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

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

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

The clinical significance of tumor infiltrating lymphoctyes in breast cancer: does subtype matter?

Tumor infiltrating lymphocytes (TILs) are commonly detected in breast tumors but their bearing on disease outcome is uncertain. The importance of TILs appears to be subtype-specific and varies depending on the histologic characteristics of the tumor. As our understanding of tumorigenesis is increasing the relevance of immunobiology will become apparent

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care

AGES observations of Abell1367 and its outskirts

The Arecibo Galaxy Environment Survey (AGES, Auld et al. 2006) will map ~200 square degrees over the next years using the ALFA feed array at the 305-m Arecibo Telescope. AGES is specifically designed to investigate various galactic environments from local voids to interacting groups and cluster of galaxies. AGES will map 20 square degrees in the Coma-Abell1367 supercluster including the Abell cluster 1367 and its outskirts (up to ~2 virial radii). In Spring 2006 we nearly completed the observations of 5 square degrees in the range 11:34< RA< 11:54, 19:20<Dec<20:20 covering all the cluster core and part of its infalling region reaching a 5 sigma detection limit of M(HI)~4×10(8)Mxs2299 (assuming a velocity width ~200 km~s(−1)) at the distance of Abell1367 (~92 Mpc). An HI selected sample has been extracted from the datacube obtaining a catalogue of fluxes, recessional velocities, positions and velocity widths. We present a preliminary analysis of the properties of the HI sources and report the discovery of HI diffuse features within interacting groups at the periphery of Abell1367