CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma

We evaluated the contribution of germline CDKN2A mutations and MC1R variants to the development of melanoma in a hospital-based study of single (SPM, n = 398) and multiple primary melanoma (MPM, n = 95). The overall frequency of CDKN2A mutations was 15.2%, and four-fold higher in MPM than in SPM cases (OR = 4.27; 95% CI 2.43-7.53). The likelihood of identifying a CDKN2A mutation increased with family history of melanoma and younger age at diagnosis in MPM cases. Compared to SPM patients, the risk of harboring a CDKN2A mutation rose as the number of primary melanomas increased and was not influenced by family history. The G101W and E27X founder mutations were the most common. Several other mutations (W15X, Q50X, R58X, A68L, A127P and H142R) were detected for the first time in Italian patients. One novel mutation, T77A, was identified. Several non-coding variants with unknown functional significance were also found (5'UTR -25C > T, -21C > T, -67G > C, IVS1 +37G > C); the novel 5'UTR -21C > T variant was not detected in controls. The CDKN2A A148T polymorphism was more frequent in MPM patients than in the control population (15.7% versus 6.6%). Compared to the SPM patients, MPM cases had a 2-fold increased probability of being MC1R variant carriers and a higher probability of carrying two or more variants. No specific association was observed between the type of variant and the number of melanomas, suggesting that the number rather than the type of MC1R variant increases the risk of MPM. We observed no interaction between CDKN2A status and the presence of MC1R variants. The high frequency of CDKN2A mutations in our MPM cases, independent of their family history, is of relevance to genetic counseling and testing in our population.     

Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease

In the last decade, treatment for castration-resistant prostate cancer has changed markedly, impacting symptom control and longevity for patients. However, a large proportion of cases progress despite androgen deprivation therapy and chemotherapy, while still being fit enough for several more lines of treatment. Overstimulation of the androgen receptor (AR) activity is the main driver of this cancer. Targeting biological functions of the AR or its co-regulators has proven very effective in this disease and led to the development of several highly effective drugs targeting the AR signalling axis. Drugs such as enzalutamide demonstrated that the improvement in anti-tumour efficacy is closely correlated with an affinity for the AR and its activity and have established the paradigm that AR remains activity in aggressive disease. However, as importantly, key insights into mechanisms of resistance are guiding the development of the next generation of AR-targeted drugs. This review outlines the historical development of these highly specific agents, their mechanism of action in the context of defective AR activity, and explores the potential for the upcoming next-generation AR inhibitors (ARI) for prostate cancer by targeting the alternative domains of AR, rather than by the conventional ligand-binding domain approach. There is huge potential in these approaches to develop new drugs with high clinical activity and further improve the outlook for patients.     

Inhibition of methanogenesis from acetate by Cr+3 and ammonia

Summary 4000 mg/l of N–NH₄ ⁺ and 12 mg/l or Cr⁺³ caused a 50% reduction in aceticlastic methanogenic activity of an anaerobic sludge.Methanosarcina-like andMethanothrix-like cells were differently affected by the toxicants. The inhibition caused by Cr⁺³ was reverted by its removal, by addition of iron and by increasing the biomass.     

Reaction of human serum albumin with aldoses

The reaction of human serum albumin (HSA) with aldoses (C3-C6) and acetaldehyde has been studied. U.v. and fluorescent spectra of the HSA-glyceraldehyde and HSA-GlcN adducts reveal yellow chromophores absorbing at 300-350 nm and emitting at 435 nm. However, even limited reaction of HSA with acetaldehyde induced perturbation in the Trp microenvironment. C.d. spectra of the adducts show an average 20% decrement in mean residual ellipticity [theta], which is independent of the extent of the reaction and the aldose used. It is concluded that most of the reactions with aldoses occur at the surface of the HSA molecule. With the exception of the GlcN adduct, the HSA adducts rearrange to produce pyrrole rings on the protein surface. I.e.f. analysis shows that the pI values of the modified HSA are almost linearly correlated with the chain length of the reacting aldose: from pI 4.2 for HSA-glyceraldehyde up to pI 5.0 for HSA-GlcN.     

Gillnet selectivity for Chilean hake (Merluccius gayi gayi Guichenot, 1848) in the bay of Valparaíso

To determine the selectivity of gillnets in the Chilean artisanal fishery for the Chilean hake Merluccius gayi gayi, an experimental net was used with three mesh sizes (5.2, 6.8 and 7.6 cm). A total of 2279 specimens of Chilean hake were caught (24–56 cm total length, TL), mainly via gilling and snagging. The catch proportion below the size of sexual maturity SSM_50% (37 cm TL) for each mesh size tested was estimated. Models were fitted separately according to the sex to compensate for differences in size compositions, with the males fitted to a binormal model and females fitted to the normal location model. Analysing both sexes combined, the model with the lowest deviance was lognormal, with estimated modal lengths of 30.9, 40.2 and 43.9 cm TL for meshes of 5.2, 6.8 and 7.6 cm, respectively. The estimated selectivity factor (SF) indicates that the modal size matches the SSM_50% with a mesh size of 6.2 cm, while the length of retention of 50% (l₅₀) coincides with the SSM_50% with a mesh size of 7.6 cm.