SRF role as a mechano-transductor in response to exercise in cancer cachexia

Introduction: Recent studies showed that physical activity increased survival in cancer patient and animal models of cancer cachexia. The underlying mechanisms, however, are still largely unknown. Methods: To identify signalling pathways involved in exercise-dependent maintenance of muscle mass and function in cachexia, we investigated the role of serum response factor (SRF)—a transcription factor playing a pivotal a role in muscular growth, differentiation and regeneration—in C26-bearing mice in the absence or presence of voluntary exercise (wheel running). Results: SRF levels are decreased at protein level in cachexia. Consistently, a decrease in the expression of SRF target genes such as MyoD and SK-actin occurs in C26-bearing mice, suggesting a decrease of SRF transcriptional activity. These tumour effects were counteracted by wheel running and associated to the rescue of muscle mass and function. However, a minimum amount of exercise (2 km/day) is necessary to keep SRF levels elevated in cachexia over a threshold which is necessary to exert beneficial effects. SRF levels inversely correlate with wasting in mice, suggesting that SRF play a role in maintaining body mass (mostly accounted for by muscle mass). We also observe the recruitment of nuclei within the muscle fibres in response to exercise, which could contribute to muscle homeostasis and is consistent with the previously observed opposite effects of tumour and exercise on MyoD and Pax7 expression. Conclusions: Our results suggest that physical activity rescues SRF expression as well as its transcriptional activity, highlighting the importance of genetic activation induced by skeletal muscle activity for muscle rescue and homeostasis. These effects could be extended to the fibre microenvironment, including myogenic stem cell activity

The mechanical stimulation of myotubes counteracts the effects of tumor-derived factors through IL-4 secretion and the modulation of the activin/follistatin ratio

Exercise counteracts cachexia, but it is unclear to which extent the exercise-dependent mechanical stimulation of muscle per se plays a role in exercise beneficial effects. To study the mechanisms underlying mechanical stimulation, we cultured C2C12 myotubes in the absence or in the presence of a cyclic mechanical stretching stimulus (MS) and in the absence or presence of C26 tumour-derived factors (C26-CM), so as to mimic the mechanical stimulation of exercise and cancer cachexia, respectively. We found that C26-CM contains activin and induces activin release by myotubes, further exacerbating its negative effects, consisting in myotube atrophy and in hampering myoblast recruitment and fusion into myotubes. A high level of circulating activin is an adverse prognostic factor in cancer patients, and our in vitro results demonstrate that activin may be a direct player and not just a marker of cachexia. We also found that MS is sufficient to counteract the adverse tumour-mediated effects on muscle cells, in association with an increased follistatin/activin ratio in the cell culture medium, indicating that myotubes actively release follistatin upon stretching. In addition, MS induces IL- 4 secretion by muscle cells. Recombinant follistatin counteracts C26 tumour effects on myotubes exclusively by rescuing fusion index, while recombinant IL-4 ameliorates fusion index, as well as the myotube size, both in terms of myotube diameter and number of nuclei per myotube. Our results indicate that tumour cells negatively affect muscle cells by releasing soluble factors and that MS is sufficient to counteract these effects, by affecting the muscle secretome with autocrine/paracrine pathways. Activin and Act-R ligands are becoming increasingly important as triggers of muscle wasting and as pharmacological targets to treat cachexia; however, since follistatin alone is incapable to entirely block the C26-CM effects, the development of novel activintargeted approaches should consider the existence of further significant tumour-secreted factors mediating cachexia

Industrialization of Ni-?SiC electrodeposition on copper moulds for steel continuous casting

Copper moulds usually used for steel continuous casting suffer from severe wear at relatively high temperaturesand low friction loads. The more severe solid friction occurs at about 10-40cm distance from the meniscus, dependingon the process parameters, where the temperature is about 300-350°C. The copper moulds have been traditionallycoated with hard chromium and actually also with thick nickel deposits even if they present lower wear resistance.The aim of this work was the development of a composite Ni-????SiC electrodeposit with higher hardness and wearresistance than the pure nickel using the existing plating bath and commercially available SiC micro-powders. Differenttypes of SiC micro-particles have been purchased and Ni-????SiC deposits have been produced and analyzed,initially, in laboratory scale to evaluate the ability of the powders to be codeposited into the nickel matrix. Afterthe choice of the SiC powder and the determination of the plating parameters a pilot 6000 lt plating tank has beenequipped with a system of Venturi pumps in order to maintain the particles in suspension. Preliminary tests havebeen performed in industrial scale to evaluate the process parameters such as anode-cathode distance, applied voltage,plating time and pumps positioning effect onto the SiC content and its distribution in the nickel matrix. Theproduced specimens have been observed by Metallographic microscope and Scanning Electron Microscope in crosssection to evaluate the SiC content and the microstructure of the nickel matrix. Vickers microhardness measurementshave been also performed in cross section and revealed that the co-deposition of the SiC micro-particles leadsto a microhardness increase of about 180%. Wear tests at both room temperature and at 350°C have been performedon pure nickel deposits and composite nickel deposits and the wear tracks have been analyzed using botha profilometer and SEM to determine the wear both coefficient and mechanism of each coating. The testing resultsrevealed that the developed Ni-????SiC deposit exhibits a much higher wear resistance in comparison to pure nickeldeposits at high temperature and the production process can be easily transferred in industrial scale with slightmodifications of the existing deposition plants. Real scale copper moulds have been finally coated with Ni-????SiCcomposite deposits and are presently under testing in actual working conditions at a steel producing plant

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2-3.4). The AER of any cancer was 1560 cases (95% CI: 1468-1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778-901), non-Hodgkin lymphoma (145, 95% CI: 119-174), lung cancer (126, 95% CI: 98.2-149), and kidney cancer (122, 95% CI: 98.0-149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6-8.6%) and 16.8% (95% CI: 16.0-17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance.Peer reviewe

Urinary secretion and extracellular aggregation of mutant uromodulin isoforms

Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein

Urinary secretion and extracellular aggregation of mutant uromodulin isoforms.

Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein

The Lactobacillus flora in vagina and rectum of fertile and postmenopausal healthy Swedish women

<p>Abstract</p> <p>Background</p> <p><it>Lactobacillus </it>species are the most often found inhabitants of vaginal ecosystem of fertile women. In postmenopausal women with low oestrogen levels, <it>Lactobacillus </it>flora is diminishing or absent. However, no studies have been performed to investigate the correlation between oestrogen levels and the lactobacilli in the gut. The aim of the present study was to investigate the relation in healthy women between vaginal and rectal microbial flora as well as possible variations with hormone levels.</p> <p>Methods</p> <p>Vaginal and rectal smears were taken from 20 healthy fertile women, average 40 years (range 28-49 years), in two different phases of the menstrual cycle, and from 20 postmenopausal women, average 60 years (range 52-85 years). Serum sex hormone levels were analyzed. Bacteria from the smears isolated on Rogosa Agar were grouped by Randomly Amplified Polymorphic DNA and identified by multiplex PCR and partial 16S rRNA gene sequencing.</p> <p>Results</p> <p><it>Lactobacillus crispatus </it>was more often found in the vaginal flora of fertile women than in that of postmenopausal (p = 0.036). Fifteen of 20 fertile women had lactobacilli in their rectal smears compared to 10 postmenopausal women (p = 0.071). There was no correlation between the number of bacteria in vagina and rectum, or between the number of bacteria and hormonal levels. Neither could any association between the presence of rectal lactobacilli and hormonal levels be found.</p> <p>Conclusion</p> <p><it>Lactobacillus crispatus </it>was more prevalent in the vaginal flora of fertile women, whereas the <it>Lactobacillus </it>flora of rectum did not correlate to the vaginal flora nor to hormonal levels.</p