Abstract Objective : The purpose of this study was to investigate the heritability of body composition measured by DXA in the Diabetes Heart Study (DHS). Research Methods and Procedures : Participants were 292 women and 262 men (age, 38 to 86 years; BMI, 17 to 57 kg/m 2 ) from 244 families. There were 492 white and 49 African‐American sibling pairs. DXA measurements of percentage fat mass (FM), whole body FM, and lean mass (LM), as well as regional measurements of trunk fat mass (TFM) and appendicular lean mass (ALM), were obtained. Heritability of FM, LM, and BMI were estimated using Sequential Oligogenic Linkage Analysis Routines. Results : After adjusting for age, gender, ethnicity, and height, the heritability estimates of various compositional attributes were %FM = 0.64, whole body FM = 0.71, TFM = 0.63, whole body LM = 0.60, ALM = 0.66, and BMI = 0.64 (all p < 0.0001). Additional adjustment for diabetes status, smoking, dietary intake, and physical activity resulted in only minor changes in the heritability estimates (ĥ 2 = 0.63 to 0.72, all p < 0.0001). Furthermore, heritability of TFM after additional adjustment for whole body FM was significant (ĥ 2 = 0.55, p < 0.0001), and heritability of ALM after additional adjustment for whole body LM was also significant (ĥ 2 = 0.51, p < 0.0001). Discussion : These data suggest that FM and LM measured by DXA are highly heritable and can be effectively used in designing linkage studies to locate genes governing body composition. In addition, regional distribution of FM and LM may be genetically determined.
Introduction: Cervical artery dissection (CeAD) of the carotid and vertebral arteries is a prevalent cause of stroke in young adults. While the pathogenesis of incident CeAD remains poorly understood, clinical and genetic associations suggest a systemic arteriopathy at time of event. Hypothesis: Individuals suffering CeAD express a distinct gene expression profile at time of event compared to (1) age and sex-matched controls and (2) convalescent profiles within the same individual at a later time point. Methods: We enrolled 37 consecutive patients with carotid or vertebral artery dissection (with and without ischemic stroke) from 2013-2016, excluding concurrence of major trauma. Cases were age and sex matched to non-CeAD ischemic stroke controls (n=16) and healthy controls (n=11). Whole blood samples were collected within four weeks from time of event, and again at 3 and 6-month follow-up. We used IlluminaHT-12 microarrays to assess differential gene expression at time of CeAD relative to controls, and relative to gene expression at >3 month follow-up within CeAD cases. Mixed effects regression models included relevant covariates of age, sex, race/ethnicity, time of enrollment, and occurrence of stroke. We used a False Discovery Rate (FDR) cutoff of 5% to account for multiple testing as well as a 1.5 fold change cutoff to identify robust, differential gene expression. Results: We identified 538 differentially expressed genes between CeAD patients and healthy controls with 30 of these genes reaching our predetermined 1.5x fold change limit. Within CeAD cases, 1,238 genes showed differential expression at a 5% FDR compared to time points at 3-6 month follow-up, with 31 genes showing at least a 1.5 fold change. Compared to controls and convalescent profiles, 12 genes were significant using the 5% FDR and 1.5 fold change cutoffs. Preliminary gene-ontology analysis indicate the largest differential expression for genes associated with oxygen and gas transport. Conclusion: In this consecutive cohort of individuals with CeAD, we identified a distinct gene expression profile associated with incident dissection. These data are limited by small sample size and results are hypothesis generating. Replication in larger, independent cohorts is warranted.
PURPOSE: To determine the effects of a 12-month physical activity intervention on inflammatory biomarkers in elderly men and women. METHODS: 424 elderly (aged 70-89 years), nondisabled, community-dwelling men and women at risk for physical disability were enrolled in a multicenter, single-blind, randomized controlled-trial. Participants were randomized to participate in either a 12-month moderate-intensity physical activity (PA) intervention or a successful aging (SA) health education intervention. Biomarkers of inflammation (IL-6sR, IL-1sRII, sTNFRI, sTNFRII, IL-8, IL-15, adiponectin, IL-1ra, IL-2sRa, and TNF-a) were measured at baseline, 6 and 12 months. RESULTS: After adjustment for gender, clinic site, diabetes status, and baseline outcome measure, IL-8 was the only inflammatory biomarker affected by the PA intervention (p=0.03). The adjusted mean IL-8 at month 12 was 9.9% (0.87 pg/mL) lower in the PA compared to the SA group. Secondary interaction analyses between baseline biomarker status and treatment showed one significant interaction (p=0.02) such that the PA intervention reduced IL-15 concentrations in participants with a baseline IL-15 above the median value of 1.67 g/mL. However, these associations were no longer significant after consideration for multiple comparisons. CONCLUSIONS: Overall, this study does not provide definitive evidence for an effect of regular exercise for altering systemic concentrations of the measured inflammatory biomarkers in older adults.
Abstract Background Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy‐induced peripheral neuropathy (CIPN), the dose‐limiting toxicity of this agent. Methods This cross‐sectional study of breast cancer patients with taxane CIPN measured nerve cross‐sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD). Results A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm 2 smaller than healthy controls ( P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm 2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R 2 0.30; P = .04). Conclusions These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.
Abstract Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4 . LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
<div>Abstract<p>Elucidating the earliest pathogenic steps in cancer development is fundamental to improving its early detection and prevention. Ovarian high-grade serous carcinoma (HGSC), a highly aggressive cancer, mostly originates from the fallopian tube epithelium through a precursor stage, serous tubal intraepithelial carcinoma (STIC). In this study, we performed spatial transcriptomic analysis to compare STICs, carcinoma, and their matched normal fallopian tube epithelium. Several differentially expressed genes in STICs and carcinomas were involved in cancer metabolism and detected in a larger independent transcriptomic dataset of ovarian HGSCs. Among these, insulin-like growth factor binding protein-2 (IGFBP2) was found to undergo DNA hypomethylation and to be increased at the protein level in STICs. Pyrosequencing revealed an association of IGFBP2 expression with the methylation state of its proximal enhancer, and 5-azacytidine treatment increased IGFBP2 expression. In postmenopausal fallopian tubes, where most STICs are detected, IGFBP2 immunoreactivity was detected in all 38 proliferatively active STICs but was undetectable in morphologically normal tubal epithelia, including those with <i>TP53</i> mutations. In premenopausal fallopian tubes, IGFBP2 expression was limited to the secretory epithelium at the proliferative phase, and estradiol treatment increased IGFBP2 expression levels. IGFBP2 knockdown suppressed the growth of IGFBP2-expressing tubal epithelial cells via inactivation of the AKT pathway. Taken together, demethylation of the proximal enhancer of IGFBP2 drives tumor development by maintaining the increased IGFBP2 required for proliferation in an otherwise estrogen-deprived, proliferation-quiescent, and postmenopausal tubal microenvironment.</p>Significance:<p>Molecular studies of the earliest precursor lesions of ovarian cancer reveal a role of IGFBP2 in propelling tumor initiation, providing new insights into ovarian cancer development.</p></div>
Abstract Convection-enhanced delivery (CED) is an emerging method for treating highly aggressive and infiltrative forms of brain cancer, like glioblastomas. However, drawbacks of utilizing CED include limited availability of tools capable of bypassing the blood-brain barrier and blood-brain tumor barrier to deliver therapeutics to saturate the tumor and adjacent tumor periphery where highly infiltrative glioma cells may be located. The consequence is that tumor recurrence at or near the original tumor site is inevitable. The Convection-Enhanced Thermo-Therapy Catheter System (CETCS) is a remote-operable device comprising of an arborizing catheter and therapeutic delivery control system designed to maximize the distribution of therapeutics in target tissue volumes. In this study, we evaluate the performance of the CETCS in agarose gel brain tissue phantoms while monitoring the volume of infusate delivered, the dispersal volume of the infusate, and the mean distribution ratio of infusate. We report high infusion flow rates increase infusate dispersal volume but can result in backflow up the microneedles tracts; constant microneedle retraction maximizes infusate dispersal volume; and finally, low infusion flow rates resulted in better control of infusion cloud shape and minimized occurrence of backflow along microneedles.
Metabolic acidosis promotes cancer metastasis. No prospective studies have examined the association between dietary acid load and breast cancer recurrence among breast cancer survivors, who are susceptible to metabolic acidosis. Hyperglycemia promotes cancer progression and acid formation; however, researchers have not examined whether hyperglycemia can modify the association between dietary acid load and breast cancer recurrence. We studied 3081 early-stage breast cancer survivors enrolled in the Women's Healthy Eating and Living study who provided dietary information through 24-hour recalls at baseline and during follow-up and had measurements of hemoglobin A1c (HbA1c) at baseline. We assessed dietary acid load using two common dietary acid load scores, potential renal acid load (PRAL) score, and net endogenous acid production (NEAP) score. After an average of 7.3 years of follow-up, dietary acid load was positively associated with recurrence when baseline HbA1c levels were ≥5.6% (median level) and ≥5.7% (pre-diabetic cut-point). In the stratum with HbA1c ≥ 5.6%, comparing the highest to the lowest quartile of dietary acid load, the multivariable-adjusted hazard ratio was 2.15 (95%CI 1.34–3.48) for PRAL and was 2.31 (95%CI 1.42–3.74) for NEAP. No associations were observed in the stratum with HbA1c levels were <5.6%. P-values for interactions were 0.01 for PRAL and 0.05 for NEAP. Our study demonstrated for the first time that even at or above normal to high HbHbA1c levels, dietary acid load was associated increased risk of breast cancer recurrence among breast cancer survivors. California Tobacco Research Foundation NIH/NCI.
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