Identifying and overcoming mechanisms of PARP 2 inhibitor resistance in homologous recombination 3 repair-deficient and repair-proficient high grade 4 serous ovarian cancer cells

High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib

Effects of Coleus Forskohlii Supplementation on Body Composition and Hematological Profiles in Mildly Overweight Women

<p>Abstract</p> <p>Purpose</p> <p>This study investigated the effects of <it>Coleus Forskohlii </it>(CF) on body composition, and determined the safety and efficacy of supplementation.</p> <p>Methods</p> <p>In a double blind and randomized manner, 23 females supplemented their diet with ForsLean™ (250 mg of 10% CF extract, (n = 7) or a placebo [P] (n = 12) two times per day for 12-wks. Body composition (DEXA), body weight, and psychometric instruments were obtained at 0, 4, 8 & 12 weeks of supplementation. Fasting blood samples and dietary records (4-d) were obtained at 0 and 12-wks. Side effects were recorded on a weekly basis. Data were analyzed by repeated measures ANOVA and are presented as mean changes from baseline for the CF and placebo groups, respectively.</p> <p>Results</p> <p>No significant differences were observed in caloric or macronutrient intake. CF tended to mitigate gains in body mass (-0.7 ± 1.8, 1.0 ± 2.5 kg, p = 0.10) and scanned mass (-0.2 ± 1.3, 1.7 ± 2.9 kg, p = 0.08) with no significant differences in fat mass (-0.2 ± 0.7, 1.1 ± 2.3 kg, p = 0.16), fat free mass (-0.1 ± 1.3, 0.6 ± 1.2 kg, p = 0.21), or body fat (-0.2 ± 1.0, 0.4 ± 1.4%, p = 0.40). Subjects in the CF group tended to report less fatigue (p = 0.07), hunger (p = 0.02), and fullness (p = 0.04). No clinically significant interactions were seen in metabolic markers, blood lipids, muscle and liver enzymes, electrolytes, red cells, white cells, hormones (insulin, TSH, T3, and T4), heart rate, blood pressure, or weekly reports of side effects.</p> <p>Conclusion</p> <p>Results suggest that CF does not appear to promote weight loss but may help mitigate weight gain in overweight females with apparently no clinically significant side effects.</p

The impact of incident vertebral and non-vertebral fractures on health related quality of life in postmenopausal women

BACKGROUND: Little empirical research has examined the multiple consequences of osteoporosis on quality of life. METHODS: Health related quality of life (HRQL) was examined in relationship to incident fractures in 2009 postmenopausal women 50 years and older who were seen in consultation at our tertiary care, university teaching hospital-affiliated office and who were registered in the Canadian Database of Osteoporosis and Osteopenia (CANDOO) patients. Patients were divided into three study groups according to incident fracture status: vertebral fractures, non-vertebral fractures and no fractures. Baseline assessments of anthropometric data, medical history, therapeutic drug use, and prevalent fracture status were obtained from all participants. The disease-targeted mini-Osteoporosis Quality of Life Questionnaire (mini-OQLQ) was used to measure HRQL. RESULTS: Multiple regression analyses revealed that subjects who had experienced an incident vertebral fracture had lower HRQL difference scores as compared with non-fractured participants in total score (-0.86; 95% confidence intervals (CI): -1.30, -0.43) and the symptoms (-0.76; 95% CI: -1.23, -0.30), physical functioning (-1.12; 95% CI: -1.57, -0.67), emotional functioning (-1.06; 95% CI: -1.44, -0.68), activities of daily living (-1.47; 95% CI: -1.97, -0.96), and leisure (-0.92; 95% CI: -1.37, -0.47) domains of the mini-OQLQ. Patients who experienced an incident non-vertebral fracture had lower HRQL difference scores as compared with non-fractured participants in total score (-0.47; 95% CI: -0.70, -0.25), and the symptoms (-0.25; 95% CI: -0.49, -0.01), physical functioning (-0.39; 95% CI: -0.65, -0.14), emotional functioning (-0.97; 95% CI: -1.20, -0.75) and the activities of daily living (-0.47; 95% CI: -0.73, -0.21) domains. CONCLUSION: Quality of life decreased in patients who sustained incident vertebral and non-vertebral fractures

Improving Efficiency and Quality of the Children’s ASD Diagnostic Pathway: Lessons Learned from Practice

The ‘autism diagnosis crisis’ and long waiting times for assessment are as yet unresolved, leading to undue stress and limiting\ud access to effective support. There is therefore a significant need for evidence to support practitioners in the development of\ud efficient services, delivering acceptable waiting times and effectively meeting guideline standards. This study reports statistically\ud significant reductions in waiting times for autism diagnostic assessment following a children’s health service improvement\ud programme. The average wait between referral and first appointment reduced from 14.2 to 10.4 weeks (t(21) = 4.3,\ud p < 0.05) and between referral and diagnosis shared, reduced from 270 to 122.5 days, (t(20) = 5.5, p < 0.05). The proportion\ud of girls identified increased from 5.6 to 2.7:1. Methods reported include: local improvement action planning; evidence based\ud pathways; systematic clinical data gathering and a training plan. This is a highly significant finding for many health services\ud wrestling with the challenges of demand and capacity for autism diagnosis and assessment

Effect of vitamin D on bone mineral density of elderly patients with osteoporosis responding poorly to bisphosphonates

BACKGROUND: Bisphosphonates are indicated in the prevention and treatment of osteoporosis. However, bone mineral density (BMD) continues to decline in up to 15% of bisphosphonate users. While randomized trials have evaluated the efficacy of concurrent bisphosphonates and vitamin D, the incremental benefit of vitamin D remains uncertain. METHODS: Using data from the Canadian Database of Osteoporosis and Osteopenia (CANDOO), we performed a 2-year observational cohort study. At baseline, all patients were prescribed a bisphosphonate and counseled on vitamin D supplementation. After one year, patients were divided into two groups based on their response to bisphosphonate treatment. Non-responders were prescribed vitamin D 1000 IU daily. Responders continued to receive counseling on vitamin D. RESULTS: Of 449 patients identified, 159 were non-responders to bisphosphonates. 94% of patients were women. The mean age of the entire cohort was 74.6 years (standard deviation = 5.6 years). In the cohort of non-responders, BMD at the lumbar spine increased 2.19% (p < 0.001) the year after vitamin D was prescribed compared to a decrease of 0.55% (p = 0.36) the year before. In the cohort of responders, lumbar spine BMD improved 1.45% (p = 0.014) the first year and 1.11% (p = 0.60) the second year. The difference between the two groups was statistically significant the first year (p < 0.001) but not the second (p = 0.60). Similar results were observed at the femoral neck but were not statistically significant. CONCLUSION: In elderly patients with osteoporosis not responding to bisphosphonates, vitamin D 1000 IU daily may improve BMD at the lumbar spine

Comparative effects of deep versus shallow squat and leg press training on vertical jumping ability and related factors

Dissertação de Mestrado em Estudos Literários e Culturais, orientada pela Doutora Catarina Isabel Caldeira Martins, apresentada ao Departamento de Línguas, Literaturas e Culturas da Faculdade de Letras da Universidade de Coimbra.Esta dissertação se propõe a analisar o romance El país de las mujeres (2010), de Gioconda Belli, com objetivo de encontrar traços que possibilitem caracterizá-lo como um romance de tese feminista. Para realizar essa análise com base nos estudos literários e culturais, buscamos em primeiro lugar, ilustrar alguns conceitos chave, como o romance de tese, a literatura feminista e a própria ideologia feminista, sobretudo da vertente ginocêntrica, desde um ponto de vista funcional para a formulação da possível tese do romance. Como pesquisa de literatura e cultura, acreditamos na importância de se entender o contexto de escrita de Belli, por isso fazemos uma breve apresentação da história do feminismo na Nicarágua e onde a autora está incluída nesse processo, além de apresentar o caminho literário da autora, desde sua primeira poesia exaltadora das mulheres e do feminino, até a publicação desse romance que afronta os poderes patriarcais desde várias fontes. A partir dessas informações, analisamos o romance sob uma perspectiva literária e cultural, a fim de descobrir se a tese encontrada no início do romance é suficiente para defini-lo como romance de tese feminista. Entendemos que a tese em questão afirma que: a valorização da feminilidade socialmente construída e sua reprodução são importantes para que existam relações sociais equitativas. Achamos importante enfatizar desde o início o caráter resistente da literatura produzida por mulheres, que permite a criação de realidades diferentes das produzidas pelo universo literário machista e que oferece às leitoras maneiras novas de perceber o mundo e de interagir em sociedade, influenciando a ruptura com as bases opressoras sustentadas pelo patriarcado.This dissertation proposes to analyze the novel El País de las mujeres (2010) by Gioconda Belli, in order to find traits that make it possible to characterize it as a feminist roman à thése. To conduct this literary and cultural analysis, we seek first to illustrate some key concepts such as roman à thèse, feminist literature and the very feminist ideology, particularly, the gynocentric aspect, from a functional point of view to formulate the possible thesis of the novel. As a research in literary and cultural studies, we believe in the importance of understanding the writing context of Belli. Therefore, we make a brief presentation of the history of feminism in Nicaragua to situate the writer in this process. We also present the literary path of the author, since her first poem exalting women and femininity, until the publication of this novel that affronts patriarchal power from several imaginable points of view. Thus, we analyze the novel under a literary and cultural perspective, in order to find out whether the thesis that we found at the beginning of the novel is enough to define it as a feminist roman à these. We understand that this thesis is stating that “the valuation of socially constructed femininity and its reproduction are important to the existence of equal social relations”. We think it's important to emphasize right from the start the resistant nature of the literature produced by women, which enables the creation of different realities from those produced by the male-dominated literary universe and offers female readers new ways of perceiving the world and to interact in society, influencing the break with the oppressing bases sustained by patriarchy

Comparative effects of deep versus shallow squat and leg press training on vertical jumping ability and related factors

Young, previously untrained healthy men (n = 10) and women (n = 8) completed 9 weeks of periodized, machine-based squat training to determine if manipulating range of motion would have a differential effect on vertical jumping ability and related measures. Subjects were pretested and then randomly assigned to 1 of 3 groups: (a) deep squats (n = 6), (b) shallow squats (n = 6), and (c) controls (n = 6). Training took place 3 days per week. Pre- and posttesting included standing (RVJ) and depth (DVJ) vertical jumps for distance; machine deep and shallow squats for 1RM (1 repetition maximum) relative strength; and velocity-controlled squats at 0.51 m·s-1 for relative peak force and at 1.43 m·s-1 for relative peak power. Based on ANCOVA posttest results, the training protocols were ineffective in eliciting improved performance (p \u3e 0.05) in VJ, slow-velocity squatting force, and moderately fast squatting power when performance was compared with the performance of control subjects. Conversely, the group training with deep squats was the only group to perform significantly (p \u3c 0.05) better than controls for 1RM shallow squats and significantly (p \u3c 0.05) better than both shallow-squat and control groups for 1RM deep squats. Furthermore, the coefficient of transfer for deep squats to both RVJ (2.32) and DVJ (1.68) was substantially greater than for shallow squats (0.31 and 0.11, respectively). It was concluded that deep-squat training appears to elicit the best improvement for both shallow-and deep-squatting performance. However, 9 weeks of machine-based, periodized squat training, regardless of depth, does not appear to appreciably enhance slow-velocity squatting force, moderately fast squatting power, or vertical jumping distance in previously untrained men and women

Effects of oral D-ribose supplementation on anaerobic capacity and selected metabolic markers in healthy males

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