Background-A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca 2ϩ current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF. Methods and Results-The miRNA transcriptome was analyzed by microarray and verified by real-time reversetranscription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223, miR-328, and miR-664 were found to be upregulated by Ͼ2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca 2ϩ channel ␣1c-and ␤1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca 2ϩ current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca 2ϩ channel protein subunits. Conclusions-miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca 2ϩ channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF. (Circulation. 2010;122:2378-2387.)

Background Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. Methods BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. Results A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. Conclusions BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway. Trial registration Clinical Trials.govNCT01767311.

BackgroundPrevious studies showed inconsistent results on the association of smoking with all-cause dementia and vascular dementia (VaD), and are limited by inclusion of a small number of studies and unexplained heterogeneity. Our review aimed to assess the risk of all-cause dementia, Alzheimer’s disease (AD) and VaD associated with smoking, and to identify potential effect modifiers.Methods and FindingsThe PubMed, Embase, Cochrane Library and Psychinfo databases were searched to identify studies that provided risk estimates on smoking and incidence of dementia. A random-effects model was used to yield pooled results. Thirty-seven studies were included. Compared with never smokers, current smokers showed an increased risk of all-cause dementia (risk ratio (RR) 1.30, 95% confidence interval (CI) 1.18–1.45), AD (RR 1.40, 95% CI 1.13–1.73) and VaD (RR 1.38, 95% CI 1.15–1.66). For all-cause dementia, the risk increased by 34% for every 20 cigarettes per day (RR 1.34, 95% CI 1.25–1.43). Former smokers did not show an increased risk of all-cause dementia (RR 1.01, 95% CI 0.96–1.06), AD (RR 1.04, 95% CI 0.96–1.13) and VaD (RR 0.97, 95% CI 0.83–1.13). Subgroup analyses indicated that (1) the significantly increased risk of AD from current smoking was seen only in apolipoprotein E ε4 noncarriers; (2) current smokers aged 65 to 75 years at baseline showed increased risk of all-cause dementia and AD compared to those aged over 75 or under 65 years; and (3) sex, race, study location and diagnostic criteria difference in risk of dementia was not found.ConclusionsSmokers show an increased risk of dementia, and smoking cessation decreases the risk to that of never smokers. The increased risk of AD from smoking is more pronounced in apolipoprotein E ε4 noncarriers. Survival bias and competing risk reduce the risk of dementia from smoking at extreme age.

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung cancer, LKB1 is somatically inactivated in 25-30% of cases, often concurrently with activating KRAS mutation. Here, we employed an integrative approach to define novel therapeutic targets in KRAS-driven LKB1 mutant lung cancers. High-throughput RNAi screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling demonstrated that Lkb1-null cells had striking decreases in multiple nucleotide metabolites as compared to the Lkb1-wt cells. Thus, LKB1 mutant lung cancers have deficits in nucleotide metabolism conferring hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors.

Prostate cancer (PC) remains the second most common cause of cancer-related death in Western countries. A previous proteomics study suggested that the nuclear membrane protein lamin A/C to be a maker to discriminate low- and high-Gleason score tumors and to identify high-risk cancers. To characterize its function in PC cells, we performed a detailed expression analysis in PC tissue and explored the consequences of down or upregulation of lamin A/C in PC cells. Our results confirm an increased lamin A/C protein expression in high-risk cancers and show association of expression with tumor cell formations at the invasion fronts of tumors and in invasion 'spearheading' tumor cell clusters. In the prostate tumor cell lines, LNCaP, DU145, and PC3 small hairpin RNA knockdown or overexpression of lamin A/C resulted in inhibition or stimulation, respectively, of cell growth, colony formation, migration and invasion. Further mechanism studies suggested that the lamin A/C-related malignant behavior is regulated through modulation of the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway. Western blot results indicated that knockdown or overexpression of lamin A/C decreased or increased, respectively, protein levels of the PI3K subunits p110 and p85 in all three cell lines; phosphor-AKT in the PTEN-negative cell lines LNCaP and PC3, and, increased or decreased, respectively, PTEN protein levels in PTEN-positive DU145 cells. Together, our data suggest that lamin A/C proteins are positively involved in malignant behavior of PC cells through the PI3K/AKT/PTEN pathway. Lamin A/C may represent a new oncogenic factor and a novel therapeutic target for PC.

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BackgroundThe association between long-term benzodiazepine use and risk of dementia remains controversial. Therefore, current study aimed to quantify this association, and to explore a potential dose–response pattern.MethodsWe searched PubMed, Embase and the Cochrane Library through August 17, 2014. We included nested case-control or prospective cohort studies that provided risk estimates on the association of benzodiazepine use with risk of dementia, and a clear definition of status of benzodiazepine use. Overall effect size was calculated using a random-effects model.FindingsSix studies were eligible for inclusion, involving 11,891 dementia cases and 45,391 participants. Compared with never users, pooled adjusted risk ratios (RRs) for dementia were 1.49 (95% confidence interval (CI) 1.30–1.72) for ever users, 1.55 (95% CI 1.31–1.83) for recent users, and 1.55 (95% CI 1.17–2.03) for past users. The risk of dementia increased by 22% for every additional 20 defined daily dose per year (RR, 1.22, 95%CI 1.18–1.25). When we restricted our meta-analyses to unadjusted RRs, all initial significant associations persisted.ConclusionsLong-term benzodiazepine users have an increased risk of dementia compared with never users. However, findings from our study should be treated with caution due to limited studies and potential reverse causation. Large prospective cohort studies with long follow-up duration are warranted to confirm these findings.

Background and Purpose-Although recent trials have suggested that stenting is worse than medical therapy for patients with severe symptomatic intracranial atherosclerotic stenosis, it is not clear whether this conclusion applies to a subset of patients with hypoperfusion symptoms. To justify for a new trial in China, we performed a multicenter prospective registry study to evaluate the safety and efficacy of endovascular stenting within 30 days for patients with severe symptomatic intracranial atherosclerotic stenosis. Methods-Patients with symptomatic intracranial atherosclerotic stenosis caused by 70% to 99% stenosis combined with poor collaterals were enrolled. The patients were treated either with balloon-mounted stent or with balloon predilation plus self-expanding stent as determined by the operators following a guideline. The primary outcome within 30 days is stroke, transient ischemic attack, and death after stenting. The secondary outcome is successful revascularization. The baseline characteristics and outcomes of the 2 treatment groups were compared. Results-From September 2013 to January 2015, among 354 consecutive patients, 300 patients (aged 58.3±9.78 years) were recruited, including 159 patients treated with balloon-mounted stent and 141 patients with balloon plus self-expanding stent. The 30-day rate of stroke, transient ischemic attack, and death was 4.3%. Successful revascularization was 97.3%. Patients treated with balloon-mounted stent were older, less likely to have middle cerebral artery lesions, more likely to have vertebral artery lesions, more likely to have Mori A lesions, less likely to have Mori C lesions, and likely to have lower degree of residual stenosis than patients treated with balloon plus self-expanding stent. Conclusions-The short-term safety and efficacy of endovascular stenting for patients with severe symptomatic intracranial atherosclerotic stenosis in China is acceptable. Balloon-mounted stent may have lower degree of residual stenosis than self-expanding stent. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01968122.