tbuckley/cabot-search huggingface dataset:
Cellular Immunotherapy for Septic Shock. A Phase I Clinical Trial
Authors: Lauralyn A. McIntyre, Duncan J. Stewart, Shirley H. J. Mei, David Courtman, Irene Watpool, John Granton, John Marshall, Claudia dos Santos, Keith R. Walley, Brent W. Winston, Kenny Schlosser, Dean A. Fergusson
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

In septic animal models mesenchymal stem (stromal) cells (MSCs) modulate inflammation, enhance tissue repair and pathogen clearance, and reduce death.To conduct a phase I dose escalation trial of MSCs in septic shock with the primary objective of examining the safety and tolerability of MSCs.We enrolled nine participants within 24 hours of admission to the ICU. A control cohort of 21 participants was enrolled before starting the MSC interventional cohort to characterize expected adverse events (AEs) and to serve as a comparator for the intervention cohort. Three separate MSC dose cohorts, with three participants per cohort, received a single intravenous dose of 0.3, 1.0, and 3.0 × 106 cells/kg. A prespecified safety plan monitored participants for the occurrence of AEs; cytokines were collected at prespecified time points.Ages of participants in the interventional versus observational cohorts were median of 71 (range, 38-91) and 61 (range, 23-95). Acute Physiology and Chronic Health Evaluation scores were median of 25 (range, 11-28) and 26 (range, 17-32). MSC doses ranged from 19 to 250 million cells. There were no prespecified MSC infusion-associated or serious unexpected AEs, nor any safety or efficacy signals for the expected AEs or the measured cytokines between the interventional and observational cohorts.The infusion of freshly cultured allogenic bone marrow-derived MSCs, up to a dose of 3 million cells/kg (250 million cells), into participants with septic shock seems safe. Clinical trial registered with www.clinicaltrials.gov (NCT02421484).
Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma
Authors: Tomonori Matsumoto, Atsushi Takai, Yuji Eso, Kazuo Kinoshita, Toshiaki Manabe, Hiroshi Seno, Tsutomu Chiba, Hiroyuki Marusawa
Journal: Cancer Research (2017)

Hepatocellular carcinoma (HCC) originates from regenerating liver cells with genetic alterations in chronically inflamed liver. Ductal cells and hepatocytes proliferate for liver regeneration, and proliferating ductal cells (PDC) derived from bile ductules have long been considered putative liver stem/progenitor cells and candidate cellular origins of HCC. The potential of PDC as tumor-originating cells, however, remains controversial in contrast to accumulating evidence that HCC originates from hepatocytes. Here, we demonstrate that PDCs expressing the established surface and cancer stem cell marker EpCAM give rise to HCC in inflamed liver. EpCAM-expressing PDCs were specifically labeled in newly developed EpcamCreERT2 mice and traced in a chemically induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. Lineage-tracing experiments revealed that labeled PDC differentiated into cholangiocytes, but not into hepatocytes, in the chemically damaged liver. Nevertheless, EpCAM-positive PDC with genetic alterations gave rise to HCC after 8 months of chemical administration. PDC-derived HCC showed histologic characteristics of concomitant ductule-like structures resembling human cholangiolocellular carcinoma (CLC) and exhibited serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. The Wnt signaling pathway was specifically upregulated in the CLC components of PDC-derived HCC. Our findings provide direct experimental evidence that EpCAM-expressing PDC could be a cellular origin of HCC, suggesting the existence of stem/progenitor-derived hepatocarcinogenesis. Cancer Res; 77(22); 6131-43. ©2017 AACR.
Abstract 17020: Patient Mortality Affects a Surgeon’s Subsequent Performance
Authors: Baron Hamman, Kay-Yut Chen, Sridhar Nerur, Edmund Prater, Morley A Herbert, LaraLee Hogg, Syma L Prince, James R Edgerton
Journal: Circulation (2016)

Introduction: Stress affects performance and surgical case outcomes. Mortality in which a surgeon is intimately involved is a common stressor. Performance in specific cardiac surgeries can be measu...
SAT0057 A double-blind, placebo-controlled study to evaluate the effects of valdecoxib, a novel cox-2 specific inhibitor, on platelet function in the elderly
Authors: PT Leese, D Recker, ME Kuss
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Valdecoxib is a novel oral COX-2 specific inhibitor. COX-2 specific inhibitors effectively treat pain and inflammation without causing many of the side effects commonly associated with conventional NSAIDs. <h3>Objectives</h3> The purpose of this study was to compare the effects of valdecoxib to ibuprofen on platelet function in healthy subjects, &gt; = 65 years of age. <h3>Methods</h3> In this single-centre, double-blind, placebo-controlled, parallel-group study, 65 healthy adults, aged 65–95 years, were randomised to receive valdecoxib 40 mg BID, ibuprofen 800 mg TID, or placebo for 7.5 days. Platelet aggregation in response to arachidonate (AA), adenosine diphosphate (ADP), or collagen; serum thromboxane B<sub>2</sub> (TxB<sub>2</sub>) concentrations; and Simplate II bleeding times were assessed at 2, 4, and 8 h after dosing on Days 1 and 8. Vital signs and adverse events were monitored throughout the study. <h3>Results</h3> Platelet aggregation responses to AA, collagen, and ADP were not affected by treatment with valdecoxib 40 mg BID. In contrast, ibuprofen resulted in marked decreases in AA-induced platelet aggregation at the 2 h and 4 h assessments on Days 1 and 8. The effects of ibuprofen on platelet aggregation in response to collagen and ADP were not as great as seen with AA. However, for all three stimuli, ibuprofen demonstrated significantly greater decreases in platelet aggregation compared to placebo and valdecoxib at several time points. Valdecoxib 40 mg BID had no effect on bleeding times or serum TxB<sub>2</sub> concentrations compared to placebo. Bleeding times were significantly prolonged (p &lt; = 0.013) and serum TxB<sub>2</sub> concentrations significantly reduced (p &lt; = 0.026) in ibuprofen-treated subjects. <h3>Conclusion</h3> Valdecoxib 40 mg BID does not affect platelet function, serum TxB<sub>2</sub> levels or bleeding times, and is well tolerated in healthy elderly subjects. However, ibuprofen significantly alters hemostasis. These findings suggest that valdecoxib can provide its previously demonstrated analgesic and anti-inflammatory therapeutic benefits without negatively influencing platelet function in subjects &gt; = 65 years. Sponsored by Pharmacia Corporation and Pfizer, Inc.
Tolerance of high and low amounts of PLGA microspheres loaded with mineralocorticoid receptor antagonist in retinal target site
Authors: Min Zhao, Esther Rodríguez-Villagra, Laura Kowalczuk, Manon Le Normand, Marianne Berdugo, Rinath Levy-Boukris, Ikram El Zaoui, Béatrice Kaufmann, Robert Gurny, Irene Bravo-Osuna, Irene T. Molina-Martínez, Rocío Herrero-Vanrell, Francine Behar-Cohen
Journal: Journal of Controlled Release (2017)
NHS doctors should be more involved in research, says research institute
Authors: Anne Gulland
Journal: BMJ (2017)

The UK’s health research agency has pledged to get more non-academic doctors involved in research.

To mark its 10 year anniversary, the National Institute for Health Research (NIHR) has announced an overhaul of its activities, streamlining all its research activities into a single academy. The academy will see the integration of all current academic training and higher career personal awards, and will host all …
Prognostic importance of emerging cardiac, inflammatory, and renal biomarkers in chronic heart failure patients with reduced ejection fraction and anaemia: RED‐HF study
Authors: Paul Welsh, Lei Kou, Changhong Yu, Inder Anand, Dirk J. van Veldhuisen, Aldo P. Maggioni, Akshay S. Desai, Scott D. Solomon, Marc A. Pfeffer, Sunfa Cheng, Lars Gullestad, Pål Aukrust, Thor Ueland, Karl Swedberg, James B. Young, Michael W. Kattan, Naveed Sattar, John J.V. McMurray
Journal: European Journal of Heart Failure (2017)

Aims To test the prognostic value of emerging biomarkers in the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED‐HF) trial. Methods and results Circulating cardiac [N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), and high‐sensitivity troponin T (hsTnT)], neurohumoral [mid‐regional pro‐adrenomedullin (MR‐proADM) and copeptin], renal (cystatin C), and inflammatory [high‐sensitivity C‐reactive protein (hsCRP)] biomarkers were measured at randomization in 1853 participants with complete data. The relationship between these biomarkers and the primary composite endpoint of heart failure hospitalization or cardiovascular death over 28 months of follow‐up ( n = 834) was evaluated using Cox proportional hazards regression, the c‐statistic and the net reclassification index (NRI). After adjustment, the hazard ratio (HR) for the composite outcome in the top tertile of the distribution compared to the lowest tertile for each biomarker was: NT‐proBNP 3.96 (95% CI 3.16–4.98), hsTnT 3.09 (95% CI 2.47–3.88), MR‐proADM 2.28 (95% CI 1.83–2.84), copeptin 1.66 (95% CI 1.35–2.04), cystatin C 1.92 (95% CI 1.55–2.37), and hsCRP 1.51 (95% CI 1.27–1.80). A basic clinical prediction model was improved on addition of each biomarker individually, most strongly by NT‐proBNP (NRI +62.3%, P &lt; 0.001), but thereafter was only improved marginally by addition of hsTnT (NRI +33.1%, P = 0.004). Further addition of biomarkers did not improve discrimination further. Findings were similar for all‐cause mortality. Conclusion Once NT‐proBNP is included, only hsTnT moderately further improved risk stratification in this group of chronic heart failure with reduced ejection fraction patients with moderate anaemia. NT‐proBNP and hsTnT far outperform other emerging biomarkers in prediction of adverse outcome.
Has Toxicity Testing Moved into the 21st Century? A Survey and Analysis of Perceptions in the Field of Toxicology
Authors: Virginia Zaunbrecher, Elizabeth Beryt, Daniela Parodi, Donatello Telesca, Joseph Doherty, Timothy Malloy, Patrick Allard
Journal: Environmental Health Perspectives (2017)

Background: Ten years ago, leaders in the field of toxicology called for a transformation of the discipline and a shift from primarily relying on traditional animal testing to incorporating advances in biotechnology and predictive methodologies into alternative testing strategies (ATS). Governmental agencies and academic and industry partners initiated programs to support such a transformation, but a decade later, the outcomes of these efforts are not well understood. Objectives: We aimed to assess the use of ATS and the perceived barriers and drivers to their adoption by toxicologists and by others working in, or closely linked with, the field of toxicology. Methods: We surveyed 1,381 toxicologists and experts in associated fields regarding the viability and use of ATS and the perceived barriers and drivers of ATS for a range of applications. We performed ranking, hierarchical clustering, and correlation analyses of the survey data. Results: Many respondents indicated that they were already using ATS, or believed that ATS were already viable approaches, for toxicological assessment of one or more end points in their primary area of interest or concern (26–86%, depending on the specific ATS/application pair). However, the proportions of respondents reporting use of ATS in the previous 12 mo were smaller (4.5–41%). Concern about regulatory acceptance was the most commonly cited factor inhibiting the adoption of ATS, and a variety of technical concerns were also cited as significant barriers to ATS viability. The factors most often cited as playing a significant role (currently or in the future) in driving the adoption of ATS were the need for expedited toxicology information, the need for reduced toxicity testing costs, demand by regulatory agencies, and ethical or moral concerns. Conclusions: Our findings indicate that the transformation of the field of toxicology is partly implemented, but significant barriers to acceptance and adoption remain. https://doi.org/10.1289/EHP1435
CETP Inhibitors — A New Inning?
Authors: Robert A. Hegele
Journal: New England Journal of Medicine (2017)

Former baseball manager Tony La Russa once said, "Even when you have three strikes, you're still not out. There is always something else you can do." This aphorism could apply to cholesteryl ester transfer protein (CETP) inhibitors, a drug class that was designed to reduce the risk of cardiovascular disease by raising plasma levels of high-density lipoprotein (HDL) cholesterol. However, when the first three CETP inhibitors were added to background statin therapy, their use either paradoxically increased the risk of cardiovascular disease and death (in the case of torcetrapib1) or had neutral outcomes (dalcetrapib2 and evacetrapib3). These three strikes, combined . . .
Differences in the survival rate between premenopausal and post menopausal women with gastric cancer: U.S. SEER database.
Authors: Nasser Ghaly Yousif
Journal: Journal of Clinical Oncology (2013)

e15092 Background: Gastric cancer is the fourth most common malignancy in the world, The presence of estrogen receptor alpha (ER a) and estrogen receptor beta (ER b) have been reported in cell and tissue level in gastric cancer, but its impact on patients' survival remains unclear. The male predominance of gastric cancer suggests that female sex hormones may have a protective effect against gastric cancer. To understand the clinical impact of the estrogen pathway, we analyzed the national SEER database to compare the outcomes for gastric cancer in premenopausal vs.postmenopausal women. Methods: Data from the national SEER registry between the years of 1985-2009 was analyzed. Women between the ages 31-50 were chosen as representative of the pre-menopausal group (n=1291) and 51-70 year-old women represented the post-menopausal group (n=3089) as defined by the American College of Obstetricians and Gynecologists. To control the effect of age alone as a determinant of outcome, we compared the survival between men were similarly divided into two categories: younger men (n = 2114) aged 31- 50 years and older men (n = 5102) aged 51 - 70 years. Survival rates were analyzed by Kaplan-Meier method and compared by Z-test through SEER*Stat software version 7.0.9. Results: The cardiac gastric cancer site type and diffuse histological subtype had statistical significance difference between premenopausal and postmenopausal groups (49% vs.72%), (44% vs. 692%) respectively. The Kaplan-Meier curve shows the survival rate in premenopausal superior to postmenopausal women in diffuse gastric cancer P=0.01, while no statistically significant difference regarding mixed sub-types P&gt;0.05 and control groups. Conclusions: The results suggest varying estrogen effects between localization and histological subtype of gastric cancer, the presence of estrogen in gastric cancer could have a protective effect against gastric cancer and support clinical strategies need to stimulate the ER pathway or use estrogen for the treatment of gastric cancer, and additional studies are warranted as well as experimental studies that can shed light on the mechanism underlying this potentially protective action.
Interventions to reduce racial and ethnic disparities in colorectal cancer care: A systematic review.
Authors: James Edward Ward, Keith Naylor, Blase N. Polite
Journal: Journal of Clinical Oncology (2012)

e16509 Background: Disparities in colorectal cancer (CRC) outcomes among underrepresented racial and ethnic minority patients continue to widen. We performed, and present here, the results of a systematic review of the literature evaluating interventions to reduce racial and ethnic disparities in CRC care. Methods: The MEDLINE, PsycINFO, CINAHL, and Cochrane databases were searched for articles that focused on interventions to reduce disparities in CRC screening, treatment, survivorship and end-of-life care from 1950 to 2010. Studies included were those that evaluated interventions in US populations that were composed of ≥50% racial/ethnic minorities (or that included a specific sub-analysis by race/ethnicity). Results: Following the electronic search, abstract and full text review, and reference reviews; a total of thirty-three studies were included in our final analysis. All of these were related to CRC screening; no studies evaluating the rest of the cancer care continuum were found. Nineteen studies (58%) were randomized controlled trials, nine (27%) were pre-test/post-test analyses, and five (15%) were cohort studies. Thirteen studies (39%) targeted African-American populations, eight (24%) targeted Hispanics, two (6%) targeted Asian populations, seven (21%) included a mixed population of ethnic minorities, and three (9%) were listed as “non-white” or included a subgroup analysis. The main results related to the magnitude of the effect of these patient-directed, patient navigator, and provider-directed interventions on CRC screening is outlined in the table below. Conclusions: Patient education involving personal contact, patient navigation services, and provider-directed education and reminder systems can modestly improve adherence to CRC screening among minority patients. Further studies targeting the rest of the colon cancer care continuum are needed. [Table: see text]
Phase 3 ELOQUENT-2 study: Extended four year follow-up (FU) of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM).
Authors: Sagar Lonial, Meletios A. Dimopoulos, Katja C. Weisel, Darrell White, Philippe Moreau, Maria-Victoria Mateos, Jesus San Miguel, Kenneth Carl Anderson, Ofer Shpilberg, Sebastian Grosicki, Ivan Spicka, Adam Walter-Croneck, Hila Magen, Andrew Belch, Donna Ellen Reece, Meral Beksac, Sabeen Mekan, Oumar Sy, Anil K. Singhal, Paul G. Richardson
Journal: Journal of Clinical Oncology (2017)

8028 Background: Elotuzumab, an immunostimulatory monoclonal antibody, has a dual mechanism of action: directly activating NK cells and tagging myeloma cells for recognition/death via antibody-dependent cell-mediated cytotoxicity. In a 3-y FU, ELOQUENT-2 (NCT01239797) showed a sustained 27% reduction in risk of disease progression/death for ELd vs Ld and OS trend in favor of ELd (Dimopoulos et al, ASH 2015). Here we present extended 4-y FU data (median FU 46 mo). Methods: RRMM patients (pts) were randomized 1:1 to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity. Coprimary endpoints: PFS, ORR. Secondary endpoint: OS. Results: Of 646 RRMM pts, 321 were randomized to ELd, 325 to Ld; ~ twice as many pts remain on therapy in ELd vs Ld (17 vs 9%) at data cut-off (Oct 18, 2016). Discontinuation was mainly due to disease progression (both arms 54%). At 4-y FU, ELd had 29% reduction in risk of progression/death vs Ld (HR 0.71, 95% CI 0.59–0.86) and relative improvement of 50% in PFS (21 vs 14%). Pts with ≥VGPR (ELd 112 [35%], Ld 95 [29%]) had greatest reduction in risk of progression/death (HR 0.65, 95% CI 0.46–0.94). ORR was 79% (ELd) vs 66% (Ld). OS will be presented. G3–4 AEs in ≥5% of pts included second primary malignancies (SPMs), vascular diseases, cardiac disorders and infections (ELd vs Ld: 9 vs 6%, 10 vs 8%, 5 vs 8%, 33 vs 26%). Overall rate (any grade) of infection and SPMs was 84 vs 75% and 17 vs 11% for ELd vs Ld. However, pts had longer exposure to ELd vs Ld (median [Q1, Q3] treatment cycles (19 [9, 42] vs 14 [6, 25]). There were fewer deaths with ELd vs Ld (165 vs 186), mainly due to disease progression and infection in both arms. Conclusions: Elotuzumab in combination with Ld consistently met its efficacy objectives at 4-y FU. ELd showed durable, clinically relevant improvement in PFS, with 29% reduction in risk of progression/death, consistent with 2-y (30%) and 3-y FU (27%). Safety, including rate of SPMs, was consistent with previous findings, with minimal incremental AEs with addition of elotuzumab to Ld. These data represent the longest median FU of an immuno-oncology agent in MM. Study funding: BMS. Writing support: C Tomas, Caudex, funded by BMS. Clinical trial information: NCT01239797.
Gastrin-releasing peptide receptor regulates leupaxin localization and Pyk2 activity
Authors: Pei-Wen Chen, Glenn S. Kroog
Journal: Cancer Research (2005)

4503  Recent evidence suggests G-protein coupled receptors (GPCRs) interact with proteins in addition to heterotrimeric G proteins. The carboxyl terminal domains (CTD) of GPCRs share less homology and therefore may be responsible for distinct signaling properties of different GPCRs. To search for proteins that interact with gastrin-releasing peptide receptor (GRPr) CTD, we screened a human B cell cDNA library using GRPr CTD as bait in the yeast two-hybrid system. We identified leupaxin (LPXN) as a potential binding partner of GRPr CTD. LPXN contains two types of protein interaction domains, 4 LD motifs and 4 LIM domains, and shares high homology with the focal adhesion protein, paxillin. Bombesin (BN, a GRPr agonist) stimulates GFP-tagged LPXN translocation from cytoplasm to focal adhesions in BALB/c mouse fibroblasts stably-expressing GRPr and GFP-LPXN. BN also stimulates LPXN translocation in PC3 human prostate cancer cells that express endogenous GRPr and LPXN. Using a fluorescent BN analog to identify GRPr, we find GRPr and GFP-LPXN might co-localize on the plasma membrane before BN treatment, but GRPr internalizes into cytosol while GFP-LPXN translocates to focal adhesions after addition of BN. We are currently determining if GRPr and LPXN co-immunoprecipitate (co-IP). Transient transfection analyses of GFP-tagged LPXN deletion mutants reveal the principle focal adhesion targeting/localizing domain lies in LIM3 and LIM4 since GFP-LIM (containing all 4 LIM domains) translocates to focal adhesions while a construct missing LIM3/4 fails to. In contrast to the cytoplasmic localization of full length LPXN, GFP-LIM is expressed in both nucleus and cytosol, suggesting that LD domain contains a nuclear export sequence. Phosphorylation of paxillin is important for its targeting to focal adhesions and LPXN is reported to be tyrosine phosphorylated. We incubated cells with 32PO4 and treated with and without BN to compare IPed GFP-LPXN complexes. GFP-LPXN phosphorylation does not detectably change, but other proteins that co-IP show increased phosphorylation after BN treatment. LPXN interacts with a focal adhesion kinase family member, Pyk2. Although BN does not affect the association between LPXN and Pyk2, BN stimulates endogenous Pyk2 phosphorylation in both transfected BALB cells and PC3 cells. GF109203X (a PKC inhibitor) fails to inhibit BN-induced Pyk2 activation, demonstrating that Pyk2 activation in PC3 cells does not require PKC. BN stimulates Pyk2 phosphorylation as well as GFP-LPXN translocation to focal adhesions in BALB cells expressing distal CTD mutants of GRPr, indicating that the distal CTD is not required for these two functions although an intact proximal CTD may be. Because focal adhesion proteins are involved in tumor metastasis and cell motility, these data suggest that BN/GRPr signaling might contribute to prostate cancer metastasis/cell motility by regulating LPXN location and Pyk2 activity.
Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Daniel V T Catenacci, Niall C Tebbutt, Irina Davidenko, André M Murad, Salah-Eddin Al-Batran, David H Ilson, Sergei Tjulandin, Evengy Gotovkin, Boguslawa Karaszewska, Igor Bondarenko, Mohamedtaki A Tejani, Anghel A Udrea, Mustapha Tehfe, Ferdinando De Vita, Cheryl Turkington, Rui Tang, Agnes Ang, Yilong Zhang, Tien Hoang, Roger Sidhu, David Cunningham
Journal: The Lancet Oncology (2017)