Is the Toxicity of Salvage Prostatectomy Related to the Primary Prostate Cancer Therapy Received?

PURPOSE: To compare the toxicity profile and oncological outcome of salvage radical prostatectomy (SRP) following focal therapy (FT) versus SRP after radiation therapies (RT) - external beam radiation therapy (EBRT) or brachytherapy (BT). MATERIALS AND METHODS: Data concerning all men undergoing SRP for recurrent prostate cancer after either FT, EBRT or BT were retrospectively collected from 4 high volume surgical centres. The primary outcome measure of the study was toxicity of SRP characterized by any 30-day post-operative Clavien-Dindo complication rate, 12-month continence rate and 12-month potency rate. The secondary outcome was oncological outcome after SRP including positive margin rate and 12-month biochemical recurrence (BCR) rate. BCR was estimated using Kaplan-Meier methods and significant differences were calculated using a log rank test. Median follow-up time was 29.5 months. RESULTS: Between April 2007 and September 2018, 185 patients underwent SRP of which 95 had SRP after FT and 90 had SRP after RT, either EBRT or BT. SRP after RT was associated with a significantly higher 30-day Clavien-Dindo I-IV complication rate (34% vs 5%, p<0.001). At 12 months following surgery, patients undergoing SRP after FT had significantly better continence (SRP after FT:83% pad-free vs RT:49%) while potency outcomes were similar (FT:14% vs RT:11%). Men undergoing SRP after RT had a significantly higher stage and grade of disease together with a higher positive surgical margin rate (37% vs 13%, p=0.001). 3-year BCR after FT was 35% compared to 32% after RT, p=0.76. In multivariable analysis, men undergoing SRP after FT experienced a higher risk of BCR (HR 0.36 [0.18-0.82], p<0.005). CONCLUSIONS: This multicentre study demonstrates the toxicity of SRP in terms of perioperative complications and long-term urinary continence recovery is dependent on initial primary prostate cancer therapy received with men undergoing SRP after FT experiencing lower postoperative complication rates and better urinary continence outcomes

A new tool for the chemical genetic investigation of the Plasmodium falciparum Pfnek-2 NIMA-related kinase

Background: Examining essential biochemical pathways in Plasmodium falciparum presents serious challenges, as standard molecular techniques such as siRNA cannot be employed in this organism, and generating gene knock-outs of essential proteins requires specialized conditional approaches. In the study of protein kinases, pharmacological inhibition presents a feasible alternative option. However, as in mammalian systems, inhibitors often lack the desired selectivity. Described here is a chemical genetic approach to selectively inhibit Pfnek-2 in P. falciparum, a member of the NIMA-related kinase family that is essential for completion of the sexual development of the parasite. Results: Introduction of a valine to cysteine mutation at position 24 in the glycine rich loop of Pfnek-2 does not affect kinase activity but confers sensitivity to the protein kinase inhibitor 4-(6-ethynyl-9H-purin-2-ylamino) benzene sulfonamide (NCL-00016066). Using a combination of in vitro kinase assays and mass spectrometry, (including phosphoproteomics) the study shows that this compound acts as an irreversible inhibitor to the mutant Pfnek2 likely through a covalent link with the introduced cysteine residue. In particular, this was shown by analysis of total protein mass using mass spectrometry which showed a shift in molecular weight of the mutant kinase in the presence of the inhibitor to be precisely equivalent to the molecular weight of NCL-00016066. A similar molecular weight shift was not observed in the wild type kinase. Importantly, this inhibitor has little activity towards the wild type Pfnek-2 and, therefore, has all the properties of an effective chemical genetic tool that could be employed to determine the cellular targets for Pfnek-2. Conclusions: Allelic replacement of wild-type Pfnek-2 with the mutated kinase will allow for targeted inhibition of Pfnek-2 with NCL-00016066 and hence pave the way for comparative studies aimed at understanding the biological role and transmission-blocking potential of Pfnek-2. © 2016 The Author(s)

Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed µCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass

Thrombus or tumor? a case of fibroelastoma as indicated during the submission process

We describe the case of a 50-year-old woman who was admitted to a pheriferal department for heart failure. The echocardiography revealed a small mass measuring about 1.3 × 1.0 cm adhering to the non-coronary cusp of the aortic valve, mild dilated cardiomiopathy and severe biventricular dysfunction. This mass had erroneously been considered a thrombotic lesion, so the patient was treated with thrombolysis and heparin e.v. Only after a transoesophageal echocardiography a tumour cardiac mass was suspected. The diagnosis of fibroelastoma was confirmed by MRI and then from the anatomic and histoligical definition after surgery

Genetic variation in Wnt/β-catenin and ER signalling pathways in female and male elite dancers and its associations with low bone mineral density: a cross-section and longitudinal study.

The association of genetic polymorphisms with low bone mineral density in elite athletes have not been considered previously. The present study found that bone mass phenotypes in elite and pre-elite dancers are related to genetic variants at the Wnt/β-catenin and ER pathways. Some athletes (e.g. gymnasts, dancers, swimmers) are at increased risk for low bone mineral density (BMD) which, if untreated, can lead to osteoporosis. To investigate the association of genetic polymorphisms in the oestrogen receptor (ER) and the Wnt/β-catenin signalling pathways with low BMD in elite and pre-elite dancers (impact sport athletes). The study included three phases: (1) 151 elite and pre-elite dancers were screened for the presence of low BMD and traditional osteoporosis risk factors (low body weight, menstrual disturbances, low energy availability); (2) a genetic association study was conducted in 151 elite and pre-elite dancers and age- and sex- controls; (3) serum sclerostin was measured in 101 pre-elite dancers and age- and sex-matched controls within a 3-year period. Eighty dancers revealed low BMD: 56.3% had at least one traditional osteoporosis risk factor, whereas 28.6% did not display any risk factor (37.2% revealed traditional osteoporosis risk factors, but had normal BMD). Body weight, menstrual disturbances and energy availability did not fully predict bone mass acquisition. Instead, genetic polymorphisms in the ER and Wnt/β-catenin pathways were found to be risk factors for low BMD in elite dancers. Sclerostin was significantly increased in dancers compared to controls during the 3-year follow-up (p < 0.05)