tbuckley/cabot-search huggingface dataset:
Analysis of the MRP4 Drug Resistance Profile in Transfected NIH3T3 Cells
Authors: K. Lee
Journal: JNCI Journal of the National Cancer Institute (2000)

Multidrug resistance-associated protein (MRP) 1 and canalicular multispecific organic anion transporter (cMOAT or MRP2) are adenosine triphosphate-binding cassette transporters that confer resistance to anticancer agents. In addition to these two transporters, there are at least four other human MRP subfamily members (MRP3 through MRP6). We and others reported previously that MRP3 is capable of conferring resistance to certain anticancer agents. In this study, we investigated whether MRP4 (MOAT-B), whose transcript accumulates to the highest levels in prostate tissue, has the capacity to confer drug resistance.MRP4-transfected NIH3T3 cells were generated, and their drug sensitivity was analyzed. The subcellular localization of MRP4 was assessed by immunohistochemical analysis in transfected cells and in prostate tissue. Statistical tests were two-sided.MRP4 was detected as a 170-kd protein that was localized in the plasma membrane and cytoplasm of transfected cells. The MRP4 transfectants displayed 5.5-fold increased resistance to methotrexate in short-term drug-exposure assays (P=.022) and exhibited decreased cellular accumulation of this agent at 4 hours (P=.006) and 24 hours (P<.001). In continuous-exposure assays, however, the MRP4 transfectants did not display increased resistance for either methotrexate or natural product cytotoxic agents (anthracyclines, etoposide, vinca alkaloids, and paclitaxel [Taxol]). However, the transfectants did show increased resistance (2.3-fold) for the anti-acquired immunodeficiency syndrome nucleoside analogue 9-(2-phosphonylmethoxyethyl)adenine (PMEA) (P=.022) in continuous-exposure assays. Consistent with MRP4's plasma membrane localization in transfected cells, analysis of prostate tissue showed that MRP4 protein was localized primarily in the basolateral plasma membranes of tubuloacinar cells.These results indicate that MRP4 confers resistance to short-term methotrexate and continuous PMEA treatment. Given its structure, drug resistance profile and subcellular localization, MRP4 probably functions as an amphipathic anion efflux pump whose substrate range includes glutamate and phosphate conjugates.
Spatial Patterns of Structural Brain Changes in Type 2 Diabetic Patients and Their Longitudinal Progression With Intensive Control of Blood Glucose
Authors: Guray Erus, Harsha Battapady, Tianhao Zhang, James Lovato, Michael E. Miller, Jeff D. Williamson, Lenore J. Launer, R. Nick Bryan, Christos Davatzikos
Journal: Diabetes Care (2014)

OBJECTIVE Understanding the effect of diabetes as well as of alternative treatment strategies on cerebral structure is critical for the development of targeted interventions against accelerated neurodegeneration in type 2 diabetes. We investigated whether diabetes characteristics were associated with spatially specific patterns of brain changes and whether those patterns were affected by intensive versus standard glycemic treatment. RESEARCH DESIGN AND METHODS Using baseline MRIs of 488 participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) study, we applied a new voxel-based analysis methodology to identify spatially specific patterns of gray matter and white matter volume loss related to diabetes duration and HbA1c. The longitudinal analysis used 40-month follow-up data to evaluate differences in progression of volume loss between intensive and standard glycemic treatment arms. RESULTS Participants with longer diabetes duration had significantly lower gray matter volumes, primarily in certain regions in the frontal and temporal lobes. The longitudinal analysis of treatment effects revealed a heterogeneous pattern of decelerated loss of gray matter volume associated with intensive glycemic treatment. Intensive treatment decelerated volume loss, particularly in regions adjacent to those cross-sectionally associated with diabetes duration. No significant relationship between low versus high baseline HbA1c levels and brain changes was found. Finally, regions in which cognitive change was associated with longitudinal volume loss had only small overlap with regions related to diabetes duration and to treatment effects. CONCLUSIONS Applying advanced quantitative image pattern analysis methods on longitudinal MRI data of a large sample of patients with type 2 diabetes, we demonstrate that there are spatially specific patterns of brain changes that vary by diabetes characteristics and that the progression of gray matter volume loss is slowed by intensive glycemic treatment, particularly in regions adjacent to areas affected by diabetes.
Evaluation of nebulised acetylcysteine and normal saline in the treatment of sputum retention following thoracotomy.
Authors: A M Gallon
Journal: Thorax (1996)

BACKGROUND: The use of acetylcysteine as a mucolytic agent is controversial. In 1962 it was claimed to be "the most effective agent ... for the liquefaction of ... secretions" but was subsequently taken off the market as a respirator solution. Normal saline, on the other hand, is becoming increasingly popular. A study was undertaken to determine which solution is more effective at clearing retained secretions following thoracotomy. METHODS: The study included 10 patients and was of single blind, two-way crossover design. Measurements taken before and after each treatment included sputum viscosity, difficulty of expectoration, weight of sputum expectorated, and oxygen saturation. RESULTS: Following nebulisation of acetylcysteine, sputum viscosity was reduced, difficulty of expectoration was reduced, the weight of sputum expectorated was increased, and oxygen saturation was increased. There were no changes after nebulisation of normal saline. CONCLUSIONS: This study shows that, following thoracotomy, nebulised acetylcysteine reduces sputum viscosity, making expectoration easier and improving oxygenation. Nebulised normal saline has no effect.
Abnormalities of the <i>TITF-1</i> Lineage-Specific Oncogene in NSCLC: Implications in Lung Cancer Pathogenesis and Prognosis
Authors: Ximing Tang, Humam Kadara, Carmen Behrens, Diane D Liu, Yun Xiao, David Rice, Adi F. Gazdar, Junya Fujimoto, Cesar Moran, Marileila Varella-Garcia, J Jack Lee, Waun Ki Hong, Ignacio I. Wistuba
Journal: Clinical Cancer Research (2011)

Emerging evidence suggests that aberrant expression of oncogenes contributes to development of lung malignancy. The thyroid transcription factor 1 (TITF-1) gene functions as a lineage survival gene abnormally expressed in a significant fraction of non-small cell lung cancers (NSCLC), in particular lung adenocarcinomas.To better characterize TITF-1 abnormality patterns in NSCLC, we studied TITF-1's gene copy number using FISH and quantitative PCR, as well as its protein expression by immunohistochemistry analysis in a tissue microarray comprising surgically resected NSCLC (N = 321) including 204 adenocarcinomas and 117 squamous cell carcinomas (SCC). TITF-1 copy number and protein expression were correlated with patients' clinicopathologic characteristics, and in a subset of adenocarcinomas with EGFR and KRAS mutation status.We found that increased TITF-1 protein expression was prevalent in lung adenocarcinomas only and was significantly associated with female gender (P < 0.001), never-smokers (P = 0.004), presence of EGFR mutations (P = 0.05), and better overall survival (all stages, P = 0.0478; stages I and II, P = 0.002). TITF-1 copy number gain(CNG) was detected by FISH analysis in both adenocarcinomas (18.9%; high CNG, 8.3%) and SCCs (20.1%; high CNG, 3.0%), and correlated significantly with the protein product (P = 0.004) and presence of KRAS mutations (P = 0.008) in lung adenocarcinomas. Moreover, multivariate analysis revealed that TITF-1 copy number gain was an independent predictor of poor survival of NSCLC (P = 0.039).Our integrative study demonstrates that the protein versus genomic patterns of TITF-1 have opposing roles in lung cancer prognosis and may occur preferentially in different subsets of NSCLC patients with distinct oncogene mutations.
EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT)
Authors: A Pendleton, N Arden, M Dougados, M Doherty, B Bannwarth, J W J Bijlsma, F Cluzeau, C Cooper, P A Dieppe, K-P Günther, H J Hauselmann, G Herrero-Beaumont, P M Kaklamanis, B Leeb, M Lequesne, S Lohmander, B Mazieres, E-M Mola, K Pavelka, U Serni, B Swoboda, A A Verbruggen, G Weseloh, I Zimmermann-Gorska
Journal: Annals of the Rheumatic Diseases (2000)

Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR Standing Committee for Clinical Trials met in 1998 to determine the methodological and logistical approach required for the development of evidence based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available treatments for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee.The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and keywords. All European language publications in the form of systematic reviews, meta-analyses, randomised controlled trials, controlled trials, and observational studies were included. During stage three all the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and, where practical, the numbers needed to treat and the effect size for each treatment were calculated. In the fourth stage key clinical propositions were determined by expert consensus employing a Delphi approach. The final stage ranked these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach.Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted.These are the first clinical guidelines on knee OA to combine an evidence based approach and a consensus approach across a wide range of treatment modalities. It is apparent that certain clinical propositions are supported by substantial research based evidence, while others are not. There is thus an urgent need for future well designed trials to consider key clinical questions.
Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma
Authors: Mary Maluccio, Anne Covey
Journal: CA A Cancer Journal for Clinicians (2012)

Abstract Hepatocellular carcinoma (HCC) is one of the few cancers in which a continued increase in incidence has been observed over several years. As such, there has been a focus on safe and accurate diagnosis and the development of treatment algorithms that take into consideration the unique complexities of this patient population. In the past decade, there have been improvements in nonsurgical treatment platforms and better standardization with respect to the diagnosis and patient eligibility for liver transplant. How to navigate patients through the challenges of treatment is difficult and depends on several factors: 1) patient‐related variables such as comorbid conditions that influence treatment eligibility; 2) liver‐related variables such as Child‐Pugh score; and 3) tumor‐related variables such as size, number, pattern of spread within the liver, and vascular involvement. The objectives of this review are to put into perspective the current treatment options for patients with HCC, the unique advantages and disadvantages of each treatment approach, and the evidence that supports the introduction of sorafenib into the multidisciplinary management of HCC. CA Cancer J Clin 2012;. © 2012 American Cancer Society.
Cancer-Testis Antigens: Expression and Correlation with Survival in Human Urothelial Carcinoma
Authors: Padmanee Sharma, Yu Shen, Sijin Wen, Dean F. Bajorin, Victor E. Reuter, Lloyd J. Old, Achim A. Jungbluth
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Vaccination against human cancer is a promising therapeutic approach but the optimal antigen or antigens remain undefined. Cancer-testis antigens (CTA), a family of tumor-associated antigens, have both potent immunogenicity and restricted expression patterns in normal adult tissues, highly desirable characteristics for targets of anticancer vaccines. These antigens were evaluated for both the degree of expression and prognostic value in cancer of the urothelium. Experimental Design: The expression patterns of nine CTAs (NY-ESO-1, LAGE-1, MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, CT7, CT10, and GAGE) were examined by immunohistochemistry and reverse transcription-PCR in a panel of high-grade urothelial carcinomas of the urinary bladder. Also assessed were correlations between the expression of CTAs by immunohistochemistry and both disease-free and overall survival. Results: At least one CTA was expressed in 77% of samples and 61% of these tumors expressed more than one CTA. Additionally, patients with CT10-positive tumors had an improved disease-free survival (P = 0.008) and overall survival (P = 0.037) compared with patients with CT10-negative tumors. Conclusions: These findings establish CTAs as potential prognostic markers and as target candidates for vaccine development for patients with urothelial carcinoma.
Optical Coherence Tomography
Authors: T. Mesud Yelbuz, Michael A. Choma, Lars Thrane, Margaret L. Kirby, Joseph A. Izatt
Journal: Circulation (2002)

Background— Optical coherence tomography (OCT) is a depth-resolved, noninvasive, non-destructive imaging modality, the use of which has yet to be fully realized in developmental biology. Methods and Results— We visualized embryonic chick hearts at looping stages using an OCT system with a 22 μm axial and 27 μm lateral resolution and an acquisition rate of 4000 A-scans per second. Normal chick embryos from stages 14 to 22 and sham-operated and cardiac neural crest-ablated embryos from stages 15 and 18 were scanned by OCT. Three-dimensional data sets were acquired and processed to create volumetric reconstructions and short video clips. The OCT-scanned embryos (2 in each group) were photographed after histological sectioning in comparable planes to those visualized by OCT. The optical and histological results showing cardiovascular microstructures such as myocardium, the cardiac jelly, and endocardium are presented. Conclusions— OCT is a powerful imaging modality which can provide new insight in assessing and understanding normal and abnormal cardiac development in a variety of animal models.
Predicting poor prognosis in COPD patients: looking for a lamp lit in the darkness of the night
Authors: E. Crisafulli
Journal: European Respiratory Journal (2014)

Night-time dyspnoea is a prevalent and relevant symptom predicting poor prognosis in COPD patients http://ow.ly/v7aQI''It was invisible, buried in the mud.I only saw it because I was looking for it.''''What!You expected to find it?''''I thought it not unlikely.''Although the study does not provide an objective measurement of nocturnal saturation (it has been proven that nocturnal hypoxaemia in COPD patients is associated with the development of adverse sequelae [6]) and the topic has previously been explored by OMACHI et al. [7] with similar findings, the paper by LANGE
Cyst Fluid Interleukin-1β (IL1β) Levels Predict the Risk of Carcinoma in Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Ajay V. Maker, Nora Katabi, Li-Xuan Qin, David S. Klimstra, Mark Schattner, Murray F. Brennan, William R. Jarnagin, Peter J. Allen
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Biomarkers for high-grade dysplasia in patients with radiographically identified intraductal papillary mucinous neoplasms (IPMN) have not been described. We hypothesized that dysplasia in IPMN invokes an immunogenic/proinflammatory microenvironment that can be identified by cyst fluid cytokine levels. Experimental Design: Pancreatic cyst fluid aspirates were collected at resection (2005–2009). Samples were grouped into low-risk [low-grade (n = 6) or moderate dysplasia (n = 15)] and high-risk groups [high-grade dysplasia (n = 13) or carcinoma (n = 6)]. Cytokine expression was determined using a multiplex sandwich immunoassay. Differences in cytokine expression were evaluated using the 2-sample t test. Sample classification was performed using a logistic regression adjusting for sample covariates. Results: IL5 and IL8 concentrations were higher in the cyst fluid from patients in the high-risk group than the low-risk group. Interleukin (IL)-1β concentrations were also higher in the cyst fluid from patients with high-grade dysplasia or cancer (n = 19) than those with low- or moderate-grade dysplasia (n = 21, 539 ± 255 pg/mL vs. 0.2 ± 0.1 pg/mL; P &amp;lt; 0.0001). IL1β remained a significant predictor of high-risk cysts after multivariate analysis. There was no significant difference in levels of IL2, IL4, IL10, IL12, IL13, TNF-α, or IFN-γ between the groups. That IL1β levels identified cysts at a high risk of malignancy was confirmed in an independent validation set. Conclusions: Cyst fluid levels of IL1β can differentiate low- from high-risk IPMN. This study introduces IL1β as a potential biomarker for validation in larger clinical studies. Clin Cancer Res; 17(6); 1502–8. ©2011 AACR.
HIV education for health-care professionals in high prevalence countries: time to integrate a pre-service approach into training
Authors: V Renggli, I De Ryck, S Jacob, H Yeneneh, S Sirgu, L Mpanga Sebuyira, A Pfitzer, J Downing, C Portillo, J Murray, S Gove, R Colebunders
Journal: The Lancet (2008)
Do<i>BRCA1</i>and<i>BRCA2</i>Mutation Carriers Have Earlier Natural Menopause Than Their Noncarrier Relatives? Results From the Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer
Authors: Ian M. Collins, Roger L. Milne, Sue Anne McLachlan, Michael Friedlander, Martha Hickey, Prue C. Weideman, Kate E. Birch, John L. Hopper, Kelly-Anne Phillips
Journal: Journal of Clinical Oncology (2013)

Purpose Limited data suggest that germline BRCA1 mutations are associated with occult primary ovarian insufficiency and that BRCA1 and BRCA2 mutation carriers might have earlier natural menopause (NM) than their noncarrier relatives. Patients and Methods Eligible women were mutation carriers and noncarriers from families segregating a BRCA1 or BRCA2 mutation. Data were self-reported using uniform questionnaires at cohort entry and every 3 years thereafter. NM was defined as the cessation of menses for 12 months without another cause. Cox proportional hazards analysis modeled time from birth to NM, adjusting for multiple potential confounders. Analysis time was censored at the earliest of the following: last follow-up, bilateral oophorectomy, hysterectomy, commencement of hormone therapy, insertion of intrauterine device, or any cancer diagnosis. Hazard ratios (HRs) were estimated as a measure of how likely mutation carriers are, relative to noncarriers, to reach NM at a given age. Results A total of 1,840 women were eligible for analysis. Overall only 19% reached NM. A lower proportion of BRCA1 and BRCA2 mutation carriers reached NM compared with noncarriers. Conversely, a higher proportion of mutation carriers were censored at cancer diagnosis or oophorectomy than noncarriers. The adjusted HR estimates for NM were 1.03 (95% CI, 0.75 to 1.40; P = .9) for 445 BRCA1 mutation carriers and 559 noncarrier relatives and 1.01 (95% CI, 0.71 to 1.42; P = .9) for 374 BRCA2 mutation carriers and 462 noncarrier relatives. Conclusion We found no evidence that BRCA1 and BRCA2 mutation carriers are at higher risk of NM at a given age than their noncarrier relatives.
A journey of 1000 miles begins with a single step
Authors: P McCrory
Journal: British Journal of Sports Medicine (2002)

In my peregrinations from the ACSM meeting in St Louis to England, Norway, and Canada recently, I found myself desperately searching the airport bookshops for something distracting to while away the hours of travel and came across an absolute cracker of a sports medicine book. No, I don't mean yet another soccer book, although I do note that the quality of the books has improved out of sight in recent years. It makes a pleasant change given that many sports books are written for fans that follow the text with their fingers! No, this book is about muscles. It is called Prime mover: a natural …
Intellectual Impairment in School-Age Children Exposed to Manganese from Drinking Water
Authors: Maryse F. Bouchard, Sébastien Sauvé, Benoit Barbeau, Melissa Legrand, Marie-Ève Brodeur, Thérèse Bouffard, Elyse Limoges, David C. Bellinger, Donna Mergler
Journal: Environmental Health Perspectives (2010)

Manganese is an essential nutrient, but in excess it can be a potent neurotoxicant. Despite the common occurrence of manganese in groundwater, the risks associated with this source of exposure are largely unknown.Our first aim was to assess the relations between exposure to manganese from drinking water and children's intelligence quotient (IQ). Second, we examined the relations between manganese exposures from water consumption and from the diet with children's hair manganese concentration.This cross-sectional study included 362 children 6-13 years of age living in communities supplied by groundwater. Manganese concentration was measured in home tap water (MnW) and children's hair (MnH). We estimated manganese intake from water ingestion and the diet using a food frequency questionnaire and assessed IQ with the Wechsler Abbreviated Scale of Intelligence.The median MnW in children's home tap water was 34 µg/L (range, 1-2,700 µg/L). MnH increased with manganese intake from water consumption, but not with dietary manganese intake. Higher MnW and MnH were significantly associated with lower IQ scores. A 10-fold increase in MnW was associated with a decrease of 2.4 IQ points (95% confidence interval: -3.9 to -0.9; p < 0.01), adjusting for maternal intelligence, family income, and other potential confounders. There was a 6.2-point difference in IQ between children in the lowest and highest MnW quintiles. MnW was more strongly associated with Performance IQ than Verbal IQ.The findings of this cross-sectional study suggest that exposure to manganese at levels common in groundwater is associated with intellectual impairment in children.