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Abstract: Introduction: Bowel endometriosis is when endometrial-like tissue penetrates the bowel serosa, or it reaches the subserous neurovascular plexus. The effect of surgery for colorectal endometriosis on infertility and pregnancy is not fully proven. Aim: The aim of the present study was to analyse the pregnancy outcome and mode of delivery of patients who underwent ’nerve sparing’ anterior resection of the colon. Method: Between 2009 and 2017, we operated 121 patients with bowel endometriosis, and built up a prospective database where we assessed their wish of pregnancy, the way of the conception, pathologies during pregnancy and mode of delivery. Statistical analysis: The relationship between endometriosis and pregnancy pathologies was tested by a χ2 probe and Fisher’s exact test, additionally the odds ratio (OR) and 95% confidence interval (CI) were determined. For p

Smartphones have rapidly become indispensable in modern life. The wide spectrum of activities and virtual interaction possibilities with the mobile device render some individuals prone to exaggerated use exhibiting core symptoms akin to substance addiction. The core common symptoms of addictions can be framed within the ‘components model of addiction.’ Based on the different pattern of smartphone use in various age groups, the symptoms and the risk of smartphone addiction may differ during various life stages. Some age groups may be more at risk of smartphone addiction than others. This hypothesis was tested utilizing data from six surveys comprising 1603 individuals representing various age groups. Results obtained through two recommended age-group analyses both confirmed that preschool children and young adults are at highest risk for smartphone-related addictive behavior. Furthermore, the various components of addiction also differed between the age groups. These results suggest that preventive measures should be primarily targeted to the two most vulnerable age groups represented by preschool children and emerging adults. The results of the present study help identify the dominant addiction symptoms in the various age groups that could pinpoint aspects which should be targeted in implementation of various measures aimed at the prevention of dysfunctional smartphone use.

Significance Standard of care for metastatic castration-resistant prostate cancer (mCRPC) mainly relies on suppression of androgen receptor (AR) signaling. This approach has no lasting benefit due to the emergence of resistance mechanisms, such as ligand-independent splicing variant AR-V7. A metabolic feature of mCRPC is the upregulation of de novo lipogenesis to provide substrates and fuel for metastatic spread. Whether increased levels of fats affect AR signaling to promote an aggressive disease remains to be determined. Using a selective and potent inhibitor of fatty acid synthase we demonstrate that suppression of this key enzyme inhibits AR, most importantly AR-V7, and reduces mCRPC growth. Our findings offer a therapeutic opportunity for mCRPC and a potential mechanism to overcome resistance to AR inhibitors., A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119–mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7–driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.

Introduction Symptoms of nicotine dependence among adolescents occur at an early stage in smoking onset and can be present even with low exposure to cigarettes. We aim to examine the early occurrence of symptoms of nicotine dependence and how they predict later smoking behavior. Methods Participants were ninety-four currently smoking 9th-graders attending high school in Targu Mures, Romania. They were followed for 6 months with two assessment points: baseline, and follow-up at 6 months. We assessed the following: 1) the number of smoked cigarettes in the last 30 days, 7 days, and 24 hours using the Minnesota Smoking Index; 2) vulnerability to addiction manifested in cessation difficulties, using the 9-item version of the Hooked On Nicotine Checklist (HONC), 3) loss of autonomy using the endorsement of at least one HONC item, and 4) dependence, using the modified Fagerström Tolerance Questionnaire (mFTQ). We performed statistical analysis with SPSS version 19, using paired-sample t-tests for comparing the differences between baseline and follow-up data. We also conducted linear regression analysis to demonstrate the predictive role of the assessed variables, such as the scores of the mFTQ and the HONC in maintaining smoking and reported smoking status. Results Regression models indicated that baseline-measures for symptoms of dependence (β=0.64, p

Abstract: Introduction and aim: To evaluate the frequency and severity of the malocclusions and treatment need in a group of adult patients in Târgu-Mureș, dividing them up according to age and gender. Method: Sixty-four, randomly selected patients were divided up according to age and gender. Ten occlusal traits related to dentofacial anomalies according to missing teeth, spacing, crowding and occlusion were used to evaluate the malocclusions on each of their study cast. The Dental Aesthetic Index (DAI) regression equation was used to obtain the DAI score that defines severity. Results: The average DAI score was 38 with a range of 18–79, showing that the majority of patients needed mandatory orthodontic treatment. No statistically significant difference was found between gender, age groups and need for treatment. Conclusion: More than two-fifths of the examined patients have a mandatory need for orthodontic treatment if the DAI scores are the main screening tool. Orv Hetil. 2018; 159(9): 352–356.

Abstract: Introduction: Depression is one of the most widespread illnesses of our time, currently affecting more than 300 million people worldwide. Literature identifies several socio-demographic risk factors in the development of the depression. Aim: We aim to examine the socio-demographic factors involved in the remission of clinically diagnosed unipolar major depression. Method: Data collection was performed during 2016, at the 1st Psychiatric Clinic from Tirgu Mures. Participants were patients reporting no other physical or psychiatric disorder. Self-reporting questionnaire assessed socio-demographic factors, such as gender, age, neighborhood, education, marital status, employment, and unemployed period. DSM-5 criteria were used in diagnosis, and the severity and status tracking was assessed with the 17-item version of the Hamilton Depression Scale. The age distribution of the sample was between 18–65 years of age, 44 male (28.9%) and 108 female (71.1%), 66 inpatients and 86 outpatients. Patients received medication for 12 weeks, and were involved in HAM-D 17 testing when hospitalized, at 8 and 12 weeks. Results: Scores of depression decreased significantly after 8 and 12 weeks of the treatment. Gender, age, and neighborhood did not influence the treatment, but patients with high education manifested less depressive symptoms at the end of treatment. Among married patients depression score was lower than among unmarried, and employees showed lower depression scores comparing to long-term unemployed patients. Conclusion: Marital status and employment were relevant predictors of remission, proving a significant effect on the treatment outcomes. Thus, psychotherapeutic intervention is recommendable in the case of single and unemployed patients. Orv Hetil. 2017; 158(43): 1715–1722.

The role of diet is crucial in the development and prevention of cardiovascular disease. The purpose of the current study was to describe dietary intake and assess health scores of children and adults by using a survey questionnaire on moldavian and transylvanian population, in order to evaluate whether it is necessary to introduce a prevention program for cardiovascular diseases in Romania. In 2015, a questionnaire was sent to 347 children and 583 adults in two counties in Romania where the climatic and topographic conditions are different. Participation rate in the children group was 56.48% moldavian / 43.51% transylvanian, respectively 39.62% moldavian / 60.37% transylvanian participants in the adult group. The questionnaire included a 44-item semi-quantitative food frequency questionnaire and questions on lifestyle for children and a 21- item semi-quantitative food frequency questionnaire and a health score for adults. Results were evaluated against the WHO recommendations of healthy diet. In Mures county the number of former smokers is significantly higher compared to Bacau county, and considerably more subjects report active smoking and exposure to passive smoking. The incidence of overweight and obesity was similar in the two counties, 68.14% in Bacau and 70.67% in Mures. More subjects from Bacau (94.35%) have regular exercise compared to those from Mures (85.38%), the difference is not quite significant. The majority of the subjects from Bacau county have a significantly healthier diet compared to those from Mures, consuming regularly eggs, meat and dairy products. Based on our data, only 16% of Romanian children reach the WHO recommendation for healthy nutrition regarding fruit and vegetable intake.Dietary habits of children and adults in Romania warrant improvements. Public health actions should be taken to increase the consumption of fruits and vegetables, decrease the consumption of saturated fats and sweets and also to increase the frequency of physical activity. These actions may be helpful in reducing the risks for overweight and cardiovascular diseases.

Abstract: Introduction and aim: In the treatment of colorectal endometriosis a multidisciplinary laparoscopic resection is suggested, for this reason the correct selection of bowel infiltration is essential before surgery. Patients and method: Between 2009 and 2015, 383 sigmoidoscopies were performed in patients with endometriosis. Where mucosal invasion was absent secondary signs (wall rigidity, impression, kinking, pain during the examination, suffusion) were analysed. In endoscopically confirmed cases multidisciplinary surgery was performed, the remaining patients were operated by a gynecologic team only. Results: Endometriosis was endoscopically confirmed in 224 patients (58.49%), 108 of them underwent multidisciplinary operation, the negative 135 cases received gynaecological surgery. Bowel endometriosis was confirmed in 103 out of 108 cases intraoperatively, while in 8 cases of the sigmoidoscopically negative patients bowel infiltration was diagnosed intraoperatively by the gynaecological team. Complete sigmoidoscopy was performed in 43.47% of the cases. Intraluminal endometriosis was found in 4.91%, secondary signs as rigidity in 38.39%, impression in 45.54%, kinking in 57.14%, pain (in cases of examination without narcosis) in 26.06% and suffusion in 3.82% of the cases was found during sigmoidoscopy. Sigmoidoscopic examination has a 92.8% specificity and 96.2% sensitivity in cases of bowel endometriosis. Conclusion: Sigmoidoscopy performed by an experienced gastroenterologist is a highly sensitive examination for the diagnosis of bowel endometriosis. Orv. Hetil., 2017, 158(7), 264–269.

Introduction: A number of the patients suffer from endometriosis increased in the past decades and the cases have became more serious. The most critical complication of bowel endometriosis is the large bowel obstruction. Up to recently, 16 similar case reports of large bowel endomteriosis causing obstruction, with detailed medical history have been published in the literature in English language. Patients: Since 2007 535 female have been treated in the 1st Gynaecological Department with endometriosis, out of them three patients from emergency surgery in the history because of large bowel obstruction. Results: Symptoms suggesting endometriosis or previous intervention due to endometriosis were detected in 59% (13/21) of the cases. Preoperative ultrasound, computertomography, magnetic resonance imaging did not give correct diagnosis. Colonoscopy was carried out before the primary operation in 61% (13/21) and after the surgery in 24% (5/21) of the cases, but none of them confirmed endometriosis. Although all the patients developed obstruction, only in 5% (1/19) of the patients was the mucosa infiltrated by the endometriosis. Conclusions: In a young female patient, intestinal obstruction can be caused by bowel endometriosis. Identification of colonoscopic signs (rigidity, impression, kinking) of endometriosis may help to avoid unnecessary extension of intestinal resection. Gynaecologists should take part in the operations. Orv. Hetil., 2016, 157(49), 1960–1966.

The goal of the study was to validate the English version of the Smartphone Application-Based Addiction Scale (SABAS; Csibi et al. 2016), which is a short and easy-to-use tool for screening the risk of smartphone application-based addiction. Another aim was to identify the most frequently used smartphone applications and their perceived importance by the participants. Data were collected online from 240 English-speaking volunteers, aged 18 to 69 years. The instruments used were the SABAS, the Nomophobia Questionnaire (NMP-Q), the Brief Sensation Seeking Scale (BSSS), the Deprivation Sensation Scale (DSS), and the Patient Health Questionnaire (PHQ-9). Participants also ranked the importance of their most frequently used smartphone applications. The six items of the SABAS yielded one component, which accounted for 52.38% of the total variance. The internal reliability of the scale was good (Cronbach’s alpha 0.81). NMP-Q was a significant predictor of SABAS, explaining 17.6% of the total variance. The regression analysis, with SABAS score as the dependent variable and NMP-Q, DSS, PHQ-9, and BSSS scores as predictors, indicated that approximately 47% of the variance in SABAS was accounted for by the predictors (R 2 = 0.47). The English version of the SABAS appears to be a valid and reliable ultra-brief tool for a quick and easy assessment of smartphone application-based addiction symptoms.

Absztrakt Bevezetés: Laparoscopos vastagbél-resectiónál a specimen transrectalis eltávolításával a hasfali metszés elkerülhető, így az invazivitás tovább csökkenthető. A módszer elfogadottságához előnyeinek és hátrányainak értékelése mellett a technika pontos kidolgozása szükséges. Cikkünk célja az általunk kidolgozott technika és első eredményeink ismertetése. Betegek és módszer: Multidiszciplináris együttműködés keretében 2014. április 16. és 2015. november 1. között 45 laparoscopos bélresectio történt belet infiltráló endometriosis miatt, amelynek során az operált betegek közül 11-nél a speciment transrectalisan távolítottuk el. Az eltávolítandó bélszakasz két végének lekötése és a resectiótól proximalis bélszakasz laparoscopos bulldoggal történő lezárása után átvágtuk a belet, majd a speciment a transrectalisan bevezetett kamerazsákon keresztül távolítottuk el. A proximalis bélvégbe laparoscoposan dohányzacskóöltést helyeztünk be, amelybe a transrectalisan bejuttatott körvarrógép fejét helyeztük. A rectumcsonk varrógéppel történő lezárása után körvarró géppel készítettük el az anastomosist. A módszert a rectum felső harmadát, illetve a szigmabelet érintő endometriosis esetén alkalmaztuk. Eredmények: A műtéti idő a transabdominalis és transrectalis specimeneltávolítás során nem különbözött szignifikánsan (108 perc vs. 118 perc). Az operált betegeknél nem volt szignifikáns különbség a postoperativ első és második napon a fehérvérsejtszámban, illetve nem észleltünk varratelégtelenséget. Következtetés: A munkacsoport által kidolgozott technikával az infekció minimálisra csökkenthető. A transrectalis specimeneltávolítás nem növeli a szövődmények esélyét, és biztonsággal alkalmazható a specimen eltávolításához bélresectio esetén.

Introduction. Smoking is an important public health issue nowadays. It causes a lot of diseases and represents also a source of carcinogenic substances. Recent studies showed an increased incidence of colorectal cancer in smokers. The aim of our study is to assess the association between smoking and colorectal cancer and to establish the prevalence of heavy smokers among the patients operated on for colorectal cancer. Methodology. We run a retrospective study of the charts belonging to the patients diagnosed with colorectal cancer and operated on in our department between 2004 and 2013. The patients were classified in smokers, former smokers and nonsmokers. The amount of tobacco was evaluated according to the number of smoked cigarettes per day, the smoking period, respectively the pack-years. The data were corroborated with the location of the tumor and analyzed using the online version of Graphpad. Results. From 982 patients diagnosed with colorectal cancer, we found 297 smokers (30.24%). Among these, 106 patients (35.69%) have smoked for over 30 years, at least 20 cigarettes per day, more than 30 pack-years. The number of heavy smokers was significantly greater (p=0.0001) in the group with rectal cancer compared to the group with colon cancer. The association of smoking with rectal cancer was also important (p=0.0015) among the former smokers. Conclusions. Smoking is related to higher incidence of colorectal cancer. Our data sustain the hypothesis of increased risk of developing rectal cancer in heavy smokers. We recommend the screening for colorectal cancer among the heavy smoker population.

STUDY OBJECTIVE We first present a detailed description of a modified NOSE-colectomy technique. Secondly, we report the postoperative outcomes of our prospective case series when compared to conventional laparoscopic bowel resection in a relatively large series of patients. DESIGN Canadian Task Force Classification II-1. SETTING University tertiary referral center. PATIENTS Patient selection The last 90 consecutive patients in our care with DIE of the bowel are presented in this study. Patients were diagnosed at the 1Department of OB/GYN Semmelweis Universtiy Budapest, Hungary. INTERVENTIONS We performed laparoscopic bowel resection using the transrectal NOSE-technique and compared the results of the new operative method (n=30) to traditional laparoscopic bowel resection (n=60). MEASUREMENTS AND MAIN RESULTS Duration of operations The median duration of surgery was 121 minutes in the control group and 96 minutes in the NOSE-group (p=.005). Postoperative complications According to Clavien-Dindo classification, we observed a severe, grade IIIb or higher, overall complication rate of 3.3% among all 90 patients. In the control group anastomosis insufficiency occurred in 3.3% of patients (2/60 cases) and in one patient with anastomotic leakage a rectovaginal fistula was observed (1.7%). There was no significant difference in rates of severe postoperative complications (p=0.55). Hospital stay The length of hospital stay in the control group was a median of 7 (5-13) days whereas in the NOSE-group this was 6 (3-11) days (p

Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor–encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function(1–6). Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function(7–11), but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.

Introduction Although web-based, multimedia smoking prevention programs have been tested in several high-income countries, their efficacy in Central and Eastern Europe is unknown. The aim of this trial was to assess the short-term effects of ASPIRA, among Romanian and Hungarian speaking ninth graders in Tirgu Mures, Romania. ASPIRA is the Romanian acronym for the translated and adapted version of ASPIRE, "A Smoking Prevention Interactive Experience," an evidence-based smoking prevention program originally developed to prevent tobacco use among high school students in the United States. Methods Sixteen high schools in Tirgu Mures, Romania were randomized to receive five weekly sessions of the ASPIRA web-based, multimedia program or to a control condition. Socio-demographic data, psychosocial characteristics, and smoking behavior were collected from students at baseline and at 6 months. A hierarchical logistic regression analysis was conducted to test the efficacy of the intervention on smoking initiation and current smoking among 1369 students. Results Never-smoker students in the intervention arm were 35% less likely to report smoking initiation 6 months after the baseline assessment (OR = 0.65, 95%CI: 0.44-0.97). Reduced smoking initiation was observed most notably among students who were exposed to at least 75% of the ASPIRA program. There was no statistically significant effect of the intervention on current tobacco use (OR = 0.80, 95%CI: 0.44-1.46). Conclusions ASPIRA, an adapted version of the evidence-based, multimedia ASPIRE program that was originally developed and tested in the United States may decrease smoking initiation among multi-ethnic adolescents in Central and Eastern Europe. Implications (1). Web-based, multimedia smoking prevention programs may be effective tools to prevent smoking initiation among multi-ethnic adolescent communities in Central and Eastern Europe. (2). The degree of exposure is critical, only high exposure to the multimedia smoking prevention program is associated with reduced smoking initiation.

International audience; The AMPactivated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.

The control of muscle cell size is a physiological process balanced by a fine tuning between protein synthesis and protein degradation. MAFbx/Atrogin-1 is a muscle specific E3 ubiquitin ligase upregulated during disuse, immobilization and fasting or systemic diseases such as diabetes, cancer, AIDS and renal failure. This response is necessary to induce a rapid and functional atrophy. To date, the targets of MAFbx/Atrogin-1 in skeletal muscle remain to be identified. We have recently presented evidence that eIF3-f, a regulatory subunit of the eukaryotic translation factor eIF3 is a key target that accounts for MAFbx/Atrogin-1 function in muscle atrophy. More importantly, we showed that eIF3-f acts as a "translational enhancer" that increases the efficiency of the structural muscle proteins synthesis leading to both in vitro and in vivo muscle hypertrophy. We propose that eIF3-f subunit, a mTOR/S6K1 scaffolding protein in the IGF-1/Akt/mTOR dependent control of protein translation, is a positive actor essential to the translation of specific mRNAs probably implicated in muscle hypertrophy. The central role of eIF3-f in both the atrophic and hypertrophic pathways will be discussed in the light of its promising potential in muscle wasting therapy.

International audience; In response to cancer, AIDS, sepsis and other systemic diseases inducing muscle atrophy, the E3 ubiquitin ligase Atrogin1/MAFbx (MAFbx) is dramatically upregulated and this response is necessary for rapid atrophy. However, the precise function of MAFbx in muscle wasting has been questioned. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome. Ectopic expression of MAFbx in myotubes induces atrophy and degradation of eIF3-f. Conversely, blockade of MAFbx expression by small hairpin RNA interference prevents eIF3-f degradation in myotubes undergoing atrophy. Furthermore, genetic activation of eIF3-f is sufficient to cause hypertrophy and to block atrophy in myotubes, whereas genetic blockade of eIF3-f expression induces atrophy in myotubes. Finally, eIF3-f induces increasing expression of muscle structural proteins and hypertrophy in both myotubes and mouse skeletal muscle. We conclude that eIF3-f is a key target that accounts for MAFbx function during muscle atrophy and has a major role in skeletal muscle hypertrophy. Thus, eIF3-f seems to be an attractive therapeutic target

Growth-promoting signaling molecules, including the mammalian target of rapamycin complex 1 (mTORC1), drive the metabolic reprogramming of cancer cells required to support their biosynthetic needs for rapid growth and proliferation [1]. Glutamine is catabolyzed to α-ketoglutarate (αKG), a tricarboxylic acid (TCA) cycle intermediate, through two deamination reactions, the first requiring glutaminase (GLS) to generate glutamate and the second occurring via glutamate dehydrogenase (GDH) or transaminases [2]. Activation of the mTORC1 pathway has been shown previously to promote the anaplerotic entry of glutamine to the TCA cycle via GDH. Moreover, mTORC1 activation also stimulates the uptake of glutamine, but the mechanism is unknown [3]. It is generally thought that rates of glutamine utilization are limited by mitochondrial uptake via GLS, suggesting that, in addition to GDH, mTORC1 could regulate GLS. Here we demonstrate that mTORC1 positively regulates GLS and glutamine flux through this enzyme. We show that mTORC1 controls GLS levels through the S6K1-dependent regulation of c-Myc (Myc). Molecularly, S6K1 enhances Myc translation efficiency by modulating the phosphorylation of eukaryotic initiation factor eIF4B, which is critical to unwind its structured 5' untranslated region (5'UTR). Finally, our data show that the pharmacological inhibition of GLS is a promising target in pancreatic cancers expressing low levels of PTEN. ispartof: Current biology : CB vol:24 issue:19 pages:2274-80 ispartof: location:England status: published

SummaryDNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression.

The eukaryotic initiation factor 3 subunit f (eIF3f) is one of the 13 subunits of the translation initiation factor complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that eIF3f plays a central role in skeletal muscle size maintenance. Accordingly, eIF3f overexpression results in hypertrophy through modulation of protein synthesis via the mTORC1 pathway. Importantly, eIF3f Was described as a target of the E3 ubiquitin ligase MAFbx/atrogin-1 for proteasome-mediated breakdown under atrophic conditions. The biological importance of the MAFbx/atrogin-1-dependent targeting of eFI3f is highlighted by the finding that expression of ad eIF3f mutant insensitive to MAFbx/atrogin-1 polyubiquitination is associated with enhanced protection against starvation-induced muscle atrophy. A better understanding of the precise role of this subunit should lead to the development of new therapeutic approaches to prevent or limit muscle wasting that prevails in numerous physiological and pathological states such as immobilization, aging, denervated conditions, neuromuscular diseases, AIDS, cancer, diabetes. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. (C) 2013 Elsevier Ltd. All rights reserved.

Correspondence to: Anthony MJ Sanchez, e-mail: anthony.mj.sanchez@hotmail.fr; International audience; In skeletal muscle, protein levels are determined by relative rates of protein synthesis and breakdown. The balance between synthesis and degradation of intracellular components determines the overall muscle fiber size. AMP-activated protein kinase (AMPK), a sensor of cellular energy status, was recently shown to increase myofibrillar protein degradation through the expression of MAFbx and MuRF1. In the present study, the effect of AMPK activation by AICAR on autophagy was investigated in muscle cells. Our results show that FoxO3a transcription factor activation by AMPK induces the expression of the autophagy-related proteins LC3B-II, Gabarapl1, and Beclin1 in primary mouse skeletal muscle myotubes and in the Tibialis anterior (TA) muscle. Time course studies reveal that AMPK activation by AICAR leads to a transient nuclear relocalization of FoxO3a followed by an increase of its cytosolic level. Moreover, AMPK activation leads to the inhibition of mTORC1 and its subsequent dissociation of Ulk1, Atg13, and FIP200 complex. Interestingly, we identify Ulk1 as a new interacting partner of AMPK in muscle cells and we show that Ulk1 is associated with AMPK under normal conditions and dissociates from AMPK during autophagy process. Moreover, we find that AMPK phosphorylates FoxO3a and Ulk1. In conclusion, our data show that AMPK activation stimulates autophagy in skeletal muscle cells through its effects on the transcriptional function of FoxO3a and takes part in the initiation of autophagosome formation by interacting with Ulk1. Here, we present new evidences that AMPK plays a crucial role in the fine tuning of protein expression programs that control skeletal muscle mass.

International audience; Ubiquitin ligase Atrogin1/Muscle Atrophy F-box (MAFbx) up-regulation is required for skeletal muscle atrophy but substrates and function during the atrophic process are poorly known. The transcription factor MyoD controls myogenic stem cell function and differentiation, and seems necessary to maintain the differentiated phenotype of adult fast skeletal muscle fibres. We previously showed that MAFbx mediates MyoD proteolysis in vitro. Here we present evidence that MAFbx targets MyoD for degradation in several models of skeletal muscle atrophy. In cultured myotubes undergoing atrophy, MAFbx expression increases, leading to a cytoplasmic-nuclear shuttling of MAFbx and a selective suppression of MyoD. Conversely, transfection of myotubes with sh-RNA-mediated MAFbx gene silencing (shRNAi) inhibited MyoD proteolysis linked to atrophy. Furthermore, overexpression of a mutant MyoDK133R lacking MAFbx-mediated ubiquitination prevents atrophy of mouse primary myotubes and skeletal muscle fibres in vivo. Regarding the complex role of MyoD in adult skeletal muscle plasticity and homeostasis, its rapid suppression by MAFbx seems to be a major event leading to skeletal muscle wasting. Our results point out MyoD as the second MAFbx skeletal muscle target by which powerful therapies could be developed

Anne Poupon: Biologie et Bioinformatique des Systèmes de Signalisation, UMR Physiologie de la Reproduction et des Comportements, INRA, Nouzilly, France. Sanchez A.M.J. : Equipe Remodelage Musculaire et Signalisation Contact: leibovs@supagro.inra.fr; The mTORC1 pathway is required for both the terminal muscle differentiation and hypertrophy by controlling the mammalian translational machinery via phosphorylation of S6K1 and 4E-BP1. mTOR and S6K1 are connected by interacting with the eIF3 initiation complex. The regulatory subunit eIF3f plays a major role in muscle hypertrophy and is a key target that accounts for MAFbx function during atrophy. Here we present evidence that in MAFbx-induced atrophy the degradation of eIF3f suppresses S6K1 activation by mTOR, whereas an eIF3f mutant insensitive to MAFbx polyubiquitination maintained persistent phosphorylation of S6K1 and rpS6. During terminal muscle differentiation a conserved TOS motif in eIF3f connects mTOR/raptor complex, which phosphorylates S6K1 and regulates downstream effectors of mTOR and Cap-dependent translation initiation. Thus eIF3f plays a major role for proper activity of mTORC1 to regulate skeletal muscle size.

International audience; Myostatin deficiency leads in skeletal muscle overgrowth but the precise molecular mechanisms underlying this hypertrophy are not well understood. In this study, to gain insight into the role of endogenous myostatin in the translational regulation, we used an in vitro model of cultured satellite cells derived from myostatin knock-out mice. Our results show that myostatin knock-out myotubes are larger than control myotubes and that this phenotype is associated with an increased activation of the Akt/mTOR signaling pathway, a known regulator of muscle hypertrophy. These results demonstrate that hypertrophy due to myostatin deficiency is preserved in vitro and suggest that myostatin deletion results in an increased protein synthesis. Accordingly, the rates of global RNA content, polysome formation and protein synthesis are all increased in myostatin-deficient myotubes while they are counteracted by the addition of recombinant myostatin. We furthermore demonstrated that genetic deletion of myostatin stimulates cap-dependent translation by positively regulating assembly of the translation preinitiation complex. Together the data indicate that myostatin controls muscle hypertrophy in part by regulating protein synthesis initiation rates, that is, translational efficiency.