tbuckley/cabot-search huggingface dataset:
Microfluidic Single-Cell Analysis Shows That Porcine Induced Pluripotent Stem Cell–Derived Endothelial Cells Improve Myocardial Function by Paracrine Activation
Authors: Mingxia Gu, Patricia K. Nguyen, Andrew S. Lee, Dan Xu, Shijun Hu, Jordan R. Plews, Leng Han, Bruno C. Huber, Won Hee Lee, Yongquan Gong, Patricia E. de Almeida, Jennifer Lyons, Fumi Ikeno, Cholawat Pacharinsak, Andrew J. Connolly, Sanjiv S. Gambhir, Robert C. Robbins, Michael T. Longaker, Joseph C. Wu
Journal: Circulation Research (2012)

Induced pluripotent stem cells (iPSCs) hold great promise for the development of patient-specific therapies for cardiovascular disease. However, clinical translation will require preclinical optimization and validation of large-animal iPSC models.To successfully derive endothelial cells from porcine iPSCs and demonstrate their potential utility for the treatment of myocardial ischemia.Porcine adipose stromal cells were reprogrammed to generate porcine iPSCs (piPSCs). Immunohistochemistry, quantitative PCR, microarray hybridization, and angiogenic assays confirmed that piPSC-derived endothelial cells (piPSC-ECs) shared similar morphological and functional properties as endothelial cells isolated from the autologous pig aorta. To demonstrate their therapeutic potential, piPSC-ECs were transplanted into mice with myocardial infarction. Compared with control, animals transplanted with piPSC-ECs showed significant functional improvement measured by echocardiography (fractional shortening at week 4: 27.2±1.3% versus 22.3±1.1%; P<0.001) and MRI (ejection fraction at week 4: 45.8±1.3% versus 42.3±0.9%; P<0.05). Quantitative protein assays and microfluidic single-cell PCR profiling showed that piPSC-ECs released proangiogenic and antiapoptotic factors in the ischemic microenvironment, which promoted neovascularization and cardiomyocyte survival, respectively. Release of paracrine factors varied significantly among subpopulations of transplanted cells, suggesting that transplantation of specific cell populations may result in greater functional recovery.In summary, this is the first study to successfully differentiate piPSCs-ECs from piPSCs and demonstrate that transplantation of piPSC-ECs improved cardiac function after myocardial infarction via paracrine activation. Further development of these large animal iPSC models will yield significant insights into their therapeutic potential and accelerate the clinical translation of autologous iPSC-based therapy.
PPAR Agonists Protect Mesangial Cells from Interleukin 1β-Induced Intracellular Lipid Accumulation by Activating the ABCA1 Cholesterol Efflux Pathway
Authors: Xiong Z. Ruan, John F. Moorhead, Ray Fernando, David C. Wheeler, Stephen H. Powis, Zac Varghese
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Previous studies have demonstrated that inflammatory cytokines such as interleukin-1β (IL-1β) promote lipid accumulation in human mesangial cells (HMC) by dysregulating the expression of lipoprotein receptors. Intracellular lipid accumulation is governed by both influx and efflux; therefore, the effect of IL-1β on the efflux of lipid from HMC was investigated. IL-1β was shown to inhibit 3H-cholesterol efflux from HMC and increase total intracellular cholesterol concentration, probably as a result of reduced expression of the adenosine triphosphate (ATP) binding cassette A1 (ABCA1), a transporter protein involved in apolipoprotein-A1 (apo-A1)–mediated lipid efflux. To ascertain the molecular mechanisms involved, expression of peroxisome proliferator-activated receptors (PPAR) and liver X receptorα (LXRα) were examined. IL-1β (5 ng/ml) reduced PPARα, PPARγ, and LXRα mRNA expression. Activation of PPARγ with the agonist prostaglandin J2 (10 μM) and of PPARα with either bezafibrate (100 μM) or Wy14643 (100 μM) both increased LXRα and ABCA1 gene expression also and enhanced apoA1-mediated cholesterol efflux from lipid-loaded cells, even in the presence of IL-1β. A natural ligand of LXRα, 25-hydroxycholesterol (25-OHC), had similar effects; when used together with PPAR agonists, an additive effect was observed, indicating co-operation between PPAR and LXRα in regulating ABCA1 gene expression. This was supported by the observation that overexpression of either PPARα or PPARγ by transfection enhanced LXRα and ABCA1 gene induction by PPAR agonists. Taken together with previous data, it appears that, in addition to increasing lipid uptake, inflammatory cytokines promote intracellular lipid accumulation by inhibiting cholesterol efflux through the PPAR-LXRα-ABCA1 pathway. These results suggest potential mechanisms whereby inflammation may exacerbate lipid-mediated cellular injury in the glomerulus and in other tissues and indicate that PPAR agonists may have a protective effect. E-mail: [email protected]
Cancer and Leukemia Group B Gastrointestinal Cancer Committee
Authors: Richard M. Goldberg, Donna Niedzwiecki, Monica Bertagnolli, A. William Blackstock, Joel E. Tepper, Robert J. Mayer
Journal: Clinical Cancer Research (2006)

Abstract The Cancer and Leukemia Group B Gastrointestinal Cancer Committee was organized in the late 1970s under the leadership of Michael Perry and Philip Schein and began full-scale operations in the mid-1980s. Today, it is a multidisciplinary team of surgeons, radiation and medical oncologists, statisticians, quality-of-life experts, pharmacogeneticists, basic scientists, and community oncologists who design studies that are conducted across the United States. The Committee has done trials in patients with esophageal, gastric, pancreatic, colon, rectal, and anal cancers. New initiatives are under way in hepatocellular cancer, cholangiocarcinoma, and neuroendocrine tumors originating in the gastrointestinal tract. The Committee has increasingly concentrated on translational studies using tumor blocks, germ-line DNA, and plasma to evaluate biological correlates of tumor response and clinical outcomes. A broad program of pharmacogenomics has been incorporated for virtually all studies, including trials that prospectively use polymorphisms in drug-metabolizing genes to assign treatments. Future efforts aim to evolve new standards of care, evaluate new therapies, and answer relevant biological questions in gastrointestinal cancer.
miRNA Biomarkers in Cyst Fluid Augment the Diagnosis and Management of Pancreatic Cysts
Authors: Hanno Matthaei, Dennis Wylie, Maura B. Lloyd, Marco Dal Molin, Jon Kemppainen, Skye C. Mayo, Christopher L. Wolfgang, Richard D. Schulick, Laura Langfield, Bernard F. Andruss, Alex T. Adai, Ralph H. Hruban, Anna E. Szafranska-Schwarzbach, Anirban Maitra
Journal: Clinical Cancer Research (2012)

The diagnosis of pancreatic cystic lesions has increased dramatically. Most are benign, whereas some, such as intraductal papillary mucinous neoplasms (IPMN), represent precursors of pancreatic adenocarcinoma. Therapeutic stratification of IPMNs is challenging without precise information on dysplasia grade and presence of invasion. We assessed the diagnostic benefit of using miRNAs as biomarkers in pancreatic cyst fluid, focusing on IPMNs because of their frequency and malignant potential.RNA was extracted from 55 microdissected formalin-fixed, paraffin-embedded (FFPE) IPMN specimens, and 65 cyst fluid specimens aspirated following surgical resection. Expression of 750 miRNAs was evaluated with TaqMan miRNA Arrays using 22 FFPE and 15 cyst fluid specimens. Differential expression of selected miRNA candidates was validated in 33 FFPE and 50 cyst fluid specimens using TaqMan miRNA Assays.We identified 26 and 37 candidate miRNAs that distinguish low-grade from high-grade IPMNs using FFPE and cyst fluid specimens, respectively. A subset of 18 miRNAs, selected from FFPE and cyst fluid data, separated high-grade IPMNs from low-grade IPMNs, serous cystadenomas (SCA) and uncommon cysts, such as solid pseudopapillary neoplasms (SPN) and cystic pancreatic neuroendocrine tumors (PanNET). A logistic regression model using nine miRNAs allowed prediction of cyst pathology implying resection (high-grade IPMNs, PanNETs, and SPNs) versus conservative management (low-grade IPMNs, SCAs), with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1.We found candidate miRNAs that helped identify patients with high-grade IPMN and exclude nonmucinous cysts. These classifiers will require validation in a prospective setting to ultimately confirm their clinical usefulness.
Risk of Arterial Thromboembolic Events With Sunitinib and Sorafenib: A Systematic Review and Meta-Analysis of Clinical Trials
Authors: Toni K. Choueiri, Fabio A.B. Schutz, Youjin Je, Jonathan E. Rosenberg, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2010)

Sunitinib and sorafenib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) used in a vast range of cancers. Arterial thromboembolic events (ATE) have been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to determine the incidence and the relative risk (RR) associated with the use of sunitinib and sorafenib.PubMed databases were searched for articles published from January 1966 to July 2009, and abstracts presented at the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) meetings held between 2004 and 2009 were searched for relevant clinical trials. Eligible studies included phase II and III trials and expanded access programs. Statistical analyses were conducted to calculate the summary incidence, RRs, and 95% CIs, using random-effects or fixed-effects models based on the heterogeneity of included studies.A total of 10,255 patients were selected for this meta-analysis. The incidence for ATE was 1.4% (95% CI, 1.2% to 1.6%). The RR of ATEs associated with sorafenib and sunitinib was 3.03 (95% CI, 1.25 to 7.37; P = .015) compared with control patients. The analysis was also stratified for the underlying malignancy (renal cell cancer v non-renal cell cancer) and TKI (sunitinib v sorafenib), but no significant differences in incidence or RR were observed.Treatment with VEGFR TKIs sunitinib and sorafenib is associated with a significant increase in the risk of ATEs.
Immunologic Proliferation Marker Ki-S2 as Prognostic Indicator for Lymph Node-Negative Breast Cancer
Authors: P. Rudolph, P. Alm, H.-J. Heidebrecht, H. Bolte, V. Ratjen, B. Baldetorp, M. Ferno, H. Olsson, R. Parwaresch
Journal: JNCI Journal of the National Cancer Institute (1999)

Proper treatment of lymph node-negative breast cancer depends on an accurate prognosis. To improve prognostic models for this disease, we evaluated whether an immunohistochemical marker for proliferating cells, Ki-S2 (a monoclonal antibody that binds to a 100-kd nuclear protein expressed in S, G2, and M phases of the cell cycle), is an accurate indicator of prognosis.We studied 371 Swedish women with lymph node-negative breast cancer; the median follow-up time was 95 months. The fraction of tumor cells in S phase was assessed by flow cytometry, and tumor cell proliferation was measured immunohistochemically with the monoclonal antibodies Ki-S2 and Ki-S5 (directed against the nuclear antigen Ki-67). A combined prognostic index was calculated on the basis of the S-phase fraction, progesterone receptor content, and tumor size.In multivariate analyses that did or did not (263 and 332 observations, respectively) include the S-phase fraction and the combined prognostic index, the Ki-S2 labeling index (percentage of antibody-stained tumor cell nuclei) emerged as the most statistically significant predictor of overall survival, disease-specific survival, and disease-free survival (all two-sided P<.0001). In the risk group defined by a Ki-S2 labeling index of 10% or less, life expectancy was not statistically significantly different from that of age-matched women without breast cancer, whereas the group with a high Ki-S2 labeling index had an increased risk of mortality of up to 20-fold.Cellular proliferation is a major determinant of the biologic behavior of breast cancer. Prognosis is apparently best indicated by the percentage of cells in S through M phases of the cell cycle. Measurement of the Ki-S2 labeling index of a tumor sample may improve a clinician's ability to make an accurate prognosis and to identify patients with a low risk of recurrence who may not need adjuvant therapy.
Persistence of systemic and splanchnic hyperkinetic circulation in liver transplant patients
Authors: Antoine Hadengue, Didier Lebrec, Richard Moreau, Philippe Sogni, François Durand, Christophe Gaudin, Jacques Bernuau, Jacques Belghiti, Brice Gayet, Serge Erlinger, Jean-Pierre Benhamou
Journal: Hepatology (1993)

Portal pressure and portal-systemic collateral circulation after orthotopic liver transplantation have not been investigated. We studied systemic and splanchnic hemodynamics in 17 patients with cirrhosis before and 205 +/- 146 days after orthotopic liver transplantation. Among the 17 orthotopic liver transplantation patients, 12 had undergone hemodynamic study in the 6 mo before orthotopic liver transplantation. Controls were 50 patients with normal liver architecture. Cardiac index remained elevated in orthotopic liver transplantation patients compared with controls (3.6 +/- 0.9 vs 3.1 +/- 0.4 L/min.m2; p < 0.05). Azygos blood flow, which was elevated before orthotopic liver transplantation (585 +/- 402 ml/min), remained elevated after orthotopic liver transplantation (553 +/- 343 ml/min). In transplant patients, hepatic blood flow was higher than it was in controls (2.26 +/- 0.86 vs. 1.38 +/- 0.57 L/min; p < 0.05). Elevated hepatic blood flow correlated with cardiac index (r = 0.647, p < 0.025). In patients with normal graft function, hepatic venous pressure gradient was normal (2 +/- 1 mm Hg). In a patient with acute rejection, a sharp elevation in the hepatic venous pressure gradient was observed; it returned to normal 45 days after treatment. We conclude that despite normal portal pressure, portal-systemic collateral blood flow remains elevated after orthotopic liver transplantation. Possibly because of persistent collateral circulation, which may keep portal tributary blood flow elevated, hepatic blood flow is increased after orthotopic liver transplantation. Elevated splanchnic blood flow, in turn, contributes to the high cardiac index in liver recipients. Finally, a sharp elevation in portal pressure, which may be observed during acute rejection and subsides after treatment, merits further study.
Expression of the serotonin 1b receptor in experimental pulmonary hypertension
Authors: B. Rondelet, R. Van Beneden, F. Kerbaul, S. Motte, P. Fesler, K. McEntee, S. Brimioulle, J-M. Ketelslegers, R. Naeije
Journal: European Respiratory Journal (2003)

The pathogenesis of pulmonary arterial hypertension (PAH) remains uncertain. Both the serotonin and endothelin (ET) systems are believed to be involved. Recent studies pointed to the importance of the serotonin 2B receptor as a limiting step. The current authors investigated the lung tissue expression of serotonin receptors and of the serotonin transporter (5-HTT) by real-time-quantitative polymerase chain reaction in chronic overcirculation-induced PAH in growing piglets, with and without treatment with the dual ET receptor blocker bosentan. Pulmonary haemodynamic changes were described by pulmonary arterial impedance spectra. Three months after the surgical anastomosis of the left subclavian artery to the pulmonary arterial trunk, there was a shift of the impedance spectra to higher ratios of pressure and flow moduli, with increases in both 0 Hz impedance and characteristic impedance, and these changes were completely prevented by bosentan therapy. There was an increase in the expression of the serotonin 1B receptor. There was no change in the expression of the 5-HTT, and of the serotonin 2B, 1D, and 4 receptors. The overexpression of the serotonin 1B receptor was partially prevented by bosentan therapy. The present authors conclude that this early pulmonary arterial hypertension model is characterised by an endothelin receptor-dependent increased expression of the serotonin 1B receptor.
Protein kinase activation and myocardial ischemia/reperfusion injury
Authors: S Armstrong
Journal: Cardiovascular Research (2003)

Myocardial ischemia and ischemia/reperfusion activate several protein kinase pathways. Protein kinase activation potentially regulates the onset of myocardial cell injury and the reduction of this injury by ischemic and pharmacologic preconditioning. The primary protein kinase pathways that are potentially activated by myocardial ischemia/reperfusion include: the MAP kinases, ERK 1/2, JNK 1/2, p38 MAPKα/β; the cell survival kinase, Akt; and the sodium–hydrogen exchanger (NHE) kinase, p90RSK. The literature does not support a role for ischemia/reperfusion in the activation of the tyrosine kinases, Src and Lck, or the translocation and activation of PKC. This review will detail the role of these protein kinases in the onset of myocardial cell death by necrosis and apoptosis and the reduction of this injury by preconditioning.
A MicroRNA-Based Test Improves Endoscopic Ultrasound–Guided Cytologic Diagnosis of Pancreatic Cancer
Authors: Randall E Brand, Alex T Adai, Barbara A Centeno, Linda S Lee, George Rateb, Shivakumar Vignesh, Charles Menard, Anna Wiechowska-Kozłowska, Hubert Bołdys, Marek Hartleb, Michael K Sanders, Johanna B Munding, Andrea Tannapfel, Stephan A Hahn, Ludomir Stefańczyk, Gregory J Tsongalis, David C Whitcomb, Darwin L Conwell, Jean A Morisset, Timothy B Gardner, Stuart R Gordon, Arief A Suriawinata, Maura B Lloyd, Dennis Wylie, Emmanuel Labourier, Bernard F Andruss, Anna E Szafranska-Schwarzbach
Journal: Clinical Gastroenterology and Hepatology (2014)
Prescription Medicines and the Risk of Road Traffic Crashes: A French Registry-Based Study
Authors: Ludivine Orriols, Bernard Delorme, Blandine Gadegbeku, Aurore Tricotel, Benjamin Contrand, Bernard Laumon, Louis-Rachid Salmi, Emmanuel Lagarde
Journal: PLoS Medicine (2010)

In recent decades, increased attention has been focused on the impact of disabilities and medicinal drug use on road safety. The aim of our study was to investigate the association between prescription medicines and the risk of road traffic crashes, and estimate the attributable fraction.We extracted and matched data from three French nationwide databases: the national health care insurance database, police reports, and the national police database of injurious crashes. Drivers identified by their national health care number involved in an injurious crash in France, between July 2005 and May 2008, were included in the study. Medicines were grouped according to the four risk levels of the French classification system (from 0 [no risk] to 3 [high risk]). We included 72,685 drivers involved in injurious crashes. Users of level 2 (odds ratio [OR] = 1.31 [1.24-1.40]) and level 3 (OR = 1.25 [1.12-1.40]) prescription medicines were at higher risk of being responsible for a crash. The association remained after adjustment for the presence of a long-term chronic disease. The fraction of road traffic crashes attributable to levels 2 and 3 medications was 3.3% [2.7%-3.9%]. A within-person case-crossover analysis showed that drivers were more likely to be exposed to level 3 medications on the crash day than on a control day, 30 days earlier (OR = 1.15 [1.05-1.27]).The use of prescription medicines is associated with a substantial number of road traffic crashes in France. In light of the results, warning messages appear to be relevant for level 2 and 3 medications and questionable for level 1 medications. A follow-up study is needed to evaluate the impact of the warning labeling system on road traffic crash prevention.
Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia
Authors: Dragana Milojkovic, Jane Apperley
Journal: Clinical Cancer Research (2009)

Targeted therapy in the form of selective tyrosine kinase inhibitors (TKI) has transformed the approach to management of chronic myeloid leukemia (CML) and dramatically improved patient outcome to the extent that imatinib is currently accepted as the first-line agent for nearly all patients presenting with CML, regardless of the phase of the disease. Impressive clinical responses are obtained in the majority of patients in chronic phase; however, not all patients experience an optimal response to imatinib, and furthermore, the clinical response in a number of patients will not be sustained. The process by which the leukemic cells prove resistant to TKIs and the restoration of BCR-ABL1 signal transduction from previous inhibition has initiated the pursuit for the causal mechanisms of resistance and strategies by which to surmount resistance to therapeutic intervention. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance, however, it is increasingly evident that the presence of mutations does not explain all cases of resistance and does not account for the failure of TKIs to eliminate minimal residual disease in patients who respond optimally. The focus of exploring TKI resistance has expanded to include the mechanism by which the drug is delivered to its target and the impact of drug influx and efflux proteins on TKI bioavailability. The limitations of imatinib have inspired the development of second generation TKIs in order to overcome the effect of resistance to this primary therapy. (Clin Cancer Res 2009;15(24):7519-27).
Subgroups of primary Sjogren's syndrome. Sjogren's syndrome in male and paediatric Greek patients
Authors: A. A Drosos, E. K Tsiakou, N. Tsifetaki, E. N Politi, A. Siamopoulou-Mavridou
Journal: Annals of the Rheumatic Diseases (1997)

To describe the clinical and serological findings in male and paediatric Sjögren's syndrome (SS) patients.Using the European criteria for the diagnosis of SS 12 male and 13 paediatric patients were identified and compared with those of 30 consecutive unselected adult female SS patients.The mean (SD) age of paediatric patients was 9.4 (2.2) years, ranging from 6 to 14 years. Recurrent parotid gland enlargement was the initial clinical manifestation in the majority of the children with a statistical significance compared with male (p < 0.01) and with female patients (p < 0.0001). Sicca manifestations were the most common clinical symptoms in male and female patients at disease onset. The systemic manifestations were similar among the three groups except that men showed lower frequency of arthritis (p < 0.05) and Raynaud's phenomenon (p < 0.05) compared with women. No differences were found among the immunological profile of children and female patients, while male patients had a lower frequency of antinuclear antibodies (p < 0.025) and antibodies to Ro(SSA) nuclear antigens (p < 0.025) compared with women.Primary SS is rare in children and men in Greece. Recurrent parotid gland enlargement is the most common clinical finding at disease onset in children. Male patients seem to have less systemic manifestations and lower frequency of autoantibodies.