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Mesial temporal lobe epilepsy (mTLE), a very common chronic neurological disorder, is frequently accompanied by neurodegeneration in the hippocampus, resulting in hippocampal sclerosis (HS); HS is the most common morphological correlate of drug resistance in mTLE patients. Incomplete knowledge of pathological changes in mTLE with HS complicates its therapy. Growing evidence indicates a role of lipid signaling pathways in epileptogenesis; thus, lipid signals emerge as potential biomarkers for the onset and evolving course of this epileptic disorder, and are potential therapeutic agents and targets. Therefore, in this study, we recruited 23 patients with medically intractable mTLE-HS and 24 non-mTLE-HS controls. We applied lipidomic analysis to identify the lipidomic profiles in the hippocampal samples of both groups. The lipidomic profiles of the hippocampus were distinctive between mTLE-HS patients and controls. We also observed that the abundance of total triglycerides showed a striking reduction in the hippocampus of mTLE-HS patients. We identified that 33 lipids were significantly differentially expressed in the hippocampus of mTLE-HS patients compared with those in the hippocampus of the controls; this might contribute to target some molecular mechanisms involved in epileptogenesis. The present study therefore reports that lipidomic changes in mTLE-HS patients may contribute to the molecular architecture of an epileptic brain. OBJECTIVE Neuropathological studies indicate that hippocampal sclerosis (HS) consists of three subtypes (ILAE types 1-3 HS). However, HS subtypes currently can only be diagnosed by pathological analysis of hippocampal tissue resected during epilepsy surgery or at autopsy. In vivo diagnosis of HS subtypes holds potential to improve our understanding of these variants in the ipsilateral as well as contralateral hippocampus. In this study, we aimed to i) evaluate the reliability of our histology-derived segmentation protocol when applied to in vivo MRI; and ii) characterize variability of HS subtypes along the hippocampal long axis in patients with epilepsy. METHODS Eleven subjects with unilateral HS were compared with ten healthy controls. THAL-SNS-032 in vitro We used 4.7 T MRI to acquire high resolution MR Images of the hippocampus in each subject. In vivo MRI-based diagnoses of HS subtypes were then determined in each patient by two methods i) hippocampal subfield volumetry of the entire hippocampal body; and ii) subfield area anstent with previous autopsy studies and highlights the necessity of studying the entire hippocampus both ipsilateral and contralateral to the seizure focus in these future studies. Pancreatic intraepithelial neoplasia (PanIN), the most common premalignant lesion of the pancreas, is a histologically well-defined precursor to invasive pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms underlying the progression of PanINs have not been fully elucidated. Previously, we demonstrated that the expression of collapsin response mediator protein 4 (CRMP4) in PDAC was associated with poor prognosis. The expression of CRMP4 was also augmented in a pancreatitis mouse model. However, the role of CRMP4 in the progression of PanIN lesions remains uncertain. In the present study, we examined the relationship between CRMP4 expression and progression of PanIN lesions using genetically engineered mouse models. PanIN lesions were induced by peritoneal injection of the cholecystokinin analog caerulein in LSL-KRASG12D; Pdx1-Cre (KC-Crmp4 wild-type, WT) mice and LSL-KRASG12D; Pdx1-Cre; Crmp4-/- (KC-Crmp4 knockout, KO) mice. We analyzed pancreatic tissue sections from these mice and evaluated PanIN grade by hematoxylin and eosin staining. CRMP4 expression was examined and the cellular components assessed by immunohistochemistry using antibodies against CRMP4, CD3, and α-smooth muscle actin (SMA). The incidence of high-grade PanIN in KC-Crmp4 WT mice was higher than that in KC-Crmp4 KO animals. CRMP4 was expressed not only in epithelial cells but also in αSMA-positive cells in stromal areas of PanIN lesions. The CRMP4 expression in stromal areas correlated with PanIN grade in WT mice. These results suggested that the expression of CRMP4 in stromal cells may underlie the incidence or progression of PanIN. BACKGROUND In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis. METHODS A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry hERG1 potassium channel, β1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up. RESULTS (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, β1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status. CONCLUSIONS hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment. ESR1 mutations in breast cancer are known as one of the mechanisms of resistance to aromatase inhibitors. These mutations often occur in the hotspot regions in the ligand binding domain (LBD), but comprehensive mutational analysis has shown that mutations are observed throughout the whole LBD. We previously developed a molecular barcode sequencing (MB-NGS) technique to detect ESR1 hotspot mutations in plasma with high sensitivity. In this study, we have developed a multiplex MB-NGS assay that covers the whole LBD of ESR1. The assay demonstrated that the background errors in the plasma DNA of 10 healthy controls were below 0.1%; thus, the limit of detection was set at 0.1%. We analyzed the plasma DNA of 54 patients with estrogen receptor-positive metastatic breast cancer. Seventeen mutations were detected in 13 patients (24%), with variant allele frequencies ranging from 0.13% to 10.67%, including six rare mutations with a variant allele frequency less then 1.0% and a novel nonhotspot mutation (A312V). Three patients had double mutations located in the same amplicons, and it was revealed that the double mutations were located in different alleles. ESR1 hotspot mutations were associated with a longer duration of aromatase inhibitor treatment under metastatic conditions and to liver metastasis. The multiplex MB-NGS assay is useful for the sensitive and comprehensive detection of mutations throughout the whole LBD of ESR1. Our assay can be applied to any specific target region of interest using tailor-made primers and can result in minimized sequencing volume and cost. BACKGROUND The long-term effects of postoperative complications following coronary artery bypass grafting (CABG) are unknown. METHODS Medicare-linked records from the Society of Thoracic Surgeons Adult Cardiac Surgery Database were queried for isolated CABG records from 2007 through 2012. Unadjusted and adjusted associations between individual postoperative complications and both mortality and all-cause rehospitalization were evaluated to 7 years using Cox proportional-hazards models and cumulative incidence functions. Because of nonproportional hazards, associations are presented as early (0 to 90 days) and late (90 days to 7 years). RESULTS Of the 294,533 isolated CABG patients who had records linked to Medicare for long-term follow-up (median age, 73 years; 30% female), 120,721 (41%) experienced at least 1 of the complications of interest, including new-onset atrial fibrillation (30.0%), prolonged ventilation (12.3%), renal failure (4.5%), reoperation (3.5%), stroke (1.9%), and sternal wound infection (0.4%). Each of the 6 postoperative complications was associated with a significantly increased risk of mortality and rehospitalization to 7 years despite adjustment for baseline characteristics and the presence of multiple complications. Although the predominant effect of postoperative complications was observed in the first 90 days, the increased risk-adjusted hazard for death and rehospitalization continued through 7 years. CONCLUSIONS Postoperative complications are associated with an increased risk of both early and late mortality and all-cause rehospitalization, particularly during the "value" window within 90 days of CABG. These findings underscore the need to develop avoidance strategies as well as cost-adjustment methods for each of these complications. BACKGROUND Experimental evidence suggests that sedentary time (ST) may contribute to cardiovascular disease by eliciting detrimental hemodynamic changes in the lower limbs. However, little is known about objectively measured ST and lower extremity peripheral artery disease (PAD). METHODS We included 7,609 Hispanic/Latinos (ages 45-74) from the Hispanic Community Health Study/Study of Latinos. PAD was measured using the ankle brachial index (≤0.9). ST was measured using accelerometry. We used multivariable logistic regression to assess associations of quartiles of ST and PAD, and then used the same logistic models with restricted cubic splines to investigate continuous nonlinear associations of ST and PAD. Models were sequentially adjusted for traditional PAD risk factors, leg pain, and moderate- to vigorous-intensity physical activity (MVPA). RESULTS Median ST was 12.2 h/d, and 5.4% of individuals had PAD. In fully adjusted restricted cubic splines models accounting for traditional PAD risk factors, leg pain, and MVPA, ST had a significant overall (P = .048) and nonlinear (P = .024) association with PAD. A threshold effect was seen such that time spent above median ST was associated with higher odds of PAD. That is, compared to median ST, 1, 2, and 3 hours above median ST were associated with a PAD odds ratio of 1.16 (95% CI = 1.02-1.31), 1.44 (1.06-1.94), and 1.80 (1.11-2.90), respectively. CONCLUSIONS Among Hispanic/Latino adults, ST was associated with higher odds of PAD, independent of leg pain, MVPA, and traditional PAD risk factors. Notably, we observed a threshold effect such that these associations were only observed at the highest levels of ST. BACKGROUND The effect of the renin angiotensin system on blood pressure (BP) values in young adults from the general population is not well studied. We investigated the relationship between the aldosterone-to-renin ratio (ARR) and various BP indices in this population. METHODS We assembled a population-based sample of adults aged 25-41 years. Conventional and 24-hour BP recordings were obtained in all patients. Direct renin concentration and plasma aldosterone concentration were measured. Multivariable regression models were constructed to assess the relationships of ARR with BP and hypertension. RESULTS We included 1,353 individuals (mean age 37 years, 56% women). The median (interquartile range) ARR, direct renin concentration, and plasma aldosterone concentration were 13.8 (8.7-22.9), 7.2 ng/L (4.4-11.0) and 94 ng/L (68-134). All BP indices were higher across sex-specific ARR quartiles. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted β-coefficients (95% CI) for conventional, 24-hour, daytime, and nighttime systolic BP were 1.
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