tbuckley/cabot-search huggingface dataset:
Levels of 25-hydroxy-vitamin D in pre-menopausal women at high risk for development of breast cancer.
Authors: CJ Fabian, BF Kimler, T Phillips, CM Zalles
Journal: Cancer Research (2009)

Abstract Abstract #5079 Background: There is biologic and epidemiologic evidence to suggest an inverse relationship between vitamin D intake and the risk of developing breast cancer, particularly for adolescent and premenopausal women. A recent meta-analysis of nested case control studies in an average risk cohort has suggested that those with &amp;gt;50 ng/ml of the pro-hormone 25-hydroxy-vitamin D, 25(OH)D, a good measure of recent vitamin D intake from all sources, have 50% fewer breast cancers than women with 25(OH)D levels regarded as severely deficient (&amp;lt;12 ng/ml) and 20% fewer breast cancers than those with levels regarded as deficient (12-20 ng/ml) or insufficient (20-30 ng/ml) [Garland et al. J Steroid Biochem Mol Biol 2007;103:708].&amp;#x2028; Materials and Methods: To determine if vitamin D supplementation should be explored as a prevention strategy in young women, we assessed the distribution of 25(OH)D levels in 100 high risk pre-menopausal women being screened for possible participation in Phase II prevention trials of a COX-2 inhibitor. These women were between the ages of 20 and 52, had undergone a random periareolar fine needle aspiration (RPFNA) and had serum frozen at -80°C within 2 months of the RPFNA. Serum was batch assayed for 25(OH)D, using the Liaison kit by DiaSorin (chemiluminescent assay) in a CLIA approved lab.&amp;#x2028; Results: Of 100 high risk women, 15% exhibited 25(OH)D levels considered severely deficient, 34% deficient, and 27% insufficient, Only 24% women exhibited 25(OH)D levels above 30 ng/ml, considered to be sufficient for bone health while only 4% had levels suggested as optimal for breast health. We have previously reported that high risk women with cytologic evidence of atypia had a 5 fold increase in their 4 year risk of developing DCIS or invasive cancer compared to those who do not [Fabian et al. J Natl Cancer Inst 2000; 92:1217]. Ninety-nine percent of women in our cohort were considered to have cytologic evidence of hyperplasia without (70%) or with (29%) atypia and median 25(OH)D levels were not different between samples regarded as hyperplastic and those assessed as atypical.&amp;#x2028; Discussion: These results indicate that 75% of high risk pre-menopausal women likely to participate in tissue biomarker-based chemoprevention trials will exhibit 25(OH)D levels that are insufficient for bone health and only 4% will have levels suggested from case control studies as being optimal for breast health. In this retrospective study, no association was observed between serum 25(OH)D levels (a marker of recent vitamin D intake) and a cytologic marker of increased breast cancer risk. A prospective trial is in progress to confirm the high prevalence of vitamin D insufficiency in young high risk women and to correlate 25(OH)D levels with a variety of tissue, imaging and serum-based risk biomarkers. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5079.
Development of a Functional Assay for Homologous Recombination Status in Primary Cultures of Epithelial Ovarian Tumor and Correlation with Sensitivity to Poly(ADP-Ribose) Polymerase Inhibitors
Authors: Asima Mukhopadhyay, Ahmed Elattar, Aiste Cerbinskaite, Sarah J. Wilkinson, Yvette Drew, Suzanne Kyle, Gerrit Los, Zdenek Hostomsky, Richard J. Edmondson, Nicola J. Curtin
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors selectively target homologous recombination (HR)–defective cells and show good clinical activity in hereditary breast and ovarian cancer associated with BRCA1 or BRCA2 mutations. A high proportion (up to 50%) of sporadic epithelial ovarian cancers (EOC) could be deficient in HR due to genetic or epigenetic inactivation of BRCA1/BRCA2 or other HR genes. Therefore, there is a potential for extending the use of PARP inhibitors to these patients if HR status can be identified. We developed a functional assay of HR status in primary cultures of EOCs based on Rad51 focus formation that correlates well with sensitivity to the potent PARP inhibitor AG014699. Experimental Design: Primary cultures were derived from ascitic fluid from patients with EOCs. HR status was investigated by γH2AX and Rad51 focus formation by immunofluorescence. Cytotoxicity to PARP inhibitors was tested by sulforhodamine B and survival assay. Results: Twenty-five cultures were evaluated for HR status and cytotoxicity to PARP inhibitor. Following exposure to AG014699, there was an increase in Rad51 foci (HR competent) in 9 of 24 (36%) but no increase (HR deficient) in 16 of 24 (64%) cultures. Cytotoxicity was observed in 15 of 16 (93%) HR-deficient samples but not in 9 of 9 HR-competent samples following 24-hour exposure to 10 μmol/L AG014699. Conclusion: HR status can be determined in primary cancer samples by Rad51 focus formation, and this correlates with in vitro response to PARP inhibition. Use of this assay as a biomarker now needs testing in the setting of a clinical trial. Clin Cancer Res; 16(8); 2344–51. ©2010 AACR.
A Model of Placebo Response in Antidepressant Clinical Trials
Authors: Bret R. Rutherford, Steven P. Roose
Journal: American Journal of Psychiatry (2013)

Placebo response in clinical trials of antidepressant medications is substantial and has been increasing. High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to trial failures and delaying the delivery of new treatments to market. Media reports seize upon increasing placebo response and modest advantages for active drugs as reasons to question the value of antidepressant medication, which may further stigmatize treatments for depression and dissuade patients from accessing mental health care. Conversely, enhancing the factors responsible for placebo response may represent a strategy for improving available treatments for major depressive disorder. A conceptual framework describing the causes of placebo response is needed in order to develop strategies for minimizing placebo response in clinical trials, maximizing placebo response in clinical practice, and talking with depressed patients about the risks and benefits of antidepressant medications. In this review, the authors examine contributors to placebo response in antidepressant clinical trials and propose an explanatory model. Research aimed at reducing placebo response should focus on limiting patient expectancy and the intensity of therapeutic contact in antidepressant clinical trials, while the optimal strategy in clinical practice may be to combine active medication with a presentation and level of therapeutic contact designed to enhance treatment response.
Phase I/II Randomized Trial Evaluating the Safety and Clinical Effects of Repifermin Administered to Reduce Mucositis in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation
Authors: Cesar O. Freytes, Voravit Ratanatharathorn, Charles Taylor, Camille Abboud, Nancy Chesser, Alejandro Restrepo, Jorge Arango, Daniel Odenheimer
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To evaluate the safety of repifermin (keratinocyte growth factor-2) administered before and after autologous hematopoietic stem cell transplantation (auto-HSCT). A preliminary analysis of the ability of keratinocyte growth factor-2 to prevent mucositis was also done. Experimental Design: Forty-two patients received intravenous repifermin (25 μg/kg or 50 μg/kg) or placebo for 3 days before their auto-HSCT conditioning regimen and for up to 10 days after auto-HSCT. Within each dose level, 14 patients were randomized to repifermin and 7 patients to placebo. Clinical evaluations of mucositis were scheduled before auto-HSCT conditioning regimen, on the day of transplant, and three times per week until mucositis resolved. Results: In general, the incidence of adverse events was similar for patients treated with repifermin and placebo. No clinically meaningful differences were noted among treatment groups for clinical laboratory variables. Treatment groups experienced similar time to engraftment. The frequency of Grade 2 to 4 mucositis was 100% for patients in the placebo group, 64% for patients in the 25 μg/kg group (P = 0.041 versus placebo), and 50% for patients in the 50 μg/kg group (P = 0.006 versus placebo). Results of other endpoints, including pain on swallowing and use of pain medication specifically for mucositis, suggested a better outcome for patients in the 50 μg/kg group compared with the placebo and 25 μg/kg groups. Conclusions: Repifermin was well tolerated. Repifermin given before and after auto-HSCT seems to be active in reducing mucositis, but a larger trial will be necessary to determine the efficacy of repifermin with this dose schedule.
Evidence That Vesicles on the Synaptic Ribbon of Retinal Bipolar Neurons Can Be Rapidly Released
Authors: Henrique von Gersdorff, Eilat Vardi, Gary Matthews, Peter Sterling
Journal: Neuron (1996)

We relate the ultrastructure of the giant bipolar synapse in goldfish retina to the jump in capacitance that accompanies depolarization-evoked exocytosis. Mean vesicle diameter is 29 ± 4 nm, giving 26.4 aF/vesicle, so the maximum evoked capacitance (150 fF within 200 ms) represents fusion of about 5700 vesicles. Two terminals contained, respectively, 45 and 65 ribbon-type synaptic outputs, and a fully loaded ribbon tethers about 110 vesicles. Thus, the tethered pool, about 6000 vesicles, corresponds to the rapidly released pool. Further, the difference between small and large terminals in number of tethered vesicles matches their difference in capacitance jump. This suggests, within a "fire and reload" model of exocytosis, that the ribbon translocates synaptic vesicles very rapidly to membrane docking sites, supporting a maximum release rate of 500 vesicles/active zone/s, until the population of tethered vesicles is exhausted.
Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert
Authors: Maya Ghoussaini, Honglin Song, Thibaud Koessler, Ali Amin Al Olama, Zsofia Kote-Jarai, Kristy E. Driver, Karen A. Pooley, Susan J. Ramus, Susanne Krüger Kjaer, Estrid Hogdall, Richard A. DiCioccio, Alice S. Whittemore, Simon A. Gayther, Graham G. Giles, Michelle Guy, Stephen M. Edwards, Jonathan Morrison, Jenny L. Donovan, Freddie C. Hamdy, David P. Dearnaley, Audrey T. Ardern-Jones, Amanda L. Hall, Lynne T. O'Brien, Beatrice N. Gehr-Swain, Rosemary A. Wilkinson, Paul M. Brown, John L. Hopper, David E. Neal, Paul D. P. Pharoah, Bruce A. J. Ponder, Rosalind A. Eeles, Douglas F. Easton, Alison M. Dunning
Journal: JNCI Journal of the National Cancer Institute (2008)

Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.
Treatment of Impetigo
Authors: M. S. Smith, E. C. Jones
Journal: BMJ (1945)

IMPETIGO MEI)ICLH 6OUR 699Only after operation was she set on the road to recovery.It is noteworthy that the insomnia, dyspepsia, and the morbid habit of magnifying the noises in her head did not disappear immediately after the operation but improved over a number of months concurrently with the remarkable change in her appear- ance.It seems reasonable to suppose that the rejuvenating effect of the operation enabled the patient gradually to emerge from her hypochondriacal state.
Transgenic Approach to the Study of Body Weight Regulation
Authors: Akio Inui
Journal: Pharmacological Reviews (2000)

Energy homeostasis is accomplished through a highly integrated and redundant neurohumoral system. Recently, novel molecular mediators and regulatory pathways for feeding and body weight regulation have been identified in the brain and the periphery. Because of the multitude and complexity of disturbances in energy intake, expenditure, and partitioning that are associated with obesity, it has been difficult to determine which abnormalities are causative versus less important phenomena that are consequences of the altered neuroendocrine and metabolic milieu. Transgenic technology has provided new opportunities to modify the complex body weight-regulating system and to assess the relative importance of the individual components. Observations of mutant mice have shed new light on the understanding of energy homeostasis equation. Once created, transgenic animal models may be useful in assessing the efficacy or determining the mode of action of potential new therapeutic agents. However, the interpretation of targeted mutation is sometimes not straightforward in unraveling the physiology because of the redundancy and compensation of the regulatory machinery, as well as the inherent problems of manipulation of the gene. Modifying the synthesis of a particular gene at all sites and developmental stages may be a relatively crude way of investigating its functions. Advanced gene-targeting strategies aimed at specific alterations (on and off) of a gene product at desired tissues and times could lead to a better understanding of the system.
Intratumoral Coadministration of Hyaluronidase Enzyme and Oncolytic Adenoviruses Enhances Virus Potency in Metastatic Tumor Models
Authors: Shanthi Ganesh, Melissa Gonzalez-Edick, Douglas Gibbons, Melinda Van Roey, Karin Jooss
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Evaluate the codelivery of hyaluronidase enzyme with oncolytic adenoviruses to determine whether it improves the spread of the virus throughout tumors, thereby leading to a greater overall antitumor efficacy in tumor models. Experimental Design: The optimal dose of hyaluronidase that provided best transduction efficiency and spread of a green fluorescent protein (GFP)-expressing adenovirus within tumors was combined with oncolytic viruses in tumor models to determine whether the combination treatment results in an improvement of antitumor efficacy. Results: In mice injected with the adenovirus Ad5/35GFP and an optimal dose of hyaluronidase (50 U), a significant increase in the number of GFP-expressing cells was observed when compared with animals injected with virus only (P &amp;lt; 0.0001). When the oncolytic adenoviruses Ad5OV or Ad5/35 OV (OV-5 or OV5T35H) were codelivered with 50 U of hyaluronidase, a significant delay in tumor progression was observed, which translated into a significant increase in the mean survival time of tumor-bearing mice compared with either of the monotherapy-treated groups (P &amp;lt; 0.0001). Furthermore, the mice that received the combination of Ad5/35 OV and hyaluronidase showed the best antitumor efficacy. Importantly, the combination treatment did not increase the metastatic potential of the tumors. Lastly, the increase in virus potency observed in animals injected with both enzyme and virus correlated with enhanced virus spread throughout tumors. Conclusion: Antitumor activity and overall survival of mice bearing highly aggressive tumors are significantly improved by codelivery of oncolytic adenoviruses and hyaluronidase when compared with either of the monotherapy-treated groups, and it may prove to be a potent and novel approach to treating patients with cancer.
Observations on the Estimation of the Quantity of Emphysema in the Lungs by the Point-sampling Method
Authors: J. A. Anderson, M. S. Dunnill
Journal: Thorax (1965)

A single lymphocyte culture system is described which produces both reliable fragile X expression and elongated chromosomes for prometaphase analysis. This system, which is based on that described by Wheater and Roberts in 1987, involves the deoxycytidine release of a thymidine block. Eight fragile X positive subjects had an average expression level of 26%, with a range of 12% to 45%, using the thymidine/deoxycytidine protocol. This was comparable to the levels obtained in parallel cultures treated with thymidine alone or fluorodeoxyuridine.
Folic Acid Does Not Improve Endothelial Function in Obese Children and Adolescents
Authors: Alexia S. Peña, Esko Wiltshire, Roger Gent, Lino Piotto, Craig Hirte, Jennifer Couper
Journal: Diabetes Care (2007)

OBJECTIVE—Obese children have severe endothelial dysfunction as measured by flow-mediated dilation (FMD). We have shown that folic acid normalizes endothelial function in children with type 1 diabetes who have a similar degree of endothelial dysfunction but lower total plasma homocyst(e)ine (tHcy) and higher folate status. Our aim was to evaluate, for the first time, the effect of folate supplementation on endothelial dysfunction in obese children. RESEARCH DESIGN AND METHODS—A total of 53 obese subjects (26 male, mean ± SD age 13.3 ± 2.2 years, and BMI Z score 2.29 ± 0.25) participated in a randomized, double-blind, placebo-controlled, parallel trial of oral folic acid (5 mg/day) or placebo for 8 weeks. Before and after the intervention, we assessed endothelial function (FMD), smooth muscle function (glyceryl trinitrate–induced dilatation [GTN]), high-sensitivity C-reactive protein (hsCRP), tHcy, serum folate, red cell folate (RCF), and lipids. RESULTS—There were no group differences at baseline. FMD did not change with the intervention (folic acid group pre- and postintervention: 6.42 ± 5.03 and 6.56 ± 4.79%, respectively, vs. placebo group: 5.17 ± 3.54 and 5.79 ± 4.26%, respectively; P = 0.6). Folate supplementation increased serum folate and RCF by 18.4 nmol/l (P &amp;lt; 0.001) and 240.1 nmol/l (P &amp;lt; 0.001), respectively, and decreased tHcy by 0.95 μmol/l (P = 0.008). The intervention did not change GTN, hsCRP, or lipids. CONCLUSIONS—Folic acid supplementation does not improve endothelial function in obese children without diabetes despite increasing folate status and reducing tHcy. This is in contrast to the response to folate in children with type 1 diabetes.
Cohort Study Based on the Seventh Edition of the TNM Classification for Gastric Cancer: Proposal of a New Staging System
Authors: Viktoria S. Warneke, Hans-Michael Behrens, Jörg T. Hartmann, Harald Held, Thomas Becker, Nicolas T. Schwarz, Christoph Röcken
Journal: Journal of Clinical Oncology (2011)

Purpose We investigated the effect of the new TNM classification on gastric cancer staging. Patients and Methods From hospital records, information from patients with gastric cancer, who had undergone either total or partial gastrectomy for adenocarcinomas of the stomach or esophagogastric junction, was retrieved. The pathologic TNM stage was determined according to the sixth and seventh editions of the International Union Against Cancer guidelines and was based on surgical pathologic examination. Results Five hundred fifty-four patients (338 men and 216 women; median age, 68 years) had undergone partial or complete gastrectomy for intestinal (n = 209) or diffuse (n = 249) adenocarcinoma of the esophagogastric junction and stomach. Survival data and date of death were available for all patients. Patient death correlated significantly with age at diagnosis, tumor type, histologic grade, local tumor growth (T category), number of metastatic lymph nodes, lymph node ratio, lymph node status (N category), and tumor stage. No major difference was noted between the sixth and seventh editions of the TNM classification. On the basis of survival data, we revised the stage grouping system; stage I and II tumors were confined to nonmetastatic tumors, and stage III and IV tumors were confined to metastatic tumors. The Kaplan-Meier plots of this modified stage grouping showed statistically significant differences between individual stage subgroups without crossing curves and demonstrated improved survival of patients with stage II disease. Conclusion The seventh edition of the TNM classification is associated with a stage migration in 60% of patients with esophagogastric and stomach cancer. This change did not improve the assessment of patient prognosis, and therefore, a revised staging system is proposed.
Top health officials face questioning by health select committee
Authors: Adrian O’Dowd
Journal: BMJ (2008)

Less than half of England is on track to meet government targets to reduce health inequalities, MPs have been told.

Across the country only 41% of local government areas (which tie in with primary care trusts (PCTs)) are expected to meet the national strategy targets of reducing inequalities in health outcomes by 10% by 2010.

Department of Health officials confirmed the figure when giving evidence to the parliamentary health select committee as part of the first evidence session of the committee’s inquiry into health inequalities.

The session took place on the same day that the department published its third update report of its Tackling Inequalities: A Programme for …
Design and Use of Performance Measures to Decrease Low-Value Services and Achieve Cost-Conscious Care
Authors: David W. Baker
Journal: Annals of Internal Medicine (2013)

Improving quality of care while decreasing the cost of health care isa national priority. The American College of Physicians recently launched its High-Value Care Initiative to help physicians and patients understand the benefits, harms, and costs of interventions and to determine whether services provide good value. Public and private payers continue to measure underuse of high-value services(for example, preventive services, medications for chronic disease),but they are now widely using performance measures to assess use of low-value interventions (such as imaging for patients with uncomplicated low back pain) and using the results for public reporting and pay-for-performance. This paper gives an overview of performance measures that target low-value services to help physicians understand the strengths and limitations of these measures,provides specific examples of measures that assess use of low-value services, and discusses how these measures can be used in clinical practice and policy.