tbuckley/cabot-search huggingface dataset:
Subcellular mechanism for Ca(2+)-dependent enhancement of delayed rectifier K+ current in isolated membrane patches of guinea pig ventricular myocytes.
Authors: J Nitta, T Furukawa, F Marumo, T Sawanobori, M Hiraoka
Journal: Circulation Research (1994)

Intracellular Ca2+ augments delayed rectifier K+ current (IK) in cardiac myocytes, which may play a major modulatory role in repolarization of action potentials. We investigated subcellular mechanisms for Ca(2+)-induced enhancement of IK in large-pipette inside-out membrane patches excised from isolated guinea pig ventricular myocytes. When [Ca2+]i was raised from 10(-8) to 10(-6) mol/L, the amplitude of IK measured at +80 mV was increased from 12.0 +/- 2.2 to 19.5 +/- 3.3 pA (P &lt; .01). The enhancement of IK by Ca2+ was dose dependent, with an EC50 of 3.8 x 10(-8) mol/L. A calmodulin antagonist, W7 (50 mumol/L), calmidazolium (100 mumol/L), or HT-74 (20 mumol/L), added to the intracellular solution abolished enhancement of IK by Ca2+, whereas the inactive form of the W7 analogue, W5, had no effect on IK. In the presence of a protein kinase inhibitor with a relatively high specificity for protein kinase C (H7), for protein kinase A (H8 or peptide-type inhibitor PKI), or for calmodulin kinase II (KN-62) or a nonspecific inhibitor of serine/threonine protein kinases (staurosporine), increases in [Ca2+]i still enhanced IK. Ca(2+)-induced enhancement of IK was also observed when Mg2+ and ATP were omitted from the intracellular solution to delete exogenous phosphate donors and when adenylylimidodiphosphate was added to preclude trapped cytoplasmic substrates. Thus, cardiac IK was enhanced by increases in [Ca2+]i at a physiological range via a calmodulin-dependent pathway, which did not involve a phosphorylation process.
Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): A meta-analysis of individual data from 1764 patients
Authors: A. Aupérin, C. Le Péchoux, J.P. Pignon, C. Koning, B. Jeremic, G. Clamon, L. Einhorn, D. Ball, M.G. Trovo, H.J.M. Groen, J.A. Bonner, T. Le Chevalier, R. Arriagada
Journal: Annals of Oncology (2006)
An open-label, fixed-dose study of bupropion effect on sexual function scores in women treated for breast cancer
Authors: C. Mathias, C.M. Cardeal Mendes, E. Pondé de Sena, E. Dias de Moraes, C. Bastos, M.I. Braghiroli, G. Nuñez, R. Athanazio, L. Alban, H.C.F. Moore, A. del Giglio
Journal: Annals of Oncology (2006)
Effects of miR-193a and sorafenib on hepatocellular carcinoma cells
Authors: Alessandro Salvi, Isabel Conde, Edoardo Abeni, Bruna Arici, Ilaria Grossi, Claudia Specchia, Nazario Portolani, Sergio Barlati, Giuseppina De Petro
Journal: Molecular Cancer (2013)

Abstract Background Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance, it is the third most common cause of cancer-related mortality worldwide. In the last years the multikinase inhibitor sorafenib has been used for advanced HCC, but some patients do not benefit from this therapy; thus, novel therapeutic options based on molecular approaches are urgently needed. microRNAs are short non coding RNAs involved in several physiological and pathological conditions including HCC and increasing evidence describes miRs as good tools for the molecular targeted therapies in HCC. The purpose of this study was to identify novel approaches to sensitize the HCC cells to sorafenib by microRNAs targeting urokinase-type plasminogen activator (uPA). Methods The miR-193a was validated as negative regulator of urokinase-type plasminogen activator (uPA) in 2 HCC undifferentiated cell lines by transient transfection of miR and anti-miR molecules. The molecular interaction between miR-193a and uPA mRNA target was verified by luciferase reporter assay. The miR-193a expression level was evaluated by stem-loop real time PCR in tumoral tissues from 39 HCC patients. The HCC cells were co-treated with sorafenib and miR-193a and the effects on cellular proliferation, apoptosis were tested. The effect of sorafenib on c-met expression levels was assessed by western blotting. Results The miR-193a has resulted a negative regulator of uPA in both the HCC cell lines tested. The miR-193a expression has resulted dysregulated in tumoral tissues from 39 HCC patients. We found miR-193a down-regulation in HCC respect to peritumoral (PT) tissues and more in the cirrhotic HCCs than in non-cirrhotic ones. Transfection of HA22T/VGH HCC cells with miR-193a decreased proliferation and increased apoptosis, and combined treatment with miR-193a and sorafenib led to further proliferation inhibition. Conclusions Our results present new advances in the post-transcriptional miR-mediated mechanisms of uPA and they suggest a new strategy to impair the aggressive behavior of HCC cells. Our findings could be helpful to explore novel approaches for multi-target and multi-agent therapies of the HCC.
A review of the management of 100 cases of benign stricture of the oesophagus
Authors: S. Raptis, D. M. Milne
Journal: Thorax (1972)

One hundred cases of benign stricture of the oesophagus treated over a period of 11 years from 1960 to 1971 under the care of the senior author (D.M.M.) at Frenchay Hospital Thoracic Unit are reviewed. The results indicate that the commonest site of the lesion is in the lower third of the oesophagus and that the commonest cause is peptic oesophagitis due to gastric reflux and associated hiatus hernia. As the disease is commoner in the elderly a conservative medical regimen of dilatation, antacids, and posturing is recommended as the first line of treatment. When this fails surgery is necessary. Collis (1965) managed 69 patients by gastroplasty. Belsey (1965) reported his experience with colon transplants, while Brain (1967) and Allison (1970) advised jejunal transplantation. Our experience has shown that in view of the old age and often poor physical condition of these patients resection of the stricture and oesophagogastric anastomosis is a relatively safe and simple procedure. The results obtained indicate that 25% of patients operated on will require future dilatations.
Ischemic acidosis causes apoptosis in coronary endothelial cells through activation of caspase-12☆
Authors: S KUMAR, S KASSECKERT, S KOSTIN, Y ABDALLAH, C SCHAFER, A KAMINSKI, H REUSCH, H PIPER, G STEINHOFF, Y LADILOV
Journal: Cardiovascular Research (2006)

Objective: Myocardial ischemia has been shown to induce apoptosis of endothelial cells (EC). However, the mechanism of this endothelial injury is still poorly understood. To analyse the signaling pathway of ischemia-induced EC apoptosis was the aim of the present study.
Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma
Authors: Yinying Lu, Wanping Xu, Junfang Ji, Dechun Feng, Carole Sourbier, Youfeng Yang, Jianhui Qu, Zhen Zeng, Chunping Wang, Xiujuan Chang, Yan Chen, Alok Mishra, Max Xu, Min‐Jung Lee, Sunmin Lee, Jane Trepel, W. Marston Linehan, Xinwei Wang, Yongping Yang, Len Neckers
Journal: Hepatology (2015)

The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced, with one isoform containing a long proline-rich region (PRR(L) ) compared to the other with a short PRR (PRR(S) ). Recently, PRR(L) was reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remains unexplored. We report here that Numb PRR(L) expression is increased in HCC and associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRR(L) generally promotes and PRR(S) suppresses proliferation, migration, invasion, and colony formation. Knockdown of PRR(S) leads to increased Akt phosphorylation and c-Myc expression, and Akt inhibition or c-Myc silencing dampens the proliferative impact of Numb PRR(S) knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor RNA-binding Fox domain containing 2 (RbFox2) and the kinase serine/arginine protein-specific kinase 2 (SRPK2). Knockdown of the former causes accumulation of PRR(L) , while SRPK2 knockdown causes accumulation of PRR(S) . The subcellular location of SRPK2 is regulated by the molecular chaperone heat shock protein 90, and heat shock protein 90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRR(S) . Finally, HCC cell lines that predominantly express PRR(L) are differentially sensitive to heat shock protein 90 inhibition.Alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable.
Professionals should be given more freedom to innovate, says King’s Fund
Authors: Adrian O’Dowd
Journal: BMJ (2008)

The future success of the NHS lies in greater freedom for health professionals and managers, an expert working group has concluded.

In the run up to the imminent publication of junior health minister Ara Darzi’s review of the NHS, a report from the healthcare think tank the King’s Fund says that clinicians and managers should have greater power to innovate and to develop services. The report, which contains 33 proposals, is based on the findings of an expert working group made up of leaders from the NHS and the private sector.

It is time for the Department …
The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents
Authors: J. R. Curtis, F. Xie, L. Chen, J. W. Baddley, T. Beukelman, K. G. Saag, C. Spettell, R. M. McMahan, J. Fernandes, K. Winthrop, E. Delzell
Journal: Annals of the Rheumatic Diseases (2011)

It is unclear whether anti-tumour necrosis factor alpha and biological agents with different mechanisms of action have similar safety. This study evaluated the incidence of hospitalised infections among rheumatoid arthritis (RA) patients starting or switching various biological agents.Using a database from a large US healthcare organisation from January 2005 to August 2009, the authors identified enrollees with RA and their treatment episodes entailing the new use of a biological agent, stratified by no biological use in the previous year ('biological-free') or switching from a different biological agent ('switchers'). Outcomes were hospitalised infections identified using previously validated algorithms. Proportional hazards models estimated the hazard ratio of hospitalised infections, comparing each biological agent with infliximab.Among 7847 biological treatment episodes, 63% were for biological-free patients and 37% for switchers. There were 364 hospitalised infections. Rates of hospitalised infection among biological-free patients and switchers were 4.6 and 7.0 per 100 person-years, respectively (p<0.0001). After multivariable adjustment controlling for biological-free/switcher status and other infection-related factors and compared with infliximab, users of abatacept (HR 0.68, 95% CI 0.48 to 0.96), adalimumab (HR 0.52, 0.39 to 0.71), etanercept (HR 0.64, 0.49 to 0.84) and rituximab (HR 0.81, 0.55 to 1.20) had lower rates of hospitalised infection. Patient risk factors contributed more to the risk of infection than did the risk associated with specific biological therapies.The rate of hospitalised infections among RA patients was highest for infliximab. Most of the variability in patients' risk of infection was driven by factors other than biological agent exposure.
Human Immunodeficiency Virus and the Brain
Authors: Jonathan D. Glass, Richard T. Johnson
Journal: Annual Review of Neuroscience (1996)

Human immunodeficiency virus (HIV) infects the nervous system in the majority of patients, causing a variety of neurological syndromes throughout the course of the disease. This review focuses on the effects of HIV in the central nervous system, with an emphasis on HIV-associated dementia. HIV-associated dementia occurs in a subset of patients with AIDS; it is unclear why these patients and not all patients develop the disease. Several factors are likely to be involved in the pathogenesis of HIV-associated dementia, including neurotoxins released from the virus and/or infected macrophages and microglia, immunologic dysregulation of macrophage function, and specific genetic strains of HIV. These factors, and their possible interactions, are discussed.
Magnesium in patients undergoing open-heart surgery
Authors: M. P. Holden, M. I. Ionescu, G. H. Wooler
Journal: Thorax (1972)

Measurements of serum and urinary magnesium levels were made together with the other electrolytes, haematocrit, pH, and albumin in patients comprising two groups—one group of 50 patients undergoing heart valve replacement, and the other, 30 patients undergoing non-perfusion thoracic operations. Low serum magnesium levels were found in some patients admitted to hospital who were or had recently been in congestive heart failure. All patients were found to have low serum magnesium levels postoperatively, but to a greater degree and for a longer period following open-heart surgery. The latter group exhibited hypomagnesuria postoperatively. The literature is reviewed in an attempt to explain the reasons for the changes in the magnesium levels. It is concluded that the changes observed in this limited study warrant further detailed investigation including the use of a double blind trial for assessing the therapeutic value of administering magnesium salts of patients undergoing open-heart surgery.
One‐year follow‐up results from AUGMENT‐HF: a multicentre randomized controlled clinical trial of the efficacy of left ventricular augmentation with Algisyl in the treatment of heart failure
Authors: Douglas L. Mann, Randall J. Lee, Andrew J.S. Coats, Gheorghe Neagoe, Dinu Dragomir, Enrico Pusineri, Massimo Piredda, Luca Bettari, Bridget‐Anne Kirwan, Robert Dowling, Maurizio Volterrani, Scott D. Solomon, Hani N. Sabbah, Andy Hinson, Stefan D. Anker
Journal: European Journal of Heart Failure (2015)
Maladaptive Role of IL-6 in Ischemic Acute Renal Failure
Authors: Mariusz L. Kielar, Reji John, Michael Bennett, James A. Richardson, John M. Shelton, Liying Chen, D. Rohan Jeyarajah, Xin J. Zhou, Hui Zhou, Brett Chiquett, Glenn T. Nagami, Christopher Y. Lu
Journal: Journal of the American Society of Nephrology (2005)

The role of IL-6 was investigated in murine ischemic acute renal failure. The renal pedicles were clamped for 17 min, and the mice were studied at various times after reperfusion. We found that serum IL-6 increased after murine ischemic renal injury. This increase was associated with increased IL-6 mRNA in the ischemic kidney but not in the contralateral kidney or the liver. Maximal IL-6 production occurred at 4 to 8 h and decreased to baseline by 24 h. Reperfusion of the kidney was required for IL-6 production. In situ hybridization and immunohistochemistry showed that macrophages infiltrated areas adjacent to the vascular bundles in the outer medulla within hours of reperfusion and showed that these macrophages produced IL-6 mRNA. For understanding how macrophages were stimulated to produce IL-6, an in vitro model in which S3 proximal tubular cells were injured by reactive oxygen species was set up. These injured cells released molecules that activated macrophages to produce IL-6 in vitro. IL-6 that was produced in response to renal ischemia was maladaptive because transgenic knockout of IL-6 ameliorated renal injury as measured by serum creatinine and histology. IL-6 transgenic knockout mice were lethally irradiated, and their bone marrow was reconstituted with wild-type IL-6 cells. Such bone marrow transfers abolished the protective effects of transgenic IL-6 knockout. It is concluded that macrophages infiltrate the area of the vascular bundles of the outer medulla, these macrophages produce IL-6, and this IL-6 exacerbates ischemic murine acute renal failure.
Interaction of COMT Val<sup>108/158</sup> Met Genotype and Olanzapine Treatment on Prefrontal Cortical Function in Patients With Schizophrenia
Authors: Alessandro Bertolino, Grazia Caforio, Giuseppe Blasi, Mariapia De Candia, Valeria Latorre, Vittoria Petruzzella, Mario Altamura, Gaetano Nappi, Sergio Papa, Joseph H Callicott, Venkata S Mattay, Antonello Bellomo, Tommaso Scarabino, Daniel R Weinberger, Marcello Nardini
Journal: American Journal of Psychiatry (2004)

Deficits in working memory and in prefrontal cortical physiology are important outcome measures in schizophrenia, and both have been associated with dopamine dysregulation and with a functional polymorphism (Val(108/158)Met) in the catechol O-methyltransferase (COMT) gene that affects dopamine inactivation in the prefrontal cortex. The purpose of the present study was to evaluate in patients with schizophrenia the effect of COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug.Thirty patients with acute untreated schizophrenia were clinically evaluated with the Positive and Negative Syndrome Scale, underwent COMT Val/Met genotyping, and entered an 8-week prospective study of olanzapine treatment. Twenty patients completed two 3-T functional magnetic resonance imaging scans at 4 and 8 weeks during performance of N-back working memory tasks.There was a significant interaction of COMT genotype and the effects of olanzapine on prefrontal cortical function. Met allele load predicted improvement in working memory performance and prefrontal physiology after 8 weeks of treatment. A similar effect was found also for negative symptoms assessed with the Positive and Negative Syndrome Scale.These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine.
CD40 Is Expressed on Human Peritoneal Mesothelial Cells and Upregulates the Production of Interleukin-15 and RANTES
Authors: ANNA BASOK, ALLA SHNAIDER, LIMOR MAN, CIDIO CHAIMOVITZ, AMOS DOUVDEVANI
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Limited data are available concerning the interaction between lymphocytes and human peritoneal mesothelial cells (HPMC) during peritonitis. CD40 is a member of the tumor necrosis factor (TNF) family of receptors whose ligand (CD154) is mainly expressed on the membrane of activated CD4-positive lymphocytes. CD154-CD40 cross-linking is a central event in antigen presentation, B-cell activation by T cells, and regulation of cytokine secretion from various types of cells. The goal of this study was to demonstrate in vitro the presence of CD40 on HPMC and to test its functionality in inducing interleukin-15 (IL-15) and RANTES. We assayed the levels of CD40 by reverse transcription-PCR and flow cytometry and IL-15 and RANTES by enzyme-linked immunosorbent assay. Genetically modified L cells that express elevated levels of CD154 (CD40L cells) were used to stimulate CD40. HPMC express CD40 mRNA and protein. After stimulation with interferon-γ (IFNγ, 5U/ml) or TNFα (1 ng/ml), there was a small increase in CD40 mRNA and protein levels; when both cytokines were applied, the increase in CD40 levels was more than threefold. CD40 ligation induced IL-15 production by HPMC and was additive to IFNγ stimulation. CD40 ligation was strongly synergistic with IFNγ in induction of RANTES (20-fold as compared with unstimulated HPMC), whereas neither ligation nor IFNγ alone could induce RANTES. Pretreatment of HPMC with TNFα and IFNγ increased the response to CD40 ligation in magnitudes that correlated with the elevation of CD40 levels induced by the pretreatment. To conclude, the presence of a functional CD40 on HPMC whose ligation induced IL-15 and RANTES production was detected. It is possible that this receptor acts as a major mediator of T-cell—regulated immune and inflammatory response during peritonitis.
Some risk factors in trampolining illustrated by six serious injuries.
Authors: A. Hammer, A. L. Schwartzbach, P. E. Paulev
Journal: British Journal of Sports Medicine (1982)

Four case histories out of 75 significant trampoline injuries (from a total of 198 injuries re-examined) plus two recent accidents (1979) are presented, illustrating that the trampoline is posing an undue risk of serious injury. It is argued that the only single factor capable of preventing trampoline injuries is a trampoline ban. This is imperative in schools. Trampoline clubs are advised to reconsider the risk factors involved.
Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer
Authors: M Gershanovich, H A Chaudri, D Campos, H Lurie, A Bonaventura, M Jeffrey, F Buzzi, I Bodrogi, H Ludwig, P Reichardt, N O'Higgins, G Romieu, P Friederich, M Lassus
Journal: Annals of Oncology (1998)
Interleukin-1α Mediates the Antiproliferative Effects of 1,25-Dihydroxyvitamin D3 in Prostate Progenitor/Stem Cells
Authors: Sophia L. Maund, Wendy W. Barclay, Laura D. Hover, Linara S. Axanova, Guangchao Sui, Jason D. Hipp, James C. Fleet, Andrew Thorburn, Scott D. Cramer
Journal: Cancer Research (2011)

Abstract Vitamin D3 is a promising preventative and therapeutic agent for prostate cancer, but its implementation is hampered by a lack of understanding about its mechanism of action. Upon treatment with 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3, vitamin D3], the metabolically active form of vitamin D3, adult prostate progenitor/stem cells (PrP/SC) undergo cell-cycle arrest, senescence, and differentiation to an androgen receptor–positive luminal epithelial cell fate. Microarray analyses of control- and vitamin D3–treated PrP/SCs revealed global gene expression signatures consistent with induction of differentiation. Interestingly, one of the most highly upregulated genes by vitamin D3 was the proinflammatory cytokine interleukin-1α (IL-1α). Systems biology analyses supported a central role for IL-1α in the vitamin D3 response in PrP/SCs. siRNA-mediated knockdown of IL-1α abrogated vitamin D3–induced growth suppression, establishing a requirement for IL-1α in the antiproliferative effects of vitamin D3 in PrP/SCs. These studies establish a system to study the molecular profile of PrP/SC differentiation, proliferation, and senescence, and they point to an important new role for IL-1α in vitamin D3 signaling in PrP/SCs. Cancer Res; 71(15); 5276–86. ©2011 AACR.