use of bone health agents bhas in patients pts with metastatic castration resistant prostate cancer mcrpc treated with radium 223 ra 223 after abiraterone abi an interim review of reassure

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Impact of hormonal therapy on the detection of promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1) in prostate cancer

BACKGROUND: In spite of excellent cure rates for prostate cancer patients with favorable tumor characteristics, patients with unfavorable characteristics after radical prostatectomy are still at a significantly increased risk of tumor progression. Early adjuvant hormonal therapy (AHT) has been shown to be of prognostic benefit in these patients. Unfortunately initiation and duration of early AHT in the individual patient is based on statistic data. PSA, as the standard prostate marker is neither able to reliably indicate minimal residual tumor disease in the early postoperative phase, nor can it be used for therapy monitoring due to the suppressive effect of hormonal therapy on PSA production. Promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1-HM) has been shown to be the most common DNA alteration of primary prostatic carcinoma which, when used as a marker, is supposed to be able to overcome some of the disadvantages of PSA. However until now information on the impact of hormonal therapy on the detection of GSTP1-HM is lacking. The purpose of our study was to assess the impact of endocrine therapy on the detection of GSTP1-HM by methylation-specific PCR (MSP) in prostate cancer. METHODS: Paraffin embedded tumor samples from the radical prostatectomy (RP) specimens from 15 patients after hormonal therapy (HT) (mean 8 months) were assessed by MSP. In 8 of the patients the GSTP-1 status of the tumors before HT was assessed on the corresponding initial diagnostic biopsies. RESULTS: Following HT MSP showed GSTP1-HM in 13/15 of the RP specimens. In two patients analysis of the RP specimens failed to show GSTP1-HM. All initial tumor samples (8/8 biopsy specimens) showed GSTP1-HM, including both patients negative for GSTP1 HM in the corresponding RP specimen. CONCLUSION: In most cases hormonal therapy appears to not alter GSTP1 HM detection. However the change from a positive to a negative GSTP1 HM status in a subset of the patients may point to an, at least partial androgen dependency. Further studies on a larger cohort of patients are necessary to assess its frequency and the exact hormonal interactions

Molecular dissection of Penelope transposable element regulatory machinery

© 2008 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in Nucleic Acids Research 36 (2008): 2522-2529, doi:10.1093/nar/gkm1166Penelope-like elements (PLEs) represent a new class of retroelements identified in more than 80 species belonging to at least 10 animal phyla. Penelope isolated from Drosophila virilis is the only known transpositionally active representative of this class. Although the size and structure of the Penelope major transcript has been previously described in both D. virilis and D. melanogaster transgenic strains, the architecture of the Penelope regulatory region remains unknown. In order to determine the localization of presumptive Penelope promoter and enhancer-like elements, segments of the putative Penelope regulatory region were linked to a CAT reporter gene and introduced into D. melanogaster by P-element-mediated transformation. The results obtained using ELISA to measure CAT expression levels and RNA studies, including RT–PCR, suggest that the active Penelope transposon contains an internal promoter similar to the TATA-less promoters of LINEs. The results also suggest that some of the Penelope regulatory sequences control the preferential expression in the ovaries of the adult flies by enhancing expression in the ovary and reducing expression in the carcass. The possible significance of the intron within Penelope for the function and evolution of PLEs, and the effect of Penelope insertions on adjacent genes, are discussed.This work was supported by grants from Russian Academy of Sciences (Cell and Molecular Biology to M.E.), and Welcome Trust Grant (075698) to M.E and D.J.F

A molecularly characterized preclinical platform of subcutaneous renal cell carcinoma (RCC) patient-derived xenograft models to evaluate novel treatment strategies

Renal cell carcinoma (RCC) is a kidney cancer with an onset mainly during the sixth or seventh decade of the patient’s life. Patients with advanced, metastasized RCC have a poor prognosis. The majority of patients develop treatment resistance towards Standard of Care (SoC) drugs within months. Tyrosine kinase inhibitors (TKIs) are the backbone of first-line therapy and have been partnered with an immune checkpoint inhibitor (ICI) recently. Despite the most recent progress, the development of novel therapies targeting acquired TKI resistance mechanisms in advanced and metastatic RCC remains a high medical need. Preclinical models with high translational relevance can significantly support the development of novel personalized therapies. It has been demonstrated that patient-derived xenograft (PDX) models represent an essential tool for the preclinical evaluation of novel targeted therapies and their combinations. In the present project, we established and molecularly characterized a comprehensive panel of subcutaneous RCC PDX models with well-conserved molecular and pathological features over multiple passages. Drug screening towards four SoC drugs targeting the vascular endothelial growth factor (VEGF) and PI3K/mTOR pathway revealed individual and heterogeneous response profiles in those models, very similar to observations in patients. As unique features, our cohort includes PDX models from metastatic disease and multi-tumor regions from one patient, allowing extended studies on intra-tumor heterogeneity (ITH). The PDX models are further used as basis for developing corresponding in vitro cell culture models enabling advanced high-throughput drug screening in a personalized context. PDX models were subjected to next-generation sequencing (NGS). Characterization of cancer-relevant features including driver mutations or cellular processes was performed using mutational and gene expression data in order to identify potential biomarker or treatment targets in RCC. In summary, we report a newly established and molecularly characterized panel of RCC PDX models with high relevance for translational preclinical research

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project

Purpose: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). Methods: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. Results: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. Conclusion: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice

Quantitative real-time RT-PCR of CD24 mRNA in the detection of prostate cancer

BACKGROUND: Gene expression profiling has recently shown that the mRNA for CD24 is overexpressed in prostate carcinomas (Pca) compared to benign or normal prostate epithelial tissues. Immunohistochemical studies have reported the usefulness of anti-CD24 for detecting prostate cancer over the full range of prostate specimens encountered in surgical pathology, e.g. needle biopsies, transurethral resection of prostate chips, or prostatectomies. It is a small mucin-like cell surface protein and thus promises to become at least a standard adjunctive stain for atypical prostate biopsies. We tested the usefulness of real-time RT-PCR for specific and sensitive detection of CD24 transcripts as a supplementary measure for discriminating between malignant and benign lesions in prostatic tissues. METHODS: Total RNA was isolated from snap-frozen chips in 55 cases of benign prostatic hyperplasia (BPH) and from frozen sections in 59 prostatectomy cases. The latter contain at least 50% malignant epithelia. Relative quantification of CD24 transcripts was performed on the LightCycler instrument using hybridization probes for detection and porphobilinogen deaminase transcripts (PBGD) for normalization. RESULTS: Normalized CD24 transcript levels showed an average 2.69-fold increase in 59 Pca-cases (mean 0.21) when compared to 55 cases of BPH (mean 0.08). This difference was highly significant (p < 0.0001). The method has a moderate specificity (47.3%) but a high sensitivity (86.4%) if the cutoff is set at 0.0498. CD24 expression levels among Pca cases were not statistically associated with the tumor and lymph-node stage, the grading (WHO), the surgical margins, or the Gleason score. CONCLUSION: The present study demonstrates the feasibility of quantitative CD24 RNA transcript detection in prostatic tissues even without previous laser microdissection

Awareness and perception of multidrug-resistant organisms and antimicrobial therapy among internists vs. surgeons of different specialties: Results from the German MR2 Survey

Background: Recently, antibiotic resistance rates have risen substantially and care for patients infected with multidrug-resistant organisms (MDRO) has become a common problem in most in &#8211; and outpatient settings. The objectives of the study were to compare the awareness, perception, and knowledge of MDRO and rational antibiotic use between physicians from different medical specialties in German hospitals. Methods: A 35-item questionnaire was sent to specialists in internal medicine (internists), gynecologists, urologists, and general surgeons (non-internists) in 18 German hospitals. Likert-scales were used to evaluate awareness and perception of personal performance regarding care for patients infected with MDRO and rational use of antibiotics. Additionally, two items assessing specific knowledge in antibiotic therapy were included. The impact of medical specialty on four predetermined endpoints was assessed by multivariate logistic regression. Results: 43.0 (456/1061) of recipients responded. Both internists and non-internists had low rates of training in antibiotic stewardship. 50.8 of internists and 58.6 of non-internists had attended special training in rational antibiotic use or care for patients infected with MDRO in the 12 months prior to the study. Internists deemed themselves more confidently to choose the indications for screening patients for colonization with methicillin-resistant Staphylococcus aureus (P=0.004) and to initiate adequate infection control measures (P=0.002) than other specialties. However, there was no significant difference between internists and other specialists regarding the two items assessing specific knowledge in antibiotic therapy and infection control. Conclusion: Among the study participants, a considerable need for advanced training in the study subjects was seen, regardless of the medical specialty

Expression of Drosophila virilis Retroelements and Role of Small RNAs in Their Intrastrain Transposition

Transposition of two retroelements (Ulysses and Penelope) mobilized in the course of hybrid dysgenesis in Drosophila virilis has been investigated by in situ hybridization on polytene chromosomes in two D. virilis strains of different cytotypes routinely used to get dysgenic progeny. The analysis has been repeatedly performed over the last two decades, and has revealed transpositions of Penelope in one of the strains, while, in the other strain, the LTR-containing element Ulysses was found to be transpositionally active. The gypsy retroelement, which has been previously shown to be transpositionally inactive in D. virilis strains, was also included in the analysis. Whole mount is situ hybridization with the ovaries revealed different subcellular distribution of the transposable elements transcripts in the strains studied. Ulysses transpositions occur only in the strain where antisense piRNAs homologous to this TE are virtually absent and the ping-pong amplification loop apparently does not take place. On the other hand small RNAs homologous to Penelope found in the other strain, belong predominantly to the siRNA category (21nt), and consist of sense and antisense species observed in approximately equal proportion. The number of Penelope copies in the latter strain has significantly increased during the last decades, probably because Penelope-derived siRNAs are not maternally inherited, while the low level of Penelope-piRNAs, which are faithfully transmitted from mother to the embryo, is not sufficient to silence this element completely. Therefore, we speculate that intrastrain transposition of the three retroelements studied is controlled predominantly at the post-transcriptional level

Key informants' perspectives on teacher learning in Scotland

This article outlines the policy context for teachers' learning and continuing professional development in Scotland and considers this in relation to the perspectives of key informants gained through interview. The analysis draws on a triple-lens conceptual framework and points to some interesting contradictions between the policy text and the expressed aspirations of the interviewees. Current policy and the associated structural arrangements are viewed as broadly positive, but interviewees express concerns that an unintended emphasis on contractual arrangements might inhibit the more transformative elements of professional learning