Homologous recombination deficiency and ovarian cancer

The discovery that PARP inhibitors block an essential pathway of DNA repair in cells harbouring a BRCA mutation has opened up a new therapeutic avenue for high-grade ovarian cancers. BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors. The first PARP inhibitor, olaparib, has now been licensed for BRCA-mutated ovarian cancers. While mutated BRCA genes are individually most commonly associated with HRD other essential HRR proteins may be mutated or functionally deficient potentially widening the therapeutic opportunities for PARP inhibitors. HRD is the first phenotypically defined predictive marker for therapy with PARP inhibitors in ovarian cancer. Several different PARP inhibitors are being trialled in ovarian cancer and this class of drugs has been shown to be a new selective therapy for high-grade ovarian cancer. Around 20% of high-grade serous ovarian cancers harbour germline or somatic BRCA mutations and testing for BRCA mutations should be incorporated into routine clinical practice. The expanded use of PARP inhibitors in HRD deficient (non-BRCA mutant) tumours using a signature of HRD in clinical practice requires validation

Real-World Delivery of Rucaparib to Patients with Ovarian Cancer: Recommendations Based on an Integrated Safety Analysis of ARIEL2 and Study 10

Treatment options for women with recurrent ovarian cancer who have received two or more prior lines of chemotherapy have recently expanded with the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals of the poly(ADP‐ribose) polymerase (PARP) inhibitor rucaparib. As more oncologists begin to use rucaparib and other PARP inhibitors as part of routine clinical practice, awareness of possible side effects and how to adequately manage toxicities is crucial. In this review, we summarize the safety and tolerability of rucaparib reported in an integrated safety analysis that supported the FDA's initial approval of rucaparib in the treatment setting. Additionally, drawing on clinical data and our personal experience with rucaparib, we provide our recommendations on the management of common side effects observed with rucaparib, including anemia, blood creatinine elevations, alanine aminotransferase and aspartate aminotransferase elevations, thrombocytopenia, gastrointestinal‐related events (e.g., nausea, vomiting), and asthenia and fatigue. These side effects, many of which appear to be class effects of PARP inhibitors, are often self‐limiting and can be managed with adequate interventions such as treatment interruption and/or dose reduction and the use of supportive therapies. Supportive therapies may include blood transfusions for patients with anemia, prophylactic medications to prevent nausea and vomiting, or behavioral interventions to mitigate fatigue. Understanding and appropriate management of potential side effects associated with rucaparib may allow patients with ovarian cancer to continue to benefit from rucaparib treatment. Implications for Practice. Rucaparib was recently approved in the U.S. and European Union for use as treatment or maintenance for recurrent ovarian cancer. This review focuses on the safety and tolerability of rucaparib in the treatment setting. Similar side effects are observed in the maintenance setting. Drawing on the authors’ clinical experience with rucaparib, rucaparib prescribing information, and published supportive cancer care guidelines, this review discusses how to optimally manage common rucaparib‐associated side effects in patients with advanced ovarian cancer in the real‐world oncology setting. Adequate management of such side effects is crucial for allowing patients with ovarian cancer to remain on treatment to receive optimal efficacy benefit

HIV continuum of care in Europe and Central Asia.

OBJECTIVES: The European Centre for Disease Prevention and Control (ECDC) supports countries to monitor progress in their response to the HIV epidemic. In line with these monitoring responsibilities, we assess how, and to what extent, the continuum of care is being measured across countries. METHODS: The ECDC sent out questionnaires to 55 countries in Europe and Central Asia in 2014. Nominated country representatives were questioned on how they defined and measured six elements of the continuum. We present our results using three previously described frameworks [breakpoints; Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets; diagnosis and treatment quadrant]. RESULTS: Forty countries provided data for at least one element of the continuum. Countries reported most frequently on the number of people diagnosed with HIV infection (37; 93%), and on the number in receipt of antiretroviral therapy (ART) (35; 88%). There was little consensus across countries in their approach to defining linkage to, and retention in, care. The most common breakpoint (>19% reduction between two adjacent elements) related to the estimated number of people living with HIV who were diagnosed (18 of 23; 78%). CONCLUSIONS: We present continuum data from multiple countries that provide both a snapshot of care provision and a baseline against which changes over time in care provision across Europe and Central Asia may be measured. To better inform HIV testing and treatment programmes, standard data collection approaches and definitions across the HIV continuum of care are needed. If countries wish to ensure an unbroken HIV continuum of care, people living with HIV need to be diagnosed promptly, and ART needs to be offered to all those diagnosed

The demography of fine roots in response to patches of water and nitrogen

Fine root demography was quantified in response to patches of increased water and nitrogen availability in a natural, second-growth, mixed hardwood forest in northern Michigan, USA. As expected, the addition of water and water plus nitrogen resulted in a significant overall increase in the production of new fine roots. New root production was much greater in response to water plus nitrogen when compared with water alone, and the duration of new root production was related to the length of resource addition in the water plus nitrogen treatments; the average difference in new root length between the 20 vs. 40 d additions of water plus nitrogen amounted to almost 600%. Roots produced in response to the additions of water and water plus nitrogen lived longer than roots in the control treatments. Thus, additions of water and water plus nitrogen influenced both the proliferation of new roots and their longevity, with both proliferation and longevity related to the type and duration of resource supply. Results suggest that root longevity and mortality may be plastic in response to changes in soil resource availability, as is well known for root proliferation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65770/1/j.1469-8137.1993.tb03905.x.pd

The Meissner effect in a strongly underdoped cuprate above its critical temperature

The Meissner effect and the associated perfect "bulk" diamagnetism together with zero resistance and gap opening are characteristic features of the superconducting state. In the pseudogap state of cuprates unusual diamagnetic signals as well as anomalous proximity effects have been detected but a Meissner effect has never been observed. Here we have probed the local diamagnetic response in the normal state of an underdoped La1.94Sr0.06CuO4 layer (up to 46 nm thick, critical temperature Tc' < 5 K) which was brought into close contact with two nearly optimally doped La1.84Sr0.16CuO4 layers (Tc \approx 32 K). We show that the entire 'barrier' layer of thickness much larger than the typical c axis coherence lengths of cuprates exhibits a Meissner effect at temperatures well above Tc' but below Tc. The temperature dependence of the effective penetration depth and superfluid density in different layers indicates that superfluidity with long-range phase coherence is induced in the underdoped layer by the proximity to optimally doped layers; however, this induced order is very sensitive to thermal excitation.Comment: 7 pages, 7 figures + Erratu

Metabolic state alters economic decision making under risk in humans

Background: Animals' attitudes to risk are profoundly influenced by metabolic state (hunger and baseline energy stores). Specifically, animals often express a preference for risky (more variable) food sources when below a metabolic reference point (hungry), and safe (less variable) food sources when sated. Circulating hormones report the status of energy reserves and acute nutrient intake to widespread targets in the central nervous system that regulate feeding behaviour, including brain regions strongly implicated in risk and reward based decision-making in humans. Despite this, physiological influences per se have not been considered previously to influence economic decisions in humans. We hypothesised that baseline metabolic reserves and alterations in metabolic state would systematically modulate decision-making and financial risk-taking in humans. Methodology/Principal Findings: We used a controlled feeding manipulation and assayed decision-making preferences across different metabolic states following a meal. To elicit risk-preference, we presented a sequence of 200 paired lotteries, subjects' task being to select their preferred option from each pair. We also measured prandial suppression of circulating acyl-ghrelin (a centrally-acting orexigenic hormone signalling acute nutrient intake), and circulating leptin levels (providing an assay of energy reserves). We show both immediate and delayed effects on risky decision-making following a meal, and that these changes correlate with an individual's baseline leptin and changes in acyl-ghrelin levels respectively. Conclusions/Significance: We show that human risk preferences are exquisitely sensitive to current metabolic state, in a direction consistent with ecological models of feeding behaviour but not predicted by normative economic theory. These substantive effects of state changes on economic decisions perhaps reflect shared evolutionarily conserved neurobiological mechanisms. We suggest that this sensitivity in human risk-preference to current metabolic state has significant implications for both real-world economic transactions and for aberrant decision-making in eating disorders and obesity

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

PARP inhibitors and the treatment of breast cancer: beyond BRCA1/2?

Poly(ADP-ribose) polymerase (PARP) inhibitors have been explored as therapeutic agents for the treatment of hereditary breast and ovarian cancers harboring mutations in BRCA1 or BRCA2. In a new study, Inbar-Rozensal and colleagues show that phenanthridine-derived PARP inhibitors promote cell cycle arrest and cell death in breast cancer cells lacking BRCA1 and BRCA2 mutations and prevent the growth of tumors from xenografts of these cells in immunocompromised mice. These results suggest a potential broader utility of PARP-1 inhibitors in the treatment of breast cancer, although further mechanistic studies are needed

A large-scale examination of the effectiveness of anonymous marking in reducing group performance differences in higher education assessment

The present research aims to more fully explore the issues of performance differences in higher education assessment, particularly in the context of a common measure taken to address them. The rationale for the study is that, while performance differences in written examinations are relatively well researched, few studies have examined the efficacy of anonymous marking in reducing these performance differences, particularly in modern student populations. By examining a large archive (N = 30674) of assessment data spanning a twelve-year period, the relationship between assessment marks and factors such as ethnic group, gender and socio-environmental background was investigated. In particular, analysis focused on the impact that the implementation of anonymous marking for assessment of written examinations and coursework has had on the magnitude of mean score differences between demographic groups of students. While group differences were found to be pervasive in higher education assessment, these differences were observed to be relatively small in practical terms. Further, it appears that the introduction of anonymous marking has had a negligible effect in reducing them. The implications of these results are discussed, focusing on two issues, firstly a defence of examinations as a fair and legitimate form of assessment in Higher Education, and, secondly, a call for the re-examination of the efficacy of anonymous marking in reducing group performance differences