Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer

Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule–dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.     

Trastuzumab-induced cardiotoxicity: heart failure at the crossroads

Trastuzumab, a drug targeting human epidermal growth factor receptor 2, improves survival rate in women with metastatic breast cancer. Symptomatic heart failure, a serious adverse effect of trastuzumab, occurs in 1% to 4% of patients treated with the antibody, whereas left ventricular ejection fraction declines substantially in 10% of patients. The prevalence of cardiotoxic effects of trastuzumab appears to increase with exposure to anthracyclines. Serial assessment of left ventricular function with 2-dimensional echocardiography or radionuclide ventriculography is the most practical means of monitoring cardiotoxicity. Patients who develop cardiotoxicity while receiving trastuzumab therapy generally improve once use of the agent is discontinued.     

Socio-economic inequalities in physical activity practice among Italian children and adolescents: a cross-sectional study

Aim  

The aim of the study was to evaluate whether socio-economic inequalities in the practice of physical activity existed among children and adolescents, using different indicators of socio-economic status (SES).     

Hipogonadismo prolongado tras la suspensión de tratamiento hormonal en pacientes con cáncer de próstata

ObjectivesTo study the levels of LH, testosterone and PSA after suspending prolonged treatment with LH-RH analogs.Materials and MethodHormonal evolution was studied in 29 patients from whom treatment had been withdrawn. The patients had previously been receiving treatment with LH-RH analog for more than one year, and with LH< 2 mUI/mL and testosterone <2.8 ng/mL. LH, testosterone and PSA were determined monthly, together with clinical assessment. The treatment was re-initiated and the period of monitoring ended before the presence of clinical progression and/or PSA ? 10 ng/mL. The cohort was described and survival was calculated using Kaplan-Meier and Cox regression.ResultsThe mean period of time without treatment for the series was 35 months (CI 95%, 15.7-54.2 months). Prolonged hypogonadism (> 24 months) was presented by 17% of the patients. The recovery of the LH-T-PSA axis, when it occurred, followed the expected sequence. The variables that influenced the period of recovery of the PSA were the PSA pretreatment and the association of an antiandrogen.ConclusionsAfter withdrawing the prolonged treatment with LH-RH analogs, most of the patients recovered the levels of LH-T-PSA, although a subgroup remained hypogonadic for more than 24 months.     

Neuroacanthocytosis and carbamazepine responsive paroxysmal dyskinesias

Neuroacanthocytosis (NA) comprises a genetically heterogeneous group of disorders characterized by dysfunction of the erythrocyte membrane, presenting with acanthocytes and several neurological manifestations. We report the case of a 42-year-old woman with NA who in addition had episodes consistent with paroxysmal dyskinesias. She was diagnosed with NA featuring mild chorea, weakness of the right lower extremity and myoclonic jerks. However, one year after onset she presented attacks of paroxysmal abnormal movements, consistent with paroxysmal kinesigenic dyskinesias. Carbamazepine markedly reduced the frequency and severity of the attacks. Our case illustrates that paroxysmal dyskinesias can be a hitherto unrecognized manifestation of neuroacanthocytosis responsive to carbamazepine.     

Benign adult familial myoclonic epilepsy (BAFME): evidence of an extended founder haplotype on chromosome 2p11.1-q12.2 in five Italian families

Benign adult familial myoclonic epilepsy (BAFME or FAME) is an autosomal dominant condition, characterized by shivering-like tremors of cortical origin, myoclonus, and epilepsy. Linkage to chromosomes 2p11.1-q12.2 and 8q23.1-q24.11 has been reported in Japanese and Italian families, respectively. We aimed to determine whether a common founder haplotype was shared by five BAFME families from southern Italy and attempted preliminary genotype-phenotype correlation analyses. Five Italian BAFME families were identified. One family has not been previously reported. DNA from 53 affected individuals was genotyped with highly polymorphic microsatellite markers spanning chromosomes 2p11.1-q12.2 and 8q23.1-q24.11. Multipoint linkage analysis was performed using LINKMAP 5.1 software assuming an autosomal dominant trait with 0.99 penetrance and frequency of 0.001. Significant linkage was found on chromosome 2p11.1-q12.2 and a maximum cumulative lod score of 18.5 was found for markers D2S2161 and D2S388. The haplotype "5332" of adjacent markers D2S388, D2S2216, D2S113, and D2S2175 segregates with the disease in all families indicating that the same mutation inherited from a common ancestor segregates in these families. Preliminary genotype-phenotype showed that patients carrying the disease haplotype show minor clinical differences, suggesting that expressivity of the founder mutation is not markedly influenced by other factors. The identification of causative mutations in BAFME requires an extensive and collaborative screening effort.     

Completed versus attempted suicide in psychiatric patients: a psychological autopsy study

The aims of this study were to identify specific risk factors associated with completed suicide in a sample of suicide victims diagnosed with mental illness and to discriminate completed suicides from attempted suicide in individuals who did not kill themselves for at least the next 2 years after the index attempt. Ninety-four adults (34 women; 60 men; mean age = 50.81 [SD = 18.08]) admitted to the Division of Psychiatry of the Department of Neurosciences of the University of Parma who died by suicide between 1994-2004 were matched for sex and age (+/- 2 years) with 94 outpatients (mean age = 50.70 [SD = 18.08]) who made at least one suicide attempt during the years of the study. Data were gathered by proxy-based interviews with referring psychiatrists and general practitioners and from examination of medical records. Suicide victims were more likely to be not married, have poor social support (OR = 5.28), and have more voluntary and compulsory admissions to hospitals (1 admission: OR = 5.44; > 1 admissions: OR= 8.84) than suicide attempters. Suicide victims were also less likely to have had stressful life events during their childhood and adolescence (OR = 0.09) and to be divorced or widowed than were the attempters.