No abstract

Epidemiological studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic “mutational signatures” that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018-ongoing), a retrospective case-only study of over 2,000 lung cancers in never smokers (LCINS) using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole genome sequencing has been completed on 1,257 samples. Here, we present Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiological studies.

Objective: To evaluate the effects of practice variability on chiropractic students' capacity to deliver spinal manipulations (SMs) of a targeted peak force. Methods: Forty students participated in an experimental session including either a variable or a constant practice protocol of 45 SMs. SMs were delivered on a computer-connected device that recorded force-time profiles. Ten SMs with a target peak force of 350-N were performed before practice, immediately following practice, and 2 days later. Mixed-design analyses of variance were used to assess the effect of practice type on SM biomechanical parameters and on the constant, the absolute error (AE), and the variable error (VE Conclusion: This experimental study showed that 1 session of SM practice including feedback leads to an increase in SM peak force accuracy and consistency, whether or not the practice period included variable practice. The current results confirmed that short practice periods with feedback should be included in the chiropractic curriculum.

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPKpathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.