Citations

Background Youth-onset diabetes mellitus (DM) is an increasing public health concern, especially among adolescents facing socioeconomic challenges. Food insecurity (FI), a key social determinant of health, has been linked to adverse metabolic outcomes, but its association with youth-onset DM and the role of preventive care remain unclear. Methods Using repeated cross-sectional data from the National Survey of Children’s Health (2016–2021), we examined the association between FI status (food secure, mild FI and moderate-to-severe FI) and youth-onset DM among adolescents aged 10–17 years. We also evaluated whether usual preventive care modified this association. Propensity score weighting (PSW) was used to reduce the imbalance of measured confounders across FI groups. These weights were applied in the least absolute shrinkage and selection operator logistic regression for variable selection and in the final multivariable logistic regression models. Results In the PSW analysis of 66 560 adolescents, 432 had youth-onset DM. Moderate-to-severe FI was associated with higher odds of DM than food-secure adolescents (OR 1.55, 95% CI 1.35 to 1.77; p<0.0001), whereas mild FI was not associated with youth-onset DM. Among adolescents with preventive care visits, both mild FI (OR 1.19, 95% CI 1.04 to 1.37; p=0.0126) and moderate-to-severe FI (OR 1.67, 95% CI 1.46 to 1.92; p<0.0001) were associated with higher odds of DM. Among those without preventive care visits, FI was associated with lower odds of having a reported DM diagnosis, especially in the moderate-to-severe FI group (OR 0.11, 95% CI 0.03 to 0.35; p=0.0002). Conclusions Moderate-to-severe FI was associated with youth-onset DM, and this relationship varied by access to preventive care. Adolescents with FI who lack regular preventive care may have fewer opportunities for DM diagnosis. Public health strategies should integrate FI screening, equitable access to preventive services and culturally responsive approaches to chronic disease prevention.

Background Sex affects the prevalence of atherosclerotic cardiovascular disease (ASCVD) risk factors but whether sex differences exist in the associations between ASCVD risk burden and cognitive function is unclear. Methods This cross‐sectional study included participants from a population‐based cohort study in China that recruited community‐dwelling adults aged 50 to 75 years without baseline cardiovascular disease and stroke. The 10‐year ASCVD risk burden was quantified with 3 multivariate risk prediction equations. Cognitive domains of memory, attention, visuospatial function, executive function, and processing speed were assessed. Multivariable linear regression models were used to examine the interaction terms between sex and ASCVD risk scores on cognition. Results The final analytical sample included 2180 participants. Mean±SD age was 60.14 (6.38) and 52.1% were women. Men showed significantly higher ASCVD risk burden than women at baseline but the effect of ASCVD risk on 2‐year cognition were amplified in women compared with men, for the domains of memory (eg, β=−0.20 [95% CI, –0.26 to −0.13] versus β=−0.11 [95% CI, –0.16 to −0.07]), executive function (eg, β=−0.23 [95% CI, –0.31 to −0.16] versus β=−0.16 [95% CI, –0.21 to −0.10]), and processing speed (eg, β=−0.33 [95% CI, –0.39 to −0.27] versus β=−0.17 [95% CI, –0.21 to −0.13]). Sex‐stratified analyses showed different neuropsychological profiles at moderate ASCVD risk burden levels, suggesting sex‐specific ASCVD‐risk related cognitive phenotypes. Conclusions Sex differences in cognitive health affected by ASCVD risk underscore the importance of sex‐specific cognitive monitoring during ASCVD risk management and better vascular risk control in women to prevent cognitive decline.

AbstractLiver fibrosis is a pathological process resulting from prolonged exposure to various injury factors. It is characterized by the abnormal proliferation and activation of hepatic stellate cells and excessive deposition of extracellular matrix. If left untreated, it can progress to cirrhosis, liver failure, and even liver cancer. There is currently no efficient and accurate clinical diagnostic method for early liver fibrosis. Therefore, there is an urgent need to address the challenge of accurate staging and early diagnosis of liver fibrosis in clinical practice. Recently, nanomaterials have demonstrated significant potential for enhancing the diagnosis of liver fibrosis. Nanomaterials possess the ability to precisely identify and target the microenvironment associated with liver fibrosis. By enhancing their enrichment in the target area, nanomaterials can improve imaging contrast of fibrosis lesions in the liver, thereby enabling accurate diagnosis of liver fibrosis. Accordingly, this review delves into the latest research and advancements concerning nanomaterials in liver fibrosis diagnosis.

Abstract BACKGROUND Congenital disorders of glycosylation (CDG) represent 1 of the largest groups of metabolic disorders with &gt;130 subtypes identified to date. The majority of CDG subtypes are disorders of N-linked glycosylation, in which carbohydrate residues, namely, N-glycans, are posttranslationally linked to asparagine molecules in peptides. To improve the diagnostic capability for CDG, we developed and validated a plasma N-glycan assay using flow injection–electrospray ionization–quadrupole time-of-flight mass spectrometry. METHODS After PNGase F digestion of plasma glycoproteins, N-glycans were linked to a quinolone using a transient amine group at the reducing end, isolated by a hydrophilic interaction chromatography column, and then identified by accurate mass and quantified using a stable isotope-labeled glycopeptide as the internal standard. RESULTS This assay differed from other N-glycan profiling methods because it was free of any contamination from circulating free glycans and was semiquantitative. The low end of the detection range tested was at 63 nmol/L for disialo-biantennary N-glycan. The majority of N-glycans in normal plasma had &lt;1% abundance. Abnormal N-glycan profiles from 19 patients with known diagnoses of 11 different CDG subtypes were generated, some of which had previously been reported to have normal N-linked protein glycosylation by carbohydrate-deficient transferrin analysis. CONCLUSIONS The clinical specificity and sensitivity of N-glycan analysis was much improved with this method. Additional CDGs can be diagnosed that would be missed by carbohydrate-deficient transferrin analysis. The assay provides novel biomarkers with diagnostic and potentially therapeutic significance.

Abstract Genome Wide Association Studies (GWAS) are designed to identify single nucleotide polymorphisms (SNPs) mapping to genomic regions associated with a particular trait or disease. Currently, 19 genomic loci associated with risk for estrogen receptor negative breast cancer have been identified. However, for most of these loci the mechanisms driving susceptibility have remained elusive. The 2p23.2 locus, defined by SNP rs67073037 (p = 4.76 x 10-9), contains 79 SNPs exhibiting genome-wide significant associations as well as four candidate genes: SPDYA, TRMT61B, WDR43, and FAM179A. Post-GWAS functional analysis revealed two candidate causal regulatory elements: an enhancer-like element defined by SNP rs44017214 located in the first intron of the WDR43 gene; and a segment in the 3’-UTR region of WDR43 defined by SNPs rs11680458 and rs11331880 which are predicted to have allele specific binding of non-coding microRNAs miR-548 and miR-376, respectively. We validated allele specific transcription factor binding to rs44017214 using competitive binding of USF1/USF2 to the risk allele in both MCF10A and CAL51 cell lines in Electrophoretic Mobility Shift Assays (EMSA). Additionally, rs44017214 was removed using CRISPR-cas9, and expression of neighboring genes was evaluated by qRT-PCR. No change in expression was found for any gene in a 2 Mb region surrounding the SNP, with the exception of PLB1. This suggests that the enhancer element in the intron of WDR43 has PLB1 as its target. To assess the miRNA binding site impact on WDR43 expression the pMIR-REPORT Luciferase allele-specific vector was co-transfected with miR-141/200, miR548, or miR-376 in MCF10A cells. The rs1131880 allele C in the WDR43 3’-UTR lead to the suppression of luciferase expression by miR-376 compared to the G allele. This study reveals two independent regulatory mechanisms within the 2p23.2 locus; (i) modulation of enhancer activity by allele specific binding of transcription factors USF1/USF2 to rs4401714, and (ii) decreasing the expression of WDR43 through the formation of a miR-376 binding site at the 3’-UTR of the WDR43 gene. Elucidating the functional significance of these common variants in the novel susceptibility loci 2p23.2 furthers our knowledge of the etiology of estrogen receptor negative breast cancer. Citation Format: Carly M. Harro, Gustavo Mendoza-Fandino, Nicholas T. Woods, Xueli Li, Fergus J. Couch, Alvaro N. Monteiro. Two distinct regulatory mechanisms underlie estrogen receptor negative breast cancer susceptibility at the 2p23.2 locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1306. doi:10.1158/1538-7445.AM2017-1306

570 Background: Vascular endothelial growth factor- (VEGF-) and mammalian target of rapamycin- (mTOR-) directed therapies represent a standard of care in metastatic renal cell carcinoma (mRCC). However, these agents are not employed based on an assessment of predictive biomarkers such as genomic alterations (GA). We sought to determine if an association exists between GA detected by comprehensive genomic profiling (CGP) and the response to VEGFR and mTOR pathway targeted therapies in a cohort of mRCC treated in a clinical practice setting. Methods: The results of CGP performed in the course of clinical care on 31 consecutive mRCC obtained from patients who had received VEGFR- and/or mTOR-inhibitors were reviewed. Duration of treatment (DOT), extent and duration of clinical response was obtained from review of medical records. All classes of genomic alterations - base substitutions, short insertions, deletions, gene fusions, rearrangements and copy number - were assessed via CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents. Results: The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%) and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT > 21 months) were more frequent amongst patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1. Conclusions: Multiple GAs are more prevalent in exceptional responders to VEGF-directed therapy. Prospective validation of these findings may lead to use of CGP to optimize therapeutic selection.

Abstract Cigarette smoking is a major risk factor in the development of non–small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the major addictive component of tobacco smoke, can induce proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) in NSCLC cell lines and promote metastasis of NSCLC in mice. Here, we demonstrate that the scaffolding protein β-arrestin-1 is necessary for nicotine-mediated induction of mesenchymal genes vimentin and fibronectin as well as EMT regulators ZEB1 and ZEB2. Nicotine induced changes in cell morphology and ablate tight junctions consistent with EMT; β-arrestin-1, but not β-arrestin-2, was required for these changes. β-Arrestin-1 promoted the expression of the mesenchymal genes, as well as ZEB1 and ZEB2, through the mediation of the E2F1 transcription factor; this required Src kinase activity. Stimulation of multiple NSCLC cell lines with nicotine led to enhanced recruitment of β-arrestin-1 and E2F1 on vimentin, fibronectin, and ZEB1 and ZEB2 promoters. Furthermore, there was significantly more β-arrestin-1 and E2F1 associated with these promoters in human NSCLC tumors, and β-arrestin-1 levels correlated with vimentin and fibronectin levels in human NSCLC samples. A549-luciferase cells lacking β-arrestin-1 showed a significantly reduced capacity for tumor growth and metastasis when orthotopically implanted into the lungs of SCID-beige mice. Taken together, these studies reveal a novel role for β-arrestin-1 in the growth and metastasis of NSCLC. Cancer Res; 75(6); 1009–20. ©2015 AACR.