Removal of electrical stimulus artifact in local field potential recorded from subthalamic nucleus by using manifold denoising.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for movement disorders such as Parkinson's disease (PD). However, local field potentials (LFPs) recorded through lead externalization during high-frequency stimulation (HFS) are contaminated by stimulus artifacts, which require to be removed before further analysis. NEW METHOD: In this study, a novel stimulus artifact removal algorithm based on manifold denoising, termed Shrinkage and Manifold-based Artifact Removal using Template Adaptation (SMARTA), was proposed to remove artifacts by deriving a template for each stimulus artifact and subtracting it from the signal. Under a low-dimensional manifold assumption, a matrix denoising technique called optimal shrinkage was applied to design a similarity metric such that the template for stimulus artifacts could be accurately recovered. RESULT: SMARTA was evaluated using semirealistic signals, which were the combination of semirealistic stimulus artifacts recorded in an agar brain model and LFPs of PD patients with no stimulation, and realistic LFP signals recorded in patients with PD during HFS. The results indicated that SMARTA removes stimulus artifacts with a modest distortion in LFP estimates. COMPARISON WITH EXISTING METHODS: SMARTA was compared with moving-average subtraction, sample-and-interpolate technique, and Hampel filtering. CONCLUSION: The proposed SMARTA algorithm helps the exploration of the neurophysiological mechanisms of DBS effects.

The downregulation of miR-509-3p expression by collagen type XI alpha 1-regulated hypermethylation facilitates cancer progression and chemoresistance via the DNA methyltransferase 1/Small ubiquitin-like modifier-3 axis in ovarian cancer cells.

BACKGROUND: MicroRNAs are a group of small non-coding RNAs that are involved in development and diseases such as cancer. Previously, we demonstrated that miR-335 is crucial for preventing collagen type XI alpha 1 (COL11A1)-mediated epithelial ovarian cancer (EOC) progression and chemoresistance. Here, we examined the role of miR-509-3p in EOC. METHODS: The patients with EOC who underwent primary cytoreductive surgery and postoperative platinum-based chemotherapy were recruited. Their clinic-pathologic characteristics were collected, and disease-related survivals were determined. The COL11A1 and miR-509-3p mRNA expression levels of 161 ovarian tumors were determined by real-time reverse transcription-polymerase chain reaction. Additionally, miR-509-3p hypermethylation was evaluated by sequencing in these tumors. The A2780CP70 and OVCAR-8 cells transfected with miR-509-3p mimic, while the A2780 and OVCAR-3 cells transfected with miR-509-3p inhibitor. The A2780CP70 cells transfected with a small interference RNA of COL11A1, and the A2780 cells transfected with a COL11A1 expression plasmid. Site-directed mutagenesis, luciferase, and chromatin immunoprecipitation assays were performed in this study. RESULTS: Low miR-509-3p levels were correlated with disease progression, a poor survival, and high COL11A1 expression levels. In vivo studies reinforced these findings and indicated that the occurrence of invasive EOC cell phenotypes and resistance to cisplatin are decreased by miR-509-3p. The miR-509-3p promoter region (p278) is important for miR-509-3p transcription regulation via methylation. The miR-509-3p hypermethylation frequency was significantly higher in EOC tumors with a low miR-509-3p expression than in those with a high miR-509-3p expression. The patients with miR-509-3p hypermethylation had a significantly shorter overall survival (OS) than those without miR-509-3p hypermethylation. Mechanistic studies further indicated that miR-509-3p transcription was downregulated by COL11A1 through a DNA methyltransferase 1 (DNMT1) stability increase. Moreover, miR-509-3p targets small ubiquitin-like modifier (SUMO)-3 to regulate EOC cell growth, invasiveness, and chemosensitivity. CONCLUSION: The miR-509-3p/DNMT1/SUMO-3 axis may be an ovarian cancer treatment target.

Design of Dual-Configuration Dual-Mode Stimulator in Low-Voltage CMOS Process for Neuro-Modulation.

A dual-configuration dual-mode stimulator for neuro-modulation is proposed and designed. All the electrical stimulation patterns that frequently used for neuro-modulation can be generated by the proposed stimulator chip. Dual-configuration represents the bipolar or monopolar structure, meanwhile dual-mode stands for the current or voltage output. No matter what stimulation circumstance is chosen, biphasic or monophasic waveforms can be fully supported by the proposed stimulator chip. The stimulator chip with 4 stimulation channels has been fabricated in 0.18-µm 1.8-V/3.3-V low-voltage CMOS process with common grounded p-type substrate, which is suitable for SoC integration. The design has conquered the overstress and reliability issues in the low-voltage transistors under the negative voltage power domain. Each channel in the stimulator chip only occupies the silicon area of 0.052 mm2, and the maximum output level of stimulus amplitude is up to ±3.6 mA and ±3.6 V. With the built-in discharge function, bio-safety concern of unbalanced charge in neuro-stimulation can be dealt with properly. Moreover, the proposed stimulator chip has been applied on both imitation measurement and in-vivo animal test successfully.

The Downregulation of miR-509-3p Expression by Collagen Type XI Alpha 1-Regulated Hypermethylation Facilitates Cancer Progression and Chemoresistance via the DNA Methyltransferase 1/Small Ubiquitin-like Modifier-3 Axis in Ovarian Cancer Cells.

Background MicroRNAs are a group of small non-coding RNAs that are involved in development and diseases such as cancer. Previously, we demonstrated that miR-335 is crucial for preventing collagen type XI alpha 1 (COL11A1)-mediated epithelial ovarian cancer (EOC) progression and chemoresistance. Here, we examined the role of miR-509-3p in EOC. Methods The patients with EOC who underwent primary cytoreductive surgery and postoperative platinum-based chemotherapy were recruited. Their clinic-pathologic characteristics were collected, and disease-related survivals were determined. The COL11A1 and miR-509-3p mRNA expression levels of 161 ovarian tumors were determined by real-time reverse transcription-polymerase chain reaction. Additionally, miR-509-3p hypermethylation was evaluated by sequencing in these tumors. The A2780CP70 and OVCAR-8 cells transfected with miR-509-3p mimic, while the A2780 and OVCAR-3 cells transfected with miR-509-3p inhibitor. The A2780CP70 cells transfected with a small interference RNA of COL11A1, and the A2780 cells transfected with a COL11A1 expression plasmid. Site-directed mutagenesis, luciferase, and chromatin immunoprecipitation assays were performed in this study. Results Low miR-509-3p levels were correlated with disease progression, a poor survival, and high COL11A1 expression levels. In vivo studies reinforced these findings and indicated that the occurrence of invasive EOC cell phenotypes and resistance to cisplatin are decreased by miR-509-3p. The miR-509-3p promoter region (p278) is important for miR-509-3p transcription regulation via methylation. The miR-509-3p hypermethylation frequency was significantly higher in EOC tumors with a low miR-509-3p expression than in those with a high miR-509-3p expression. The patients with miR-509-3p hypermethylation had a significantly shorter overall survival (OS) than those without miR-509-3p hypermethylation. Mechanistic studies further indicated that miR-509-3p transcription was downregulated by COL11A1 through a DNA methyltransferase 1 (DNMT1) phosphorylation and stability increase. Moreover, miR-509-3p targets small ubiquitin-like modifier (SUMO)-3 to regulate EOC cell growth, invasiveness, and chemosensitivity. Conclusion The miR-509-3p/DNMT1/SUMO-3 axis may be an ovarian cancer treatment target.

Verification of the beta oscillations in the subthalamic nucleus of the MPTP-induced parkinsonian minipig model.

The development of the closed-loop deep brain stimulator (DBS) for clinical trials requires verification of its safety and effectiveness in a large animal model. Due to the financial and ethical challenges of using non-human primates, it is reasonable to use an alternative large animal model. It was reported that minipigs are suitable for the establishment of the MPTP-induced parkinsonian model. However, there is currently no evidence of whether beta oscillations, the symptom-related biomarker, exist in the subthalamic nucleus (STN) of the parkinsonian minipig model. This study was to verify whether the beta oscillations could be recorded in the STN of the parkinsonian minipig model. Parkinsonism was induced by injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Through a protocol involving up to nine subcutaneous or intramuscular injections, delivering a cumulative dose of 8-10 mg/kg MPTP, the minipigs developed notable movement disturbance. By stereotactic surgery and microelectrode recording, beta oscillations were recorded in the STN of the MPTP-injected minipigs. Immunohistochemistry of the tyrosine hydroxylase (TH) was performed in the substantia nigra pars compacta (SNc) of each animal. Compared with the control animal injected with saline, the TH-positive cells in the SNc were significantly reduced in the MPTP-injected minipigs. This study showed that beta oscillations could be recorded in the STN of the MPTP-induced parkinsonian minipig model. This large animal model is suitable as an alternative pre-clinical model for developing closed-loop DBS in the future.

Predictors of personal recovery for individuals with schizophrenia spectrum disorders living in the community.

INTRODUCTION: Personal recovery is a complex construct frequently used as outcome measure in people with schizophrenia spectrum disorders. This study examined potential predictors of personal recovery using the two most common assessment tools for people with schizophrenia spectrum disorders living in the community: the Chinese version of the Questionnaire about the Process of Recovery and the Chinese version of the Recovery Assessment Scale. METHODS: Ninety-one individuals (57 women) diagnosed with schizophrenia spectrum disorders participated in the study (mean age: 47.41 ± 9.41 years). All participants lived in the community and received community psychiatric services. The participants were evaluated via interviews, questionnaires and standardized assessments. Potential predictors included four domains: personal, disease-related, functional and social. Stepwise multiple linear regression was used to analyse the potential predictors of the recovery and recovery assessment scale. RESULTS: Resilience and social support were the only significant predictors of the Chinese versions of the Questionnaire about the Process of Recovery and Chinese version of the Recovery Assessment Scale. The primary predictor of the Chinese version of the Questionnaire about the Process of Recovery was social support from family and institutional staff. Conversely, resilience was the major predictor of the Chinese version of the Recovery Assessment Scale. DISCUSSION: For people with schizophrenia spectrum disorders living in the community, social support and resilience significantly predicted personal recovery. Age, educational level, disease-related and functional factors were not significant predictors of personal recovery. Therefore, it is important to develop successful personal recovery-oriented practices that enhance resilience and promote social support.

Collagen XI Alpha 1 Chain, a Novel Therapeutic Target for Cancer Treatment.

The extracellular matrix (ECM) plays an important role in the progression of cancer. Collagen is the most abundant component in ECM, and is involved in the biological formation of cancer. Although type XI collagen is a minor fibrillar collagen, collagen XI alpha 1 chain (COL11A1) expression has been found to be upregulated in a variety of human cancers including colorectal, esophagus, glioma, gastric, head and neck, lung, ovarian, pancreatic, salivary gland, and renal cancers. High levels of COL11A1 usually predict poor prognosis, owing to its association with angiogenesis, invasion, and drug resistance in cancer. However, little is known about the specific mechanism through which COL11A1 regulates tumor progression. Here, we have organized and summarized recent developments regarding the interactions between COL11A1 and intracellular signaling pathways and selected therapeutic agents targeting COL11A1, as these indicate its potential as a target for treatment of cancers, especially epithelial ovarian cancer.

miR-335 Restrains the Aggressive Phenotypes of Ovarian Cancer Cells by Inhibiting COL11A1.

High collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. MicroRNAs (miRNAs) are dysregulated in multiple cancers, including epithelial ovarian carcinoma (EOC); however, the regulation of COL11A1 by miRNAs in EOC remains unclear. We examined the role of miRNAs in regulating COL11A1 expression. We identified miR-509 and miR-335 as the candidate miRNAs through an online database search. EOC cell treatment with miR-335 mimics abrogated COL11A1 expression and suppressed cell proliferation and invasion, besides increasing the sensitivity of EOC cells to cisplatin. Conversely, treatment with miR-335 inhibitors prompted cell growth/invasiveness and chemoresistance of EOC cells. miR-335 inhibited COL11A1 transcription, thus reducing the invasiveness and chemoresistance of EOC cells via the Ets-1/MMP3 and Akt/c/EBPß/PDK1 axes, respectively. Furthermore, it did not directly regulate PDK1 but increased PDK1 ubiquitination and degradation through COL11A1 inhibition. In vivo findings highlighted significantly decreased miR-335 mRNA expressions in EOC samples. Furthermore, patients with low miR335 levels were susceptible to advanced-stage cancer, poor response to chemotherapy, and early relapse. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.

COL11A1 activates cancer-associated fibroblasts by modulating TGF-ß3 through the NF-κB/IGFBP2 axis in ovarian cancer cells.

Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-ß3 activation. The CAF-cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-ß3 antibody. Human tumors with high TGF-ß3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-ß3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.

Prophylactic clipping after endoscopic mucosal resection of large nonpedunculated colorectal lesions: A meta-analysis.

BACKGROUND AND AIM: It is not clear whether prophylactic clipping after endoscopic mucosal resection (EMR) of large nonpedunculated colorectal lesions (LNPCLs) prevents delayed bleeding (DB). We aimed to conduct a meta-analysis to clarify the efficacy of prophylactic clipping in prevention of DB following EMR of LNPCLs. METHODS: We searched PubMed, EMBASE, Web of Science, ScienceDirect, Cochrane Library databases, and ClinicalTrials.gov for studies that compared clipping versus (vs) nonclipping in prevention of DB following EMR of LNPCLs. Pooled odds ratio (OR) was determined using a random effects model. The pooled ORs of DB, perforation, and post-polypectomy syndrome in the clipping group compared with the nonclipping group comprised the outcomes. Subgroup analyses based on study design, polyp location, and completeness of wound closure were performed. RESULTS: Five studies with a total of 3112 LNPCLs were extracted. Prophylactic clipping reduced the risk of DB compared with nonclipping (3.3% vs 6.2%, OR: 0.494, P = 0.002) following EMR of LNPCLs. In subgroup analysis, prophylactic clipping reduced DB of LNPCLs at proximal location (3.8% vs 9.8%, P = 0.029), but not of them at distal location (P = 0.830). Complete wound closure showed superior efficacy to prevent DB compared with partial closure (2.0% vs 5.4%, P = 0.004). No benefit of clipping for preventing perforation or post-polypectomy syndrome was observed (P = 0.301 and 0.988, respectively). CONCLUSIONS: Prophylactic clipping can reduce DB following EMR of LNPCLs at proximal location. Besides, complete wound closure showed superior efficacy to prevent DB compared with partial closure. Further cost analyses should be conducted to implement the most cost-effective strategies.

Miniaturized Intracerebral Potential Recorder for Long-Term Local Field Potential of Deep Brain Signals.

A miniaturized intracerebral potential recorder for long-term local field potential (LFP) of deep brain signals is proposed. LFP can be recorded by deep brain electrodes. The abnormal beta-band oscillation of LFP in subthalamic nucleus and internal globus pallidus in patients with Parkinson's disease (PD) are associated with the severity of the symptoms. The LFP signal from patients who have been implanted with deep brain electrode can be monitored by our system for at least 24 hours in real time. Graphical user interface has also been developed for use by medical personnel. Imitation experiments and in vivo experiments were performed to successfully verify that our system can measure LFP signals. With 24-hour intracerebral signals, researchers can analyze what is happened in the brain in daily life. In the future, more effective PD treatment can be developed, such as intelligent closed-loop deep brain stimulation.

Population Monitoring, Egg Parasitoids, and Genetic Structure of the Invasive Litchi Stink Bug, Tessaratoma papillosa in Taiwan.

Here we assessed population dynamics, natural enemy fauna (with emphasis on egg parasitoid), and population genetic structure (based on mitochondrial DNA) of the invasive litchi stink bug (LSB), Tessaratoma papillosa in Taiwan. Our major findings include: (1) fluctuations of LSB in numbers of adults, mating pairs, and egg masses over a 2-year period in Taiwan generally resemble those in the native populations; (2) Anastatus dexingensis and A. fulloi are among the most dominant LSB egg parasitoids, with the former consistently outnumbering the latter throughout Taiwan; (3) the presence of two genetically distinct clades suggests LSB in Taiwan most likely derived from multiple invasions. All these data practically improve our understanding of this invasive insect pest, particularly its ecological and genetic characteristics in the introduced area, which represents critical baseline information for the design of future integrated pest management strategies.

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment.

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the KRAS mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.

Risk of Parkinson's disease among patients with herpes zoster: a nationwide longitudinal study.

OBJECTIVE: Several studies suggested a potential role of viral infection in the pathophysiology of Parkinson's disease (PD). However, the association between herpes zoster and PD was not investigated well till now. METHODS: Using the Taiwan National Health Insurance Research Database, 13 083 patients aged ≥45 years with herpes zoster and 52 332 (1:4) age-/sex-matched controls were enrolled between 1998 and 2008 and followed to the end of 2011. Those who developed PD during the follow-up period were identified. RESULTS: The Cox regression analysis with adjustment of demographic characteristics, health system utilization, and comorbidities demonstrated that patients with herpes zoster had an increased risk (hazard ratio [HR]: 1.80, 95% confidence interval [CI]: 1.43-2.28) of developing PD in later life compared to the control group. Sensitivity tests after excluding the first year (HR: 1.50, 95% CI: 1.16-1.93) and first 2-year (HR: 1.44, 95% CI: 1.10-1.88) observation periods showed consistent results. CONCLUSIONS: Patients with herpes zoster were more likely to develop PD in later life compared to the controls. Additional studies are necessary for validating our results and to clarify the underlying pathophysiology between herpes zoster and PD.

Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression.

We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels, as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66-sensitized chemoresistant cells to cisplatin and paclitaxel treatment, and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPß), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin. This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance, and supports the application of SC66 as a therapy for ovarian cancer.

Implementation of a national quality improvement program to enhance hand hygiene in nursing homes in Taiwan.

BACKGROUND/PURPOSE: This study investigated the cause of hand hygiene deficit, and further implemented a quality improvement program using WHO's hand-hygiene strategy to enhance the compliance of hand hygiene in the nursing home in Taiwan. METHODS: This prospective study was conducted in eleven nursing homes in Taiwan from January 2015 to December 2016. After intervention, we monitor the compliance, and accuracy of hand hygiene. In addition, we also calculated the number of episodes of infection per 1000 resident-days in each nursing home in the intervention period (July-December 2015) and post-intervention period (January-October 2016). RESULTS: Overall, the consumption of alcohol-based handrubs increased from 10.1 ml per resident-day in intervention period to 12.2 ml per resident-day in post intervention period. The compliance of hand hygiene increased from 74% in intervention period to 79% in post-intervention period and the rate of correct hand hygiene increased from 81% in intervention period to 87% in post-intervention period. Most importantly, the infection density decreased from 2.39 per 1000 resident-day in intervention period to 1.89 per 1000 resident-day. CONCLUSIONS: A national quality-improvement program using WHO's hand-hygiene strategy to enhance hand hygiene and reduce healthcare associated infection is effective in nursing homes in Taiwan.

Human Clinical-Grade Parthenogenetic ESC-Derived Dopaminergic Neurons Recover Locomotive Defects of Nonhuman Primate Models of Parkinson's Disease.

Clinical application of stem cell derivatives requires clinical-grade cells and sufficient preclinical proof of safety and efficacy, preferably in primates. We previously successfully established a clinical-grade human parthenogenetic embryonic stem cell (hPESC) line, but the suitability of its subtype-specific progenies for therapy is not clear. Here, we compared the function of clinical-grade hPESC-derived midbrain dopaminergic (DA) neurons in two canonical protocols in a primate Parkinson's disease (PD) model. We found that the grafts did not form tumors and produced variable but apparent behavioral improvement for at least 24 months in most monkeys in both groups. In addition, a slight DA increase in the striatum correlates with significant functional improvement. These results demonstrated that clinical-grade hPESCs can serve as a reliable source of cells for PD treatment. Our proof-of-concept findings provide preclinical data for China's first ESC-based phase I/IIa clinical study of PD (ClinicalTrials.gov number NCT03119636).

Cognitive Frailty and Its Association with All-Cause Mortality Among Community-Dwelling Older Adults in Taiwan: Results from I-Lan Longitudinal Aging Study.

The definition of cognitive frailty and its prediction for adverse outcome of community-living older adults remains controversial. This study aims to evaluate the association between cognitive frailty and all-cause mortality among community-living older adults. Data of the I-Lan Longitudinal Aging Study (ILAS) were retrieved for study. Frailty was defined by Fried's criteria, and a series of neuropsychological assessments, including the Mini-Mental State Examination, Center for Epidemiology Studies-Depression, the delayed free recall in the Chinese Version Verbal Learning Test, the Boston Naming Test, the category (animal) Verbal Fluency Test, the Taylor Complex Figure Test, the digital backward, and the Clock Drawing Test were performed. All participants received blood sampling after 10-hour overnight fast for various biochemical markers. Cognitive frailty was defined as the concomitant presence of dynapenia and cognitive declines in any domains. Overall, data of 678 participants aged 65 years and older (mean age: 73.3 ± 5.3 years) were obtained for the study. The prevalence of cognitive frailty in this study was 13.3%. People with cognitive frailty were significantly older, having higher multimorbidity burden, more likely to be women, and had less skeletal muscle mass. Adjusted for age and gender, both dynapenia without cognitive impairment (hazard ratio [HR]: 5.402; 95% confidence interval [CI]: 1.463-19.954; p = 0.011) and cognitive frailty (HR: 6.682; 95% CI: 1.803-26.116; p = 0.005) were significantly associated with all-cause mortality. The prevalence of cognitive frailty was 13.3% in Taiwan and was predictive for all-cause mortality. Further study is needed to explore the pathophysiology and reversibility of cognitive frailty.

Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription.

Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D-binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC.Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines.Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor-binding protein-2/Akt axis, and induced suppression of vitamin D-responsive genes. A NF-κB p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation.Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC. Clin Cancer Res; 24(13); 3217-28. ©2018 AACR.