tbuckley/cabot-search huggingface dataset:
Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Gemcitabine/Cisplatin Alone or With Sorafenib for the First-Line Treatment of Advanced, Nonsquamous Non–Small-Cell Lung Cancer
Authors: Luis G. Paz-Ares, Bonne Biesma, David Heigener, Joachim von Pawel, Timothy Eisen, Jaafar Bennouna, Li Zhang, Meilin Liao, Yan Sun, Steven Gans, Kostas Syrigos, Etienne Le Marie, Maya Gottfried, Johan Vansteenkiste, Vincente Alberola, Uwe Phillip Strauss, Elaine Montegriffo, Teng Jin Ong, Armando Santoro
Journal: Journal of Clinical Oncology (2012)

This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non-small-cell lung cancer (NSCLC).Between February 2007 and March 2009, 904 patients were randomly assigned to daily sorafenib (400 mg twice a day) or matching placebo plus gemcitabine (1,250 mg/m(2) per day on days 1 and 8) and cisplatin (75 mg/m(2) on day 1) for up to six 21-day cycles. Because of safety findings from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE) trial, patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS) and time-to-progression (TTP).The primary analysis population consisted of 772 patients (sorafenib, 385; placebo, 387); the two groups had similar demographic and baseline characteristics. Median OS was similar in the sorafenib and placebo groups (12.4 v 12.5 months; hazard ratio [HR], 0.98; P = .401). By investigator assessment, sorafenib improved median PFS (6.0 v 5.5 months; HR, 0.83; P = .008) and TTP (6.1 v 5.5 months; HR, 0.73; P < .001). Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included hand-foot skin reaction (8.6% v 0.3%), fatigue (7.3% v 3.6%), rash (5.7% v 0.5%), and hypertension (4.2% v 1.8%). No unexpected toxicities were observed.This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.
Counterpoint: Inpatient Glucose Management
Authors: Silvio E. Inzucchi, Julio Rosenstock
Journal: Diabetes Care (2005)

Recently, the attention of the diabetes community has shifted to glycemic management in the inpatient setting, where there has been a rising chorus in support of stricter blood glucose control. We applaud the spirit of the current American College of Endocrinology (ACE) recommendations, which attempt to improve the hospital management of hyperglycemia (1). However, as we examine the very limited evidence upon which these guidelines are based, we are concerned about such prematurely stringent glucose targets. Indeed, there is a paucity of well-controlled randomized trials in which the feasibility and safety of specific insulin strategies in the variety of inpatient settings have been validated. Moreover, few have assessed actual outcomes at different glycemic ranges.

We all recognize that several cross-sectional studies have consistently demonstrated that hyperglycemia correlates with increased morbidity and mortality in the acutely ill, particularly in the critically ill and in the perioperative setting (2–4). This association holds for both patients with previously diagnosed diabetes and those with newly recognized hyperglycemia (5). However, the directionality of this relationship remains controversial. Does acute hyperglycemia lead to poor clinical outcomes or is it a reflection of sicker patients, due to increased counterregulatory forces that simply manifest their stress in the form of elevated blood glucose? Is an elevated blood glucose a marker or a pathogenic mechanism of disease in these patients?

Experimental evidence has clearly supported a cause-and-effect relationship. Leukocyte action, immunoglobulin production, wound healing, collagen production, endothelial function, cardiac performance, and fluid balance are each impaired in the setting of hyperglycemia, particularly when severe (6,7). Admittedly, most data stem from in vitro observations and from in vivo investigations employing animal models (8–10). Moreover, these studies were typically designed to contrast markedly elevated versus normal ambient glucose concentrations (8–10). And, because insulin …
Morphology of BALB/c Mice Inoculated With Rauscher Virus
Authors: Thelma B. Dunn, Arleigh W. Green
Journal: JNCI Journal of the National Cancer Institute (1966)

A morphologic study was made of inbred BALB/c mice inoculated with the Rauscher virus. The initial effect was a rapid proliferation of erythroblastic cells in the red pulp of the spleen. Later the spleen was enormously enlarged and resembled a blood-filled sponge. Erythroblastic proliferation also appeared in the liver. Two groups of mice, one that received an early virus preparation and the other a virus recovered from rats, developed lymphocytic leukemia. Thymectomy had no apparent effect on the erythroblastic reaction, while splenectomy intensified the process in the liver and erythroblastic foci appeared in the lymph nodes. Granulocytopoiesis was also stimulated in some mice. The mechanism by which the virus produced the intense blood cell proliferation was not determined. The variability in the reactions of mice to the inoculation of the Rauscher virus is emphasized.
Influence of Casein Kinase II in Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Rhabdomyosarcoma Cells
Authors: Kamel Izeradjene, Leslie Douglas, Addison Delaney, Janet A. Houghton
Journal: Clinical Cancer Research (2004)

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via the death receptors DR4 and DR5 in transformed cells in vitro and exhibits potent antitumor activity in vivo with minor side effects. Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli and is aberrantly elevated in a variety of human cancers. Rhabdomyosarcoma tumors are the most common soft-tissue sarcoma in childhood. In this investigation, we demonstrate that CK2 is a key survival factor that protects tumor cells from TRAIL-induced apoptosis. We have demonstrated that inhibition of CK2 phosphorylation events by 5,6-dichlorobenzimidazole (DRB) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis. CK2 inhibition also induced rapid cleavage of caspase-8, -9, and -3, as well as the caspase substrate poly(ADP-ribose) polymerase after TRAIL treatment. Overexpression of Bcl-2 protected cells from TRAIL-induced apoptosis in the presence of the CK2 inhibitor. Death signaling by TRAIL in these cells was Fas-associated death domain and caspase dependent because dominant negative Fas-associated death domain or the cowpox interleukin 1β-converting enzyme inhibitor protein cytokine response modifier A prevented apoptosis in the presence of DRB. Analysis of death-inducing signaling complex (DISC) formation demonstrated that inhibition of CK2 by DRB increased the level of recruitment of procaspase-8 to the DISC and enhanced caspase-8-mediated cleavage of Bid, thereby increasing the release of the proapoptotic factors cytochrome c, HtrA2/Omi, Smac/DIABLO, and apoptosis inducing factor (AIF) from the mitochondria, with subsequent degradation of X-linked inhibitor of apoptosis protein (XIAP). To further interfere with CK2 function, JR1 and Rh30 cells were transfected with either short hairpin RNA targeted to CK2α or kinase-inactive CK2α (K68M) or CK2α′ (K69M). Data show that the CK2 kinase activity was abrogated and that TRAIL sensitivity in both cell lines was increased. Silencing of CK2α expression with short hairpin RNA was also associated with degradation of XIAP. These findings suggest that CK2 regulates TRAIL signaling in rhabdomyosarcoma by modulating TRAIL-induced DISC formation and XIAP expression.
Unconjugated bile salts shuttle through hepatocyte peroxisomes for taurine conjugation
Authors: Krzysztof P. Rembacz, Jannes Woudenberg, Mark Hoekstra, Elles Z. Jonkers, Fiona A.J. van den Heuvel, Manon Buist-Homan, Titia E. Woudenberg-Vrenken, Jana Rohacova, M. Luisa Marin, Miguel A. Miranda, Han Moshage, Frans Stellaard, Klaas Nico Faber
Journal: Hepatology (2010)

Bile acid-CoA:amino acid N-acyltransferase (BAAT) conjugates bile salts to glycine or taurine, which is the final step in bile salt biosynthesis. In addition, BAAT is required for reconjugation of bile salts in the enterohepatic circulation. Recently, we showed that BAAT is a peroxisomal protein, implying shuttling of bile salts through peroxisomes for reconjugation. However, the subcellular location of BAAT remains a topic of debate. The aim of this study was to obtain direct proof for reconjugation of bile salts in peroxisomes. Primary rat hepatocytes were incubated with deuterium-labeled cholic acid (D4CA). Over time, media and cells were collected and the levels of D4CA, D4-tauro-CA (D4TCA), and D4-glyco-CA (D4GCA) were quantified by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Subcellular accumulation of D4-labeled bile salts was analyzed by digitonin permeabilization assays and subcellular fractionation experiments. Within 24 hours, cultured rat hepatocytes efficiently (>90%) converted and secreted 100 μM D4CA to D4TCA and D4GCA. The relative amounts of D4TCA and D4GCA produced were dependent on the presence of glycine or taurine in the medium. Treatment of D4CA-exposed hepatocytes with 30-150 μg/mL digitonin led to the complete release of D4CA, D4GCA, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (cytosolic marker). Full release of D4TCA, catalase, and BAAT was only observed at 500 μg/mL digitonin, indicating the presence of D4TCA in membrane-enclosed organelles. D4TCA was detected in fractions of purified peroxisomes, which did not contain D4CA and D4GCA. Conclusion: We established a novel assay to study conjugation and intra- and transcellular transport of bile salts. Using this assay, we show that cholic acid shuttles through peroxisomes for taurine-conjugation. (HEPATOLOGY 2010)
Brain Surface Anatomy in Adults With Autism
Authors: Christine Ecker, Cedric Ginestet, Yue Feng, Patrick Johnston, Michael V. Lombardo, Meng-Chuan Lai, John Suckling, Lena Palaniyappan, Eileen Daly, Clodagh M. Murphy, Steven C. Williams, Edward T. Bullmore, Simon Baron-Cohen, Michael Brammer, Declan G. M. Murphy, for the MRC AIMS Consortium
Journal: JAMA Psychiatry (2012)

<h3>Context</h3>Neuroimaging studies of brain anatomy in autism spectrum disorder (ASD) have mostly been based on measures of cortical volume (CV). However, CV is a product of 2 distinct parameters, cortical thickness (CT) and surface area (SA), that in turn have distinct genetic and developmental origins.<h3>Objective</h3>To investigate regional differences in CV, SA, and CT as well as their relationship in a large and well-characterized sample of men with ASD and matched controls.<h3>Design</h3>Multicenter case-control design using quantitative magnetic resonance imaging.<h3>Setting</h3>Medical Research Council UK Autism Imaging Multicentre Study.<h3>Participants</h3>A total of 168 men, 84 diagnosed as having ASD and 84 controls who did not differ significantly in mean (SD) age (26 [7] years vs 28 [6] years, respectively) or full-scale IQ (110 [14] vs 114 [12], respectively).<h3>Main Outcome Measures</h3>Between-group differences in CV, SA, and CT investigated using a spatially unbiased vertex-based approach; the degree of spatial overlap between the differences in CT and SA; and their relative contribution to differences in regional CV.<h3>Results</h3>Individuals with ASD differed from controls in all 3 parameters. These mainly consisted of significantly increased CT within frontal lobe regions and reduced SA in the orbitofrontal cortex and posterior cingulum. These differences in CT and SA were paralleled by commensurate differences in CV. The spatially distributed patterns for CT and SA were largely nonoverlapping and shared only about 3% of all significantly different locations on the cerebral surface.<h3>Conclusions</h3>Individuals with ASD have significant differences in CV, but these may be underpinned by (separable) variations in its 2 components, CT and SA. This is of importance because both measures result from distinct developmental pathways that are likely modulated by different neurobiological mechanisms. This finding may provide novel targets for future studies into the etiology of the condition and a new way to fractionate the disorder.
Anti-tumor activity of liposomal glucocorticoids: The relevance of liposome-mediated drug delivery, intratumoral localization and systemic activity
Authors: Ewelina Kluza, Sin Yuin Yeo, Sophie Schmid, Daisy W.J. van der Schaft, Renate W. Boekhoven, Raymond M. Schiffelers, Gert Storm, Gustav J. Strijkers, Klaas Nicolay
Journal: Journal of Controlled Release (2010)
Contribution of Dexamethasone to Control of Chemotherapy-Induced Nausea and Vomiting: A Meta-Analysis of Randomized Evidence
Authors: John P. A. Ioannidis, Paul J. Hesketh, Joseph Lau
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To synthesize the available randomized evidence on the efficacy of dexamethasone when used for protection against acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic cancer chemotherapy. MATERIALS AND METHODS: A meta-analysis was performed using trials identified through MEDLINE (1966 to April 1999), Embase, Derwent Drug File, and the Cochrane Library’s Database of Controlled Trials. Data on acute and delayed emesis and nausea were collected. All randomized studies comparing dexamethasone to placebo, no treatment, or other antiemetics qualified, including cross-over trials providing first-cycle data. RESULTS: Of 1,200 citations screened, 32 studies with 42 pertinent comparisons and 5,613 patients were included in the meta-analysis. Dexamethasone was superior to placebo or no treatment for complete protection from acute emesis (odds ratio, 2.22; 95% confidence interval [CI], 1.89 to 2.60) and for complete protection from delayed emesis (odds ratio, 2.04; 95% CI, 1.63 to 2.56). The results were similar for complete protection from nausea. The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively). The beneficial effect was similar in subgroups defined by various study design parameters. No trial addressed the efficacy of dexamethasone in the delayed phase without having administered dexamethasone for acute-phase protection as well. CONCLUSION: Dexamethasone is clearly effective in protecting from emesis both in the acute and delayed phases, with emesis avoided in one patient out of six treated. Future trials should determine whether the delayed-phase effect is independent of the acute-phase benefit.
Bronchoscopic Photodynamic Therapy of Bronchial Carcinoma
Authors: K. Häußinger, R. M. Huber, M. Krug, R. Baumgartner, H. Stepp, E. Unsöld, D. Jocham, O. Karg, R. Sroka
Journal: Endoscopy (1989)

Photodynamic therapy with photosensitizers is a new method of treating malignant tumors. In the area of bronchoscopy it is employed for the selective therapy of early carcinomas at central localizations. We report on our first attempts at treatment with hematoporphyrin derivative in an inoperable patient. The modalities of irradiation and the recurrence-free progress of, to date, 2.5 years, are described.
Magnetic resonance imaging in sports medicine--an overview.
Authors: T Featherstone
Journal: British Journal of Sports Medicine (1994)

As more Britons become health conscious and are involved in a variety of sporting events, sports-related injuries are a daily occurrence. Although evaluation of bony abnormalities resulting from acute and chronic sports injury by conventional radiography and bone scintigraphy has been satisfactory, the assessment of soft tissue and tendinous injury is more difficult and imprecise. Due to its superior contrast sensitivity and multiplanar imaging capability, magnetic resonance imaging has already shown great promise in delineating soft-tissue and tendinous abnormalities. In addition, marrow pathology is exquisitely displayed.
STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection
Authors: Peter Ferenci, Tarik Asselah, Graham R. Foster, Stefan Zeuzem, Christoph Sarrazin, Christophe Moreno, Denis Ouzan, Marina Maevskaya, Filipe Calinas, Luis E. Morano, Javier Crespo, Jean-François Dufour, Marc Bourlière, Kosh Agarwal, Daniel Forton, Marcus Schuchmann, Elmar Zehnter, Shuhei Nishiguchi, Masao Omata, George Kukolj, Yakov Datsenko, Miguel Garcia, Joseph Scherer, Anne-Marie Quinson, Jerry O. Stern
Journal: Journal of Hepatology (2015)
WT1 Mutation and 11P15 Loss of Heterozygosity Predict Relapse in Very Low-Risk Wilms Tumors Treated With Surgery Alone: A Children's Oncology Group Study
Authors: Elizabeth J. Perlman, Paul E. Grundy, James R. Anderson, Lawrence J. Jennings, Daniel M. Green, Jeffrey S. Dome, Robert C. Shamberger, E. Cristy Ruteshouser, Vicki Huff
Journal: Journal of Clinical Oncology (2010)

Children's Oncology Group defines very low-risk Wilms tumors (VLRWT) as stage I favorable histology Wilms tumors weighing less than 550 g in children younger than 24 months of age. VLRWTs may be treated with nephrectomy alone. However, 10% to 15% of VLRWTs relapse without chemotherapy. Previous studies suggest that VLRWTs with low WT1 expression and/or 11p15 loss of heterozygosity (LOH) may have increased risk of relapse. The current study validates these findings within prospectively identified children with VLRWT who did not receive adjuvant chemotherapy.Fifty-six VLRWTs (10 relapses) were analyzed for mutation of WT1, CTNNB1, and WTX; for 11p15 LOH using microsatellite analysis; and for H19DMR and KvDMR1 methylation.11p15 LOH was identified in 19 (41%) of 46 evaluable VLRWTs and was significantly associated with relapse (P < .001); 16 of 19 were isodisomic for 11p15. WT1 mutation was identified in nine (20%) of 45 evaluable VLRWTs and was significantly associated with relapse (P = .004); all nine cases also had 11p15 LOH. All evaluable tumors showing LOH by microsatellite analysis also showed LOH by methylation analysis. Retention of the normal imprinting pattern was identified in 24 of 42 evaluable tumors, and none relapsed. Loss of imprinting at 11p15 was identified in one of 42 tumors.WT1 mutation and 11p15 LOH are associated with relapse in patients with VLRWTs who do not receive chemotherapy. These may provide meaningful biomarkers to stratify patients for reduced chemotherapy in the future. VLRWTs show a different incidence of WT1 mutation and 11p15 imprinting patterns than has been reported in Wilms tumors of all ages.
The Science of Neural Interface Systems
Authors: Nicholas G. Hatsopoulos, John P. Donoghue
Journal: Annual Review of Neuroscience (2009)

The ultimate goal of neural interface research is to create links between the nervous system and the outside world either by stimulating or by recording from neural tissue to treat or assist people with sensory, motor, or other disabilities of neural function. Although electrical stimulation systems have already reached widespread clinical application, neural interfaces that record neural signals to decipher movement intentions are only now beginning to develop into clinically viable systems to help paralyzed people. We begin by reviewing state-of-the-art research and early-stage clinical recording systems and focus on systems that record single-unit action potentials. We then address the potential for neural interface research to enhance basic scientific understanding of brain function by offering unique insights in neural coding and representation, plasticity, brain-behavior relations, and the neurobiology of disease. Finally, we discuss technical and scientific challenges faced by these systems before they are widely adopted by severely motor-disabled patients.
Top-Down and Bottom-Up Approaches to Health Care Quality: The Impacts of Regulation and Report Cards
Authors: Dana B. Mukamel, Simon F. Haeder, David L. Weimer
Journal: Annual Review of Public Health (2013)

The high cost of the US health care system does not buy uniformly high quality of care. Concern about low quality has prompted two major types of public policy responses: regulation, a top-down approach, and report cards, a bottom-up approach. Each can result in either functional provider responses, which increase quality, or dysfunctional responses, which may lower quality. What do we know about the impacts of these two policy approaches to quality? To answer this question, we review the extant literature on regulation and report cards. We find evidence of both functional and dysfunctional effects. In addition, we identify the areas in which additional research would most likely be valuable.
Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice
Authors: Chi Him Eddie Ma, Takao Omura, Enrique J. Cobos, Alban Latrémolière, Nader Ghasemlou, Gary J. Brenner, Ed van Veen, Lee Barrett, Tomokazu Sawada, Fuying Gao, Giovanni Coppola, Frank Gertler, Michael Costigan, Dan Geschwind, Clifford J. Woolf
Journal: Journal of Clinical Investigation (2011)

Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it resulted from a lack of motor end plate reinnervation. Tg mice expressing high levels of Hsp27 demonstrated enhanced restoration of motor function after nerve transection/resuture by enabling motor synapse reinnervation, but only within 5 weeks of injury. In humans with peripheral nerve injuries, shorter wait times to decompression surgery led to improved functional recovery, and, while a return of sensation occurred in all patients, motor recovery was limited. Thus, absence of motor recovery after nerve damage may result from a failure of synapse reformation after prolonged denervation rather than a failure of axonal growth.