tbuckley/cabot-search huggingface dataset:
Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma
Authors: John M. Kirkwood, Lars Bastholt, Caroline Robert, Jeff Sosman, James Larkin, Peter Hersey, Mark Middleton, Mireille Cantarini, Victoria Zazulina, Karin Kemsley, Reinhard Dummer
Journal: Clinical Cancer Research (2011)

To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma.This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m(2)/d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival.Two hundred patients were randomized. Progression-free survival did not differ significantly between selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86-1.32). Objective response was observed in six (5.8%) patients receiving selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six selumetinib partial responders were BRAF mutated. Frequently reported adverse events with selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide.No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF/NRAS mutations, who received therapy with selumetinib or temozolomide. Five of six patients with partial response to selumetinib had BRAF mutant tumors.
HNRNPAB Induces Epithelial–Mesenchymal Transition and Promotes Metastasis of Hepatocellular Carcinoma by Transcriptionally Activating <i>SNAIL</i>
Authors: Zheng-Jun Zhou, Zhi Dai, Shao-Lai Zhou, Zhi-Qiang Hu, Qing Chen, Yi-Ming Zhao, Ying-Hong Shi, Qiang Gao, Wei-Zhong Wu, Shuang-Jian Qiu, Jian Zhou, Jia Fan
Journal: Cancer Research (2014)

Expression of heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) has been reported to be dysregulated in tumors, but its specific contributions to tumor formation and progression are not fully understood. Here, we demonstrate that HNRNPAB is overexpressed in highly metastatic cells and tumor tissues from patients with hepatocellular carcinoma (HCC) with recurrence. We found that HNRNPAB overexpression promoted epithelial-mesenchymal transition (EMT) in a manner associated with HCC metastasis in vitro and in vivo. RNA interference-mediated silencing of the EMT factor SNAIL attenuated HNRNPAB-enhanced cell invasion in vitro and lung metastasis in vivo. Mechanistically, HNRNPAB acted to transactivate SNAIL1 transcription, which in turn inhibited transcription of the pivotal SNAIL target gene E-cadherin. Overexpression of HNRNPAB in HCC samples correlated with higher SNAIL levels, shorter overall survival, and higher tumor recurrence. HNRNPAB overexpression, alone or in combination with SNAIL, was found to be a significant independent risk factor for recurrence and survival after curative resection. In conclusion, our findings define HNRNPAB as an activator of EMT and metastasis in HCC that predicts poor clinical outcomes.
Age and height dependence of lung clearance index and functional residual capacity
Authors: Sooky Lum, Janet Stocks, Sanja Stanojevic, Angie Wade, Paul Robinson, Per Gustafsson, Meghan Brown, Paul Aurora, Padmaja Subbarao, Ah-fong Hoo, Samatha Sonnappa
Journal: European Respiratory Journal (2012)

The lung clearance index (LCI) is more sensitive than spirometry in detecting abnormal lung function in children with cystic fibrosis. LCI is thought to be independent of age, but recent evidence suggests that the upper limit of normal is higher in infants and preschool children than in older subjects. This study examines whether LCI remains independent of body size throughout childhood. Multiple-breath washout data from healthy children and adolescents were collated from three centres using the mass spectrometer system and the inert gas sulfur hexafluoride. Reference equations for LCI and functional residual capacity (FRC) were constructed using the LMS (lambda-mu-sigma) method. Data were available from 497 subjects (2 weeks to 19 years of age) tested on 659 occasions. LCI was dependent on body size, decreasing in a nonlinear pattern as height increased. Changes were particularly marked in the first 5 years of life. Height, age and sex were all independent predictors of FRC. Minimal between-centre differences allowed unified reference equations to be developed. LCI is not independent of body size. Although a constant upper normal limit would suffice for cross-sectional clinical assessments from 6 years of age, appropriate reference equations are essential for accurate interpretation of results during early childhood.
Vaginal microbiome and sexually transmitted infections: an epidemiologic perspective
Authors: Rebecca M. Brotman
Journal: Journal of Clinical Investigation (2011)

Vaginal bacterial communities are thought to help prevent sexually transmitted infections. Bacterial vaginosis (BV) is a common clinical syndrome in which the protective lactic acid-producing bacteria (mainly species of the Lactobacillus genus) are supplanted by a diverse array of anaerobic bacteria. Epidemiologically, BV has been shown to be an independent risk factor for adverse outcomes including preterm birth, development of pelvic inflammatory disease, and acquisition of sexually transmitted infections. Longitudinal studies of the vaginal microbiome using molecular techniques such as 16S ribosomal DNA analysis may lead to interventions that shift the vaginal microbiota toward more protective states.
Diagnosis and treatment of sciatica
Authors: B W Koes, M W van Tulder, W C Peul
Journal: BMJ (2007)

Sciatica affects many people. The most important symptoms are radiating leg pain and related disabilities. Patients are commonly treated in primary care but a small proportion is referred to secondary care and may eventually have surgery. Many synonyms for sciatica appear in the literature, such as lumbosacral radicular syndrome, ischias, nerve root pain, and nerve root entrapment.

#### Summary points 

In about 90% of cases sciatica is caused by a herniated disc with nerve root compression, but lumbar stenoses and (less often) tumours are possible causes. The diagnosis of sciatica and its management varies considerably within and between countries—for example, the surgery rates for lumbar discectomy vary widely between countries.w1 A recent publication confirmed this large variation in disc surgery, even within countries.1 This may in part be caused by a paucity of evidence on the value of diagnostic and therapeutic interventions and a lack of clear clinical guidelines or reflect differences in healthcare and insurance systems. This review presents the current state of science for the diagnosis and treatment of sciatica.

#### Sources and selection criteria

We identified systematic reviews in the Cochrane Library evaluating the effectiveness of conservative and surgical interventions for sciatica. Medline searches up to December 2006 were carried out to find other relevant systematic reviews on the diagnosis …
Tid-1 Interacts with the von Hippel-Lindau Protein and Modulates Angiogenesis by Destabilization of HIF-1α
Authors: Moon-Kyoung Bae, Joo-Won Jeong, Se-Hee Kim, Soo-Young Kim, Hye Jin Kang, Dong-Min Kim, Soo-Kyung Bae, Il Yun, Grace A. Trentin, Maria Rozakis-Adcock, Kyu-Won Kim
Journal: Cancer Research (2005)

Abstract The von Hippel-Lindau protein (pVHL) is a major tumor suppressor protein and also associated with the inhibition of angiogenesis via HIF-1α ubiquitination and proteasomal degradation. To further elucidate the biological activity of pVHL in angiogenesis, pVHL-interacting proteins were screened using the yeast two-hybrid system. We found that a mouse homologue of the long form of Drosophila tumor suppressor l(2)tid, Tid-1L, directly interacts with pVHL in vitro and in vivo. Furthermore, Tid-1L protein; enhanced the interaction between HIF-1α and pVHL, leading to the destabilization of HIF-1α protein; therefore, Tid-1L protein decreased vascular endothelial growth factor expression and inhibited angiogenesis in vivo and in vitro. These findings propose that Tid-1L may play a critical role in pVHL-mediated tumor suppression by modulating the pVHL-dependent HIF-1α stability.
Decrease in sensitisation rate and intestinal anaphylactic response after nitric oxide synthase inhibition in a food hypersensitivity model.
Authors: M J Fargeas, V Theodorou, B Weirich, J Fioramonti, L Bueno
Journal: Gut (1996)

Regulation of intracellular calcium influences neuronal excitability, synaptic plasticity, gene expression, and neurotoxicity. In this study, we investigated the role of calcium in mechanisms underlying nicotine-mediated neuroprotection from glutamate excitotoxicity. Neuroprotection by nicotine in primary cortical cultures was not seen in knock-out mice lacking the β2 subunit of the nicotinic acetylcholine receptor (nAChR). Neuroprotection was partially blocked in wild-type cultures by α-bungarotoxin, an antagonist of the α7 nAChR subtype, suggesting a potential cooperative role for these subtypes. Pretreatment with nicotine decreased glutamate-mediated calcium influx in primary cortical cultures by 41%, an effect that was absent in cultures from knock-out mice lacking the β2 subunit of the nAChR. This effect was dependent on calcium entry through L-type channels during nicotine pretreatment in wild-type cultures. The ability of nicotine to decrease glutamate-mediated calcium influx was occluded by cotreatment with nifedipine during glutamate application, suggesting that nicotine pretreatment decreased subsequent activity of L-type calcium channels. Treatment with the calcineurin antagonists FK506 and cyclosporine during pretreatment eliminated both nicotine-mediated neuroprotection and the effects of nicotine on L-type channels. We conclude that neuroprotective effects of nicotine in cortical neurons involve both β2- and α7-containing nAChRs, activation of calcineurin, and decreased intracellular calcium via L-type channels.
Differentiating Primary From Secondary Negative Symptoms in Schizophrenia: A Study of Neuroleptic-Naive Patients Before and After Treatment
Authors: Victor Peralta, Manuel J. Cuesta, Alfredo Martinez-Larrea, Jose F. Serrano
Journal: American Journal of Psychiatry (2000)

The study examined the primary versus secondary character of negative symptoms in a group of first-episode, neuroleptic-naive psychotic patients before and after they started neuroleptic treatment.Forty-seven inpatients with a first episode of schizophrenia or related psychotic disorders were examined for the presence of negative symptoms, psychosis, depression, and parkinsonism at admission to an inpatient psychiatric unit, before receiving neuroleptics, and at discharge an average 3.3 weeks later, after starting neuroleptic treatment.Although patients' mean scores on measures of positive, negative, and depressive symptoms decreased significantly over the treatment period, the mean rating of nonakinetic parkinsonism worsened. The mean rating of akinetic parkinsonism did not change significantly over the treatment period. Negative symptoms at admission were not predicted by positive or depressive symptoms at admission. Residual negative symptoms at discharge were mainly predicted by negative symptoms at admission (i.e., primary symptoms) and to a negligible degree by residual positive and depressive symptoms. Change in negative symptoms over the observation period was predicted to a marginal degree by change in depressive symptoms.Negative symptoms rated during a first psychotic episode before and after starting antipsychotic treatment are mainly primary in character and should be considered as a direct manifestation of the basic dysfunctions of schizophrenia.
Equipment for the Disabled: Wheelchairs
Authors: M. A. Chamberlain
Journal: Annals of the Rheumatic Diseases (1983)

296 Gran, Husby, Thorsby related HLA antigen.Only 7 patients (5%) out of 142 lacked DR4, a positive family history of RA, and RF in serum.A combination of these 3 factors could therefore be helpful in the diagnosis of RA.
Liver Transplantation for Advanced Liver Disease with Alpha-1antitrypsin Deficiency
Authors: John M. Hood, Lawrence J. Koep, Robert L. Peters, Gerhard P. J. Schröter, Richard Weil, Allan G. Redeker, Thomas E. Starzl
Journal: New England Journal of Medicine (1980)

ALPHA-I-antitrypsin deficiency associated with n chronic obstructive airway disease was recognized in 1963 by Laurell and Ericksson.I In 1969, .Sharp' described the first cases of alpha-l-antitrypsin-deficiency disease in children with cirrhosis.Since then, this •inborn error has been recognized as one of the more common factors in cirrhosis of infancy and childhood,] including "neonatal hepatitis."4 Alpha-tantitrypsin is a glycoprotein that accounts for a major portion of the alpha-l globulin fraction of the serum.S It is responsible for approximately 90 per cent of the antitrypsin activity' of the serum, and it also inhibits several other plasma enzymes, including plasmin,' elastase,' collagenase,' and chymotrypsin.'o Cirrhosis de\;e1ops in about 15 per cent •of patients with homozygous phenotype PiZZ (Pi = protease inhibitor), II and there have been a few recent reports of cirrhosis in heterozygous patients. 12• n There has been no effective, specific medical treatment for such patients.This report will examine the place of orthotopic liver transplantation in the treatment of seven white patients who had end-stage Ih'er disease due to alpha-I-antitrypsin deficiency.After transplantation, the phenotypes of the recipients became those of the donors, and alpha-'l--antitrypsin levels were restored to normal.Thus, the metabolic basis of the
Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity
Authors: Laura A. Smit, Delfine Y.H. Hallaert, René Spijker, Bart de Goeij, Annelieke Jaspers, Arnon P. Kater, Marinus H.J. van Oers, Carel J.M. van Noesel, Eric Eldering
Journal: Blood (2006)
Basolateral Na+/HCO3– cotransport activity is regulated by the dissociable Na+/H+ exchanger regulatory factor
Authors: Angelito A. Bernardo, Felicidad T. Kear, Anna V.P. Santos, Jianfei Ma, Debra Steplock, R. Brooks Robey, Edward J. Weinman
Journal: Journal of Clinical Investigation (1999)

In the renal proximal tubule, the activities of the basolateral Na(+)/HCO(3)(-) cotransporter (NBC) and the apical Na(+)/H(+) exchanger (NHE3) uniformly vary in parallel, suggesting that they are coordinately regulated. PKA-mediated inhibition of NHE3 is mediated by a PDZ motif-containing protein, the Na(+)/H(+) exchanger regulatory factor (NHE-RF). Given the common inhibition of these transporters after protein kinase A (PKA) activation, we sought to determine whether NHE-RF also plays a role in PKA-regulated NBC activity. Renal cortex immunoblot analysis using anti-peptide antibodies directed against rabbit NHE-RF demonstrated the presence of this regulatory factor in both brush-border membranes (BBMs) and basolateral membranes (BLMs). Using a reconstitution assay, we found that limited trypsin digestion of detergent solubilized rabbit renal BLM preparations resulted in NBC activity that was unaffected by PKA activation. Co-reconstitution of these trypsinized preparations with a recombinant protein corresponding to wild-type rabbit NHE-RF restored the inhibitory effect of PKA on NBC activity in a concentration-dependent manner. NBC activity was inhibited 60% by 10(-8)M NHE-RF; this effect was not observed in the absence of PKA. Reconstitution with heat-denatured NHE-RF also failed to attenuate NBC activity. To establish further a physiologic role for NHE-RF in NBC regulation, the renal epithelial cell line B-SC-1, which lacks detectable endogenous NHE-RF expression, was engineered to express stably an NHE-RF transgene. NHE-RF-expressing B-SC-1 cells (B-SC-RF) exhibited markedly lower basal levels of NBC activity than did wild-type controls. Inhibition of NBC activity in B-SC-RF cells was enhanced after 10 microM of forskolin treatment, consistent with a postulated role for NHE-RF in mediating the inhibition of NBC activity by PKA. These findings not only suggest NHE-RF involvement in PKA-regulated NBC activity, but also provide a unique molecular mechanism whereby basolateral NBC and apical NHE3 activities may be coordinately regulated in renal proximal tubule cells.
Combined Functional and Immunochemical Analysis of Normal and Abnormal Human Factor X
Authors: Daryl S. Fair, Edward F. Plow, Thomas S. Edgington
Journal: Journal of Clinical Investigation (1979)

Human Factor X was isolated from Cohn fraction III and characterized by polyacrylamide gel electrophoresis, amino acid composition, and isoelectric focusing. Two molecular forms with biological activity were observed at isoelectric points of 4.8 and 5.0. Antisera generated to Factor X was monospecific and used to establish an equilibrium competitive inhibition radioimmunoassay. This assay was specific for human Factor X and did not cross-react with human prothrombin or bovine Factor X within the sensitivity range of 6-300 ng Factor X antigen/ml. The mean concentration of Factor X based on the antigen was 11.9 μg/ml, whereas concentration values based on coagulant activity was 7.8 μg/ml. This 30% difference in measurement appears to result from the presence of a subpopulation of Factor X molecules devoid of coagulant activity. The radioimmunoassay was used to qualitatively and quantitatively compare purified Factor X to plasmic Factor X obtained from normal, warfarintreated, acquired Factor X-deficient, and congenitaldeficient patients. In all but one case, the Factor X present in these plasmas was immunochemically identical to the purified Factor X and permitted precise quantitation of these abnormal Factor X molecules. Factor X procoagulant activity was analyzed relative to Factor X antigen and the specific activities were used to characterize normal and abnormal Factor X molecules. Reduced Factor X activity in plasmas from warfarin-treated and acquired Factor X-deficient patients was attributed to both decreases in Factor X antigen and decreased function of the Factor X molecules. Congenitally deficient patients, in general, showed a reduction in Factor X antigen in parallel with Factor X procoagulant activities resulting from comparable decreases in specific biological activity of the molecules.
Treatment with low-dose everolimus in patients with sporadic lymphangioleiomyomatosis (LAM)
Authors: Sergey Avdeev, Marina Makarova, Zamira Merzhoeva, Alexander Chuchalin
Journal: European Respiratory Journal (2014)

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor, was recently shown to stabilize lung function and reduce the size of chylous effusions in patients with LAM. The optimal doses of mTOR inhibitors for the treatment of LAM are not clear, but in recent retrospective trail low-dose therapy with sirolimus was clinically beneficial in LAM patients (Ando K et al., Respir Invest 2013; 51: 175-183). We present here our first experience of low-dose everolimus treatment in LAM patients.   Methods:   Ten women with sporadic LAM (mean age 41.4 ± 6.4 years) with clinically significant lung disease (FEV1 42.3±16.7%, FVC 77.9± 22.6%, DLCO 33.3±11.7%) were included in our open-label study. Five patients had abdominal angiomyolipomas (AML), four patients had chylous effusion, and one - chylous ascite. Patients received everolimus 1-2 mg daily from 6 month to 3 years (in all patients the blood trough levels of everolimus was lower than 5 ng/mL).   Results:   There was a complete resolution of chylous complications in all four patients within 1 to 2 months after the initiation of therapy with everolimus. A significant shrinkage of ALM was noted in four women. PFTs also showed substantial improvement: after first 6 months of treatment FEV1 were 46.6±17.9%, FVC - 80.6±13.9% and DLCO - 40.0± 20.6%. The distance in 6-MWD increased by 56.5±19.3 meters. The therapy with low-dose everolimus was well tolerated, and only two patients experienced adverse events: headache (1) and hypercholesterolemia (1).   Conclusions:   Our findings suggest a potential role for low-dose everolimus treatment in patients with sporadic LAM.
Use of Mutant-Specific Ion Channel Characteristics for Risk Stratification of Long QT Syndrome Patients
Authors: Christian Jons, Jin O-Uchi, Arthur J. Moss, Matthias Reumann, John J. Rice, Ilan Goldenberg, Wojciech Zareba, Arthur A. M. Wilde, Wataru Shimizu, Jorgen K. Kanters, Scott McNitt, Nynke Hofman, Jennifer L. Robinson, Coeli M. B. Lopes
Journal: Science Translational Medicine (2011)

Inherited long QT syndrome (LQTS) is caused by mutations in ion channels that delay cardiac repolarization, increasing the risk of sudden death from ventricular arrhythmias. Currently, the risk of sudden death in individuals with LQTS is estimated from clinical parameters such as age, gender, and the QT interval, measured from the electrocardiogram. Even though a number of different mutations can cause LQTS, mutation-specific information is rarely used clinically. LQTS type 1 (LQT1), one of the most common forms of LQTS, is caused by mutations in the slow potassium current (I(Ks)) channel α subunit KCNQ1. We investigated whether mutation-specific changes in I(Ks) function can predict cardiac risk in LQT1. By correlating the clinical phenotype of 387 LQT1 patients with the cellular electrophysiological characteristics caused by an array of mutations in KCNQ1, we found that channels with a decreased rate of current activation are associated with increased risk of cardiac events (hazard ratio=2.02), independent of the clinical parameters usually used for risk stratification. In patients with moderate QT prolongation (a QT interval less than 500 ms), slower activation was an independent predictor for cardiac events (syncope, aborted cardiac arrest, and sudden death) (hazard ratio = 2.10), whereas the length of the QT interval itself was not. Our results indicate that genotype and biophysical phenotype analysis may be useful for risk stratification of LQT1 patients and suggest that slow channel activation is associated with an increased risk of cardiac events.
Drill biopsy in the diagnosis of lung lesions.
Authors: P Shatapathy, R C Sahoo, K M Rao, K V Krishnan, P V Rau, A Padhee
Journal: Thorax (1987)

A high speed pneumatic drill was used to perform 190 percutaneous transthoracic biopsies in 161 patients. The resultant cores of tissue provided a definite diagnosis in 146 patients, giving a success rate of 90.7%. Complications occurred in 58 patients, subcutaneous emphysema being the most common, though only seven patients required active treatment, giving a rate of 3.7% for important complications. One patient died within 24 hours of the biopsy procedure owing to asphyxia resulting from aspiration of the contents of an acutely dilated stomach. Our experience clearly establishes that the drill biopsy as used by us is simple and safe and can be carried out in an outpatient department, yielding better overall results than any other procedure for closed biopsy of the lung currently practised.