tbuckley/cabot-search huggingface dataset:
MEK1/2 Inhibition Decreases Lactate in BRAF-Driven Human Cancer Cells
Authors: Maria Falck Miniotis, Vaitha Arunan, Thomas R. Eykyn, Richard Marais, Paul Workman, Martin O. Leach, Mounia Beloueche-Babari
Journal: Cancer Research (2013)

Abstract The RAS/BRAF/MEK/ERK signaling pathway is a central driver in cancer with many BRAF and MEK inhibitors being evaluated in clinical trials. Identifying noninvasive biomarkers of early pharmacodynamic responses is important for development of these targeted drugs. As increased aerobic glycolysis is often observed in cancer, we hypothesized that MEK1/2 (MAP2K1/MAP2K2) inhibitors may reduce lactate levels as detected by magnetic resonance spectroscopy (MRS), as a metabolic biomarker for the pharmacodynamic response. MRS was used to monitor intracellular and extracellular levels of lactate in human cancer cells in vitro and in melanoma tumors ex vivo. In addition, we used 1H MRS and a fluorescent glucose analog to evaluate the effect of MEK inhibition on glucose uptake. MEK1/2 signaling inhibition reduced extracellular lactate levels in BRAF-dependent cells but not BRAF-independent cells. The reduction in extracellular lactate in BRAF-driven melanoma cells was time-dependent and associated with reduced expression of hexokinase-II driven by c-Myc depletion. Taken together, these results reveal how MEK1/2 inhibition affects cancer cell metabolism in the context of BRAF oncogene addiction. Furthermore, they offer a preclinical proof-of-concept for the use of MRS to measure lactate as a noninvasive metabolic biomarker for pharmacodynamic response to MEK1/2 inhibition in BRAF-driven cancers. Cancer Res; 73(13); 4039–49. ©2013 AACR.
Striking Increase of Natriuresis by Low-Dose Spironolactone in Congestive Heart Failure Only in Combination With ACE Inhibition
Authors: J. Bauersachs, D. Fraccarollo, G. Ertl, N. Gretz, M. Wehling, M. Christ
Journal: Circulation (2000)

Background —A marked reduction of overall mortality in patients with severe congestive heart failure (CHF) has been demonstrated by addition of the mineralocorticoid receptor antagonist spironolactone to ACE inhibition. The aim of the present study was to examine a hypothesized interaction of spironolactone and ACE inhibitors in renal electrolyte and volume regulation. Methods and Results —Wistar rats with extensive myocardial infarction or sham operation were treated with either placebo, the ACE inhibitor trandolapril, low-dose spironolactone, or a combination of the 2. Twelve weeks after infarction, rats were housed in metabolic cages. Urinary volume and sodium excretion were significantly increased in CHF rats on a combined treatment with spironolactone and trandolapril (21.2±2.6 mL/d, 2489±320 mmol/d, mean±SD; P &lt;0.05 versus other experimental groups) versus placebo-treated rats (16.7±5.6 mL/d, 1431±458 mmol/d),whereas these parameters were not affected in rats on either spironolactone (16.1±6.6 mL/d, 1153±273 mmol/d) or trandolapril alone (15.9±4.2 mL/d, 1392±294 mmol/d). The effects on natriuresis coincided with a significant reduction of left ventricular end-diastolic pressure (LVEDP) in rats on trandolapril and spironolactone (10.8±8.2 mm Hg; P &lt;0.05 versus CHF placebo: 23.3±7.2 mm Hg; sham-operated rats: 5.1±0.9 mm Hg), whereas LVEDP remained elevated in rats treated with either compound alone. Conclusions —In the present study, we found an unexpected interaction of low-dose spironolactone and the ACE inhibitor trandolapril in experimental CHF leading to marked effects on renal electrolyte and volume regulation that were not apparent by treatment with either drug alone. These findings may explain the beneficial effects of spironolactone in CHF patients.
LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis
Authors: Thomas R. Cox, Demelza Bird, Ann-Marie Baker, Holly E. Barker, Melisa W-Y. Ho, Georgina Lang, Janine T. Erler
Journal: Cancer Research (2013)

Abstract Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer. Cancer Res; 73(6); 1721–32. ©2012 AACR.
BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non–Small-Cell Lung Cancer
Authors: Caicun Zhou, Yi-Long Wu, Gongyan Chen, Xiaoqing Liu, Yunzhong Zhu, Shun Lu, Jifeng Feng, Jianxing He, Baohui Han, Jie Wang, Guoliang Jiang, Chunhong Hu, Hao Zhang, Gang Cheng, Xiangqun Song, You Lu, Hongming Pan, Wenjuan Zheng, Anny-Yue Yin
Journal: Journal of Clinical Oncology (2015)

Purpose The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. Patients and Methods Patients age ≥ 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non–small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m 2 ) intravenously (CP) on day 1 of each 3-week cycle, for ≤ six cycles, plus placebo (Pl+CP) or bevacizumab (B+CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. Results A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B+CP versus Pl+CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P &lt; .001). Objective response rate was improved with B+CP compared with Pl+CP (54% v 26%, respectively). Overall survival was also prolonged with B+CP compared with Pl+CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P = .0154). Median PFS was 12.4 months with B+CP and 7.9 months with Pl+CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation–positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B+CP in NSCLC; no new safety signals were observed. Conclusion The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC.
Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma
Authors: Kazuhiko Arima, Ritsuko Umeshita-Suyama, Yasuhisa Sakata, Mina Akaiwa, Xiao-Quan Mao, Tadao Enomoto, Yoshio Dake, Shin-ichiro Shimazu, Tetsuji Yamashita, Naoto Sugawara, Scott Brodeur, Raif Geha, Raj K. Puri, Mohamad H. Sayegh, Chaker N. Adra, Naotaka Hamasaki, Julian M. Hopkin, Taro Shirakawa, Kenji Izuhara
Journal: Journal of Allergy and Clinical Immunology (2002)
TRIM30α negatively regulates TLR-mediated NF-κB activation by targeting TAB2 and TAB3 for degradation
Authors: Mude Shi, Weiwen Deng, Enguang Bi, Kairui Mao, Yongyong Ji, Guomei Lin, Xiaodong Wu, Zhiyun Tao, Zhenhu Li, Xinfen Cai, Shuhui Sun, Charlie Xiang, Bing Sun
Journal: Nature Immunology (2008)
The inflammation and insulin resistance in obstructive sleep apnea
Authors: Emel Bulcun, Mehmet Ekici, Ucler Kisa, Aydanur Ekici
Journal: European Respiratory Journal (2012)

Objectives:  The association between obstructive sleep apnea (OSA) and insulin resistance (IR) remains controversial. Sleep apnea and obesity may increase IR and inflammation by different mechanisms. This study investigated the relationship between sleep apnea and obesity with IR, and pro-inflammatory state.   Method:  A total of 133 consecutive subjects who were referred for polysomnography. 112 were documented to have OSA defined as apnea-hypopnea index (AHI) >5 and 21 control subjects with AHI  30).   Result:  IR was higher in the obese patients with OSA than in the non-obese patients with OSA and control group. However, AHI and BMI were the determinants of IR as independent of each other in all subjects according to multivariable linear regression analyses.  All of inflamatory cytokines (CRP, hs CRP, TNF-α, IL-6) were significantly higher in the obese patients with sleep apnea than in the control group. All of inflammatory cytokines showed significant associations with BMI while did not AHI, AI, ESS.   Conclusion:  It may be considered that the impairment in glucose homeostasis is associated with both sleep disorders and obesity. Obesity in patients with OSA cases aggravate of IR and inflammation.
Co-Occurring Mental and Substance Use Disorders: The Neurobiological Effects of Chronic Stress
Authors: Kathleen T. Brady, Rajita Sinha
Journal: American Journal of Psychiatry (2005)

The high rate of co-occurrence of substance use disorders and other psychiatric disorders is well established. The population of people with co-occurring disorders is heterogeneous, and the prevalence of comorbidity differs by diagnostic group. One of the overarching issues in the area of comorbidity is the nature of the connection between psychiatric disorders and substance use disorders. The rapid development of technical advances in the neurosciences has led to a better understanding of the molecular biology, neurotransmitter systems, and neural circuitry involved in mental illness and substance use disorders. The authors discuss the neurobiological interface between substance use disorders and other psychiatric disorders with an emphasis on emerging data concerning four psychiatric disorders that commonly co-occur with substance use disorders: depression/mood disorders, posttraumatic stress disorder, attention deficit hyperactivity disorder, and schizophrenia. Better understanding of the connection between substance use disorders and psychiatric disorders could have a profound effect on prevention and treatment.
Natural and Experimental Rhinovirus Infections of the Lower Respiratory Tract
Authors: Sebastian L. Johnston
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Rhinoviruses are the cause of the majority of common colds, but their role in lower respiratory disorders is less clear. Recent studies using the polymerase chain reaction to detect rhinoviruses have established respiratory viral infections as major factors in the induction of acute exacerbations of asthma in both adults and children, both in mild exacerbations and in more severe exacerbations leading to hospital admission. Rhinoviruses were the major virus type detected in these studies, accounting for two-thirds of viruses detected. It is not known whether rhinoviruses produce their effects by directly invading the lower airway or by indirect means. Previous clinical studies provide some evidence that rhinoviruses are capable of infecting the lower airway. However, the immunologic response, both in the upper and lower airways, remains poorly defined. Recent studies have provided evidence of increased cellular activation in peripheral blood and in bronchial biopsies in atopic subjects compared with normal subjects during experimental rhinovirus infections. The reasons for these different cellular responses are unclear. Rhinoviruses as well as other respiratory viruses have been shown to increase levels of a variety of cytokines from respiratory epithelium, monocytes, or macrophages. Prominent among these cytokines is interleukin (IL)-8. We have detected increased levels of IL-8 in nasal secretions from subjects with wild-type rhinovirus infections. We studied the mechanisms of rhinovirus-induced IL-8 production and and found protein release from both pulmonary epithelial and peripheral blood mononuclear cells. This protein production was accompanied by increased mRNA expression and evidence of infection of both pulmonary epithelial and monocyte cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)
Preliminary Comparison between AQUA and Centralised ER/PgR Analysis within the TEAM Pathology Study.
Authors: J. Bartlett, D. Rimm, C. Brookes, M. Dolled-Filhart, T. Robson, C. van de Velde, L. Billingham, F. Campbell, A. Hasenburg, E. Hille, D. Kieback, H. Putter, C. Markopoulos, J. Christiansen, M. Gustavson, E. Mallon, E. Meershoek-Klein Kranenburg, R. Parideans, C. Seynaeve, D. Rea
Journal: Cancer Research (2009)

Abstract Background: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial identified quantitative relationships between ER/PgR (Can Res 69:83S) and patient prognosis, and suggested that high ER expression might be predictive for benefit from aromatase inhibitors. Conventional immunohistochemical assays, even when performed centrally, appear to be more variable than fluorescent immunohistochemical assays analysed by automated image analysis such as the AQUA system. However, output from the two systems may provide subtly different results for biomarkers. We have performed analysis of ER/PgR using AQUA technology in the TEAM pathology cohort and will present data on the full anlaysis of ER/PgR by central IHC and AQUA in 4600 cases. Preliminary data on ER (using a single TMA core) are included in the current analysis.Patients &amp; Methods: TMAs from 4598 TEAM patients were analysed by AQUA and image analysis using established algorithms performed. Comparisons between IHC and AQUA were performed and outcome data will be analysed and presented.Results: Interim AQUA results from a single core were available from 2319 TEAM cases. Analysis of results suggested incremental increases in AQUA scores across conventional Allred categories (2-8). Regression analysis suggests that multiple cores may be required adequate representation of ER expression. PgR data will be presented.Conclusion: Initial comparison between AQUA and ER expression by central IHC suggests these methods are comparable. Further data is required to assess the potential value of AQUA scores and will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3045.
Thalassemia‐like abnormalities of the red cell membrane in hemoglobin E trait and disease
Authors: E. Dorléac, L. Morlé, O. Gentilhomme, P. Jaccoud, C. Baudonnet, J. Delaunay
Journal: American Journal of Hematology (1984)

Abstract In recent studies, we observed a decrease of K Mapp , an abnormally biphasic kinetics of the red cell membrane neutral phosphatase and an increased binding of hemoglobin to the membrane in various forms of β‐thalassemia. Since the gene encoding the β chain (β E chain) of hemoglobin E (HbE) is endowed with some thalassemic characteristics, we studied the erythrocyte membrane in 25 individuals with Hb E trait or disease. The apparent Michaelis‐Menten constant for p‐nitrophenylphosphate (the artificial substrate used) was significantly decreased, as in β‐thalassemia. However, the kinetics was monophasic in all the heterozygotes and in four of the homozygotes. It was biphasic only in the three other homozygotes. V max was also significantly reduced, a fact that is masked, when not reversed in β‐thalassemia, owing to the rejuvenation of the red cell population. In 5 mM phosphate buffer (pH 8.00), the binding of Hb E to the erythrocyte ghosts was increased in the homozygotes. In the heterozygotes, Hb A binding was also increased, as is the case in β‐thalassemia. This latter fact suggests that the membrane binding site(s) of hemoglobin is (are) altered. We found a highly significant increase of Hb F in EE subjects. The present study extends to the red cell membrane the β‐thalassemic phenotype associated with the β E gene.
Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study
Authors: F Nacci, A Righi, M L Conforti, I Miniati, G Fiori, D Martinovic, D Melchiorre, T Sapir, M Blank, Y Shoenfeld, A M. Pignone, M M. Cerinic
Journal: Annals of the Rheumatic Diseases (2007)

In systemic sclerosis (SSc), joint involvement may reduce the functional capacity of the hands. Intravenous immunoglobulins have previously been shown to benefit patients with SSc.To verify the efficacy of intravenous immunoglobulins on joint involvement and function in SSc.7 women with SSc, 5 with limited and 2 with diffuse SSc, with a severe and refractory joint involvement were enrolled in the study. Methotrexate and cyclophosphamide pulse therapy did not ameliorate joint symptoms. Hence, intravenous immunoglobulins therapy was prescribed at a dosage of 2 g/kg body weight during 4 days/month for six consecutive courses. The presence of joint tenderness and swelling, and articular deformities (due to primary joint involvement and not due to skin and subcutaneous changes) were evaluated. Before and after 6 months of treatment, patients were subjected to (1) Ritchie Index (RI) evaluation of joint involvement; (2) Dreiser Algo-Functional Index (IAFD) evaluation of hand joint function; (3) pain visual analogue scale (VAS) to measure joint pain; (4) Health Assessment Questionnaire (HAQ) to evaluate the limitations in everyday living and physical disability; and (5) modified Rodnan Skin Score for skin involvement.After 6 months of intravenous immunoglobulins therapy, joint pain and tenderness, measured with the VAS, decreased significantly (p<0.03), and hand function (IAFD) improved significantly (p<0.02), together with the quality of life (HAQ; p<0.03). All patients significantly improved, except for one. The skin score after 6 months of intravenous immunoglobulins therapy was significantly reduced (p<0.003).This pilot study suggests that intravenous immunoglobulins may reduce joint pain and tenderness, with a significant recovery of joint function in patients with SSc with severe and refractory joint involvement. The cost of intravenous immunoglobulins might limit their use only to patients who failed disease-modifying antirheumatic drugs.
US lifts immigration restrictions for Cuban doctors
Authors: S. C. de Albornoz
Journal: BMJ (2006)

The United States has announced a change in its immigration policy, with immediate effect, that promotes legal and safe immigration to the US for Cuban medical personnel in third countries. This new measure affects more than 20 000 Cuban doctors currently working in more than 70 countries around the world, mostly in Venezuela. Until now, the only way they could go to the US was as illegal immigrants, claiming political asylum on arrival. The new arrangement will allow them to enter the country legally.
Changes in plasma arginine vasopressin concentrations in cyclists participating in a 109-km cycle race
Authors: T Hew-Butler, J P Dugas, T D Noakes, J G Verbalis
Journal: British Journal of Sports Medicine (2008)

Objective To evaluate the osmotic and non-osmotic regulation of arginine vasopressin (AVP) during endurance cycling. Design Observational study. Setting 109 km cycle race. Participants 33 Cyclists. Interventions None. Main outcome measurements Plasma sodium concentration ([Na + ]), plasma volume (PV) and plasma arginine vasopressin (AVP) concentration ([AVP] p ). Results A fourfold increase in [AVP] p occurred despite a 2-mmol l −1 decrease in plasma [Na + ] combined with only modest (5%) PV contraction. A significant inverse correlation was noted between [AVP] p Δ and urine osmolality Δ (r = −0.41, p&lt;0.05), whereas non-significant inverse correlations were noted between [AVP] p and both plasma [Na + ] Δ and % PV Δ. Four cyclists finished the race with asymptomatic hyponatraemia. The only significant difference between the entire cohort with this subset of athletes was postrace plasma [Na + ] (137.7 vs 133.5 mmol l −1 , p&lt;0.001) and plasma [Na + ] Δ (−1.9 vs −5.1 mmol l −1 , p&lt;0.05). The mean prerace [AVP] p of these four cyclists was just below the minimum detectable limit (0.3 pg ml −1 ) and increased marginally (0.4 pg ml −1 ) despite the decline in plasma [Na + ]. Conclusions The osmotic regulation of [AVP] p during competitive cycling was overshadowed by non-osmotic AVP secretion. The modest decrease in PV was not the primary non-osmotic stimulus to AVP. Partial suppression of AVP occurred in four (12%) cyclists who developed hyponatraemia during 5 h of riding. Therefore, these results confirm that non-osmotic AVP secretion and exercise-associated hyponatraemia does, in fact, occur in cyclists participating in a 109 km cycle race. However, the stimuli to AVP is likely different between cycling and running.
Management of Diabetes and Hyperglycemia in Hospitals
Authors: Stephen Clement, Susan S. Braithwaite, Michelle F. Magee, Andrew Ahmann, Elizabeth P. Smith, Rebecca G. Schafer, Irl B. Hirsch
Journal: Diabetes Care (2004)

Diabetes increases the risk for disorders that predispose individuals to hospitalization, including coronary artery, cerebrovascular and peripheral vascular disease, nephropathy, infection, and lower-extremity amputations. The management of diabetes in the hospital is generally considered secondary in importance compared with the condition that prompted admission. Recent studies (1,2) have focused attention to the possibility that hyperglycemia in the hospital is not necessarily a benign condition and that aggressive treatment of diabetes and hyperglycemia results in reduced mortality and morbidity. The purpose of this technical review is to evaluate the evidence relating to the management of hyperglycemia in hospitals, with particular focus on the issue of glycemic control and its possible impact on hospital outcomes. The scope of this review encompasses adult nonpregnant patients who do not have diabetic ketoacidosis or hyperglycemic crises.

For the purposes of this review, the following terms are defined (adapted from the American Diabetes Association [ADA] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus) (3): 

The prevalence of diabetes in hospitalized adult patients is not known. In the year 2000, 12.4% of hospital discharges in the U.S. listed diabetes as a diagnosis. The average length of stay was 5.4 days (4). Diabetes was the principal diagnosis in only 8% of these hospitalizations. The accuracy of using hospital discharge diagnosis codes for identifying patients with …