Integrative Expression,Survival Analysis and Cellular miR-2909 Molecular Interplay in MRN Complex Check Point Sensor Genes (MRN-CSG) Involved in Breast Cancer

BackgroundBreast cancer, an emerging global challenge, is evidenced by recent studies of miRNAs involvement in DNA repair gene variants (MRE11, RAD50, and NBN as checkpoint sensor genes (CSG) – MRN-CSG). The identification of various mutations in MRN-CSG and their interactions with miRNAs is still not understood. The emerging studies of miR-2909 involvement in other cancers led us to explore its role as molecular mechanistic marker in breast cancer.Materials and MethodsThe genomic and proteomic data of MRN-CSG of breast cancer patients (8426 samples) was evaluated to identify the mutation types linked with the patient's survival rate. Additionally, molecular, 3D-structural and functional analysis was performed to identify miR-2909 as regulator of MRN-CSG.ResultsThe genomic and proteomic data analysis shows genetic alterations with majority of missense mutations [RAD50 (0.7%), MRE11 (1.5%), and NBN (11%)], though with highest MRE11 mRNA expression in invasive ductal breast carcinoma as compared to other breast cancer types. The Kaplan–Meier survival curves suggest higher survival rate for unaltered groups as compared to the altered group. Network analysis and disease association of miR-2909 and MRN-CSG shows strong interactions with other partners. The molecular hybridization between miR-2909-RAD50 and miR-2909-MRE11 complexes showed thermodynamically stable structures. Further, argonaute protein, involved in RNA silencing, docking studies with miR-MRE11-mRNA and miR-RAD50-mRNA hybridized complexes showed strong binding affinity.ConclusionThe results suggest that miR-2909 forms strong thermodynamically stable molecular hybridized complexes with MRE11 and RAD50 mRNAs which further strongly interacts with argonaute protein to show potential molecular mechanistic role in breast cancer.     

Socioeconomic Deprivation and Premature Cardiovascular Mortality in the United States

ObjectiveTo determine the variability in county cardiovascular (CV) premature mortality explained by integrated metrics of socioeconomic deprivation and to explore temporal trends in CV mortality by county socioeconomic deprivation.MethodsThis is a cross-sectional analysis of US county-level death certificate data from 1999 to 2018 of age-adjusted premature (25 to 64 years) CV mortality. Integrated metrics of socioeconomic deprivation (Social Deprivation Index [SDI] and county Area Deprivation Index [ADI]) were associated with mortality using linear regression analysis. Relative change in county CV mortality from 1999 to 2018 was associated with indices using linear regression analysis.ResultsCounties with higher quartile SDI and ADI had significantly higher total, non-Hispanic Black/African American, and female premature CV mortality (P<.001). Both SDI and ADI were significantly associated with CV mortality by linear regression (P<.001) explaining 40% and 44% of county variability in CV mortality, respectively. Counties with lower deprivation indices experienced a larger decreased in premature CV mortality (P<.001).ConclusionThis study demonstrates an association between multiple integrated metrics of socioeconomic deprivation and premature cardiovascular mortality and shows potentially worsening disparities.     

Depression embodied: an ambiguous striving against fading

Although depression is associated to physical discomfort, meanings of the body in depression are rarely addressed in clinical research. Drawing on the concept of the lived body, this study explores depression as an embodied phenomenon. Using a hermeneutic phenomenological approach, the analysis of narrative‐based interviews with 11 depressed adults discloses a thematic structure of an embodied process of an ambiguous striving against fading. Five subthemes elicit different dimensions of this process, interpreted as disabling or enabling: feeling estranged, feeling confined, feeling burdensome, sensing life and seeking belongingness. In relation to clinical practice, we suggest that the interdisciplinary team can focus on enhancing the enabling dimensions, for example through guided physical activities to support the patient to feel more alive, capable and connected. Moreover, we suggest that the treatment process benefits from an increased awareness of the ambiguity in the patient's struggle, acknowledging both destructive and recharging elements of the withdrawing, and the perceived conflict in‐between.     

Vascular and Chronological Age in Subjects with Erectile Dysfunction: A Cross-Sectional Study

IntroductionVascular age, as derived from the SCORE project algorithm for cardiovascular (CV) risk estimation, is an effective way for communicating CV risk. However, studies on its clinical correlates are scanty.AimTo evaluate if the difference between vascular and chronological age (Δage), in a population of subjects with erectile dysfunction (ED), can identify men with a worse risk profile.MethodsA consecutive series of 2,853 male patients attending the outpatient clinic for erectile dysfunction (ED) for the first time was retrospectively studied. Among them, 85.4% (n = 2,437) were free of previous MACE and were analyzed.Main Outcome MeasuresSeveral clinical, biochemical, and penile color Doppler parameters were studied. Vascular age was derived from the SCORE project algorithm, and the Δage was considered.ResultsHigher Δage is associated with several conventional (family history of CV diseases, hyperglycemia, elevated triglycerides, and increased prevalence of metabolic syndrome) and unconventional (severity of ED, frequency of sexual activity, alcohol abuse, lower education level, fatherhood, extramarital affairs, compensated hypogonadism, and low prolactin levels) risk factors. Δage is inversely related to penile color Doppler parameters, including flaccid and dynamic peak systolic velocity and flaccid acceleration (β = −0.125, −0.113, and −0.134, respectively, all P < 0.0001).ConclusionsIn subjects referring for ED without a personal history of CV events, Δage is associated with an adverse cardio-metabolic profile and worse penile color Doppler ultrasound parameters. Δage provides a simple method for identifying high-risk men that must undergo significant modification in their lifestyle and risk factors. In addition, it can be considered a simple, inexpensive, and safe surrogate marker of penile arterial damage.     

Periodontal CGRP contributes to orofacial pain following experimental tooth movement in rats

Calcitonin-related gene peptide (CGRP) plays an important role in orofacial inflammatory pain. The aim of this study was to determine whether periodontal CGRP contributes to orofacial pain induced by experimental tooth movement in rats. Male Sprague–Dawley rats were used in this study. Closed coil springs were used to deliver forces. Rats were euthanized on 0 d, 1 d, 3 d, 5 d, 7 d, and 14 d following experimental tooth movement. Then, alveolar bones were obtained for immunostaining of periodontal tissues against CGRP. Two hours prior to euthanasia on each day, orofacial pain levels were assessed through rat grimace scale. CGRP and olcegepant (CGRP receptor antagonist) were injected into periodontal tissues to verify the roles of periodontal CGRP in orofacial pain induced by experimental tooth movement. Periodontal CGRP expression levels and orofacial pain levels were elevated on 1 d, 3 d, 5 d, and 7 d following experimental tooth movement. The two indices were significantly correlated with each other and fitted into a dose–response model. Periodontal administration of CGRP could elevate periodontal CGRP expressions and exacerbate orofacial pain. Moreover, olcegepant administration could decrease periodontal CGRP expressions and alleviate orofacial pain. Therefore, periodontal CGRP plays an important role in pain transmission and modulation following experimental tooth movement. We suggest that it may participate in a positive feedback aiming to amplify orofacial pain signals.