Multiple primary melanoma in association with other personal and familial cancers.

BACKGROUND: Multiple primary melanoma (MPM) is known to be associated with familial melanoma. However, the association between MPM and other personal and familial cancers is not well documented. The objective of this study was to evaluate the association between MPM and personal history of other cancers or cancer history among first-degree relatives (FDRs). METHODS: We performed a retrospective case-control study including cases with gender-matched MPM and single primary melanoma (SPM) at a 1:2 ratio from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The associations between MPM and other cancers were evaluated using univariable and multivariable logistic regression models. RESULTS: In total, 378 patients (44.2% men; median age 52 years) were enrolled, including 252 with SPM and 126 with MPM. In comparison to patients with SPM, patients with MPM were more likely to have squamous cell carcinoma (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.001-3.79, p = 0.047) and prostate cancer (OR 2.72, 95% CI 1.07-7.01, p = 0.034). FDRs of patients with MPM had higher prevalence of melanoma (OR 2.37, 95% CI 1.31-4.28, p = 0.004) and prostate cancer (OR 2.92, 95% CI 1.47-6.14, p = 0.002) but not other cancers. In multivariable analysis, the association remained significant between MPM and squamous cell carcinoma (OR 2.18, 95% CI 1.08-4.39, p = 0.028), prostate cancer (OR 2.85, 95% CI 1.09-7.54, p = 0.032), FDR history of melanoma (OR 2.37, 95% CI 1.31-4.29, p = 0.004), and FDR history of prostate cancer (OR 3.26, 95% CI 1.59-6.83, p = 0.001). CONCLUSIONS: Patients with MPM have a higher prevalence of personal and FDR histories of nonmelanoma skin cancers and prostate cancer.

Proportions of Early Specializers Varies According to Methods and Skill Level.

Sport researchers have warned about the lack of a clear and consistent definition of early specialization, while others have raised concerns around the validity of methods used to classify athletes as 'specializers'. The current investigation includes two studies examining the implications of varying classification methods for exploring both specialization and early specialization in sport. Study 1 examined whether different approaches to defining and measuring specialization affected the classification of athletes throughout development and provided a 'profile' of the sample in terms of developmental milestones related to specialization. Results indicated the proportion of athletes classified as specializers varied depending on the method used and athletes generally met specialization milestones after the age of 12. Study 2 examined the proportions of athletes who achieved 'elite', 'pre-elite', and 'non-elite' status in adulthood who were early specializers as determined by different methods. Results showed the method used changed the proportion of athletes classified as specializers at each level and there was no clear advantage or disadvantage to being a specializer. Combined, these studies provide intriguing data regarding the implications of different measures for assessing specialization in young athletes.

The pseudo-caspase FLIP(L) regulates cell fate following p53 activation.

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

Comparing Developmental Trajectories of Elite Able-Bodied and Wheelchair Basketball Players.

Little is known about the factors influencing Paralympic athletes' journey to expertise and whether these athletes have trajectories similar to those of their able-bodied (AB) peers. The purpose of this project was to compare the developmental trajectories of wheelchair and AB basketball players. A total of 150 participants completed the Developmental History of Athletes Questionnaire. Results revealed that while AB athletes reached early career milestones at a significantly younger age, athletes with congenital impairments reached midcareer milestones at similar ages to AB athletes. In addition, athletes with acquired impairments were able to reach key late-career performance milestones (i.e., national and international debuts) at a similar age to the other two groups. The findings from this study suggest complex developmental pathways that may not be reflected in current developmental models. Therefore, the authors suggest that scientists and practitioners be cognizant of context-specific needs when providing training recommendations.

Parental sport achievement and the development of athlete expertise.

This study sought to examine how parental sport involvement and attainment were related to the eventual level of competitive sport attained by their children. Athletes (n = 229) were divided into three skill level groups (elite: n = 139; pre-elite: n = 33; non-elite: n = 57), based on the peak competition level achieved in their career, which were compared using chi-squares tests of independence and analyses of variance according to parents sport characteristics provided through the Developmental History of Athletes Questionnaire. Parental recreational and competitive sport participation was overrepresented among elite athletes, as were parents who reached an elite level of sport themselves. Results were found to differ according to parent sex, with athlete skill level significantly related to the sport participation and skill level of fathers, but not mothers. Results suggest parental sport experiences at different levels of competition influence the development of athletes, although these relationships are subject to many factors.