Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas

<p>Abstract</p> <p>Background</p> <p>DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure.</p> <p>Results</p> <p>Of 115 primary sporadic ovarian carcinomas, 39 (34%) had low BRCA1 protein and 49 (42%) had low BRCA2 expression. BRCA1 and BRCA2 protein expression were highly concordant (p < 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary neoplasms. BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards). In paired specimens, BRCA1 protein expression increased in 13/21 (62%) and BRCA2 protein expression increased in 15/21 (71%) of recurrent carcinomas with low or intermediate protein in the paired primary. In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%). Similar frequencies of MLH1, BRCA1, and FANCF promoter methylation occurred in primary carcinomas without previous chemotherapy, after neoadjuvant chemotherapy, or in recurrent neoplasms.</p> <p>Conclusion</p> <p>Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival. Recurrent ovarian carcinomas commonly have increased BRCA1 and/or BRCA2 protein expression post chemotherapy exposure which could mediate resistance to platinum based therapies. However, alterations in expression of these proteins after chemotherapy are not commonly mediated by promoter methylation, and other regulatory mechanisms are likely to contribute to these alterations.</p

The speaking vocabulary of grade two

Thesis (M.A.)--Boston Universit

Integrating remote sensing products and GIS tools to support marine spatial management in West Hawai'i

Marine protected areas (MPAs) represent a form of spatial management, and geospatial information on living marine resources and associated habitat is extremely important to support best management practices in a spatially discrete MPA. Benthic habitat maps provide georeferenced information on the geomorphic structure and biological cover types in the marine environment. This information supports an enhanced understanding of ecosystem function and species habitat utilization patterns. Benthic habitat maps are most useful for marine management and spatial planning purposes when they are created at a scale that is relevant to management actions. We sought to improve the resolution of existing benthic habitat maps created during a regional mapping effort in Hawai`i. Our results complemented these existing regional maps and provided more detailed, finer-scale habitat maps for a network of MPAs in West Hawai`i. The map products created during this study allow local planners and managers to extract information at a spatial scale relevant to the discrete management units, and appropriate for local marine management efforts on the Kona Coast. The resultant benthic habitat maps were integrated in a geographic information system (GIS) that also included aerial imagery, underwater video, MPA regulations, summarized ecological data and other relevant and spatially explicit information. The integration of the benthic habitat maps with additional “value added” geospatial information into a dynamic GIS provide a decision support tool with pertinent marine resource information available in one central location and support the application of a spatial approach to the management of marine resources. Further, this work can serve as a case study to demonstrate the integration of remote sensing products and GIS tools at a fine spatial scale relevant to local-level marine spatial planning and management efforts

Capturing health and eating status through a nutritional perception screening questionnaire (NPSQ9) in a randomised internet-based personalised nutrition intervention : the Food4Me study

BACKGROUND: National guidelines emphasize healthy eating to promote wellbeing and prevention of non-communicable diseases. The perceived healthiness of food is determined by many factors affecting food intake. A positive perception of healthy eating has been shown to be associated with greater diet quality. Internet-based methodologies allow contact with large populations. Our present study aims to design and evaluate a short nutritional perception questionnaire, to be used as a screening tool for assessing nutritional status, and to predict an optimal level of personalisation in nutritional advice delivered via the Internet. METHODS: Data from all participants who were screened and then enrolled into the Food4Me proof-of-principle study (n = 2369) were used to determine the optimal items for inclusion in a novel screening tool, the Nutritional Perception Screening Questionnaire-9 (NPSQ9). Exploratory and confirmatory factor analyses were performed on anthropometric and biochemical data and on dietary indices acquired from participants who had completed the Food4Me dietary intervention (n = 1153). Baseline and intervention data were analysed using linear regression and linear mixed regression, respectively. RESULTS: A final model with 9 NPSQ items was validated against the dietary intervention data. NPSQ9 scores were inversely associated with BMI (β = -0.181, p < 0.001) and waist circumference (Β = -0.155, p < 0.001), and positively associated with total carotenoids (β = 0.198, p < 0.001), omega-3 fatty acid index (β = 0.155, p < 0.001), Healthy Eating Index (HEI) (β = 0.299, p < 0.001) and Mediterranean Diet Score (MDS) (β = 0. 279, p < 0.001). Findings from the longitudinal intervention study showed a greater reduction in BMI and improved dietary indices among participants with lower NPSQ9 scores. CONCLUSIONS: Healthy eating perceptions and dietary habits captured by the NPSQ9 score, based on nine questionnaire items, were associated with reduced body weight and improved diet quality. Likewise, participants with a lower score achieved greater health improvements than those with higher scores, in response to personalised advice, suggesting that NPSQ9 may be used for early evaluation of nutritional status and to tailor nutritional advice. TRIAL REGISTRATION: NCT01530139 .Peer reviewedFinal Published versio

Real-world Use of Mold-Active Triazole Prophylaxis in the Prevention of Invasive Fungal Diseases: Results From a Subgroup Analysis of a Multicenter National Registry

BACKGROUND: Antifungal prophylaxis can prevent invasive fungal diseases (IFDs) in high-risk, immunocompromised patients. This study assessed the real-world use of mold-active triazoles (MATs) for the prevention of IFDs. METHODS: This subgroup analysis of a multicenter, observational, prospective registry in the United States from March 2017 to April 2020 included patients who received MATs for prophylaxis (isavuconazole, posaconazole, and voriconazole) at study index/enrollment. The primary objective was to describe patient characteristics and patterns of MAT use. Exploratory assessments included the frequency of breakthrough IFDs and MAT-related adverse drug reactions (ADRs). RESULTS: A total of 1177 patients (256 isavuconazole, 397 posaconazole, 272 voriconazole, and 252 multiple/sequenced MATs at/after index/enrollment) were included in the prophylaxis subgroup analysis. Patient characteristics were similar across MAT groups, but risk factors varied. Hematological malignancy predominated (76.5%) across all groups. Breakthrough IFDs occurred in 7.1% (73/1030) of patients with an investigator\u27s assessment (5.0% [11/221] isavuconazole; 5.3% [20/374] posaconazole; 4.0% [9/226] voriconazole; and 15.8% [33/209] multiple/sequenced MATs). CONCLUSIONS: Breakthrough IFDs were uncommon in patients who received MATs for prophylaxis

Early blood pressure, antihypotensive therapy and outcomes at 18–22 months’ corrected age in extremely preterm infants

Investigate relationships between early blood pressure (BP) changes, receipt of anti-hypotensive therapy, and 18 – 22 month corrected age (CA) outcomes for extremely preterm infants

Artificially extended photoperiod administered to pre-partum mares via blue light to a single eye : observations on gestation length, foal birth weight and foal hair coat at birth

In seasonally breeding animals, photoperiod perception is crucial for timing of important physiological events. In the horse, long day photoperiod influences the onset of ovulation and cyclicity, shedding of the heavier winter coat and the timing of parturition. In this compilation of studies, conducted across three breeding seasons and two countries, the impact of artificially extended day length was investigated on gestation length, foal birth weight and foal hair coat at birth. The light therapy was administered to pre-partum mares via mobile head worn masks which provided short wavelength blue light to a single eye. In Study 1, reductions in gestation lengths were observed following administration of artificially extended day length (124.8 ± 15.11 days) in the final months of pregnancy to a group of Thoroughbred mares compared to controls (P < 0.05; 339.7 ± 9.56 days vs 350.6 ± 9.13). Study 2 revealed that pre-partum exposure to artificially extended day length (104.6 ± 9.89 days) increased foal birth weight compared to controls (47.13 ± 2.93 kg vs 43.51 ± 6.14 kg; P < 0.05) in mares bred early in the year. In Study 3, artificially extended day length (87.53 ± 19.6 days) administered to pre-partum mares affected the coat condition of foals at birth with respect to hair weight (P < 0.0001) and hair length (P < 0.0001) compared to controls (0.34 ± 0.20 μg vs 0.59 ± 0.12 μg and 1.93 ± 0.56 cm vs 2.56 ± 0.32 cm, respectively). Collectively, these studies serve to highlight the influential role of the circa-annual changes in photoperiod length on the pre-partum mare for normal foetal development during the natural breeding season. It also emphasizes the potential that exists to improve breeding efficiency parameters by artificially simulating this important environmental cue in the latter stages of gestation against the backdrop of an economically driven early breeding season.Study 2 was supported by an Enterprise Ireland Commercialisation Fund grant to B. A. Murphy.http://www.theriojournal.com2018-09-15hj2017Production Animal Studie

Climate shocks and migration: an agent-based modeling approach

This is a study of migration responses to climate shocks. We construct an agent-based model that incorporates dynamic linkages between demographic behaviors, such as migration, marriage, and births, and agriculture and land use, which depend on rainfall patterns. The rules and parameterization of our model are empirically derived from qualitative and quantitative analyses of a well-studied demographic field site, Nang Rong district, Northeast Thailand. With this model, we simulate patterns of migration under four weather regimes in a rice economy: 1) a reference, ‘normal’ scenario; 2) seven years of unusually wet weather; 3) seven years of unusually dry weather; and 4) seven years of extremely variable weather. Results show relatively small impacts on migration. Experiments with the model show that existing high migration rates and strong selection factors, which are unaffected by climate change, are likely responsible for the weak migration response