tbuckley/cabot-search huggingface dataset:
P08.09 Prostanoid metabolism as a potential target for improved drug response in gliomas
Authors: A. Panagopoulos, F. Serachi, R. Gomes, L. Rossetti, J. Veiga, A. Colquhoun
Journal: Neuro-Oncology (2017)

Introduction: Gliomas are difficult to treat primary brain tumours classified into grades I-IV by the WHO. One problem is the development of multiple drug resistance (MDR) in response to repeated cycles of chemotherapy. MDR occurs through the increased expression of ATP-binding cassette transporters (ABC transporters). Several ABC transporters are linked to drug resistance in human tumours and include MDR1/P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and the multiple drug resistance proteins, ABCC1 and ABCC2. Cyclooxygenase2 (COX-2) can cause up-regulation of ABCB1 and a correlation exists between COX-2 and ABCB1 in breast cancer. Considering the fact that gliomas can develop MDR and express high levels of COX-2, the aim of the study was to investigate the importance of COX-1 and COX-2 to the expression and activity of the ABC transporters ABCB1 and ABCC1-5 in the absence or presence of vincristine-induced MDR. Materials and Methods: The human glioma cell lines A172, T98G, U87MG, U138MG and U251MG were used. mRNA and protein expression of COX-1, COX-2, microsomal ­prostaglandin E synthase 1, 2 and cytosolic prostaglandin E synthase (mPGES1, mPGES2 and cPGES), ABCB1 and ABCC1-5 were determined by qPCR and Western blotting in the absence or presence of COX-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or gamma-linolenic acid (GLA). ABC transporter activity was determined using fluorescent probes. The response of vincristine-resistant cells was studied as vincristine is used in gliomas in PCV (procarbazine, CCNU, vincristine) treatment and is a known substrate for the ABC transporters ABCB1 and ABCC2. Tumour samples from grade II-IV gliomas were also analysed for ABCB1 and ABCC1-4 expression by immunohistochemical staining and compared with COX1, COX2, mPGES1, mPGES2 and cPGES expression. Results: The results showed constitutive expression of COX-1 and COX-2 in the panel of human glioma cells as well as the expression of all the ABC transporters studied, although considerable variations in expression were found among the different cell lines. Inhibition of COX-1 and COX-2 caused a decrease in the expression and activity of several ABC transporters. The presence of GLA also led to changes in COX-1, COX-2 and ABC transporter expression in the glioma cell lines. Vincristine-resistant cells showed an increase in expression of both COX enzymes and ABC transporters which was altered by COX inhibition. Patient samples had variable expression of COX enzymes and ABC transporters. Conclusions: The potential for altering the expression profile and activity of ABC transporters through the manipulation of COX-2 and/or prostaglandin metabolism may lead to improved tumour response to chemotherapy in the future. Financial support: FAPESP (15/08777-0), CNPq, CAPES.
Abstract P021: Adipose-Derived Stromal Cell Therapy Stabilizes Cardiac Function and Improves Border Zone Remodeling After Coronary Occlusion in Rats
Authors: Antonio C Campos de Carvalho, Luiza Bagno, João Pedro Werneck de Castro, Patricia Oliveira, Marcia Abreu, Nazareth Rocha, Tais Kasai Brunswick, Vivian Miranda, Regina Goldenberg
Journal: Circulation Research (2011)

Recent studies have identified adipose tissue as a new source of mesenchymal stem cells for therapy. The purpose of this study was to investigate the therapy with rat adipose derived stromal cells (ASC) in a rat model of healed myocardial infarction (MI). ASC from inguinal subcutaneous adipose tissue of male Wistar rats were isolated by enzymatic digestion and filtration. Cells were then cultured until passage 3. Four weeks after ligation of the left coronary artery of female rats, a suspension of either 100µl with PBS + Matrigel + 2 x 106 ASC labeled with Hoechst (n=11) or 100µ;l of PBS + Matrigel (n=10) was injected along the borders of the ventricular wall scar tissue. A sham operated group (n=5) was submitted to the same surgical procedure except permanent ligation of left coronary artery. Cardiac performance was assessed by electro and echocardiogram. Echo was performed prior to injections (baseline-BL) and six weeks after injections (follow-up - FU), and values after treatment were normalized by values obtained before treatment. Hemodynamic measurements were performed 6 weeks after injections. All data are expressed as mean ± SEM. Student's paired or unpaired T test was used to compare the same group in two different times or two distinct groups, while two way ANOVA was used to compare more than two groups along different times and p was set at &lt;0.05. All infarcted animals exhibited cardiac function impairment. Ejection fraction (EF), shortening fractional area (SFA) and left ventricular akynesia (LVA) were similar between infarcted groups before treatment. Six weeks after therapy, ASC group showed significant improvement in all three Echo indexes in comparison to vehicle group. In non-anesthetized animals dp/dt+ was also significantly higher in ASC when compared to vehicle. In agreement with functional improvement scar area was diminished in the ASC group. We conclude that ASC stabilize cardiac function in infarcted rats when administered directly to the myocardium.
Abstract P243: Simultaneous Decrease in Glucose Uptake, Increase in Glucose Oxidation, and Improved Contractile Function by Hearts from Sucrose-Fed Rats
Authors: Romain Harmancey, Truong Lam, Genna Lubrano, Deborah Vela, Heinrich Taegtmeyer
Journal: Circulation Research (2011)

The heart responds to acute hemodynamic stress by increasing carbohydrate oxidation. This metabolic response is impaired in diabetes when excess fatty acid availability inhibits glucose oxidation (Randle's “glucose-fatty acid cycle”). Impaired glucose uptake and oxidation are believed to result in energy deficiency and poor contractile function. We now propose that in the heart insulin resistance, defined by impaired uptake of glucose in response to insulin, is an endogenous protective mechanism which prevents excess uptake of fuel when supply is increased. To test this we fed Sprague-Dawley rats either a high-sucrose diet or regular chow diet. After 5 to 8 weeks systemic insulin sensitivity was impaired in sucrose-fed rats. Hearts were then perfused ex vivo in the working mode to measure function and metabolism. Rates of glucose uptake by the heart of sucrose-fed animals were decreased in response to insulin. Cardiac power remained unchanged in hearts perfused with either normal (5mM glucose; 0.4mM oleate; 0.5ng/ml insulin) or high (25mM glucose; 0.8mM oleate; 5ng/ml insulin) concentrations of substrates. However, cardiac power increased for the insulin-resistant hearts compared to controls when a hemodynamic stress (afterload raised from 100 to 140cm H 2 O; 1µM epinephrine) was superimposed on nutrient stress. The ratio of glucose-to-oleate oxidation was also markedly increased in these hearts, as was cardiac efficiency. Higher glucose oxidation rates correlated with increased pyruvate dehydrogenase (PDH) activity, and lower uncoupling protein 3 (UCP3) expression. In conclusion, insulin resistance promotes adaptation of the stressed heart by increasing glucose oxidation while limiting excess fuel uptake. Our findings call for a new interpretation of the glucose-fatty acid cycle in the heart.
Analysis of pathways involved in the antiproliferative activity of the novel progesterone receptor antagonist ZK-230211 in breast cancer
Authors: Jan Kunde, Anette Sommer, Henrik Seidel, Daniel Korr, Jens Hoffmann
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4336 

Blocking progesterone receptor (PR) function by using progesterone receptor antagonists (PRA) allows the modulation of endocrine processes. In breast cancer cells that functionally express PR, progesterone is essential for cell proliferation. Hence, PRAs could inhibit the growth of breast tumours.

We have developed a highly potent PRA ZK-230211 that has a considerable potential not only for therapeutic intervention but rather may prevent breast cancer more efficiently.

The majority of patients with hormone positive, advanced breast cancer initially respond to endocrine treatment. In some cases tumor progression is observed, indicating intrinsic or acquired resistance. The development of a novel compound therefore should be accompanied by translational research, strongly supporting clinical development by providing: early (bio)markers for response, profound knowledge on molecular mechanisms of action, rationale for combinations, extended indications, and (bio)markers for the occurrence of endocrine resistance.

During our in-depth pharmacological characterization of PRA ZK-230211 we showed strong rationale for use in palliative, adjuvant and prophylactic treatment of breast cancer. We evaluated markers for proliferation (Ki67) and apoptosis as early predictors of response.

In order to learn more about additional mechanisms of action, i.e. apoptosis induction, of PRA ZK-230211, we analysed the expression and status of a panel of cell cycle regulating proteins on breast cancer cells treated with the compound.

Mechanisms of resistance to PRA ZK-230211 were investigated in ER and PR-positive MXT breast tumours transplanted on BDF1 mice. Response of these tumors to the treatment with PRA ZK-230211 is, like often to other anti-hormones, rather heterogeneous. Gene expression in tumors from responders and non-responders was compared to identify new (bio)markers for the stratification of patients.

A subset of exclusively in non-responders up regulated genes was identified and validated by qRT-PCR. For further validation of the respective gene set, a panel of 20 human breast cancer cell lines is being analyzed regarding to their response to PRA ZK-230211 in correlation with protein and gene expression.
The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity
Authors: Susan L. Holbeck, Richard Camalier, James A. Crowell, Jeevan Prasaad Govindharajulu, Melinda Hollingshead, Lawrence W. Anderson, Eric Polley, Larry Rubinstein, Apurva Srivastava, Deborah Wilsker, Jerry M. Collins, James H. Doroshow
Journal: Cancer Research (2017)

Abstract To date, over 100 small-molecule oncology drugs have been approved by the FDA. Because of the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations. Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed. In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity. Screening results were compiled into a database, termed the NCI-ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations), publicly available at https://dtp.cancer.gov/ncialmanac. Subsequent in vivo experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations in vivo supported the initiation of two phase I clinical trials at the NCI to evaluate clofarabine with bortezomib and nilotinib with paclitaxel in patients with advanced cancer. Consequently, the hypothesis-generating NCI-ALMANAC web-based resource has demonstrated value in identifying promising combinations of approved drugs with potent anticancer activity for further mechanistic study and translation to clinical trials. Cancer Res; 77(13); 3564–76. ©2017 AACR.
Diabetes Self-Management Education Programs in Nonmetropolitan Counties — United States, 2016
Authors: Stephanie A. Rutledge, Svetlana Masalovich, Rachel J. Blacher, Magon M. Saunders
Journal: MMWR Surveillance Summaries (2017)

Diabetes self-management education (DSME) is a clinical practice intended to improve preventive practices and behaviors with a focus on decision-making, problem-solving, and self-care. The distribution and correlates of established DSME programs in nonmetropolitan counties across the United States have not been previously described, nor have the characteristics of the nonmetropolitan counties with DSME programs.July 2016.DSME programs recognized by the American Diabetes Association or accredited by the American Association of Diabetes Educators (i.e., active programs) as of July 2016 were shared with CDC by both organizations. The U.S. Census Bureau's census geocoder was used to identify the county of each DSME program site using documented addresses. County characteristic data originated from the U.S. Census Bureau, compiled by the U.S. Department of Agriculture's Economic Research Service into the 2013 Atlas of Rural and Small-Town America data set. County levels of diagnosed diabetes prevalence and incidence, as well as the number of persons with diagnosed diabetes, were previously estimated by CDC. This report defined nonmetropolitan counties using the rural-urban continuum code from the 2013 Atlas of Rural and Small-Town America data set. This code included six nonmetropolitan categories of 1,976 urban and rural counties (62% of counties) adjacent to and nonadjacent to metropolitan counties.In 2016, a total of 1,065 DSME programs were located in 38% of the 1,976 nonmetropolitan counties; 62% of nonmetropolitan counties did not have a DSME program. The total number of DSME programs for nonmetropolitan counties with at least one DSME program ranged from 1 to 8, with an average of 1.4 programs. After adjusting for county-level characteristics, the odds of a nonmetropolitan county having at least one DSME program increased as the percentage insured increased (adjusted odds ratio [AOR] = 1.10, 95% confidence interval [CI] = 1.08-1.13), the percentage with a high school education or less decreased (AOR = 1.06, 95% CI = 1.04-1.07), the unemployment rate decreased (AOR = 1.19, 95% CI = 1.11-1.23), and the natural logarithm of the number of persons with diabetes increased (AOR = 3.63, 95% CI = 3.15-4.19).In 2016, there were few DMSE programs in nonmetropolitan, socially disadvantaged counties in the United States. The number of persons with diabetes, percentage insured, percentage with a high school education or less, and the percentage unemployed were significantly associated with whether a DSME program was located in a nonmetropolitan county.Monitoring the distribution of DSME programs at the county level provides insight needed to strategically address rural disparities in diabetes care and outcomes. These findings provide information needed to assess lack of availability of DSME programs and to explore evidence-based strategies and innovative technologies to deliver DSME programs in underserved rural communities.
Cola drinks and rehydration in acute diarrhea [letter]
Authors: Weizman Z
Journal: New England Journal of Medicine (1986)

Cola drinks are often recommended as rehydration solutions for acute diarrhea.  Although several other commercial solutions are available cola drinks are still very popular worldwide.  I have analyzed the electrolyte content and osmolality of Coca-Cola in Israel and have taken the opportunity to review all reported data in this regard in the literature.  Like data reported from other countries my results demonstrated that cola drinks are not suitable for use as rehydration solution since they have a very low electrolyte content and an extremely high osmolality (Table 1).  Thus adequate electrolyte replacement is not possible and induction of osmotic diarrhea may worsen the situation.  For comparison the content recommended by the WHO is also presented in the table.  Contrary to the general impression cola drinks should not be recommended as rehydration solutions for acute diarrhea in general or for infantile diarrhea in particular.  (full text)
Safety and Efficacy of Antiviral Therapy for Prevention of Cytomegalovirus Reactivation in Immunocompetent Critically Ill Patients
Authors: Nicholas J. Cowley, Andrew Owen, Sarah C. Shiels, Joanne Millar, Rebecca Woolley, Natalie Ives, Husam Osman, Paul Moss, Julian F. Bion
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Latent cytomegalovirus (CMV) infection is present in more than half the adult population, and a viral reactivation (ie, when the virus becomes measurable in body fluids such as blood) can occur in up to one-third of these individuals during episodes of critical illness. <h3>Objective</h3> To determine whether antiviral therapy is safe and effective for preventing CMV reactivation in a general population of critically ill patients. <h3>Design, Setting, and Participants</h3> A single-center, open-label, randomized, controlled clinical trial recruited 124 CMV-seropositive patients undergoing mechanical ventilation for at least 24 hours in the intensive care unit between January 1, 2012, and January 31, 2014. The mean baseline Acute Physiology and Chronic Health Evaluation II score of all patients was 17.6. <h3>Interventions</h3> Patients were randomized to receive anti-CMV prophylaxis with valacyclovir hydrochloride (n = 34) or low-dose valganciclovir hydrochloride (n = 46) for up to 28 days to suppress viral reactivation, or to a control group with no intervention (n = 44). <h3>Main Outcomes and Measures</h3> Time to first CMV reactivation in blood within the 28-day follow-up period following initiation of the study drug. <h3>Results</h3> Among the 124 patients in the study (46 women and 78 men; mean [SD] age, 56.9 [16.9] years), viral reactivation in the blood occurred in 12 patients in the control group, compared with 1 patient in the valganciclovir group and 2 patients in the valacyclovir group (combined treatment groups vs control: hazard ratio, 0.14; 95% CI 0.04-0.50). Although this trial was not powered to assess clinical end points, the valacyclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41.2%) had died by 28 days, compared with 5 of 37 (13.5%) patients in the control arm at the point of the decision to halt this arm. Other safety end points showed similar outcomes between groups. <h3>Conclusions and Relevance</h3> Antiviral prophylaxis with valacyclovir or low-dose valganciclovir suppresses CMV reactivation in patients with critical illness. However, given the higher mortality, a large-scale trial would be needed to determine the clinical efficacy and safety of CMV suppression. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01503918
Differential function of VDR in the presence or absence of its ligand in breast cancer cells
Authors: Xinjian Peng, Fatouma Alimirah, Karen Torres, Avani Vaishnav, Michael McCormick, Rajendra Mehta
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3807 

Previous studies in the literature including our own have shown that CYP24, a target gene of VDR is upregulated when the cells are incubated with vitamin D and the receptor is liganded. The present study focused on the functional role of unliganded VDR by investigating the correlation between VDR protein-expression and basal mRNA expression level of CYP24 in breast cancer cell lines. Analysis of multiple breast cancer cell lines using western blot and quantitative RT-PCR techniques demonstrates the reverse correlation of VDR protein expression and CYP24 mRNA expression level. In MCF-7 cells, immunofluorescent staining shows that VDR is distributed in the nuclei in the absence of ligand and appears to be functional. VDR overexpression by transfection of VDR expression plasmid in MCF-7 cells and MDA-MB231 cells significantly decreased CYP24 mRNA expression levels, while knock-down of VDR using siRNA technique in MCF-7 and T47D cells significantly increased CYP24 mRNA expression. Through co-transfection of VDR expression plasmid and CYP24 promoter -reporter construct in MCF-7 cells, we also found that overexpression of VDR with a polymorphic site (FokI-FF) at its AF-1 domain which makes VDR shorter by three amino acids failed to repress CYP24 promoter activity. In addition, TSA (histone deacetylation inhibitor) treatment of MDA-MB231 cells decreased CYP24 mRNA expression by 37%; ChiP assay demonstrates that TSA treatment increased the binding of VDR to CYP24 promoter region. These results suggest a regulatory role of VDR on the catabolism of vitamin D in breast cancer cells (Supported by R03 CA121365 (XP) and R01 CA82316 (RGM)).
CONCUSSION IN RUGBY UNION: IMPROVED REPORTING, A MORE CONSERVATIVE APPROACH OR AN INCREASED RISK?
Authors: Matthew Cross, Grant Trewartha, Simon Kemp, Colin Fuller, Aileen Taylor, Stephen West, Keith Stokes
Journal: British Journal of Sports Medicine (2017)

Background Epidemiology studies from 2002 to 2011 reported a stable concussion incidence in professional Rugby Union. From 2011, multiple player welfare initiatives have been introduced to increase the awareness, identification and management of concussion. Objective To investigate the incidence of reported concussion and players' time to return to play following match concussions in professional Rugby Union. Design In a five-season (2011–2016) prospective cohort study, match concussions and the time taken for players to return to play were recorded. The seasonal incidences of concussion were calculated alongside all injury incidence and contact injury incidence (both excluding concussion) and mean player body mass and height. Setting English Premiership Professional Rugby Union. Participants 788 players. Independent Variables Player match exposure (hours). Main Outcome Measurement Match injury incidence (concussion and all injuries) was calculated as injuries/1000 player-hours with 95% confidence intervals (CI). Results Mean incidence of time-loss match concussions over the period was 10.4 (95% CI: 9.4–11.5). The incidence increased year-on-year: 2011–12, 5.1 (95% CI: 3.8–6.9); 2012–13, 6.7 (95% CI: 5.1–8.7); 2013–14, 10.5 (95% CI: 8.5–13.0); 2014–15, 13.4 (95% CI: 11.1–16.2); 2015–16, 15.9 (95% CI 13.2–19.1). This rise occurred in the absence of any significant change in the incidence of all time-loss injuries, contact time-loss injuries and player size. Conclusions Since 2011, the reported incidence of concussion in professional Rugby Union has risen season-by-season, highlighting the need for a focused injury prevention strategy. It is not possible to separate the effect of an improvement in reporting practice from an inherent increased risk of concussion, but the stable incidence of other time-loss injuries and player size over the same period suggests that changes in reporting behaviour, a lowering of the diagnostic threshold and increased awareness have all had a major influence on the reporting of concussion in recent years.
The Berlin 2016 process: a summary of methodology for the 5th International Consensus Conference on Concussion in Sport
Authors: Willem H Meeuwisse, Kathryn J Schneider, Jiří Dvořák, Onutobor (Tobi) Omu, Caroline F Finch, K. Alix Hayden, Paul McCrory
Journal: British Journal of Sports Medicine (2017)

The purpose of this paper is to summarise the methodology for the 5th International Consensus Conference on Concussion in Sport. The 18 months of preparation included engagement of a scientific committee, an expert panel of 33 individuals in the field of concussion and a modified Delphi technique to determine the primary questions to be answered. The methodology also involved the writing of 12 systematic reviews to inform the consensus conference and submission and review of scientific abstracts. The meeting itself followed a 2-day open format, a 1-day closed expert panel meeting and two additional half day meetings to develop the Concussion Recognition Tool 5 (Pocket CRT5), Sport Concussion Assessment Tool 5 (SCAT5) and Child SCAT5.