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The National Institutes of Health leveled new focus on sex as a biological variable with the goal of understanding sex-specific differences in health and physiology. We previously published a functional assessment of the impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology (Ruetten H, Wegner KA, Zhang HL, Wang P, Sandhu J, Sandhu S, Mueller B, Wang Z, Macoska J, Peterson RE, Bjorling DE, Ricke WA, Marker PC, Vezina CM. Am J Physiol Renal Physiol 317: F996–F1009, 2019). Here, we measured and compared five characteristics of urethral histology (urethral lumen diameter and area, epithelial cell count, epithelial and rhabdosphincter thickness, epithelial cell area, and total urethral area) in male and female 9-wk-old C57BL/6J mice using hematoxylin and eosin staining. We also compared male mice with castrated male mice, male and female mice treated with the steroid 5α-reductase inhibitor finasteride or testosterone, or male mice harboring alleles ( Pbsn4cre/+; R26RDta/+) that reduce prostate lobe mass. The three methods used to reduce prostate mass (castration, finasteride, and Pbsn4cre/+; R26RDta/+) changed urethral histology, but none feminized male urethral histology (increased urethral epithelial area). Exogenous testosterone caused increased epithelial cell count in intact females but did not masculinize female urethral histology (decrease epithelial area). Our results lay a critical foundation for future studies as we begin to parse out the influence of hormones and cellular morphology on male and female urinary function.

Benign prostatic hyperplasia/lower urinary tract dysfunction (LUTD) affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging paradigms about when this disease process begins. We delivered a single dose of a widespread environmental contaminant present in the serum of most Americans [2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 1 µg/kg], and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues, and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood., Summary: We describe a new mechanism of benign prostate disease, initiated by fetal chemical exposure, which durably increases prostatic noradrenergic axon density and causes smooth muscle hyperactivity and urinary voiding dysfunction.

Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (∼85-95%), with approximately 5-15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized a Kras-driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-KrasG12D ; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant KrasG12D gene. Although the driver gene mutation KrasG12D is present in anus of both sexes, only female KC mice develop Kras-mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.

In RPA V-VI glioblastoma patients both hypofractionated radiotherapy and exclusive temozolomide can be used; the purpose of this trial is to compare these treatment regimens in terms of survival and quality of life. Patients with histologic diagnosis of glioblastoma were randomized to hypofractionated radiotherapy (RT–30 Gy in 6 fractions) and exclusive chemotherapy (CHT–emozolomide 200 mg/m2/day 5 days every 28 days). Overall (OS) and progression free survival (PFS) were evaluated with Kaplan Maier curves and correlated with prognostic factors. Quality- adjusted survival (QaS) was evaluated according to the Murray model (Neurological Sign and Symptoms–NSS) From 2010 to 2015, 31 pts were enrolled (CHT: 17 pts; RT: 14pts). Four pts were excluded from the analysis. RPA VI (p = 0.048) and absence of MGMT methylation (p = 0.001) worsened OS significantly. Biopsy (p = 0.048), RPA class VI (p = 0.04) and chemotherapy (p = 0.007) worsened PFS. In the two arms the initial NSS scores were overlapping (CHT: 12.23 and RT: 12.30) and progressively decreased in both group and became significantly worse after 5 months in CHT arm (p = 0.05). Median QaS was 104 days and was significantly better in RT arm (p = 0.01). The data obtained are limited by the poor accrual. Both treatments were well tolerated. Patients in RT arm have a better PFS and QaS, without significant differences in OS. The deterioration of the NSS score would seem an important parameter and coincide with disease progression rather than with the toxicity of the treatment.

Non-invasive tests to identify age and early disease-associated pathology within the kidney are needed. Specific populations of urinary extracellular vesicles (EVs) could potentially be used for such a diagnostic test. Random urine samples were obtained from age- and sex-stratified living kidney donors before kidney donation. A biopsy of the donor kidney was obtained at the time of transplantation to identify nephron hypertrophy (larger glomerular volume, cortex per glomerulus and mean profile tubular area) and nephrosclerosis (% fibrosis, % glomerulosclerosis and arteriosclerosis). Renal parenchymal-derived EVs in cell-free urine were quantified by digital flow cytometry. The relationship between these EV populations and structural pathology on the kidney biopsy was assessed. Clinical characteristics of the kidney donors (n=138, age range: 20–70 years, 50% women) were within the normative range. Overall, urine from women contained more EVs than that from men. The number of exosomes, juxtaglomerular cells and podocyte marker–positive EVs decreased (p

On the wake of the results obtained so far at the SPARC_LAB test-facility at the Laboratori Nazionali di Frascati (Italy), we are currently investigating the possibility to design and build a new multi-disciplinary user-facility, equipped with a soft X-ray Free Electron Laser (FEL) driven by a ∼ 1 GeV high brightness linac based on plasma accelerator modules. This design study is performed in synergy with the EuPRAXIA design study. In this paper we report about the recent progresses in the on going design study of the new facility. On the wake of the results obtained so far at the SPARC\_LAB test-facility at the Laboratori Nazionali di Frascati (Italy), we are currently investigating the possibility to design and build a new multi-disciplinary user-facility, equipped with a soft X-ray Free Electron Laser (FEL) driven by a $\sim$1 GeV high brightness linac based on plasma accelerator modules. This design study is performed in synergy with the EuPRAXIA design study. In this paper we report about the recent progresses in the on going design study of the new facility.

The implementation of a real-time 16-kb/s speech codec is described, which has been tailored to the specific needs of digital mobile radio. The source coder belongs to the class of split-band adaptive predictive coders (SB-APC) and uses vector quantization (VQ) and dynamic bit-allocation. The transmitter and receiver ends have been implemented on a single board by using one TMS32020 digital signal processor for protection against errors, has been ensured by using a combination of a Golay code and a Hamming code as a forward-error-correcting code (FEC). The FEC algorithm has been implemented on an additional board with the same kind of digital signal processor as the speech codec. >

We show by numerical simulations a procedure for the evaluation of the size (area or volume) of an elastic inclusion in an elastic body by means of work data measurements collected from the exterior. In this paper we focus especially on the case when the unknown inclusion is harder than the surrounding material. The computations are performed both in a 2-D and in a 3-D setting.