Use of mesh to repair the submuscolar pocket in breast reconstruction: a new possible technique

The reconstruction of the female breast after mastectomy has become a crucial part of primary breast cancer therapy. Setting of an implant is possible only in case of locally abounding soft tissue coverage and when no radiation has before performed. It is necessary a complete integrity of the submuscolar pocket and good blood supply of the skin to avoid failure of the procedure. In Author's experience, started since 1994, an immediate breast reconstruction after mastectomy is performed using gel-silicon implants directly when it was possible or setting first an expander. In six cases the condition of major pectoralis muscle after mastectomy was so foul that an immediate breast reconstruction with prosthesis was not realizable. However, the Authors tried a new technique using polypropylene mesh sutured on the major pectoralis muscle to cover the muscle partially destroyed. Preliminary data from the 6 pts seems to be encouraging.     

HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.     

Isomyosin redistribution in chronic pressure overload: comparison between peptide mapping and electrophoresis under non-denaturing conditions

Summary Chronic pressure overload induces a redistribution in myosin isoenzymes as demonstrated by Ca⁺⁺-activated ATPase activity, electrophoresis under non-denaturing conditions and immunohistochemistry.We compared, in two groups of renal hypertensive rats and control rats, the isoenzymic patterns obtained by electrophoresis under non-denaturing conditions with those observed after heavy chains digestion with S. Aureus V8 protease.In the hypertensive animals in which a shift towards the slow V₂ and V₃ isomyosins was evident, peptide mapping always gave origin to a band which was not present in the controls.Since we consider this peptide as a marker of the redistribution towards the slow isoforms, peptide mapping according to Cleveland appears to be a simple and useful method to assess differences in isomyosin composition, at least between hypertrophic pressure-overloaded and normal rat ventricles. Moreover, in our experience this technique is simple, the patterns obtained from highly purified substrates are very reproducible and the digestion allows easy and clear comparisons.     

Biochemical characterization of ventricular myosin from spontaneously hypertensive turkeys

Several stimuli are able to alter the synthesis of cardiac myosin isoenzymes. Particularly in the rat a shift toward a low-ATPase isomyosin is generally observed during development and in cardiac hypertrophy due to pressure overload. On the contrary in spontaneously hypertensive turkeys both ageing and the increasing degree of cardiac hypertrophy are accompanied by a different behaviour of ventricular myosin. In fact in a previous study we have shown that the Ca2+-activated ATPase activity of ventricular myosin increases about three folds from young normotensive to old hypertensive animals. Accordingly the peptide pattern obtained after chymotryptic digestion of myosin showed that some peptides, which are not evident or barely discernible in young animals, are present in the adult ones. In this study we compare the ventricular myosin from young normotensive and adult hypertensive turkeys with atrial myosin. The results obtained suggest that in the ventricles of hypertensive turkeys the synthesis of an isomyosin with biochemical properties close to those of atrial myosin occurs.     

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia‐inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Micronuclei frequencies in hospital workers occupationally exposed to low levels of ionizing radiation: influence of smoking status and other factors

In the context of a medical surveillance program aimed at preventing cancer risk from exposure to ionizing radiation, we investigated chromosomal damage in peripheral lymphocytes from 37 hospital workers exposed to low levels of ionizing radiation and 37 controls. The micronuleus (MN) assay was used as a biomarker of genetic damage. The influence of confounding factors like smoking status, age and gender was investigated by multiple regression analysis. The results indicated that, overall, MN frequency was higher in exposed workers than in controls, although the difference was not statistically significant. Interestingly, smoking status significantly raised MN frequency among the exposed workers but not among controls. This suggests that smoking can influence chromosomal damage induced in humans by ionizing radiation. Among both exposed workers and controls, MN frequency was found to increase with age. Female gender influenced the increase in MN frequency in the exposed group. Our results suggest that the effect of cigarette smoking should be carefully factored into genetic monitoring studies assessing the risks associated with low level radiation exposure.