tbuckley/cabot-search huggingface dataset:
Novel approaches and future directions in castration-resistant prostate cancer
Authors: C. Nabhan, B. Parsons, E.Z. Touloukian, W.M. Stadler
Journal: Annals of Oncology (2011)

Recent advances in the treatment of castration-resistant prostate cancer (CRPC) have started to change the therapeutic landscape allowing clinicians to choose from a broad range of treatment options. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state has enabled investigators to explore critical pathways involved in such process allowing for rational therapeutic design. These novel therapies complement the modest success that chemotherapy has demonstrated in recent years. In this review, we discuss the different mechanisms that render PCA castration resistant and elaborate on the nonchemotherapy approaches evolving in CRPC. These include agents targeting the epidermal growth factor receptor, endothelin receptor antagonists, angiogenesis inhibitors, immunomodulatory agents, immunotherapy, novel antiandrogens, and delivery of cytotoxic agents via therapeutic antibodies. This timely review coincides with the identification of newer therapies in this setting affirming our steady movement towards better disease control.
A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
Authors: Chris H. Polman, Paul W. O'Connor, Eva Havrdova, Michael Hutchinson, Ludwig Kappos, David H. Miller, J. Theodore Phillips, Fred D. Lublin, Gavin Giovannoni, Andrzej Wajgt, Martin Toal, Frances Lynn, Michael A. Panzara, Alfred W. Sandrock
Journal: New England Journal of Medicine (2006)

Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis.Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years.Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent).Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).
Review: Celecoxib increases risk for cardiovascular events; risks are greatest with higher doses
Authors: Bruce Rothschild
Journal: Annals of Internal Medicine (2008)

Source Citation Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the Cross Trial Safety Analysis. Circulation. 2008;117:2104-13. 18378608
Expression of Chicken Ovalbumin Upstream Promoter-Transcription Factor II Enhances Invasiveness of Human Lung Carcinoma Cells
Authors: Roya Navab, Juana Maria Gonzalez-Santos, Michael R. Johnston, Jiang Liu, Pnina Brodt, Ming-Sound Tsao, Jim Hu
Journal: Cancer Research (2004)

Abstract Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays an essential role in angiogenesis and development. It is differentially expressed in tumor cell lines, but its role in carcinogenesis is largely unknown. We demonstrate here that noninvasive human lung cancer cells become invasive when COUP-TFII was expressed. The expression of extracellular matrix degrading proteinases, such as matrix metalloproteinase 2 and urokinase-type plasminogen activator, was up-regulated in these cells. This finding was confirmed by transduction of different human lung cancer cell lines with COUP-TFII protein and also by using antisense expression. We observed disorganization of actin filaments and focal adhesion kinase phosphorylation in COUP-TFII-transfected human lung cancer cells in addition to the increase in extracellular metalloproteinase activity. These results suggest that COUP-TFII may be considered as a new target for anticancer therapies.
Stat3 Programs Th17-Specific Regulatory T Cells to Control GN
Authors: Malte A. Kluger, Michael Luig, Claudia Wegscheid, Boeren Goerke, Hans-Joachim Paust, Silke R. Brix, Isabell Yan, Hans-Willi Mittrücker, Beate Hagl, Ellen D. Renner, Gisa Tiegs, Thorsten Wiech, Rolf A.K. Stahl, Ulf Panzer, Oliver M. Steinmetz
Journal: Journal of the American Society of Nephrology (2014)

A pathogenic role for Th17 cells in inflammatory renal disease is well established. The mechanisms underlying their counter-regulation are, however, largely unknown. Recently, Th17 lineage-specific regulatory T cells (Treg17) that depend on activation of the transcription factor Stat3 were identified. We studied the function of Treg17 in the nephrotoxic nephritis (NTN) model of crescentic GN. The absence of Treg17 cells in Foxp3(Cre)×Stat3(fl/fl) mice resulted in the aggravation of NTN and skewing of renal and systemic immune responses toward Th17. Detailed analysis of Stat3-deficient Tregs revealed that the survival, activation, proliferation, and suppressive function of these cells remained intact. However, Tregs from Foxp3(Cre)×Stat3(fl/fl) mice lacked surface expression of the chemokine receptor CCR6, which resulted in impaired renal trafficking. Furthermore, aggravation of NTN was reversible in the absence of Th17 responses, as shown in CD4(Cre)×Stat3(fl/fl) mice lacking both Treg17 and Th17 cells, suggesting that Th17 cells are indeed the major target of Treg17 cells. Notably, immunohistochemistry revealed CCR6-bearing Treg17 cells in kidney biopsy specimens of patients with GN. CCR6 expression on human Treg17 cells also appears dependent on STAT3, as shown by analysis of Tregs from patients with dominant-negative STAT3 mutations. Our data indicate the presence and involvement of Stat3/STAT3-dependent Treg17 cells that specifically target Th17 cells in murine and human crescentic GN, and suggest the kidney-specific action of these Treg17 cells is regulated by CCR6-directed migration into areas of Th17 inflammation.
Characterization of aldosterone-induced potassium secretion in rat distal colon.
Authors: J H Sweiry, H J Binder
Journal: Journal of Clinical Investigation (1989)

The role of apical and basolateral membranes in aldosterone-induced active potassium (K) secretion in rat distal colon was investigated by measuring mucosal-to-serosal (Jms) and serosal-to-mucosal (Jsm) 42K fluxes (mueq.h-1.cm-2) across isolated stripped mucosa under short-circuit conditions in normal and secondary-hyperaldosterone animals. In normal colons mucosal tetraethylammonium (TEA; 30 mM) or barium (Ba; 5 mM), but not cesium (Cs; 15 mM), reduced Jsm without affecting Jms. In aldosterone animals (a) net K secretion (-0.54 +/- 0.11) was converted to net K absorption (0.63 +/- 0.15) by mucosal TEA, which produced a marked reduction in Jsm (0.82 +/- 0.07) and an increase in Jms (0.35 +/- 0.07). In contrast mucosal Ba resulted in a relatively smaller reduction in JK(sm) without altering JK(ms), whereas mucosal Cs was ineffective; (b) serosal bumetanide or the removal of serosal Na or Cl markedly inhibited JK(sm and abolished net K secretion; and (c) serosal ouabain (1 mM) produced qualitatively similar effects to those of serosal bumetanide. These results demonstrate that (a) normal rat distal colon contains apical TEA- and Ba-sensitive K channels; (b) aldosterone induces TEA-sensitive and Ba-sensitive apical K channels; (c) aldosterone-induced K secretion requires both the Na,K-pump and Na-K-2Cl cotransport for K uptake across the basolateral membrane; and (d) alteration of any of these processes results in inhibition of aldosterone-induced active K secretion simultaneously with stimulation of K absorption.
INK4a-ARF alterations in liver cell adenoma
Authors: A Tannapfel, C Busse, F Geissler, H Witzigmann, J Hauss, C Wittekind
Journal: Gut (2002)

The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16(INK4a) and p14(ARF), whose functions are inactivated in many human cancers.To evaluate p14(ARF) and p16(INK4a) alterations in liver cell adenoma.After microdissection, DNA from 25 liver cell adenomas and corresponding normal liver tissue were analysed for INK4-ARF inactivation by DNA sequence analysis, methylation specific polymerase chain reaction, restriction enzyme related-polymerase chain reaction (RE-PCR), mRNA expression, microsatellite analysis, and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INK4a) were assessed by differential PCR.Methylation of p14(ARF) was found in 3/25 cases (12%) and alterations in p16(INK4a) occurred in 6/25 liver cell adenomas (24%) which correlated with loss of mRNA transcription. We failed to detect microdeletions or specific mutations of both exons. p16(INK4a) methylation appeared in the context of an unmethylated p14(ARF) promoter in six cases. In normal liver tissue, p14(ARF) or p16(INK4a) alterations were not observed.Our data suggest that p14(ARF) methylation occurs independently of p16(INK4a) alterations in liver cell adenomas. Furthermore, methylation of p14(ARF) and p16(INK4a) may be a result of cell cycle deregulation and does not seem to be a prerequisite of malignancy.
From Pump to Molecules
Authors: John Ross
Journal: Circulation Research (2003)

n response to Eduardo Marbán's invitation to prepare a brief reminiscence on the occasion of the 50th anniversary of Circulation Research, I recount here a few of the ideas and events that have marked my 47 years in research.My research career began when, fresh from a surgical internship at the Johns Hopkins Hospital, I arrived at the then National Heart Institute in 1956.There, having watched Andrew Morrow perform transbronchial left heart catheterization, I thought there must be a better way.I soon became immersed in developing a method for transseptal left heart catheterization, first in dogs, then in human cadavers, and finally in patients; thus, my first research experience proved to be "translational."It was satisfying to later see this approach used for balloon mitral valvuloplasty and in cardiac electrophysiology.
Biliary Sludge and Gallstones in Pregnancy: Incidence, Risk Factors, and Natural History
Authors: Alberto Maringhini
Journal: Annals of Internal Medicine (1993)

To evaluate the incidence and symptoms of and risk factors for biliary sludge and gallstones during pregnancy and to assess the natural history of these conditions in the first year after delivery.Cohort study.A total of 272 pregnant women recruited in the first trimester.Biliary sludge and gallstones were diagnosed using ultrasonography, both during pregnancy and after delivery. Predictors of the presence or disappearance of sludge and stones were examined.Overall, from the first trimester of pregnancy until the immediate postpartum period, 67 women were newly diagnosed with biliary sludge, and 6 women were newly diagnosed with gallstones. The respective incidence rates were 31% (95% Cl, 25% to 37%) and 2% (95% Cl, 0.2% to 4%). During pregnancy, 28% of women experienced biliary pain, which was associated only with presence of stones. After delivery, 92 women had sludge and 23 had stones. Sludge disappeared in 61% of these women (Cl, 50% to 73%) after a mean follow-up of 5 months, and stones disappeared in 28% of women (Cl, 10% to 46%) after 9.7 months of follow-up.Biliary sludge occurred frequently during pregnancy but was generally asymptomatic and often disappeared spontaneously after delivery. Gallstones were much less frequent and were more likely to be associated with biliary pain.
Differentiation and Definition of Vascular-Targeted Therapies
Authors: Dietmar W. Siemann, Michael C. Bibby, Graham G. Dark, Adam P. Dicker, Ferry A.L.M. Eskens, Michael R. Horsman, Dieter Marmé, Patricia M. LoRusso
Journal: Clinical Cancer Research (2005)

Abstract The therapeutic potential of targeting the tumor vascular supply is now widely recognized. Intense research and development activity has resulted in a variety of investigational agents, a number of which are currently in clinical development. As these novel agents are quite distinct from the cytotoxic drugs conventionally used in the treatment of solid tumors, it will be particularly important to ensure early differentiation of these vascular-targeted therapies in order to encourage widespread understanding of their potential benefits and application in the clinic. Two distinct groups of vascular-targeted therapies have evolved: antiangiogenic agents and vascular-disrupting approaches. These differ in three key respects: their physiologic target, the type or extent of disease that is likely to be susceptible, and the treatment scheduling. Inhibitors of angiogenesis interfere with new vessel formation and therefore have a preventative action, require chronic administration, and are likely to be of particular benefit in early-stage or asymptomatic metastatic disease. Vascular-disrupting agents target the established tumor blood vessels, resulting in tumor ischemia and necrosis. These agents are therefore given acutely, show more immediate effects, and may have particular efficacy against advanced disease. It is essential that these agents can be readily distinguished from conventional therapies and that an understanding of key differences between the two types of vascular-targeted therapies is fostered. Here, a simple taxonomy and nomenclature is proposed in anticipation that the therapeutic potential of this novel class can be realized as these approaches advance in clinical settings and a new anticancer strategy becomes available in the clinic.
HYPOPROTEINEMIA AS PROTECTION AGAINST MERCURIC CHLORIDE INJURY IN DOGS
Authors: Russell L. Holman, G. L. Donnelly
Journal: The Journal of Experimental Medicine (1942)

Twelve control dogs receiving a single intravenous injection of mercuric chloride, 3.0 mg. per kg., all died within 4 to 11 days afterwards with marked nitrogen retention and extensive necrosis and calcification of the epithelium lining the proximal convoluted tubules. Three dogs of comparable age and weight were reduced to a standard hypoproteinemic state by repeated plasmapheresis. Each dog then received the same dose of mercuric chloride as the controls. None of these dogs became sick, none showed any elevation of non-protein nitrogen, and the kidneys- both in the gross and histologically-appeared normal when they were examined 8 to 45 days later. As tested thus far intensive plasmapheresis following the injection of mercuric chloride has been without effect in preventing the classical changes of mercuric chloride injury observed in the control dogs. The simplest explanation for these phenomena is that mercuric chloride acts on a more or less specific substance (presumably fabricated or concentrated in the renal cortex) which is depleted in the standard hypoproteinemic state. Other possibilities are mentioned. These findings are in sharp contrast to the results of similar experiments with uranium nitrate. The hypoproteinemic state appears to render the animals more susceptible to uranium injury (3). This probably indicates that the mode of action of the two heavy metals is different.
Symptom Correlates of Prepulse Inhibition Deficits in Male Schizophrenic Patients
Authors: David L. Braff, Neal R. Swerdlow, Mark A. Geyer
Journal: American Journal of Psychiatry (1999)

Information processing, inhibitory, and gating deficits in human and animal model studies of schizophrenia are demonstrated by using prepulse inhibition of the startle reflex. Prepulse inhibition deficits in schizophrenic patients correlate with core cognitive symptoms, such as thought disorder and distractibility, but their relationship to positive and negative symptoms of schizophrenia is less clear.Fifty-one male schizophrenic patients and 26 male normal comparison subjects were tested for prepulse inhibition of the eyeblink component of the startle reflex measured by electromyogram recording. Startling stimuli (118 dB) were presented alone (pulse only) or were preceded 60 msec by discrete prepulse stimuli of 2, 4, 8, or 16 dB above the background 70-dB noise level. In addition, patients were assessed for demographic variables, generalized symptoms (Brief Psychiatric Rating Scale), and positive and negative symptoms.Schizophrenic and comparison groups differed significantly in the amount of prepulse inhibition produced by the 16-dB prepulse, with schizophrenic patients showing the expected deficient prepulse inhibition. Latency of the eyeblink response was generally slower for the schizophrenic patients, but the prepulse-induced latency facilitation for schizophrenic patients and comparison subjects did not differ significantly. The pattern of prepulse inhibition deficits in schizophrenic patients remained, with age and education controlled, in an analysis of covariance and subgroup matching. Deficient prepulse inhibition correlated with both positive and negative symptoms of schizophrenia.Under these experimental conditions, schizophrenia-linked deficits in prepulse inhibition detected with a relatively strong prepulse are correlated with both positive and negative symptoms of schizophrenia. The level of correlation, while significant in this cohort, is not as robust as that in previous reports linking prepulse inhibition deficits with other measures, such as thought disorder. Future work should probably focus on the relationship of prepulse inhibition deficits to measures such as thought disorder rather than positive and negative symptoms.
Does Degree of Androgen Suppression Matter in Hormone-Sensitive Prostate Cancer?
Authors: Daniel L. Suzman, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2015)

In men with metastatic prostate cancer, androgen-deprivation therapy (ADT) is the mainstay of therapy. Through reduction of serum testosterone from normal levels (approximately 250 to 950 ng/dL [8 to 32 nmol/L]) to castrate levels, ADT has been shown to reduce tumor burden and alleviate symptoms and may improve survival. Although ADT can suppress circulating testosterone levels by 90% to 95%, not all men achieve a testosterone level in the castrate range; others may initially achieve castrate levels but then experience testosterone breakthrough above that level. Castration has historically been defined as serum testosterone of less than 20 ng/dL (0.7 nmol/L), although a threshold of less than 50 ng/dL (1.7 nmol/L) was adopted by the Prostate Cancer Working Group 2 for the purposes of clinical trial accrual.1 However, this was essentially an arbitrary threshold, and the clinical significance of the testosterone level and the optimal degree of testosterone suppression following ADT remain in question.
Prostate-Specific Antigen (PSA) Isoform p2PSA Significantly Improves the Prediction of Prostate Cancer at Initial Extended Prostate Biopsies in Patients with Total PSA Between 2.0 and 10 ng/ml: Results of a Prospective Study in a Clinical Setting
Authors: Giorgio Guazzoni, Luciano Nava, Massimo Lazzeri, Vincenzo Scattoni, Giovanni Lughezzani, Carmen Maccagnano, Fernanda Dorigatti, Ferruccio Ceriotti, Marina Pontillo, Vittorio Bini, Massimo Freschi, Francesco Montorsi, Patrizio Rigatti
Journal: European Urology (2011)
Percutaneous Coronary Intervention “Dominates” Coronary Artery Bypass Graft Surgery for High-Risk Patients
Authors: Martha J. Radford
Journal: Circulation (2006)

n this issue of Circulation, Stroupe and colleagues present a cost-effectiveness analysis of the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) trial 1 that challenges physicians, hospitals, and healthcare planners to address how to best evaluate emerging, evolving, and mature technologies for their safety, efficacy, and impact on the health of our society.
Cardiovascular disease in kidney donors: matched cohort study
Authors: A. X. Garg, A. Meirambayeva, A. Huang, J. Kim, G. V. R. Prasad, G. Knoll, N. Boudville, C. Lok, P. McFarlane, M. Karpinski, L. Storsley, S. Klarenbach, N. Lam, S. M. Thomas, C. Dipchand, P. Reese, M. Doshi, E. Gibney, K. Taub, A. Young
Journal: BMJ (2012)

<b>Objective</b> To determine whether people who donate a kidney have an increased risk of cardiovascular disease. <b>Design</b> Retrospective population based matched cohort study. <b>Participants</b> All people who were carefully selected to become a living kidney donor in the province of Ontario, Canada, between 1992 and 2009. The information in donor charts was manually reviewed and linked to provincial healthcare databases. Matched non-donors were selected from the healthiest segment of the general population. A total of 2028 donors and 20 280 matched non-donors were followed for a median of 6.5 years (maximum 17.7 years). Median age was 43 at the time of donation (interquartile range 34-50) and 50 at the time of follow-up (42-58). <b>Main outcome measures</b> The primary outcome was a composite of time to death or first major cardiovascular event. The secondary outcome was time to first major cardiovascular event censored for death. <b>Results</b> The risk of the primary outcome of death and major cardiovascular events was lower in donors than in non-donors (2.8 <i>v</i> 4.1 events per 1000 person years; hazard ratio 0.66, 95% confidence interval 0.48 to 0.90). The risk of major cardiovascular events censored for death was no different in donors than in non-donors (1.7 <i>v</i> 2.0 events per 1000 person years; 0.85, 0.57 to 1.27). Results were similar in all sensitivity analyses. Older age and lower income were associated with a higher risk of death and major cardiovascular events in both donors and non-donors when each group was analysed separately. <b>Conclusions</b> The risk of major cardiovascular events in donors is no higher in the first decade after kidney donation compared with a similarly healthy segment of the general population. While we will continue to follow people in this study, these interim results add to the evidence base supporting the safety of the practice among carefully selected donors.