Trans-disciplinary research approaches: integration of fluid mechanics with cell biology

At the level of the individual molecule, outstanding discoveries leading the the 2012 Nobel Prize in Chemistry clarified G-protein coupled receptors (GPCRs) crystallographic structures and functions. Nevertheless, a large number of such receptors cooperate to ultimately determine the cell response. Henceforth, understanding their group effects becomes crucial to predict the activity of the GPCRs populating the various cell aggregates

Epigenetic Alterations in RASSF1A in Human Aberrant Crypt Foci

CpG island methylation (CIM) is an epigenetic mechanism for transcriptional silencing that occurs at various stages of colon tumorigenesis. CIM has been found in serrated adenomas and hyperplastic polyps. There is also evidence for hypermethylation in aberrant crypt foci (ACF) that are found in resected colons from cancer patients. Our study addresses promoter methylation of a tumor suppressor gene, RASSF1A, within the colonic epithelium of subjects undergoing screening colonoscopies in the absence of synchronous tumors. Patients included in this study were at elevated risk for colorectal cancer (CRC) based on family history, but without a previously occurring or synchronous colon carcinoma. ACF were identified using close-focus magnifying chromendoscopy and collected by biopsy in situ. We isolated ACF and adjacent normal colonic epithelium by laser capture microdissection (LCM) and studied methylation of the RASSF1A promoter region in ACF and in adjacent normal mucosa. Expression of RASSF1A was verified using quantitative real-time polymerase chain reaction (QRT–PCR). We found that 8.6% (3 out of 35) of ACF had K-ras mutations and 24% (6 out of 25) had RASSF1A hypermethylation. Our results demonstrate that RASSF1A hypermethylation and K-ras mutations are not mutually exclusive and are present in patients at elevated risk of CRC. Importantly, CIM of RASSF1A is an early epigenetic aberration, occurring in the absence of synchronous colon tumors and is not accompanied by field effects into the surrounding epithelium

Relation of Change in Weight Status to the Development of Hypertension in Children and Adolescents

Background/Aims: This study examined the association of body mass index (BMI) percentile and change in BMI percentile to change in blood pressure (BP) percentile and development of hypertension in children and adolescents. Methods: This retrospective cohort included 101,725 subjects aged 3–17 years from three health systems across the United States. Height, weight, age, sex and BP measures were extracted from electronic health records, and then age/sex/height-adjusted BP percentiles and BMI percentiles were computed. Mixed linear regression estimated change in systolic BP percentile, and proportional hazards regression was used to estimate risk of incident hypertension associated with BMI percentile and change in BMI percentile. Results: The largest increases in BP percentile were observed among children and adolescents who became obese or maintained obesity. Over a median 3.1-year follow-up, 0.4% of subjects developed hypertension. Obese children aged 3–11 had 3.5-fold increased risk of developing hypertension compared with normal weight. Obese adolescents aged 12–17 had 3.2-fold increased risk of developing hypertension compared with normal weight. Children and adolescents who stayed obese had 5.4- and 4.8-fold increased risk of developing hypertension, respectively, compared with those who maintained a normal weight. Children who became obese and adolescents who became overweight had 2.6- and 2.3-fold increased risk of developing hypertension, respectively. Conclusion: We observed a strong, statistically significant association between increasing BMI percentile and increases in BP percentile, with risk of incident hypertension primarily associated with obesity. The adverse impact of weight gain and obesity in this young cohort over a short period of time underscores the need for effective strategies for prevention of overweight and obesity in youth to slow progression toward diabetes and cardiovascular disease later in life