Objectives
This study aimed to examine the association between statin exposure and dementia risk in individuals with hypercholesterolaemia using data from the NHIS‐HEALS database between 2002 and ...2015.
Methods
Subjects were classified into statin exposure and statin nonexposure groups according to medication possession ratio. Dementia was defined as those with primary diagnostic dementia codes such as F00‐F03, G30, G31.1, G31.9 or G31.82. Cox proportional hazards regression models were adopted after stepwise adjustment for confounders to investigate the prospective association between statin exposure and dementia risk.
Results
During the follow‐up period (median follow‐up 11.7 years), 711 cases of dementia occurred, accounting for 11.5% of the total study population (statin exposure group, 8.2%; statin nonexposure group, 12.9%). Compared to the statin nonexposure group, fully adjusted hazard ratios (HRs) (95% confidence intervals CIs) for overall dementia in the statin exposure group were 0.63 (0.43–0.91) and 0.62 (0.50–0.78) in men and women, respectively. Compared to the statin nonexposure group, the HRs (95% CIs) for Alzheimer’s disease and related dementia, vascular dementia and other types of dementia in the statin exposure group were 0.54 (0.32–0.91), 2.45 (0.69–8.68) and 0.59 (0.32–1.07), respectively, in men and 0.53 (0.38–0.73), 1.29 (0.42–3.96) and 0.70 (0.51–0.96), respectively, in women.
Conclusions
Hypercholesterolaemic individuals exposed to statin had a lower risk of overall dementia and Alzheimer’s disease and related dementia in both sexes, and a lower risk of other types of dementia in women, than subjects who were not exposed to statins.
We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).
The ...PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected toin vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.
The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations ofFGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib.
FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
Summary In a candidate gene association study, we found that the variations of calcitonin receptor (CALCR) gene were related to the risk of vertebral fracture and increased bone mineral density ...(BMD). Introduction Calcitonins through calcitonin receptors inhibit osteoclast-mediated bone resorption and modulate calcium ion excretion by the kidney and also prevent vertebral bone loss in early menopause. Methods To identify genetically susceptible factors of osteoporosis, we discovered the variations in CALCR gene, genotyped in Korean postmenopausal women (n = 729), and examined the potential involvement of seven single-nucleotide polymorphism (SNPs) and their haplotypes in linkage disequilibrium block (BL_hts). Results The SNPs, +43147G > C (intron 7), +60644C > T (exon13, 3' untranslated region), and their haplotypes, BL2_ht1 and BL2_ht2, showed a significant association with risk of vertebral fracture (p = 0.048-0.004) and BL2_ht1 showed a highly significant protective effect. Moreover, the polymorphism +60644C > T showed a highly significant association with BMD at both lumbar spine and femoral neck. The subjects carrying CC and CT genotypes with the SNP, +60644C > T, had higher BMD values at the lumbar spine (p = 0.01-0.001) and femoral neck (p = 0.025-0.009). Conclusion These results indicate that the CALCR gene may regulate bone metabolism, and +60644C > T in the CALCR gene may genetically modulate bone phenotype.
alpha-Synuclein gene (SNCA) multiplication was found in familial Parkinson disease (PD). We examined SNCA multiplication in patients with familial and sporadic PD and multiple system atrophy (MSA).
...We screened 1,106 patients with parkinsonism (PD = 906, MSA = 200) for SNCA multiplication by multiplex PCR. Fluorescent in situ hybridization was done to confirm the multiplication. (123)IN-omega-Fluoropropyl-2 beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ((123)IFP-CIT) SPECT was done in the patients with SNCA multiplication and their family members.
Three patients were identified as having SNCA duplication. One patient had a positive family history, and two patients were sporadic. Each patient had asymptomatic carriers in their families. The familial case had early onset parkinsonism with rapidly progressive course, cognitive impairment, and dysautonomia. Sporadic cases were more typical of PD. (123)IFP-CIT SPECT was abnormal in the patients and normal in the asymptomatic carriers.
SNCA multiplication is present in sporadic Parkinson disease (PD) and needs to be screened. Low penetrance, clinical heterogeneity, and normal dopamine transporter imaging in asymptomatic carriers may suggest the presence of other genetic modifiers or environmental triggers that play a role in the pathogenesis of PD due to SNCA duplication.
This study was conducted to investigate the inhibitory effects of the cell‐free culture supernatant of Lactobacillus curvatus Wikim 38 (LC38‐CS) on RANKL‐induced osteoclast differentiation and bone ...loss in a mice model of ovariectomy‐induced post‐menopausal osteoporosis. LC38‐CS inhibited the RANKL‐induced differentiation of bone marrow‐derived macrophages (BMDMs) into osteoclasts in a dose‐dependent manner. F‐actin ring formation and bone resorption were also reduced by LC38‐CS treatment of RANKL‐treated BMDMs. In addition, LC38‐CS decreased the RANKL‐induced activation of the TRAF6/NF‐κB/MAPKs axis at the early stage and the expression of osteoclastogenesis‐related genes in BMDMs treated with RANKL. PRMT1 and ADMA levels, new biomarkers for osteoclastogenesis, were decreased by LC38‐CS treatment. The administration of LC38‐CS increased bone volume and bone mineral density in ovariectomized mice in μ‐CT analysis. These findings suggest that LC38‐CS inhibited RANKL‐induced osteoclast differentiation by the downregulation of molecular mechanisms and exerted anti‐osteoporotic effects.
Significance and Impact of the Study: Half of women older than 50 years will experience an osteoporosis‐related fracture in their lifetime, and thus novel therapies are needed to combat post‐menopausal bone loss. Recent studies suggest an important role for microbiota in regulating bone health. This study proposes that the administration of postbiotic of Lactobacillus curvatus Wikim 38, may be a therapeutic candidate for destructive bone diseases.
Summary
Background
Autophagy and neutrophil extracellular DNA traps (NETs) are implicated in asthma; however, their roles in asthma pathogenesis have not been elucidated.
Objectives
We compared ...autophagy and NET production levels from peripheral blood neutrophils (PBNs) of patients with severe asthma (SA) and non‐severe asthma (NSA). Additionally, we investigated the inflammatory effects of NETs on human airway epithelial cells (AECs) and peripheral blood eosinophils (PBEs).
Methods
Peripheral blood neutrophils from patients with SA (n = 30) and NSA (n = 38) were treated with interleukin (IL)‐8 (100 ng/mL). Autophagy (light chain 3‐II expression) and NET production levels were evaluated by Western blot, immunofluorescence microscopy, and PicoGreen assay. The effects of NETs on AECs were assessed by investigating cell death, cell detachment, expression of occludin and claudin‐1, and IL‐8 production; the effects of NETs on PBEs were examined by investigating the activation and release of eosinophil cationic protein (ECP) and eosinophil‐derived neurotoxin (EDN).
Results
Untreated and IL‐8‐treated PBNs from the SA group produced higher autophagy and NET levels compared with those from the NSA group (P < 0.01). IL‐8 increased autophagy and NET levels in PBNs from the SA group, but not from the NSA group. NET levels were correlated with autophagy levels in PBNs (P < 0.001). IL‐8‐induced NET production levels negatively were correlated with FEV1/FVC (r = −0.700, P = 0.016). NETs induced cell death, detachment, degradation of occludin and claudin‐1, and IL‐8 production from AECs. Higher levels of NET‐induced ECP and EDN were released from PBEs in SA compared with NSA groups.
Conclusions and Clinical Relevance
Neutrophil autophagy and NETs could enhance asthma severity by damaging airway epithelium and triggering inflammatory responses of AECs and PBEs. Modulating neutrophil autophagy and NET production may be a new target therapy for SA.
Post-induction hypotension is common and associated with postoperative complications. We hypothesised that pneumatic leg compression reduces post-induction hypotension in elderly patients undergoing ...robot-assisted laparoscopic prostatectomy. In this double-blind randomised study, patients were allocated randomly to the pneumatic leg compression group (n = 50) or control (n = 50). In the intervention group, pneumatic leg compression was initiated before induction of anaesthesia. In the control group, pneumatic leg compression was initiated 20 min after anaesthesia induction. The primary outcome was the incidence of post-induction hypotension in these groups. Post-induction hypotension was defined as systolic blood pressure < 90 mmHg during the first 20 min after induction. Haemodynamic variables and area under the curve of post-induction systolic blood pressure over time were assessed. Complications associated with pneumatic leg compression were recorded, including: peripheral neuropathy; compartment syndrome; extensive bullae beneath the leg sleeves; and pulmonary thromboembolism. The incidence of post-induction hypotension decreased in the pneumatic leg compression group compared with that in the control group; 5 (10%) vs. 29 (58%), respectively, p < 0.001. In the pneumatic leg compression group, the lowest systolic, diastolic and mean blood pressures 20 min after induction of anaesthesia were significantly greater than the control group. Pneumatic leg compression resulted in an increased area under the curve of systolic blood pressure in the first 20 min after induction, p = 0.001. There were no pneumatic leg compression-related complications. Pneumatic leg compression reduced post-induction hypotension in elderly patients undergoing robot-assisted laparoscopic prostatectomy, suggesting that it is an effective and safe intervention to prevent post-induction hypotension among elderly patients undergoing general anaesthesia.
Gene fusion is involved in the development of various types of malignancies. Recent advances in sequencing technology have facilitated identification of gene fusions and have stimulated the research ...of this field in cancer. In the present study, we performed next-generation transcriptome sequencing in order to discover novel gene fusions in gastric cancer. A total of 282 fusion transcript candidates were detected from 12 gastric cancer cell lines by bioinformatic filtering. Among the candidates, we have validated 19 fusion transcripts, which are 7 inter-chromosomal and 12 intra-chromosomal fusions. A novel DUS4L-BCAP29 fusion transcript was found in 2 out of 12 cell lines and 10 out of 13 gastric cancer tissues. Knockdown of DUS4L-BCAP29 transcript using siRNA inhibited cell proliferation. Soft agar assay further confirmed that this novel fusion transcript has tumorigenic potential. We also identified that microRNA-coding gene PVT1, which is amplified in double minute chromosomes in SNU-16 cells, is recurrently involved in gene fusion. PVT1 produced six different fusion transcripts involving four different genes as fusion partners. Our findings provide better insight into transcriptional and genetic alterations of gastric cancer: namely, the tumorigenic effects of transcriptional read-through and a candidate region for genetic instability.
BackgroundThe secondary cell wall is a defining feature of xylem cells and allows them to resist both gravitational forces and the tension forces associated with the transpirational pull on their ...internal columns of water. Secondary walls also constitute the majority of plant biomass. Formation of secondary walls requires co-ordinated transcriptional regulation of the genes involved in the biosynthesis of cellulose, hemicellulose and lignin. This co-ordinated control appears to involve a multifaceted and multilayered transcriptional regulatory programme.ScopeTranscription factor MYB46 (At5g12870) has been shown to function as a master regulator in secondary wall formation in Arabidopsis thaliana. Recent studies show that MYB46 not only regulates the transcription factors but also the biosynthesis genes for all of the three major components (i.e. cellulose, hemicellulose and lignin) of secondary walls. This review considers our current understanding of the MYB46-mediated transcriptional regulatory network, including upstream regulators, downstream targets and negative regulators of MYB46.Conclusions and OutlookMYB46 is a unique transcription factor in that it directly regulates the biosynthesis genes for all of the three major components of the secondary wall as well as the transcription factors in the biosynthesis pathway. As such, MYB46 may offer a useful means for pathway-specific manipulation of secondary wall biosynthesis. However, realization of this potential requires additional information on the ‘MYB46-mediated transcriptional regulatory programme’, such as downstream direct targets, upstream regulators and interacting partners of MYB46.
The objective of this study was to evaluate the validity and clinical impact of positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) using ...18-fluoro-2-deoxy-D-glucose in the posttherapy surveillance of patients with endometrial carcinoma. Eighty-eight patients previously treated for histopathologically diagnosed endometrial adenocarcinoma underwent 99 PET or PET/CT scans at follow-up visits at Asan Medical Center, Seoul, Korea, between 2001 and 2007. The standard of reference for tumor recurrence consisted of histopathologic confirmation or follow-up information at least 6 months after PET or PET/CT. Of the 88 patients, 24 underwent PET (n = 11) and/or PET/CT (n = 14) scans due to suspected disease recurrence. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of PET and/or PET/CT in detecting recurrence in these patients were 100%, 83.3%, 96%, 95%, and 100%, respectively. Especially, PET/CT revealed true-positive findings in three patients with elevated tumor markers but negative CT findings. The remaining 64 patients underwent PET (n = 8) and/or PET/CT (n = 66) as part of routine posttherapy surveillance; these patients were asymptomatic, with no evidence of disease. The sensitivity, specificity, accuracy, PPV, and NPV of PET and/or PET/CT in detecting recurrence in these patients were all 100%. Clinical decisions on treatment were changed in 14 (21.9%) patients by introducing PET or PET/CT into their conventional posttherapy surveillance program. PET and/or PET/CT were highly effective in discriminating true recurrence in patients with suspected recurrence, highly sensitive in detecting recurrence in asymptomatic patients, and had impacts on clinical decisions in a considerable portion of patients.
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