Project description:The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.
Project description:ObjectiveThis randomized controlled trial tested the efficacy of early intervention to prevent adult psychopathology and improve well-being in early-starting conduct-problem children.MethodKindergarteners (N=9,594) in three cohorts (1991-1993) at 55 schools in four communities were screened for conduct problems, yielding 979 early starters. A total of 891 (91%) consented (51% African American, 47% European American; 69% boys). Children were randomly assigned by school cluster to a 10-year intervention or control. The intervention goal was to develop social competencies in children that would carry them throughout life, through social skills training, parent behavior-management training with home visiting, peer coaching, reading tutoring, and classroom social-emotional curricula. Manualization and supervision ensured program fidelity. Ninety-eight percent participated during grade 1, and 80% continued through grade 10. At age 25, arrest records were reviewed (N=817, 92%), and condition-blinded adults psychiatrically interviewed participants (N=702; 81% of living participants) and a peer (N=535) knowledgeable about the participant.ResultsIntent-to-treat logistic regression analyses indicated that 69% of participants in the control arm displayed at least one externalizing, internalizing, or substance abuse psychiatric problem (based on self- or peer interview) at age 25, in contrast with 59% of those assigned to intervention (odds ratio=0.59, CI=0.43-0.81; number needed to treat=8). This pattern also held for self-interviews, peer interviews, scores using an "and" rule for self- and peer reports, and separate tests for externalizing problems, internalizing problems, and substance abuse problems, as well as for each of three cohorts, four sites, male participants, female participants, African Americans, European Americans, moderate-risk, and high-risk subgroups. Intervention participants also received lower severity-weighted violent (standardized estimate=-0.37) and drug (standardized estimate=-0.43) crime conviction scores, lower risky sexual behavior scores (standardized estimate=-0.24), and higher well-being scores (standardized estimate=0.19).ConclusionsThis study provides evidence for the efficacy of early intervention in preventing adult psychopathology among high-risk early-starting conduct-problem children.
Project description:Scientific evidence indicates that genetic factors may contribute to differences in lung cancer risk for individuals with similar levels of tobacco exposure, which is the main environmental risk factor of lung cancer. Moreover, lung cancer patients show large differences in clinical staging and survival; these differences seem to be attributable, at least partially, to the genetic background. The analysis of the molecular properties (e.g., germline variations and genome-wide expression levels) of non-involved tissue from lung cancer patients may contribute in the identification of genetic factors involved in the development and progression of this pathology. To this aim, we analyzed two series (discovery series, n = 204, and validation series, n = 78) of non-tumor lung tissue samples from smokers that underwent surgical lobectomy for adenocarcinoma in Milan, Italy. First, we examined the whole transcriptome of these two series to define the candidate genes and pathways associated with either lung cancer risk or prognosis in this cohort. Moreover, as sex and age are known to strongly influence the pathophysiology of human lungs, we used transcriptome data from the same samples to identify sex- and age-related transcriptional differences in lung.