Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC), which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17). This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC

Evidence for Proportionate Partition Between the Magnetic Field and Hot Gas in Turbulent Cassiopeia A

We present a deep X-ray observation of the young Galactic supernova remnant Cas A, acquired with the ROSAT High Resolution Imager. This high dynamic range (232 ks) image reveals low-surface-brightness X-ray structure, which appears qualitatively similar to corresponding radio features. We consider the correlation between the X-ray and radio morphologies and its physical implications. After correcting for the inhomogeneous absorption across the remnant, we performed a point by point (4" resolution) surface brightness comparison between the X-ray and radio images. We find a strong (r = 0.75) log-log correlation, implying an overall relationship of $\log(\Sigma_{_{\rm X-ray}}) \propto (2.21\pm0.05) \times \log(\Sigma_{_{\rm radio}})$. This is consistent with proportionate partition (and possibly equipartition) between the local magnetic field and the hot gas --- implying that Cas A's plasma is fully turbulent and continuously amplifying the magnetic field.Comment: 8 pages with embedded bitmapped figures, Accepted by ApJ Letters 5/1/9

Optimal treatment for metastatic bladder cancer

Rak pęcherza moczowego z przerzutami jest chorobą prowadzącą do zgonu. Standardem leczenia pierwszej linii jest chemioterapia oparta na cisplatynie, podawanej w skojarzeniu z gemcytabiną oraz metotreksatem, winblastyną i doksorubicyną. Leczenie drugiej linii wykazuje niewielką skuteczność, nie wpływając na poprawę wyników. Stosowano też chemioterapię w skojarzeniu z lekami ukierunkowanymi na cele molekularne w obrębie szlaków sygnałowych związanych ze wzrostem, przeżyciem i proliferacją komórek, ale dotychczas nie potwierdzono istotnej korzyści klinicznej. Obiecujące okazało się modulowanie odpowiedzi immunologicznej gospodarza przeciwko antygenom nowotworowym, a obecnie wiele nowych sposobów terapii jest w trakcie badań. Metody sekwencjonowania nowej generacji zastosowane w przypadku inwazyjnych raków urotelialnych dostarczyły wielu nowych informacji dotyczących biologii choroby oraz potencjalnych celów terapeutycznych. W zaawansowanej chorobie obejmują one zmiany kinazy tyrozynowej receptora/szlaku Ras oraz kinazy fosfatydyloinozytolu 3/białkowej kinazy B/szlaku ssaczego celu rapamycyny, przy czym obecnie trwają badania nad rozwojem wielu nowych leków. Opublikowane ostatnio dane z obserwacji chorych na raka pęcherza moczowego w ramach Cancer Genome Atlas Research Network oraz inne badania sugerują, że mutacje w genach regulujących chromatynę są bardzo powszechne w przebiegu inwazyjnego raka pęcherza moczowego i występują częściej niż w innych nowotworach. Odkrycie nowych zmian genomowych stanowi wyzwanie dla procesu opracowywania nowych leków, mających na celu zmianę przebiegu choroby.Metastatic bladder cancer is a lethal disease. Cisplatin-based chemotherapy, including the combination regimens gemcitabine–cisplatin and methotrexate–vinblastine–doxorubicin–cisplatin, are the standard first-line therapies. Second- line therapies have modest activity and no significant improvement in patient outcomes. Agents targeting growth, survival, and proliferation pathways have been added to cytotoxic therapy with limited added benefit to date. Modulating host immune response to cancer-associated antigens appears promising, with multiple new therapeutic approaches being pursued. Next-generation sequencing of invasive urothelial carcinoma has provided insights into the biology of this disease and potential actionable targets. Alterations in the receptor tyrosine kinase/Ras pathway and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway represent potential therapeutic targets in advanced disease, and novel agents are in development. Recent data from the Cancer Genome Atlas Research Network bladder cancer cohort and other efforts suggest that mutations in chromatin-regulatory genes are very common in invasive bladder tumors, and are more frequent than in other studied tumors. The discovery of new genomic alterations challenges drug development to change the course of this disease

The Economic Impact of Non-Communicable Disease in China and India: Estimates, Projections, and Comparisons

The views expressed in this paper are those of the author(s) and not necessarily those of the Harvard Initiative for Global Health. The Program on the Global Demography of Aging receives funding from the National Institute on Aging, Grant No. 1 P30 AG024409-08

Hawks and Doves: Perceptions and Reality of Faculty Evaluations

OBJECTIVES: Internal medicine clerkship grades are important for residency selection, but inconsistencies between evaluator ratings threaten their ability to accurately represent student performance and perceived fairness. Clerkship grading committees are recommended as best practice, but the mechanisms by which they promote accuracy and fairness are not certain. The ability of a committee to reliably assess and account for grading stringency of individual evaluators has not been previously studied. METHODS: This is a retrospective analysis of evaluations completed by faculty considered to be stringent, lenient, or neutral graders by members of a grading committee of a single medical college. Faculty evaluations were assessed for differences in ratings on individual skills and recommendations for final grade between perceived stringency categories. Logistic regression was used to determine if actual assigned ratings varied based on perceived faculty\u27s grading stringency category. RESULTS: Easy graders consistently had the highest probability of awarding an above-average rating, and hard graders consistently had the lowest probability of awarding an above-average rating, though this finding only reached statistical significance only for 2 of 8 questions on the evaluation form ( CONCLUSIONS: Perceived differences in faculty grading stringency have basis in reality for clerkship evaluation elements. However, final grades recommended by faculty perceived as stringent or lenient did not differ. Perceptions of hawks and doves are not just lore but may not have implications for students\u27 final grades. Continued research to describe the hawk and dove effect will be crucial to enable assessment of local grading variation and empower local educational leadership to correct, but not overcorrect, for this effect to maintain fairness in student evaluations

Modelling, Design And Diagnostics For A Photoionised Plasma Experiment

Photoionised plasmas are common in astrophysical environments and new high resolution spectra from such sources have been recorded in recent years by the Chandra and XMM-Newton satellites. These provide a wealth of spectroscopic information and have motivated recent efforts aimed at obtaining a detailed understanding of the atomic-kinetic and radiative characteristics of photoionised plasmas. The Z-pinch facility at the Sandia National Laboratories is the most powerful terrestrial source of X-rays and provides an opportunity to produce photoionised plasmas in a well characterised radiation environment. We present modelling work and experimental design considerations for a forthcoming experiment at Sandia in which X-rays from a collapsing Z-pinch will be used to photoionise low density neon contained in a gas cell. View factor calculations were used to evaluate the radiation environment at the gas cell; the hydrodynamic characteristics of the gas cell were examined using the Helios-CR code, in particular looking at the heating, temperature and ionisation of the neon and the absorption of radiation. Emission and absorption spectra were also computed, giving estimates of spectra likely to be observed experimentally

Extrapolating non-target risk of Bt crops from laboratory to field

The tiered approach to assessing ecological risk of insect-resistant transgenic crops assumes that lower tier laboratory studies, which expose surrogate non-target organisms to high doses of insecticidal proteins, can detect harmful effects that might be manifested in the field. To test this assumption, we performed meta-analyses comparing results for non-target invertebrates exposed to Bacillus thuringiensis (Bt) Cry proteins in laboratory studies with results derived from independent field studies examining effects on the abundance of non-target invertebrates. For Lepidopteran-active Cry proteins, laboratory studies correctly predicted the reduced field abundance of non-target Lepidoptera. However, laboratory studies incorporating tri-trophic interactions of Bt plants, herbivores and parasitoids were better correlated with the decreased field abundance of parasitoids than were direct-exposure assays. For predators, laboratory tri-trophic studies predicted reduced abundances that were not realized in field studies and thus overestimated ecological risk. Exposure to Coleopteran-active Cry proteins did not significantly reduce the laboratory survival or field abundance of any functional group examined. Our findings support the assumption that laboratory studies of transgenic insecticidal crops show effects that are either consistent with, or more conservative than, those found in field studies, with the important caveat that laboratory studies should explore all ecologically relevant routes of exposure

HIV and early hospital readmission: evaluation of a tertiary medical facility in Lilongwe, Malawi

Abstract Background Delivery of quality healthcare in resource-limited settings is an important, understudied public health priority. Thirty-day (early) hospital readmission is often avoidable and an important indicator of healthcare quality. Methods We investigated the prevalence of all-cause early readmission and its associated factors using age and sex adjusted risk ratios (RR) and 95% confidence intervals (CI). A retrospective review of the medical ward database at Kamuzu Central Hospital in Lilongwe, Malawi was conducted between February and December 2013. Results There were 3547 patients with an index admission of which 2776 (74.4%) survived and were eligible for readmission. Among these patients: 49.7% were male, mean age was 39.7 years, 36.1% were HIV-positive, 34.6% were HIV-negative, and 29.3% were HIV-unknown. The prevalence of early hospital readmission was 5.5%. Diagnoses associated with 30-day readmission were HIV-positive status (RR = 2.41; 95% CI: 1.64–3.53) and malaria (RR = 0.45; 95% CI: 0.22–0.91). Other factors associated with readmission were multiple diagnoses (excluding HIV) (RR = 1.52; 95% CI: 1.11–2.06), and prolonged length of stay (≥ 16 days) at the index hospitalization (RR = 3.63; 95% CI: 1.72–7.67). Conclusion Targeting HIV-infected inpatients with multiple diagnoses and longer index hospitalizations may prevent early readmission and improve quality of care

RNA-controlled nucleocytoplasmic shuttling of mRNA decay factors regulates mRNA synthesis and a novel mRNA decay pathway

mRNA level is controlled by factors that mediate both mRNA synthesis and decay, including the 5' to 3' exonuclease Xrn1. Here we show that nucleocytoplasmic shuttling of several yeast mRNA decay factors plays a key role in determining both mRNA synthesis and decay. Shuttling is regulated by RNAcontrolled binding of the karyopherin Kap120 to two nuclear localization sequences (NLSs) in Xrn1, location of one ofwhich is conserved fromyeast to human. The decaying RNA binds and masks NLS1, establishing a link between mRNA decay and Xrn1 shuttling. Preventing Xrn1 import, either by deleting KAP120 or mutating the two Xrn1 NLSs, compromises transcription and, unexpectedly, also cytoplasmic decay, uncovering a cytoplasmic decay pathway that initiates in the nucleus.MostmRNAs are degraded by both pathways - the ratio between them represents a full spectrum. Importantly, Xrn1 shuttling is required for proper responses to environmental changes, e.g., fluctuating temperatures, involving proper changes in mRNA abundance and in cell proliferation rate