High-Grade Prostate Cancer: Favorable Results in the Modern Era Regardless of Initial Treatment

Purpose. We performed a retrospective study to determine the outcome of a modern cohort of patients with high-grade (Gleason score ≥ 8) prostate cancer treated with radical prostatectomy, radiation therapy, or hormone therapy. Methods. We identified 404 patients in the South Texas Veteran's Healthcare System Tumor Registry diagnosed with high grade prostate cancer between 1998 and 2008. Mean follow-up was 4.62 ± 2.61 years. End points were biochemical failure-free survival, overall survival, metastasis-free survival, and cancer-specific survival. Results. 5-year overall survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 88.9%, 76.3%, and 58.9%, respectively. 5-year metastasis-free survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 96.8%, 96.6%, and 88.4%, respectively, and 5-year cancer-specific survival was 97.2%, 100%, and 89.9%, respectively. Patients with a Gleason score of 10 and pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year biochemical failure-free and cancer-specific survival. Patients with a pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year overall survival. Discussion. Even for patients with high-grade disease, the outcome is not as dire in the modern era regardless of primary treatment modality chosen. While there is room for improvement, we should not have a nihilistic impression of how these patients will respond to treatment

Preservation of endopelvic fascia, puboprostatic ligaments, dorsal venous complex and hydrodissection of the neurovascular bundles during robot-assisted radical prostatectomy: a video demonstration and propensity score matched outcomes

Introduction: We sought to report the oncologic and functional outcomes of endopelvic fascia (EPF), puboprostatic ligaments (PPL), and dorsal venous complex (DVC) preservation with hydrodissection of the neurovascular bundles (NVB) during robot-assisted radical prostatectomy (RARP). Materials and Methods: A retrospective review of our prospectively maintained prostate cancer database was performed. Patients who underwent bilateral or unilateral nerve sparing were identified. Propensity score matching was performed in a ratio of 1:1.6 between new technique (Group 1) and a historical group (Group 2). Data were reviewed for perioperative, oncologic, and functional outcomes. Cumulative incidence curves were used to depict perfect continence (0 pads), social continence (0-1 pads), and potency (SHIM≥17 with or without erectile aids). Multivariate models were used to elicit variables associated with continence and potency. Results: 76 patients in Group 1 and 126 patients in Group 2 were included. Median follow up was 17 months. Group 1 showed higher perfect continence rates at 1 month (9% vs 3%), 3 months (24% vs 19%), and 6 months (54% vs 34%) compared to Group 2 respectively (log rank p\u3c0.01). Group 1 also showed higher social continence rates at 1 month (15% vs 3%), 3 months (77% vs 32%), and 6 months (87% vs 53%) compared to Group 2 respectively (log rank p\u3c0.01). Group 1 had a similar potency rate compared to Group 2 (log rank p=0.25). Multivariate analysis showed that Group 1 was associated with improved perfect (Possibility ratio (PR) 1.82, 95% CI 1.29–2.58, p\u3c0.01) and social continence (PR 2.54, 95% CI 1.83 – 3.52, p\u3c0.01), but not potency. Conclusions: EPF, PPL, and DVC preservation with hydrodissection of the NVB offered similar oncological outcomes, but earlier and improved urinary continence rates compared to standard dissection

Meiosis-Specific Loading of the Centromere-Specific Histone CENH3 in Arabidopsis thaliana

Centromere behavior is specialized in meiosis I, so that sister chromatids of homologous chromosomes are pulled toward the same side of the spindle (through kinetochore mono-orientation) and chromosome number is reduced. Factors required for mono-orientation have been identified in yeast. However, comparatively little is known about how meiotic centromere behavior is specialized in animals and plants that typically have large tandem repeat centromeres. Kinetochores are nucleated by the centromere-specific histone CENH3. Unlike conventional histone H3s, CENH3 is rapidly evolving, particularly in its N-terminal tail domain. Here we describe chimeric variants of CENH3 with alterations in the N-terminal tail that are specifically defective in meiosis. Arabidopsis thaliana cenh3 mutants expressing a GFP-tagged chimeric protein containing the H3 N-terminal tail and the CENH3 C-terminus (termed GFP-tailswap) are sterile because of random meiotic chromosome segregation. These defects result from the specific depletion of GFP-tailswap protein from meiotic kinetochores, which contrasts with its normal localization in mitotic cells. Loss of the GFP-tailswap CENH3 variant in meiosis affects recruitment of the essential kinetochore protein MIS12. Our findings suggest that CENH3 loading dynamics might be regulated differently in mitosis and meiosis. As further support for our hypothesis, we show that GFP-tailswap protein is recruited back to centromeres in a subset of pollen grains in GFP-tailswap once they resume haploid mitosis. Meiotic recruitment of the GFP-tailswap CENH3 variant is not restored by removal of the meiosis-specific cohesin subunit REC8. Our results reveal the existence of a specialized loading pathway for CENH3 during meiosis that is likely to involve the hypervariable N-terminal tail. Meiosis-specific CENH3 dynamics may play a role in modulating meiotic centromere behavior

Epidemiology of Chlamydia trachomatis in the Middle East and north Africa: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: The epidemiology of Chlamydia trachomatis in the Middle East and north Africa is poorly understood. We aimed to provide a comprehensive epidemiological assessment of C trachomatis infection in the Middle East and north Africa. METHODS: We did a systematic review of C trachomatis infection as well as a meta-analysis and meta-regression of C trachomatis prevalence. We searched PubMed and Embase, as well as regional and national databases up to March 13, 2019, using broad search terms with no language or year restrictions. Any document or report including biological measures for C trachomatis prevalence or incidence was eligible for inclusion. We extracted all measures of current (genital or rectal), recent, and ever infection with C trachomatis. We estimated pooled average prevalence in different populations using random-effects meta-analysis. Factors associated with prevalence and sources of between-study heterogeneity were determined using meta-regression. FINDINGS: We identified a total of 1531 citations, of which 255 reports contributed to 552 C trachomatis prevalence measures from 20 countries. No incidence measures were identified. Pooled prevalence of current genital infection was 3·0% (95% CI 2·3-3·8) in general populations, 2·8% (1·0-5·2) in intermediate-risk populations, 13·2% (7·2-20·7) in female sex workers, 11·3% (9·0-13·7) in infertility clinic attendees, 12·4% (7·9-17·7) in women with miscarriage, 12·4% (9·4-15·7) in symptomatic women, and 17·4% (12·5-22·8) in symptomatic men. Pooled prevalence of current rectal infection was 7·7% (4·2-12·0) in men who have sex with men. Substantial between-study heterogeneity was found. Multivariable meta-regression explained 29·0% of variation. Population type was most strongly associated with prevalence. Additional associations were found with assay type, sample size, country, and sex, but not with sampling methodology or response rate (about 90% of studies used convenience sampling and >75% had unclear response rate). There was no evidence for temporal variation in prevalence between 1982 and 2018. INTERPRETATION: C trachomatis prevalence in the Middle East and north Africa is similar to other regions, but higher than expected given its sexually conservative norms. High prevalence in infertility clinic attendees and in women with miscarriage suggests a potential role for C trachomatis in poor reproductive health outcomes in this region. FUNDING: National Priorities Research Program from the Qatar National Research Fund (a member of Qatar Foundation)

Drebrin-mediated microtubule-actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection

Neuronal migration from a germinal zone to a final laminar position is essential for the morphogenesis of neuronal circuits. While it is hypothesized that microtubule–actomyosin crosstalk is required for a neuron's ‘two-stroke' nucleokinesis cycle, the molecular mechanisms controlling such crosstalk are not defined. By using the drebrin microtubule–actin crosslinking protein as an entry point into the cerebellar granule neuron system in combination with super-resolution microscopy, we investigate how these cytoskeletal systems interface during migration. Lattice light-sheet and structured illumination microscopy reveal a proximal leading process nanoscale architecture wherein f-actin and drebrin intervene between microtubules and the plasma membrane. Functional perturbations of drebrin demonstrate that proximal leading process microtubule–actomyosin coupling steers the direction of centrosome and somal migration, as well as the switch from tangential to radial migration. Finally, the Siah2 E3 ubiquitin ligase antagonizes drebrin function, suggesting a model for control of the microtubule–actomyosin interfaces during neuronal differentiation