tbuckley/cabot-search huggingface dataset:
miR-92b controls glioma proliferation and invasion through regulating Wnt/beta-catenin signaling via Nemo-like kinase
Authors: Kun Wang, Xuan Wang, Jian Zou, Anling Zhang, Yingfeng Wan, Peiyu Pu, Zhengfei Song, Cong Qian, Yili Chen, Shuxu Yang, Yirong Wang
Journal: Neuro-Oncology (2013)

Nemo-like kinase (NLK) is an evolutionarily conserved protein kinase involved in Wnt/beta-catenin signaling, which has been reported to be associated with gliomagenesis. In the present study, we aimed to identify a concrete mechanism of Wnt/beta-catenin pathway regulation by microRNAs (miRNAs) in glioma. Quantitative reverse-transcription polymerase chain reaction and in situ hybridization were conducted to detect the expression of miR-92b. The cell proliferation rate and cell cycle kinetics were detected using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay and flow cytometry, cell invasion and migration were evaluated using Transwell assay and wound healing assay, and cell apoptosis was detected using annexin V staining. Furthermore, the relevant molecules regulating proliferation and invasion were examined using Western blot analysis, immunohistochemistry, and immunofluorescence staining. Luciferase reporter assay was used to identify the direct regulation of NLK by miR-92b and beta-catenin/TCF4 activity. We first showed that the expression of miR-92b was elevated in both glioma samples and glioma cells. Furthermore, down-regulation of miR-92b triggered growth inhibition, induced apoptosis, and suppressed invasion of glioma in vitro and in vivo. Luciferase assay and Western blot analysis revealed that NLK is a direct target of miR-92b. Restoring expression of NLK inhibited glioma proliferation and invasion. Mechanistic investigation revealed that miR-92b deletion suppressed beta-catenin/TCF-4 transcription activity by targeting NLK. Moreover, expression of NLK was inversely correlated with miR-92b in glioma samples and was predictive of patient survival in a retrospective analysis. Our findings identify a role for miR-92b in glioma proliferation and invasion after activation of Wnt/beta-catenin signaling via NLK.
Devolution in health policy is threatening unity of the NHS
Authors: Adrian O’Dowd
Journal: BMJ (2008)

Conflict between the four devolved governments in the United Kingdom is increasingly likely and will affect the NHS, according to an influential report.

The report about devolution by the health policy think tank The Nuffield Trust says that differences in health policy in the UK could become a growing tension that tears at medical training, puts pressure on representative organisations, and leads to educational divergence.

The report is based on a series of high level seminars held with government officials, profession leaders, advisers, academics, and other health policy makers in the four countries.

It says, “Having repeatedly reformed its …
Development of a Diagnostic Method for Detecting Increased Muscle Protein Degradation in Patients with Catabolic Conditions
Authors: Biruh T. Workeneh, Helbert Rondon-Berrios, Liping Zhang, Zhaoyong Hu, Gashu Ayehu, Arny Ferrando, Joel D. Kopple, Huiyun Wang, Thomas Storer, Mario Fournier, Seoung Woo Lee, Jie Du, William E. Mitch
Journal: Journal of the American Society of Nephrology (2006)

Muscle atrophy in catabolic illnesses is due largely to accelerated protein degradation. Unfortunately, methods for detecting accelerated muscle proteolysis are cumbersome. The goal of this study was to develop a method for detecting muscle protein breakdown and assess the effectiveness of anticatabolic therapy. In rodent models of catabolic conditions, it was found that accelerated muscle protein degradation is triggered by activation of caspase-3. Caspase-3 cleaves actomyosin/myofibrils to form substrates for the ubiquitin-proteasome system and leaves a characteristic 14-kD actin fragment in the insoluble fraction of a muscle lysate. Muscle biopsies were obtained from normal adults and three groups of patients: 14 who were undergoing hip arthroplasty, 28 hemodialysis patients who were participating in exercise programs, and seven severely burned patients. In muscle of patients who were undergoing hip arthroplasty, the 14-kD actin fragment level was correlated (r = 0.787, P < 0.01) with the fractional rate of protein degradation. In muscle of hemodialysis patients who were undergoing endurance exercise training, the 14-kD actin fragment decreased to values similar to levels in normal adults; strength training did not significantly decrease the actin fragment. Severely burned patients had increased muscle protein degradation and actin fragment levels, but the two measures were not significantly correlated. The experimental results suggest that the 14-kD actin fragment in muscle biopsies is increased in catabolic states and could be used in conjunction with other methods to detect and monitor changes in muscle proteolysis that occur in patients with mild or sustained increases in muscle proteolysis.
Neurophysiological Correlates of the Intellectual Function of Elderly Persons Living in the Community
Authors: H. SHAN WANG, WALTER D. OBRIST, EWALD W. BUSSE
Journal: American Journal of Psychiatry (1970)

EEG examinations and cerebral blood flow determinations were carried out in two groups of relatively healthy aged community volunteers who participated in a longitudinal study. Intellectual function, as assessed by the WAIS, was correlated with these cerebral physiological variables. Dominant brain wave frequency, the presence of temporal lobe EEG foci, and estimates of grey matter blood flow were found to be significantly related to intelligence test performance. The results emphasize the value of longitudinal observations in aging studies.
2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults
Authors: Sharon Ann Hunt, William T. Abraham, Marshall H. Chin, Arthur M. Feldman, Gary S. Francis, Theodore G. Ganiats, Mariell Jessup, Marvin A. Konstam, Donna M. Mancini, Keith Michl, John A. Oates, Peter S. Rahko, Marc A. Silver, Lynne Warner Stevenson, Clyde W. Yancy
Journal: Circulation (2009)
Radioembolization for hepatocellular carcinoma with portal vein thrombosis: Impact of liver function on systemic treatment options at disease progression
Authors: Khairuddin Memon, Laura Kulik, Robert J. Lewandowski, Mary F. Mulcahy, Al B. Benson, Daniel Ganger, Ahsun Riaz, Ramona Gupta, Michael Vouche, Vanessa L. Gates, Frank H. Miller, Reed A. Omary, Riad Salem
Journal: Journal of Hepatology (2012)
Heterosynaptic Dopamine Neurotransmission Selects Sets of Corticostriatal Terminals
Authors: Nigel S Bamford, Hui Zhang, Yvonne Schmitz, Nan-Ping Wu, Carlos Cepeda, Michael S Levine, Claudia Schmauss, Stanislav S Zakharenko, Leonard Zablow, David Sulzer
Journal: Neuron (2004)
Electrical conductance of mouse connexin45 gap junction channels is modulated by phosphorylation
Authors: T van Veen
Journal: Cardiovascular Research (2000)

In this study we report about the modulation of connexin45 (Cx45) gap junction channel properties by phosphorylation of the connexin molecules through different protein kinases. Phosphorylation of Cx45 was studied in HeLa cells transfected with mouse Cx45 (mCx45). Using Western blotting (WB) and immunocytochemistry, these cells were found exclusively positive for Cx45 and the protein was separated as a doublet of bands with a calculated mass of 46 and 48 kD. After dephosphorylation using calf intestine phosphatase (CIP), the 48 kD band disappeared almost completely leaving a single band at 46 kD. This effect can be prevented by including phosphatase inhibitors during CIP treatment. These results indicate that the 48 kD signal represents a phosphorylated form of Cx45. To investigate the effects of (de)phosphorylation of Cx45 on the conductive properties of gap junction channels built of this connexin, cell pairs were subjected to dual voltage clamp experiments and coupling was determined before and after addition of PMA, 4α-PDD, cAMP, cGMP, and pervanadate to the superfusate. 100 nM of the PKC activating phorbol ester PMA increased normalized junctional conductance by 50.9±28%. 100 nM of the inactive phorbol ester 4α-PDD had no significant effect. Activation of PKA with 1 mM 8-Br-cAMP decreased coupling by 20.9±5.7% while 1 mM 8-Br-cGMP (PKG-activation) was ineffective. 100 μM pervanadate, a tyrosine phosphatase inhibitor, reduced coupling by 43.7±11.1%. Single channel measurements, under identical phosphorylating conditions, were not significantly different from each other and all frequency histograms exhibited two conductance peaks at approximately 20 and 40 pS. WB analysis revealed, as compared to control conditions, a relative increase of the 48 kD signal upon stimulation with pervanadate (142±42%) and 8-Br-cAMP (50±23%) whereas neither stimulation with PMA nor 8-Br-cGMP had a significant effect. These experiments show that electrical intercellular conductance via Cx45 gap junction channels is differentially regulated by phosphorylation. However, regulation does not act by changing single channel conductance, but most likely by modulation of the open probability of Cx45 gap junction channels.
Somatic loss of polycystic disease genes contributes to the formation of isolated and polycystic liver cysts: Table 1
Authors: Manoe J Janssen, Jody Salomon, Wybrich R Cnossen, Carsten Bergmann, Rolph Pfundt, Joost P H Drenth
Journal: Gut (2014)

We read with interest the paper by Urribarri et al 1 which describes that metalloprotease hyperactivity plays an important role in cyst expansion and that metalloprotease inhibition reduces cyst proliferation. As such, these results help to identify potential drug targets.2 We hypothesise that the expansion and maintenance of the cyst is preceded by mutational events that trigger cytogenesis, and we used genetic analysis to provide additional insight into this process. The majority of polycystic diseases are autosomal dominant disorders where every patient cell possesses one germ line mutation (first hit).3 As somatic second-hit mutations play an important role in liver and renal cyst formation,4–6 it was hypothesised that patients with polycystic disease have a DNA repair defect and accumulate somatic mutations.7 This was supported by a comparative genomic hybridisation study where renal cysts harboured multiple chromosomal aberrations, similar to cancers.8 ,9 In addition, patients without a germ line mutation can still develop …
Gemcitabine, Cisplatin, and Radiotherapy for Patients With Locally Advanced Pancreatic Adenocarcinoma: Results of the North Central Cancer Treatment Group Phase II Study N9942
Authors: Michael G. Haddock, Revathi Swaminathan, Nathan R. Foster, Mark D. Hauge, James A. Martenson, John K. Camoriano, Philip J. Stella, Richard C. Tenglin, Paul L. Schaefer, Dennis F. Moore, Steven R. Alberts
Journal: Journal of Clinical Oncology (2007)

A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma.Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m2) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life.Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook.The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.
Burnout in ICU Caregivers
Authors: Paolo Merlani, Mélanie Verdon, Adrian Businger, Guido Domenighetti, Hans Pargger, Bara Ricou
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Rationale: The stressful work environment of ICUs can lead to burnout. Burnout can impact on the welfare and performance of caregivers, and may lead them to resign their job. The shortage of ICU caregivers is becoming a real threat for health care leaders.Objectives: To investigate the factors associated with burnout on a national level in order to determine potential important factors.Methods: Prospective, multicenter, observational survey of all caregivers from 74 of the 92 Swiss ICUs, measuring the prevalence of burnout among the caregivers and the pre-specified center-, patient- and caregiver-related factors influencing its prevalence.Measurements and Main Results: Out of the 4322 questionnaires distributed from March 2006 to April 2007, 3052 (71%) were returned, with a response rate of 72% by center, 69% from nurse-assistants, 73% from nurses and 69% from physicians. A high proportion of female nurses among the team was associated with a decreased individual risk of high burnout (OR 0.98, 95% CI:0.97–0.99 for every %). The caregiver-related factors associated with a high risk of burnout were being a nurse-assistant, being a male, having no children and being under 40 years old.Conclusions: The findings of this study seem to open a new frontier concerning burnout in ICUs, highlighting the importance of team composition. Our results should be confirmed in a prospective multicenter, multinational study. Whether our results can be exported to other medical settings where team-working is pivotal remains to be investigated.
Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C–related fibrosis: A systematic review
Authors: Abdel Aziz M. Shaheen, Robert P. Myers
Journal: Hepatology (2007)

The development of noninvasive markers of liver fibrosis is a clinical and research priority. The aspartate aminotransferase-to-platelet ratio index (APRI) is a promising tool with limited expense and widespread availability. Our objective was to systematically review the performance of the APRI in hepatitis C virus (HCV)-infected patients. Random effects meta-analyses and areas under summary receiver operating characteristic curves (AUC) were examined to characterize APRI accuracy for significant fibrosis (stages 2-4) and cirrhosis. In 22 studies (n = 4,266), the summary AUCs of the APRI for significant fibrosis and cirrhosis were 0.76 [95% confidence interval (CI), 0.74-0.79] and 0.82 (95%CI, 0.79-0.86), respectively. For significant fibrosis, an APRI threshold of 0.5 was 81% sensitive and 50% specific. At a 40% prevalence of significant fibrosis, this threshold had a negative predictive value (NPV) of 80%, but could reduce the necessity of liver biopsy by only 35%. For cirrhosis, a threshold of 1.0 was 76% sensitive and 71% specific. At a 15% cirrhosis prevalence, the NPV of this threshold was 91%. Higher APRI thresholds had suboptimal positive predictive values except in settings with a high prevalence of cirrhosis. APRI accuracy was not affected by the prevalence of advanced fibrosis, or study and biopsy quality. However, the accuracy for cirrhosis was greater in studies including human immunodeficiency virus (HIV)/HCV-co-infected patients.The major strength of the APRI is the exclusion of significant HCV-related fibrosis. Future studies of novel markers should demonstrate improved accuracy and cost-effectiveness compared with this economical and widely available index.
Effects of pulmonary rehabilitation (PR) in idiopathic pulmonary arterial hypertension (PAHI)
Authors: Fabricio Fontoura, Juliessa Florian, Fernanda Spilimbergo, Guilherme Watte, Elenice Rode, Gisela Meyer
Journal: European Respiratory Journal (2013)

Exercise training can be performed as an alternative therapy in the clinical management of patients with pulmonary arterial hypertension (PAH). We present a case of a 31 years old male patient, diagnosed with PAHI in 2007 with mean pulmonary artery pressure of 70 mmHg in right heart catheterization. In 2011 patient had progressive clinical deterioration despite medical therapy optimization, worsening to class IV, unresponsive to triple PAH therapy. The Patient was referred to lung transplantation in March 2012 and started PR in May 2012 as part of the routine protocol. PR lasted six months, three times per week, 1 hour and 30 minutes each session and consisted of aerobic training and peripheral muscle strength training with free weights. We assessed dyspnea, functional capacity and life quality using modified Medical Research Council (mMRC) scale, six minute walk test (6MWT) and the Medical Outcomes Study 36 - Item Short Form Health Survey (SF36). Medical therapy was not changed from the lung transplant inclusion date until the end of the six months rehabilitation period. Dyspnea decreased after 3 months and at the end of 6 months. Quality of life showed improvement. The patient had decreased dyspnea, increased functional capacity and improvement of life quality after supervised PR without changing any medical therapy.Figure1: values of 6MW distance and dyspnea Borg scale.

![Figure][1]  [1]: pending:yes
Inhibition of Matrix Metalloproteinases by Lung TIMP-1 Gene Transfer or Doxycycline Aggravates Pulmonary Hypertension in Rats
Authors: Antoine Vieillard-Baron, Eric Frisdal, Saadia Eddahibi, Isabelle Deprez, Andrew H. Baker, Andrew C. Newby, Patrick Berger, Micheline Levame, Bernadette Raffestin, Serge Adnot, Marie-Pia d’Ortho
Journal: Circulation Research (2000)

Abstract —Chronic hypoxic pulmonary hypertension (PH) results from persistent vasoconstriction, excess muscularization, and extracellular matrix remodeling of pulmonary arteries. The matrix metalloproteinases (MMPs) are a family of proteinases implicated in extracellular matrix turnover and hence in smooth muscle and endothelial cell migration and proliferation. Because MMP expression and activity are increased in PH, we designed the present study to investigate whether inhibition of lung MMPs in rats subjected to chronic hypoxia (CH) contributes to or protects against vascular remodeling and PH. To achieve lung MMP inhibition, rats exposed to 10% O 2 for 15 days were treated with either doxycycline (20 mg/kg per day by gavage starting 2 days before and continuing throughout the CH period) or a single dose of recombinant adenovirus (Ad) for the human tissue inhibitors of metalloproteinases-1 (hTIMP-1) gene (Ad.hTIMP-1, 10 8 plaque-forming units given intratracheally 2 days before CH initiation). Control groups either received no treatment or were treated with an adenovirus containing no gene in the expression cassette (Ad.Null). Efficacy of hTIMP-1 gene transfer was assessed both by ELISA on bronchoalveolar lavages and by hTIMP-1 immunofluorescence on lung sections. MMP inhibition in lungs was evaluated by in situ zymography and gelatinolytic activity assessment using [ 3 H]gelatin. Rats treated with either doxycycline or Ad.hTIMP-1 had higher pulmonary artery pressure and right heart ventricular hypertrophy more severe than their respective controls. Worsening of PH was associated with increased muscularization and periadventitial collagen accumulation in distal arteries. In conclusion, our study provides compelling evidence that MMPs play a pivotal role in protecting against pulmonary artery remodeling.
Immune response to the carcinoembryonic antigen in patients treated with an anti-idiotype antibody vaccine.
Authors: K A Foon, M Chakraborty, W J John, A Sherratt, H Köhler, M Bhattacharya-Chatterjee
Journal: Journal of Clinical Investigation (1995)

We have generated an IgG1 murine monoclonal anti-idiotype antibody (Ab2) designated 3H1, which mimics a specific epitope on the carcinoembryonic antigen (CEA). Patients with CEA positive tumors are immunologically "tolerant" to CEA. We used 3H1 as a surrogate for CEA for vaccine therapy of 12 patients with advanced colorectal cancer. Each of the patients received a minimum of four intracutaneous injections of aluminum hydroxide precipitated 3H1 at either 1, 2, or 4 mg dosage per injection. 9 of 12 patients demonstrated anti-anti-idiotypic (Ab3) response to 3H1. All nine patients generated specific anti-CEA antibody demonstrated by reactivity with radiolabeled purified CEA; some cases were confirmed by immunoprecipitation of purified CEA. We also demonstrated Ab3 stained both autologous and allogeneic colonic tumors. 7 of 12 patients demonstrated idiotype specific T cell proliferative responses and four also showed T cell proliferation to CEA. Toxicity was limited to local reaction with mild fever and chills. All 12 patients eventually progressed after finishing 4-13 dosages. This is the first report demonstrating that a vaccine therapy is capable of breaking "immune tolerance" to CEA in patients with CEA positive tumors. Future studies will focus on treating patients with minimal residual disease.
Histidinemia in mice: A metabolic defect treated using a novel approach to hepatocellular transplantation
Authors: Clare Selden, Denis Calnan, Neil Morgan, Hervey Wilcox, Edward Carr, Humphrey J. F. Hodgson
Journal: Hepatology (1995)

Histidinemia in mice and in humans is an autosomal recessive disorder of histidine metabolism that leads to high-histidine levels in both plasma and urine and is caused by a lack of hepatic histidine-alpha-deaminase (histidase). We have used a novel approach to hepatocellular transplantation to effect a complete phenotypic cure of histidinemia in a mouse model. Mice lacking histidase were treated with isolated liver cells (approximately 18 x 10(6) hepatocytes and 9 x 10(6) nonparenchymal cells) from histidase-competent donors transplanted into the peritoneum (active transplant group). Recipient mice showed a dramatic decrease, by more than 75%, in urinary histidine levels from day one throughout the course of the experiment, resulting in levels within the normal range for wild-type mice. In comparison, there was no change in urinary histidine levels in the control group of histidase-deficient mice treated with isolated liver cells from mice lacking histidase (statistical comparison between the two groups, P < .003, two-way ANOVA). Histologically, ectopic liver tissue was seen in the peritoneum in association with abdominal wall, pancreas, and peritoneal connective tissue; immunohistochemical evidence showed expression of histidase in the ectopic liver tissue in the active transplant group. This report is the first to show complete correction of a defective biochemical phenotype achieved by hepatocellular transplantation.