Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Trends in Residency Academic Productivity of Ophthalmic Plastic and Reconstructive Surgery Fellows Between 2012 and 2019.

PURPOSE: To characterize research productivity of ophthalmic plastic and reconstructive surgery (OPRS) fellows during residency. METHODS: A database was compiled of OPRS fellows listed on the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) Annual Fall Scientific Symposium program books who began their fellowship between 2012 and 2019. PubMed was searched for all publications published between July 1st of the year they began residency and September 30th of the year they began fellowship training. Bibliometric variables captured for each fellow included: the number of publications, first-author publications, and ophthalmology-related publications. RESULTS: A total of 197 OPRS fellows who began their fellowship training between 2012 and 2019 published a mean (± SD) of 2.42 ± 2.80 publications, 1.43 ± 1.85 first-author publications, and 2.33 ± 2.74 ophthalmology-related publications during residency. Linear regression revealed that the number of publications ( P < 0.001), first-author publications ( P < 0.001), and ophthalmology-related publications ( P < 0.001) that OPRS fellows published during residency have all significantly increased over the time assessed. CONCLUSIONS: The academic productivity of OPRS fellows during residency was quantified through bibliometric analysis to establish a national benchmark for the benefit of both prospective applicants and program directors. Residency research output of OPRS fellows has significantly increased between 2012 and 2019. Since ASOPRS program requirements necessitate academic productivity and thesis completion, publication records and involvement in research become valuable considerations when evaluating fellowship applicants. The knowledge of what accepted fellows have published provides the opportunity to make historical comparisons and may prove useful in the evaluation of the competitiveness of a given year's applicant pool.

Anatomic Variation of Sacral Mesh Attachment During Minimally Invasive Sacrocolpopexy.

IMPORTANCE: Although anatomic level of mesh attachment to the sacrum varied during minimally invasive sacrocolpopexy with a large proportion above S1, this was not associated with pelvic organ prolapse recurrence. OBJECTIVE: This study aimed to describe the anatomic level of sacral mesh attachment and its association with prolapse recurrence after minimally invasive sacrocolpopexy. STUDY DESIGN: This study included a retrospective cohort of women who underwent minimally invasive sacrocolpopexy with subsequent abdominal and pelvic imaging (magnetic resonance imaging or computed tomography) between 2010 and 2019 at a single academic institution. Anatomic level of attachment was determined by a radiologist. Prolapse recurrence was defined as a composite of self-reported bulge symptoms, any prolapse measure beyond the hymen, and any retreatment with pessary or surgery. χ 2 Tests were used for comparative outcomes. RESULTS: Analyses included 212 women. The mean ± SD age was 58.8 ± 9.9 years, the majority have preoperative stage III/IV prolapse (81.1%), and the median follow-up was 269 days (interquartile range, 57-825 days). Mesh was attached using titanium tacks (n = 136 [64.2%]) and suture (n = 76 [35.8%]) at the level of the L5-S1 intervertebral space (n = 113 [53.3%]) or overlying S1 (n = 89 [42.0%]).The surgical approach was significantly associated with attachment location with a greater proportion of laparoscopy cases demonstrating mesh attachment above S1 (85 [62.5%] vs robotically, 30 [39.5%]; P < 0.01). Dichotomized level of attachment was not associated with composite prolapse recurrence (above S1, n = 18 [22.2%] vs below S1, n = 24 [24.7%]; P = 0.69) or any compartment recurrence ( P ≥ 0.36). CONCLUSIONS: Mesh was primarily attached to the anterior longitudinal ligament at the level of the L5-S1 intervertebral space or S1. Level of mesh attachment was not associated with composite prolapse recurrence.