No abstract

The canonical Wnt signaling pathway is of paramount importance in development and disease. An emergent question is whether the upstream cascade of the canonical Wnt pathway has physiologically relevant roles beyond β-catenin-mediated transcription, which is difficult to study due to the pervasive role of this protein. Here, we show that transcriptionally silent spermatozoa respond to Wnt signals released from the epididymis and that mice mutant for the Wnt regulator Cyclin Y-like 1 are male sterile due to immotile and malformed spermatozoa. Post-transcriptional Wnt signaling impacts spermatozoa through GSK3 by (1) reducing global protein poly-ubiquitination to maintain protein homeostasis; (2) inhibiting septin 4 phosphorylation to establish a membrane diffusion barrier in the sperm tail; and (3) inhibiting protein phosphatase 1 to initiate sperm motility. The results indicate that Wnt signaling orchestrates a rich post-transcriptional sperm maturation program and invite revisiting transcription-independent Wnt signaling in somatic cells as well.

No abstract

E 6 4 7What ' s known on the subject? and What does the study add? Different spacing agents have been tested to reduce incidential radiation exposure of the rectum during radiotherapy to the prostate. These agents all had certain drawbacks; either the created space was too small or the agents used did not stay in place during radiotherapy treatment.The study describes the transperineal injection technique of a spacing agent in detail. Furthermore it shows the safety and effi cacy of the spacing hydrogel used and shows that it overcomes some of the drawbacks of the previously examined spacing agents. OBJECTIVE• To describe the technique used to apply a hydrogel spacer between the prostate and rectum so as to decrease the radiation dose to the rectum in patients with prostate cancer who are undergoing radiotherapy. METHODS• A prospective study evaluating the safety and effi cacy of prostate -rectum spacer injection was conducted in 29 male patients with prostate cancer scheduled for radiotherapy.• Spacing hydrogel was injected into the perirectal space using a transperineal approach under real-time transrectal ultrasonography guidance.• With the needle tip positioned beyond the rectourethralis muscle, saline injection opened the space between Denonvilliers ' fascia and the anterior rectal wall, allowing needle advancement to the mid-prostate without rectal wall injury. Injection of hydrogel precursors further opened this space, which was then maintained as a result of hydrogel polymerization.• Procedure duration and adverse events were monitored. Computed tomography and/or magnetic resonance imaging simulation scans were performed before and after injection. The hydrogel-created space was measured and the reduction in percent volume of the rectum receiving at least 70 Gy (rectal V70) was determined. RESULTS• Hydrogel injection resulted in mean ( SD ) additional prostate -rectum space relative to baseline of 9.87 (5.92) mm.• The mean ( SD ) procedure time, as measured by needle insertion and removal, was 6.3 (3.2) min.• The relative reduction in rectal V70 was 60.6%.• There were no unanticipated adverse events associated with the hydrogel procedure or the hydrogel. CONCLUSIONS• Hydrogel spacer injection using hydrodissection is a fast and effective procedure to separate the rectal wall from the prostate in order to avoid rectal toxicity.• Hydrogel spacer injection resulted in the addition of ∼ 1 cm of space • Computed incidental radiation exposure, the rectal V70, was substantially reduced.

No abstract

Purpose: Magnetic resonance imaging-guided transurethral ultrasound ablation uses directional thermal ultrasound under magnetic resonance imaging thermometry feedback control for prostatic ablation. We report 12-month outcomes from a prospective multicenter trial (TACT). Materials and Methods: A total of 115 men with favorable to intermediate risk prostate cancer across 13 centers were treated with whole gland ablation sparing the urethra and apical sphincter. The co-primary 12-month endpoints were safety and efficacy. Results: In all, 72 (63%) had grade group 2 and 77 (67%) had NCCNÒ intermediate risk disease. Median treatment delivery time was 51 minutes with 98% (IQR 95e99) thermal coverage of target volume and spatial ablation precision of AE1.4 mm on magnetic resonance imaging thermometry. Grade 3 adverse events occurred in 9 (8%) men. The primary endpoint (U.S. Food and Drug Administration mandated) of prostate specific antigen reduction !75% was achieved in 110 of 115 (96%) with median prostate specific antigen reduction of 95% and nadir of 0.34 ng/ml. Median prostate volume decreased from 37 to 3 cc. Among 68 men with pretreatment grade group 2 disease, 52 (79%) were free of grade group 2 disease on 12-month biopsy. Of 111 men with 12-month biopsy data, 72 (65%) had no evidence of cancer. Erections (International Index of Erectile Function question 2 score 2 or greater) were maintained/regained in 69 of 92 (75%). Multivariate predictors of persistent grade group 2 at 12 months included intraprostatic calcifications at screening, suboptimal magnetic resonance imaging thermal coverage of target volume and a PI-RADSÔ 3 or greater lesion at 12-month magnetic resonance imaging (p <0.05). Conclusions: The TACT study of magnetic resonance imaging-guided transurethral ultrasound whole gland ablation in men with localized prostate cancer

Intratumoural heterogeneity (ITH) is a major cause of cancer-associated lethality. Extensive genomic ITH has previously been reported in clear cell renal cell carcinoma (ccRCC). Here we address the question whether ITH increases with malignant progression and can hence be exploited as a prognostic marker. Unexpectedly, precision quantitative image analysis reveals that the degree of functional ITH is virtually identical between primary ccRCCs of the lowest stage and advanced, metastatic tumours. Functional ITH was found to show a stage-independent topological pattern with peak proliferative and signalling activities almost exclusively in the tumour periphery. Exome sequencing of matching peripheral and central primary tumour specimens reveals various region-specific mutations. However, these mutations cannot directly explain the zonal pattern suggesting a role of microenvironmental factors in shaping functional ITH. In conclusion, our results indicate that ITH is an early and general characteristic of malignant growth rather than a consequence of malignant progression.

No abstract