tbuckley/cabot-search huggingface dataset:
Colon and Rectal Cancer: Laparoscopic or Open?
Authors: Anne-Marie Boller, Heidi Nelson
Journal: Clinical Cancer Research (2007)

Early experiences with laparoscopic colectomy were unfavorable, with higher than expected rates of wound tumor implants and concerns about short and long-term compromised oncologic outcomes. Several international randomized controlled trials were initiated to address concerns regarding compromised oncologic outcomes. Each of the trials was designed to test the hypothesis that level 1 evidence supports the general feasibility and recovery advantage as well as cancer equivalence of laparoscopic colectomy in curable colon cancer. The following four phase III randomized controlled trials have completed accrual and reported early data on recovery benefits for laparoscopic colectomy: Barcelona, Clinical Outcomes of Surgical Therapy Study Group (COSTSG), Colon Cancer Laparoscopic or Open Resection (COLOR), and Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC). These trials have uniformly and consistently shown a significant reduction in the use of narcotics and oral analgesics and length of hospital stay, as well as a faster return of diet and bowel function, with laparoscopic colectomy. Two of the trials, Barcelona and COSTSG, have sufficient maturation and follow-up to report recurrence and survival data, and neither has found a survival disadvantage in patients treated with laparoscopic colectomy. Results of the Barcelona trial suggest a cancer-related survival advantage in patients treated with laparoscopic colectomy, based solely on differences in patients with stage III disease; this is not confirmed by the COSTSG trial. Results of the CLASICC and COLOR trials, as well as 5-year data from the COSTSG trial, should definitively address survival results. The investigational experience with laparoscopic rectal cancer is not as mature; the subset of rectal cancer patients (n = 253) in the CLASICC trial provides the only available randomized controlled trial data. Laparoscopic colectomy in patients with curable cancer is accepted as an alternative to open colectomy, whereas the viability of laparoscopic rectal cancer resection requires further investigation.
Prophylactic Cranial Irradiation in Operable Stage IIIA Non–Small-Cell Lung Cancer Treated With Neoadjuvant Chemoradiotherapy: Results From a German Multicenter Randomized Trial
Authors: Christoph Pöttgen, Wilfried Eberhardt, Andreas Grannass, Soenke Korfee, Georg Stüben, Helmut Teschler, Georgios Stamatis, Horst Wagner, Bernward Passlick, Volker Petersen, Volker Budach, Hans Wilhelm, Isabel Wanke, Herbert Hirche, Hans-Jochen Wilke, Martin Stuschke
Journal: Journal of Clinical Oncology (2007)

To investigate the role of prophylactic cranial irradiation (PCI) within a trimodality protocol (chemotherapy, chemoradiotherapy, surgery) for patients with operable stage IIIA non-small-cell lung cancer (NSCLC).After mediastinoscopic staging, patients with operable stage IIIA NSCLC were enrolled to a German multicenter trial and randomly assigned to receive either primary resection followed by adjuvant thoracic radiation therapy (50 to 60 Gy; arm A) or preoperative chemotherapy (cisplatin/etoposide [PE]; three cycles) followed by concurrent chemoradiotherapy (PE plus 45 Gy; 1.5 Gy twice per day) and definitive surgery (arm B), respectively. Patients in arm B were scheduled to receive PCI (30 Gy; 2 Gy daily fractions).One hundred twelve patients were randomly assigned between November 1994 and July 2001. One hundred six patients were eligible (arm A: 51, arm B: 55), 90 males and 16 females, 50 with squamous cell, 16 with large cell, five with adenosquamous, and 35 with adenocarcenoma (median age, 57 years; range, 37 to 71 years). Forty-three patients received PCI as scheduled in arm B. Eleven long-term survivors (arm A: four; arm B: seven) underwent a comprehensive neuropsychological examination. PCI significantly reduced the probability of brain metastases as first site of failure (7.8% at 5 years v 34.7%; P = .02), the overall brain relapse rate was reduced comparably (9.1% at 5 years v 27.2%; P = .04). A slightly reduced neurocognitive performance in comparison with the age-matched normal population was found for patients in both treatment groups. No significant difference between patients who were treated with or without PCI could be noted.PCI is effective in preventing brain metastases following this aggressive trimodality approach. Neurocognitive late effects are not significantly different between patients treated with or without PCI.
Regulation of male fertility by CFTR and implications in male infertility
Authors: Hui Chen, Ye Chun Ruan, Wen Ming Xu, Jing Chen, Hsiao Chang Chan
Journal: Human Reproduction Update (2012)

BACKGROUNDThe cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl− and HCO3− conducting channel, mutations of which are known to be associated with male infertility. However, the underlying mechanisms remain elusive.
Serotonin receptor modulation in irritable bowel syndrome: one step forwards and one step backwards
Authors: P J WHORWELL
Journal: Gut (2001)

The pharmacological treatment of irritable bowel syndrome (IBS) is currently far from satisfactory and there have been no new drug developments for many years. Recently, there has been a surge of interest in serotonin and the gut with particular emphasis, where IBS is concerned, on 5-HT3 and 5-HT4 receptors. A number of agonists and antagonists of these receptors are now under investigation and alosetron (a 5-HT3 antagonist) was the first to reach the market in the USA.

In the study reported here which was confined to women, alosetron was found to be significantly superior to placebo in providing “adequate relief of pain/discomfort” in patients with diarrhoea and improving bowel function in patients with both diarrhoea and an alternating bowel habit. A particularly noteworthy feature was that the advantage of alosetron was promptly lost when treatment was stopped, suggesting a real effect. The main side effect of treatment was constipation but one case of ischaemic colitis was also reported.

IBS is notorious for its disparate symptomatology1 and the varying importance that patients place on a particular symptom.2 Thus defining a primary outcome measure for trials is fraught with difficulties, an issue which has recently been addressed by the Rome II Consensus Conference.3 It was suggested that a global outcome measure that integrates the key symptoms is probably the most preferable. Thus the “adequate relief of pain/discomfort” used in this study does not quite meet this standard but this trial was designed before the publication …
Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure
Authors: Julie Wallis, Craig A. Lygate, Alexandra Fischer, Michiel ten Hove, Jürgen E. Schneider, Liam Sebag-Montefiore, Dana Dawson, Karen Hulbert, Wen Zhang, Mei Hua Zhang, Hugh Watkins, Kieran Clarke, Stefan Neubauer
Journal: Circulation (2005)

Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT).We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66+/-6 nmol/mg protein in WT versus 133+/-52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5+/-4.3 microL in WT versus 33.1+/-9.6 microL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64+/-9% in WT versus 49+/-13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=-0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dt(max) (r=-0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels.Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.
Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma
Authors: John G. Kuhn, Susan M. Chang, Patrick Y. Wen, Timothy F. Cloughesy, Harry Greenberg, David Schiff, Charles Conrad, Karen L. Fink, H. Ian Robins, Minesh Mehta, Lisa DeAngelis, Jeffrey Raizer, Kenneth Hess, Kathleen R. Lamborn, Janet Dancey, Michael D. Prados
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue. Experimental Design: Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis. Results: Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus. Conclusions: Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.
A NOTE ON THE SPECIFICITY OF CYTOTOXINS
Authors: Robert A. Lambert
Journal: The Journal of Experimental Medicine (1914)

1. The plasma of guinea pigs treated by injections of rat sarcoma exhibits a toxic action in tissue culture preparations on the cells of both rat sarcoma and rat embryo skin. Similarly, the plasma of guinea pigs immunized by injections of rat embryo skin is toxic for cells of both types. 2. Injection of rat blood immunizes against both sarcoma and embryo skin, although not so strongly as injections of the two tissues. 3. Guinea pigs receiving injections of either chick embryo heart or intestine develop cytotoxic substances for both of these tissues. 4. The preceding findings tend to show that cytotoxins formed after the injection of different body tissues into a foreign species are to no extent specific for the tissues injected.
Panoramic optical mapping shows wavebreak at a consistent anatomical site at the onset of ventricular fibrillation
Authors: Elliot B. Bourgeois, Hugh D. Reeves, Gregory P. Walcott, Jack M. Rogers
Journal: Cardiovascular Research (2011)

AimsThe first seconds of ventricular fibrillation (VF) are well organized and can consist of just one to two rotating waves (rotors). New rotors are spawned when local propagation block causes wave fragmentation. We hypothesized that this process, which leads to fully developed VF, begins at a consistent anatomic site.
Anxiety and Outcome in Bipolar Disorder
Authors: William Coryell, David A Solomon, Jess G Fiedorowicz, Jean Endicott, Pamela J Schettler, Lewis L Judd
Journal: American Journal of Psychiatry (2009)

Important differences exist between bipolar disorder with and without comorbid anxiety, but little is known about the long-term prognostic significance of coexisting anxiety in bipolar disorder. The authors sought to identify the anxiety features most predictive of subsequent affective morbidity and to evaluate the persistence of the prognostic relationship.Probands with bipolar I or II disorder from the National Institute of Mental Health Collaborative Depression Study were followed prospectively for a mean of 17.4 years (SD=8.4) and were characterized according to various manifestations of anxiety present at baseline. A series of general linear model analyses examined the relationship between these measures and the proportion of follow-up weeks in episodes of major depression and in episodes of mania or hypomania.Patients whose episode at intake included a depressive phase spent nearly three times as many weeks in depressive episodes than did those whose intake episode was purely manic. Psychic and somatic anxiety ratings, but not the presence of panic attacks or of any lifetime anxiety disorder, added to the predictive model. Combined ratings of psychic and somatic anxiety were associated in a stepwise fashion with a greater proportion of weeks in depressive episodes, and this relationship persisted over the follow-up period.The presence of higher levels of anxiety during bipolar mood episodes appears to mark an illness of substantially greater long-term depressive morbidity.
Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy
Authors: Zhengyi Wang, William Kutschke, Kenneth E. Richardson, Mohsen Karimi, Joseph A. Hill
Journal: Circulation (2001)

Background Myocyte hypertrophy accompanies many forms of heart disease, but its contribution to electrical remodeling is unknown. Methods and Results We studied mouse hearts subjected to pressure overload by surgical thoracic aortic banding. In unbanded control hearts, action potential duration (APD) was significantly longer in subendocardial myocytes compared with subepicardial myocytes. Hypertrophy-associated APD prolongation was significantly greater in subendocardial myocytes compared with subepicardial myocytes, indicating stress-induced amplification of repolarization dispersion. To investigate the underlying basis, we performed voltage-clamp recordings on dissociated myocytes. Under control unoperated conditions, subendocardial myocytes exhibited significantly less transient outward current (I to ) than did subepicardial cells. Hypertrophy was not associated with significant changes in I to , sustained current, or inward rectifier current densities, but peak L-type Ca 2+ current density (I Ca,L ) increased 26% ( P &lt;0.05). Recovery from I Ca,L inactivation was accelerated in hypertrophied myocytes. Inhibition of calcineurin with cyclosporin A prevented increases in heart mass and myocyte size but was associated with an intermediate APD. The hypertrophy-associated increase in I Ca,L and the accelerated recovery from inactivation were blocked by cyclosporin A. Conclusions These data reveal regional variation in the electrophysiological response within the left ventricle by way of a mechanism involving upregulated Ca 2+ current and calcineurin. Furthermore, these results reveal partial uncoupling of electrophysiological and structural remodeling in hypertrophy.
Interferon gamma receptor deficient mice are resistant to endotoxic shock.
Authors: B D Car, V M Eng, B Schnyder, L Ozmen, S Huang, P Gallay, D Heumann, M Aguet, B Ryffel
Journal: The Journal of Experimental Medicine (1994)

Antibody neutralization studies have established interferon gamma (IFN-gamma) as a critical mediator of endotoxic shock. The advent of IFN-gamma receptor negative (IFN gamma R-/-) mutant mice has enabled a more direct assessment of the role of IFN-gamma in endotoxin (lipopolysaccharide [LPS]-induced shock. We report that IFN gamma R-/- mice have an increased resistance to LPS-induced toxicity, this resistance manifesting well before the synthesis and release of LPS-induced IFN-gamma. LPS-induced lymphopenia, thrombocytopenia, and weight loss seen in wild-type mice were attenuated in IFN gamma R-/- mice. IFN gamma R-/- mice tolerated 100-1,000 times more LPS than the minimum lethal dose for wild-type mice in a D-galactosamine (D-GalN)/LPS model. Serum tumor necrosis factor (TNF) levels were 10-fold reduced in mutant mice given LPS or LPS/D-GalN. Bone marrow and splenic macrophages from IFN gamma R-/- mice had a four- to sixfold decreased LPS-binding capacity which correlated with similar reduction in CD14. Serum from mutant mice reduced macrophage LPS binding by a further 50%, although LPS binding protein was only 10% reduced. The expression of TNF receptor I (p55) and II (p75) was identical between wild-type and mutant mice. Thus, depressed TNF synthesis, diminished expression of CD14, and low plasma LPS-binding capacity, in addition to blocked IFN-gamma signaling in the mutant mice, likely to combine to manifest in the resistant phenotype of IFN gamma R-/- mice to endotoxin.
Genomics of Renal Cell Cancer: The Biology Behind and the Therapy Ahead
Authors: Jon Jones, Towia A. Libermann
Journal: Clinical Cancer Research (2007)

Abstract Renal cell cancer (RCC) is the most lethal of the urological cancers and accounts for 3% of all adult malignancies. Despite numerous recent advances in diagnostic imaging, surgical therapy, and basic molecular understanding, many patients still experience metastatic disease. For metastatic disease patients, response rates to conventional therapies rarely exceed 15% to 25% and are associated with serious adverse effects. The recent development of novel targeted therapies based on the precise biological pathways deregulated in a particular patient has paved the way for individualized, targeted patient management. Nevertheless, to achieve this goal, it is important to delineate the molecular mechanisms underlying cancer development and progression. Genomic approaches have revolutionized the field of cancer research and have led to the rapid discovery of multiple, parallel disease hypotheses, which ultimately have to be validated in large cohorts of patients and in downstream biological experiments for translation into clinical applications. The variable course of RCC and, until recently, a paucity of therapeutic options in the event of metastasis have led to the search for diagnostic and prognostic markers. We and others have used transcriptional profiling to classify different subtypes of RCC and to identify subtype- and metastasis-specific gene signatures predictive for outcome. We discuss herein recent genomic approaches to RCC and the emerging biological pathways underlying RCC development and progression. We also speculate how genomics may affect drug development and the management of patients with RCC.
Diagnosis of Whooping-cough
Authors: A. G. Moore
Journal: BMJ (1938)

Opioids play an important role in pain relief, but repeated exposure results in tolerance and dependence. To make opioids more effective and useful, research in the field has focused on reducing the tolerance and dependence for chronic pain relief. Here, we showed the effect of A20-binding inhibitor of nuclear factor-<i>κ</i>B (ABIN-1) in modulating morphine function. We used hot-plate tests and conditioned place preference (CPP) tests to show that overexpression of ABIN-1 in the mouse brain attenuated morphine dependence. These effects of ABIN-1 are most likely mediated through the formation of ABIN-1–<i>β</i>-arrestin2 complexes, which accelerate <i>β</i>-arrestin2 degradation by ubiquitination. With the degradation of <i>β</i>-arrestin2, ABIN-1 overexpression also decreased <i>μ</i> opioid receptor (MOR) phosphorylation and internalization after opioid treatment, affecting the <i>β</i>-arrestin2–dependent signaling pathway to regulate morphine tolerance. Importantly, the effect of ABIN-1 on morphine tolerance was abolished in <i>β</i>-arrestin2–knockout mice. Taken together, these results suggest that the interaction between ABIN-1 and <i>β</i>-arrestin2 inhibits MOR internalization to attenuate morphine tolerance, revealing a novel mechanism for MOR regulation. Hence, ABIN-1 may be a therapeutic target to regulate MOR internalization, thus providing a foundation for a novel treatment strategy for alleviating morphine tolerance and dependence. <h3>SIGNIFICANCE STATEMENT</h3> A20-binding inhibitor of nuclear factor-<i>κ</i>B (ABIN-1) overexpression in the mouse brain attenuated morphine tolerance and dependence. The likely mechanism for this finding is that ABIN-1–<i>β</i>-arrestin2 complex formation facilitated <i>β</i>-arrestin2 degradation by ubiquitination. ABIN-1 targeted <i>β</i>-arrestin2 to regulate morphine tolerance. Therefore, the enhancement of ABIN-1 is an important strategy to prevent morphine tolerance and dependence.