since DCA caused a sharp increase in membrane cholesterol and depleting membrane cholesterol with Methyl-β-Cyclodextrin suppressed DCA-induced apoptosis. Since bile acids are cholesterol derivatives, we hypothesize that bile acids may be acting on the membrane by displacing cholesterol and interfering with the negative regulatory function of caveolin-1 on signal transduction.