A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models.

Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of severe combined immunodeficient (SCID)/Beige and nonobese diabetic (NOD)/SCID/IL-2γ-receptor null (NSG) mice under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (∼21% and ∼19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were "triple-negative" [estrogen receptor (ER)-progesterone receptor (PR)-HER2+; n = 19]. However, we established lines from 3 ER-PR-HER2+ tumors, one ER+PR-HER2-, one ER+PR+HER2-, and one "triple-positive" (ER+PR+HER2+) tumor. Serially passaged xenografts show biologic consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including 2 ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis

Return to Employment After Stroke in Young Adults: How Important Is the Speed and Energy Cost of Walking?

Background and Purpose- A quarter of individuals who experience a stroke are under the age of 65 years (defined as young adults), and up to 44% will be unable to return to work poststroke, predominantly because of walking difficulties. No research study has comprehensively analyzed walking performance in young adult's poststroke. The primary aim of this study is to investigate how a stroke in young adults affects walking performance (eg, walking speed and metabolic cost) compared with healthy age-matched controls. The secondary aim is to determine the predictive ability of walking performance parameters for return to employment poststroke. Methods- Forty-six individuals (18-40 years: n=6, 41-54 years: n=21, 55-65 years: n=19) who have had a stroke and 15 healthy age-matched able-bodied controls were recruited from 6 hospital sites in Wales, United Kingdom. Type, location, cause of stroke, and demographic factors (eg, employment status) were recorded. Temporal and spatial walking parameters were measured using 3-dimensional gait analysis. Metabolic energy expenditure and metabolic cost of walking were captured during 3 minutes of walking at self-selected speed from measurements of oxygen consumption. Results- Stroke participants walked slower (P<0.004) and less efficiently (P<0.002) than the controls. Only 23% of stroke participants returned to employment poststroke. Walking speed was the strongest predictor (sensitivity, 0.90; specificity, 0.82) for return to work (P=0.004) with a threshold of 0.93 m/s identified: individuals able to walk faster than 0.93 m/s were significantly more likely to return to work poststroke than those who walked slower than this threshold. Conclusions- This study is the first to capture walking performance parameters of young adults who have had a stroke and identifies slower and less efficient walking. Walking speed emerged as the strongest predictor for return to employment. It is recommended that walking speed be used as a simple but sensitive clinical indicator of functional performance to guide rehabilitation and inform readiness for return to work poststroke

A novel TOPSIS–CBR goal programming approach to sustainable healthcare treatment

Cancer is one of the most common diseases worldwide and its treatment is a complex and time-consuming process. Specifically, prostate cancer as the most common cancer among male population has received the attentions of many researchers. Oncologists and medical physicists usually rely on their past experience and expertise to prescribe the dose plan for cancer treatment. The main objective of dose planning process is to deliver high dose to the cancerous cells and simultaneously minimize the side effects of the treatment. In this article, a novel TOPSIS case based reasoning goal-programming approach has been proposed to optimize the dose plan for prostate cancer treatment. Firstly, a hybrid retrieval process TOPSIS–CBR [technique for order preference by similarity to ideal solution (TOPSIS) and case based reasoning (CBR)] is used to capture the expertise and experience of oncologists. Thereafter, the dose plans of retrieved cases are adjusted using goal-programming mathematical model. This approach will not only help oncologists to make a better trade-off between different conflicting decision making criteria but will also deliver a high dose to the cancerous cells with minimal and necessary effect on surrounding organs at risk. The efficacy of proposed method is tested on a real data set collected from Nottingham City Hospital using leave-one-out strategy. In most of the cases treatment plans generated by the proposed method is coherent with the dose plan prescribed by an experienced oncologist or even better. Developed decision support system can assist both new and experienced oncologists in the treatment planning process

The Pediatric Choroidal and Ciliary Body Melanoma Study A Survey by the European Ophthalmic Oncology Group

Purpose: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. Design: Retrospective, multicenter observational study. Participants: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. Methods: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. Main Outcome Measures: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. Results: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. Conclusions: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups. (C) 2016 by the American Academy of Ophthalmology.Peer reviewe

Benzodiazepine use among adults residing in the urban settlements of Karachi, Pakistan: A cross sectional study

<p>Abstract</p> <p>Background</p> <p>There are hardly any studies carried out in Pakistan on the usage of benzodiazepines at the level of community. This research was aimed to determine the frequency of benzodiazepine use, along with its associations with socio-demographic and clinical characteristics among community dwelling adults, residing in two urban settlements of Karachi, Pakistan.</p> <p>Methods</p> <p>We performed a cross sectional study from August 2008 to December 2009, in 2 areas of Karachi, namely Garden and Sultanabad. We followed the systematic sampling strategy to randomly select the households, with an adult of either sex and of age 18 years or more. Data collection was carried out through interview, using a pre-tested questionnaire, with items on socio-demographic position, medical history and benzodiazepine use. Student's t-test and χ²test was employed to determine the associations between socio-demographic and clinical characteristics, and their relationship with benzodiazepine use was determined using applied logistic regression.</p> <p>Results</p> <p>The overall percentage of benzodiazepine consumption was estimated to be 14%. There were significantly more benzodiazepine users in the peri-urban Sultanabad community to the urban community of Garden (p-value = 0.001). The mean age (± SD) for users was 51.3 (± 15.6) years compared to 37.1 (± 14.4) years among non-users. Bromazepam was the most widely used benzodiazepine (29%); followed by diazepam, with a median duration on primary use being 144 weeks (IQR = 48-240). The adjusted logistic regression model revealed that increasing age, location, female sex, unemployment and psychiatric consultation were associated with increased likelihood of benzodiazepine use.</p> <p>Conclusion</p> <p>We believe the unregulated over-the-counter sales of benzodiazepines and social conditions might be playing a role in this high consumption of benzodiazepines in the community.</p

Gene Expression Rhythms in the Mussel Mytilus galloprovincialis (Lam.) across an Annual Cycle

Seasonal environmental changes may affect the physiology of Mytilus galloprovincialis (Lam.), an intertidal filter-feeder bivalve occurring commonly in Mediterranean and Atlantic coastal areas. We investigated seasonal variations in relative transcript abundance of the digestive gland and the mantle (gonads) of males and females. To identify gene expression trends – in terms of relative mRNA abundance- we used a medium-density cDNA microarray (1.7 K probes) in dual-color competitive hybridization analyses. Hierarchical clustering of digestive gland microarray data showed two main branches, distinguishing profiles associated with the “hot” months (May–August) from the other months. Genes involved in chitin metabolism, associated with mussel nutrition and digestion showed higher mRNA levels during summer. Moreover, we found different gene transcriptomic patterns in the digestive glands of males when compared to females, during the four stages of mussel gonadal development. Microarray data from gonadal transcripts also displayed clear patterns during the different developmental phases respect to the resting period (stage I) with peak relative mRNA abundance at the ripe phase (stage III) for both sexes. These data showed a clear temporal pattern in transcriptomic profiles of mussels sampled over an annual cycle. Physiological response to thermal variation, food availability, and reproductive status across months may contribute to variation in relative mRNA abundance

The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone

The M235T Polymorphism in the AGT Gene and CHD Risk: Evidence of a Hardy-Weinberg Equilibrium Violation and Publication Bias in a Meta-Analysis

BACKGROUND: The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD). METHODOLOGY/PRINCIPAL FINDINGS: A case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias. CONCLUSIONS/SIGNIFICANCE: The pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases