Multi-institution analysis of racial disparity among African- American men eligible for prostate cancer active surveillance

There is a significant controversy on whether race should be a factor in considering active surveillance for low-risk prostate cancer. To address this question, we analyzed a multi-institution database to assess racial disparity between African-American and White-American men with low risk prostate cancer who were eligible for active surveillance but underwent radical prostatectomy. A retrospective analysis of prospectively collected clinical, pathologic and oncologic outcomes of men with low-risk prostate cancer from seven tertiary care institutions that underwent radical prostatectomy from 2003–2014 were used to assess potential racial disparity. Of the 333 (14.8%) African-American and 1923 (85.2%) White-American men meeting active surveillance criteria, African-American men were found to be slightly younger (57.5 vs 58.5 years old; p = 0.01) and have higher BMI (29.3 v 27.9; p \u3c 0.01), pre-op PSA (5.2 v 4.7; p \u3c 0.01), and maximum percentage cancer on biopsy (15.1% v 13.6%; p \u3c 0.01) compared to White-American men. Univariate and multivariate analysis demonstrated similar rates of upgrading, upstaging, positive surgical margin, and biochemical recurrence between races. These results suggest that single institution studies recommending more stringent AS enrollment criteria for AA men with a low-risk prostate cancer may not capture the complete oncologic landscape due to institutional variability in cancer outcomes. Since all seven institutions demonstrated no significant racial disparity, current active surveillance eligibility should not be modified based upon race until a prospective study has been completed. © Dinizo et al

Vasoactive intestinal polypeptide mediates circadian rhythms in Mammalian olfactory bulb and olfaction

Accumulating evidence suggests that the olfactory bulbs (OBs) function as an independent circadian system regulating daily rhythms in olfactory performance. However, the cells and signals in the olfactory system that generate and coordinate these circadian rhythms are unknown. Using real-time imaging of gene expression, we found that the isolated olfactory epithelium and OB, but not the piriform cortex, express similar, sustained circadian rhythms in PERIOD2 (PER2). In vivo, PER2 expression in the OB of mice is circadian, approximately doubling with a peak around subjective dusk. Furthermore, mice exhibit circadian rhythms in odor detection performance with a peak at approximately subjective dusk. We also found that circadian rhythms in gene expression and odor detection performance require vasoactive intestinal polypeptide (VIP) or its receptor VPAC2R. VIP is expressed, in a circadian manner, in interneurons in the external plexiform and periglomerular layers, whereas VPAC2R is expressed in mitral and external tufted cells in the OB. Together, these results indicate that VIP signaling modulates the output from the OB to maintain circadian rhythms in the mammalian olfactory system.Fil: Kang Miller, Jae Eun. Washington University in St. Louis; Estados UnidosFil: Granados Fuentes, Daniel. Washington University in St. Louis; Estados UnidosFil: Wang, Thomas. Washington University in St. Louis; Estados UnidosFil: Marpegan, Luciano. Washington University in St. Louis; Estados Unidos. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Holy, Timothy E.. Washington University in St. Louis; Estados UnidosFil: Herzog, Erik D.. Washington University in St. Louis; Estados Unido

Flux Dendrites of Opposite Polarity in Superconducting MgB2_2 rings observed with magneto-optical imaging

Magneto-optical imaging was used to observe flux dendrites with opposite polarities simultaneously penetrate superconducting, ring-shaped MgB$_2$ films. By applying a perpendicular magnetic field, branching dendritic structures nucleate at the outer edge and abruptly propagate deep into the rings. When these structures reach close to the inner edge, where flux with opposite polarity has penetrated the superconductor, they occasionally trigger anti-flux dendrites. These anti-dendrites do not branch, but instead trace the triggering dendrite in the backward direction. Two trigger mechanisms, a non-local magnetic and a local thermal, are considered as possible explanations for this unexpected behaviour. Increasing the applied field further, the rings are perforated by dendrites which carry flux to the center hole. Repeated perforations lead to a reversed field profile and new features of dendrite activity when the applied field is subsequently reduced.Comment: 6 pages, 6 figures, accepted to Phys. Rev.

Loss of the tumor suppressor, Tp53, enhances the androgen receptor-mediated oncogenic transformation and tumor development in the mouse prostate.

Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 mutation are among the most frequently observed alterations in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess the molecular mechanisms for these genetic abnormalities. Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic human prostate cancer cells. These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors in comparison with mice harboring only the AR transgene. Histological analysis showed prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses identified a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. Master regulator analysis revealed SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a coregulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. Our data demonstrate a critical role of SOX2 in prostate tumorigenesis and provide mechanistic insight into prostate tumor aggressiveness and progression mediated by aberrant AR and p53 signaling pathways

Collecting Duct Renal Cell Carcinoma Found to Involve the Collecting System During Partial Nephrectomy: A Case Report

Collecting duct carcinoma (CDC) is a rare and aggressive form of renal cell carcinoma (RCC) arising from the principal cells of the collecting duct.  One third of cases present with metastatic disease, but many present in a manner similar to conventional RCC or urothelial carcinoma (UC).  We discuss a case of CDC which presented as a small mass at the cortico-medullary junction, and was discovered at robotic partial nephrectomy (RPN) to be grossly involving the collecting system. A 62-year-old man presented with a small renal mass suspicious for RCC, which was found on computed tomography (CT) after an episode of gross hematuria.  After thorough workup, RPN was attempted; however, intraoperatively the mass was found to be involving the collecting system.  Radical nephroureterectomy was performed, and the pathology report revealed CDC.  CDC is a rare and aggressive form of RCC.  While many cases are metastatic at diagnosis, most patients present with the incidental finding of a small renal mass.  There are no reports of a CDC involving the collecting system at RPN after negative ureteroscopy preoperatively.  The adjuvant therapeutic options for CDC are limited, and long term survival is poor

Fractional vortex lattice structures in spin triplet superconductors

Motivated by recent interest in spin triplet superconductors, we investigate the vortex lattice structures for this class of unconventional superconductors. We discuss how the order parameter symmetry can give rise to U(1)$\times$U(1) symmetry in same sense as in spinor condensates, making half-quantum vortices (HQV) topologically stable. We then calculate the vortex lattice structure of HQV's, with particular attention on the roles of the crystalline lattice, the Zeeman coupling, and Meissner screening, all absent in spinor condensates. Finally, we consider how spin-orbit coupling leads to a breakdown of the U(1)$\times$U(1) symmetry in free energy and whether the HQV lattice survives this symmetry breaking. As examples, we examine simpler spin-triplet models proposed in the context of NaxCoO2$\cdot$yH2O and Bechgaard salts, as well as the better known and more complex model for Sr2RuO4.Comment: 13 pages, 6 figures. The version published in New Journal of Physics focus issue on 'Superconductors with Exotic Symmetry' with added reference

Does race impact functional outcomes in patients undergoing robotic partial nephrectomy?

Background: The role of race on functional outcomes after robotic partial nephrectomy (RPN) is still a matter of debate. We aimed to evaluate the clinical and pathologic characteristics of African American (AA) and Caucasian patients who underwent RPN and analyzed the association between race and functional outcomes. Methods: Data was obtained from a multi-institutional database of patients who underwent RPN in 6 institutions in the USA. We identified 999 patients with complete clinical data. Sixty-three patients (6.3%) were AA, and each patient was matched (1:3) to Caucasian patients by age at surgery, gender, Charlson Comorbidity Index (CCI) and renal score. Bivariate and multivariate logistic regression analyses were used to evaluate predictors of acute kidney injury (AKI). Kaplan-Meier method and multivariable semiparametric Cox regression analyses were performed to assess prevalence and predictors of significant eGFR reduction during follow-up. Results: Overall, 252 patients were included. AA were more likely to have hypertension (58.7% Conclusions: Although African American patients were more likely to have hypertension, renal function outcomes of robotic partial nephrectomies were not significantly different when stratified by race. However, future studies with larger cohorts are necessary to validate these findings

Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue