The Effect of Massage Force on Relieving Nonspecific Low Back Pain: A Randomized Controlled Trial.

OBJECTIVE: To investigate the effect of force applied during massage on relieving nonspecific low back pain (LBP). METHODS: This single-blinded, randomized controlled trial enrolled 56 female patients with nonspecific LBP at a single medical center. For each participant, the therapist performed a 30 min massage session (20 min general massage and 10 min focal massage) using a special instrument with a force sensor inserted, for a total of six sessions in 3 weeks. During the 10 min focal massage, HF and LF groups received high force (HF, ≥2 kg) and low force (LF, ≤1 kg) massage, respectively. The primary outcome was pain intensity (i.e., visual analog scale (VAS), 0-10), and secondary outcomes comprised pain pressure threshold, trunk mobility, LBP-associated disability, and quality of life. RESULTS: No significant between-group differences were observed in baseline characteristics. The HF group exhibited significantly lower VAS than did the LF group, with a mean difference of -1.33 points (95% CI: -2.17 to -0.5) at the end of the intervention, but no significant difference was noted at the end of the follow-up. A significant time effect (p < 0.05) was detected in all secondary outcomes except the pain pressure threshold and trunk mobility. A significant time × group interaction (p < 0.05) was found only for the VAS and pain pressure threshold. CONCLUSIONS: Compared with LF massage, HF massage exerted superior effects on pain relief in female patients with nonspecific LBP at the end of intervention. Applying different levels of force showed no effects on LBP-associated disabilities and quality of life.

Impaired Chromatin Remodeling Predicts Better Survival to Modified Gemcitabine and S-1 plus Nivolumab in Advanced Biliary Tract Cancer: A Phase II T1219 Study.

PURPOSE: Modified gemcitabine and S-1 (GS) is an active regimen for patients with advanced biliary tract cancer (ABTC) in our previous study. Herein, we report the results of a single-arm phase II of nivolumab plus modified GS (NGS) as first-line treatment in ABTC. PATIENTS AND METHODS: Patients received nivolumab 240 mg and 800 mg/m2 gemcitabine on day 1 plus daily 80/100/120 mg of S-1 (based on body surface area) on days 1 to 10, in a 2-week cycle. The primary endpoint was the objective response rate (ORR). The correlation between therapeutic efficacy and genetic alterations with signatures identified by targeted next-generation sequencing panels was explored. RESULTS: Between December 2019 and December 2020, 48 eligible patients were enrolled. After a median of 17.6 months of follow-up, the ORR was 45.9% [95% confidence interval (CI), 31.4%-60.8%]. The median progression-free survival (PFS) and overall survival (OS) was 9.1 (95% CI, 5.8-9.6) and 19.2 (95% CI, 11.6-not reached) months, respectively. All grade 3/4 treatment-related adverse events (AE) were less than 10%, except fatigue (14.6%) and skin rash (10.4%). Eighteen patients (35.4%) experienced immune-related AEs without treatment-related death. High tumor mutational burden (TMB-H; top 20%; ≥7.1 mut/Mb) only predicted prolonged median PFS but not OS. Up to 28.9% of patients who harbored loss-of-function mutations in chromatin remodeling genes demonstrated significantly longer median PFS and OS than those without alterations. CONCLUSIONS: NGS is a safe and promising regimen in ABTC. Impaired functions of chromatin remodeling genes may be a potential surrogate biomarker with predictive value in this study.

Efficacy and safety of Duhuo Jisheng Decoction add-on bisphosphonate medications in patients with osteoporosis: A meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Duhuo Jisheng Decoction (DHJSD) is the most frequently prescribed herbal formula for the treatment of osteoporosis. However, efficacy and safety of DHJSD add-on bisphosphonate medications remain unclear. AIM OF THE STUDY: The purpose of this study was to reveal efficacy and safety of DHJSD add-on bisphosphonate medications in patients with osteoporosis through a systematic review with meta-analysis of randomized controlled trials (RCTs). METHODS: Five important databases were searched for RCTs on this topic, and two authors individually extracted information and data concerning study design, baseline characteristics, efficacy rate, bone mineral density (BMD), pain score, and adverse event. Meta-analysis was done mainly with risk ratio (RR) and standardized mean difference (SMD) for BMD and pain, using random-effects model; while Peto odds ratios (PORs) were used for pooling adverse event rates due to sparse data. Point estimate was reported with 95% confidence intervals (CIs). RESULTS: Seventeen RCTs (n = 1526) met eligibility criteria, and were included in this synthesis. Pooled estimates demonstrated that as compared with no DHJSD, DHJSD-B led to significantly higher efficacy rates (RR = 1.25, 95%CI: 1.19-1.31; I2 = 0%), more lumbar BMD (SMD = 0.61, 95%CI: 0.25-0.96; I2 = 20%), lower pain score (SMD = -1.10, 95%CI: 1.40-0.79; I2 = 33%), and lower overall adverse event rates (POR = 0.40; 95%CI: 0.20-0.97; I2 = 27%). CONCLUSION: Adding DHJSD on bisphosphonate medications seems to be an effective and safe strategy in treating patients with osteoporosis.

Pdia4 regulates ß-cell pathogenesis in diabetes: molecular mechanism and targeted therapy.

Loss of ß-cell number and function is a hallmark of diabetes. ß-cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in ß-cells. This expression was up-regulated in ß-cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated ß-cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in ß-cells via its action on the pathway of Ndufs3 and p22phox . Finally, we found that 2-ß-D-glucopyranosyloxy1-hydroxytrideca 5,7,9,11-tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of ß-cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes.

CMV infection, CD19+ B cell depletion, and Lymphopenia as predictors for unexpected admission in the institutionalized elderly.

BACKGROUND: Chronic infections played a detrimental role on health outcomes in the aged population, and had complex associations with lymphocyte subsets distribution. Our study aimed to explore the predictive roles of chronic infections, lymphopenia, and lymphocyte subsets on unexpected admission and mortality in the institutionalized oldest-old during 3 year follow-up period. RESULTS: There were 163 participants enrolled prospectively with median age of 87.3 years (IQR: 83.1-90.2), male of 88.3%, and being followed for 156.4 weeks (IQR: 136.9-156.4 weeks). The unexpected admission and mortality rates were 55.2 and 24.5% respectively. The Cox proportional hazards models demonstrated the 3rd quartile of cytomegalovirus IgG (OR: 3.26, 95% CI: 1.55-6.84), lymphopenia (OR: 2.85, 95% CI: 1.2-6.74), and 1st quartile of CD19+ B cell count (OR: 2.84, 95% CI: 1.29-6.25) predicted elevated risks of unexpected admission after adjusting for potential confounders; while the 3rd quartile of CD3+ T cell indicated a reduced risk of mortality (OR: 0.19, 95% CI: 0.05-0.71). Negative association between CMV IgG and CD19+ B cell count suggested that CMV infection might lead to B cell depletion via decreasing memory B cells repertoire. CONCLUSIONS: CMV infection, lymphopenia, and CD19+ B cell depletion might predict greater risk of unexpected admission, while more CD3+ T cell would suggest a reduced risk of mortality among the oldest-old population. A non-linear or U-shaped relationship was supposed between health outcomes and CMV infection, CD3+ T cell, or CD19+ B cell counts. Further prospective studies with more participants included would be needed to elucidate above findings.

DBPR108, a novel dipeptidyl peptidase-4 inhibitor with antihyperglycemic activity.

AIMS: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles. MAIN METHODS: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Upon an oral administration of DBPR108, the serum active GLP-1 and insulin levels of the rats challenged with an oral glucose ingestion were measured. Oral glucose tolerance test in diet-induced obese mice was performed to examine if DBPR108 increases the glucose tolerability in animals. KEY FINDINGS: Orally administered DBPR108 inhibited the systemic plasma DPP-4 activities in rats, dogs and diabetic mice in a dose-dependent manner. DBPR108 caused elevated serum levels of active GLP-1 and insulin in the rats. DBPR108 dose-dependently increased the glucose tolerability in diet-induced obese (DIO) mice and, furthermore, DIO mice treated with DBPR108 (0.1 mg/kg) in combination with metformin (50 or 100 mg/kg) showed a prominently strong increase in the glucose tolerability. SIGNIFICANCE: DBPR108 is a novel DPP-4-selective inhibitor of small molecule that demonstrated potent in vivo pharmacological effects and good safety profiles in animals. DBPR108 is now a drug candidate being further developed in the clinical studies as therapeutics for treating diabetes.

BPRDP056, a novel small molecule drug conjugate specifically targeting phosphatidylserine for cancer therapy.

Zinc(II)-dipicolylamine (Zn-DPA) has been shown to specifically identify and bind to phosphatidylserine (PS), which exists in bulk in the tumor microenvironment. BPRDP056, a Zn-DPA-SN38 conjugate was designed to provide PS-targeted drug delivery of a cytotoxic SN38 to the tumor microenvironment, thereby allowing a lower dosage of SN38 that induces apoptosis in cancer cells. Micro-Western assay showed that BPRDP056 exhibited apoptotic signal levels similar to those of CPT-11 in the treated tumors growing in mice. Pharmacokinetic study showed that BPRDP056 has excellent systemic stability in circulation in mice and rats. BPRDP056 is accumulated in tumors and thus increases the cytotoxic effects of SN38. The in vivo antitumor activities of BPRDP056 have been shown to be significant in subcutaneous pancreas, prostate, colon, liver, breast, and glioblastoma tumors, included an orthotopic pancreatic tumor, in mice. BPRDP056 shrunk tumors at a lower (~20% only) dosing intensity of SN38 compared to that of SN38 conjugated in CPT-11 in all tumor models tested. A wide spectrum of antitumor activities is expected to treat all cancer types of PS-rich tumor microenvironments. BPRDP056 is a first-in-class small molecule drug conjugate for cancer therapy.

The Inflammatory Cytokine Profile of Patients with Malignant Pleural Effusion Treated with Pleurodesis.

Patients with malignant pleural effusion (MPE) who underwent successful pleurodesis survive longer than those for whom it fails. We hypothesize that the therapy-induced inflammatory responses inhibit the cancer progression, and thereby lead to a longer survival. Thirty-three consecutive patients with MPE that were eligible for bleomycin pleurodesis between September 2015 and December 2017 were recruited prospectively. Nineteen patients (57.6%) achieved fully or partially successful pleurodesis, while 14 patients either failed or survived less than 30 days after pleurodesis. Two patients without successful pleurodesis were excluded because of missing data. Interleukin (IL)-1 beta, IL-6, IL-10, transforming growth factor beta, tumor necrosis factor alpha (TNF-α), and vascular endothelial growth factor in the pleural fluid were measured before, and after 3 and 24 h of pleurodesis. Their pleurodesis outcome and survival were monitored and analyzed. Patients who underwent successful pleurodesis had a longer survival rate. Patients without successful pleurodesis had significantly higher TNF-α and IL-10 levels in their pleural fluid than in the successful patients before pleurodesis. Following pleurodesis, there was a significant increment of IL-10 in the first three hours in the successful patients. In contrast, significant increments of TNF-α and IL-10 were found in the unsuccessful patients between 3 and 24 h after pleurodesis. The ability to produce specific cytokines in the pleural space following pleurodesis may be decisive for the patient's outcome and survival. Serial measurement of cytokines can help allocate the patients to adequate treatment strategies. Further study of the underlying mechanism may shed light on cytokine therapies as novel approaches.

Epidemiology of frailty and associated factors among older adults living in rural communities in Taiwan.

Frailty is a well-known geriatric syndrome with strong adverse health impact to older people. The socio-economic status and the accessibility of health services in rural communities may increase the risk of frailty. We conducted a cross-sectional study in rural districts of New Taipei City, Taiwan, to explore the epidemiology and associated factors of frailty. Data of 1014 participants (mean age: 78.7 ± 8.0 years, 66.3 % females) were obtained with the prevalence of frailty and pre-frailty 17.6 % and 23.1 %, respectively. The mean Barthel Index was 98.5 ± 5.8, and their mean Instrumental Activities of Daily Living (IADL) were 7.2 ± 1.5. Frail older people tended perform worse in timed up-and-go tests (24.7 % in frailty and 0.4 % in robust). The mean mini-mental state examination (MMSE) score for all participants was 23.3 ± 5.1, but was lower in frail older for around 5 points. Depressive symptoms were more common in frail older persons than robust ones (31.5 % vs 14.3 %), which was similar in the nutritional status. Results of the logistic regression showed that better education, IADL and MMSE scores were protective factors against frailty. The presence of depressive symptoms, urinary incontinence, abnormal performance of TUG, and the presence of the risk for malnutrition were all independent assciated factors for frailty. In conclusion, the prevalence of frailty was higher among older adults living in rural communities that deserves specific public health attentions. Further intervention study covering special needs in rural communities is needed to promote health of older people.

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy.

Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and -resistant non-small cell lung cancer.

Synthesis and biological evaluation of N-glucosyl indole derivatives as sodium-dependent glucose co-transporter 2 inhibitors.

Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion-independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N-glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2. Of these sixteen, acethydrazide-containing N-glucosyl indole 9d was found to be the most potent SGLT2 inhibitor, and caused a significant elevation in urine glucose excretion in rats at 50 mg/kg, relative to the vehicle control.

The Emerging Role of Nutritional Vitamin D in Secondary Hyperparathyroidism in CKD.

In chronic kidney disease (CKD), hyperphosphatemia induces fibroblast growth factor-23 (FGF-23) expression that disturbs renal 1,25-dihydroxy vitamin D (1,25D) synthesis; thereby increasing parathyroid hormone (PTH) production. FGF-23 acts on the parathyroid gland (PTG) to increase 1α-hydroxylase activity and results in increase intra-gland 1,25D production that attenuates PTH secretion efficiently if sufficient 25D are available. Interesting, calcimimetics can further increase PTG 1α-hydroxylase activity that emphasizes the demand for nutritional vitamin D (NVD) under high PTH status. In addition, the changes in hydroxylase enzyme activity highlight the greater parathyroid 25-hydroxyvitmain D (25D) requirement in secondary hyperparathyroidism (SHPT); the higher proportion of oxyphil cells as hyperplastic parathyroid progression; lower cytosolic vitamin D binding protein (DBP) content in the oxyphil cell; and calcitriol promote vitamin D degradation are all possible reasons supports nutritional vitamin D (NVD; e.g., Cholecalciferol) supplement is crucial in SHPT. Clinically, NVD can effectively restore serum 25D concentration and prevent the further increase in PTH level. Therefore, NVD might have the benefit of alleviating the development of SHPT in early CKD and further lowering PTH in moderate to severe SHPT in dialysis patients.

Interleukin-18 promoter genotype is associated with the risk of nasopharyngeal carcinoma in Taiwan.

BACKGROUND: The incidence rate of nasopharyngeal carcinoma (NPC) has been documented to be high in Southeast Asia. Interleukin-18 (IL-18) is a multifunctional cytokine that augments interferon-γ production and acts as an important immunomediator in the development of several types of cancer. PATIENTS AND METHODS: This case-control study evaluated the role of IL-18 in NPC at the DNA level by genotyping its promoter polymorphisms at positions -656, -607, and -137 in a Taiwanese population. A total of 176 patients with NPC and age- and gender-matched 352 noncancer controls were included in this study. RESULTS: The CC genotype of the IL-18-607 polymorphism was found to be associated with significantly decreased risks of NPC compared to the AA genotype (crude OR =0.50, 95% CI =0.29-0.84, P=0.0093). This significant difference persisted even in the dominant and recessive models. A significantly lower C allele frequency at position -607 was detected in the NPC group(41.8% vs 50.3%; OR =0.77; 95% CI =0.63-1.04, P=0.0089). Regarding IL-18-656 and -137 polymorphisms, there were no differential distributions of their genotypes between the NPC and control groups. After substratification of the subjects according to their smoking, alcohol consumption, and areca chewing status, the genotype distribution of the IL-18-607 polymorphism was found to be different only among nonsmokers between the NPC and control subgroups. CONCLUSION: This study suggests that IL-18 plays an important role in the carcinogenesis of NPC in Taiwan and that the genotype-phenotype correlation of IL-18-607 polymorphism and its contribution to NPC need to be investigated further.

The contribution of interleukin-8 genotypes and expression to nasopharyngeal cancer susceptibility in Taiwan.

The incidence rate of nasopharyngeal cancer (nasopharyngeal carcinoma [NPC]) is much higher in Southeast Asia than in western countries. Interleukin-8 (IL-8), a chemokine produced by macrophages, epithelial cells, airway smooth muscle cells, and endothelial cells, is an important immuno-mediator in the development and progression of many types of cancer. Genetic variations in IL-8 have been associated with the risks of NPC and other cancers. In the current study, we evaluated the role of IL-8 in NPC at the levels of DNA, RNA, and protein in a Taiwanese population. First, in a case-control study, 176 NPC patients and 352 cancer-free controls were genotyped, and the associations of IL-8 T - 251A, C + 781T, C + 1633T, and A + 2767T polymorphisms with NPC risk were evaluated. Second, the NPC tissue samples were assessed for their IL-8 mRNA and protein expression by real-time quantitative reverse transcription polymerase chain reaction (PCR) and Western blotting, respectively. Regarding the IL-8 promoter T - 251A, the TA and AA genotypes were associated with significantly decreased risks of NPC compared with the wild-type TT genotype (adjusted odds ratio = 0.61 and 0.52, 95% confidence interval = 0.47-0.93 and 0.37-0.91, P = .0415 and .0289, respectively). The mRNA and protein expression levels for NPC tissues revealed no significant associations among the 20 NPC samples with different genotypes. These findings suggest that IL-8 may play an important role in the carcinogenesis of NPC in Taiwan.

FNIH-defined Sarcopenia Predicts Adverse Outcomes Among Community-Dwelling Older People in Taiwan: Results From I-Lan Longitudinal Aging Study.

Background: To evaluate the predictive validity of sarcopenia defined by the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project among Asian older adults. Methods: Data of the I-Lan Longitudinal Aging Study were obtained for analysis. Overall, 1,839 community-dwelling people aged 50 years and older, capable of completing a 6-m walk, with life expectancy of more than 6 months, and not institutionalized at time of data collection were enrolled for study. Data for subjects aged 65 years and older were obtained for study. The outcome measures were all-cause mortality and a composite adverse outcome which includes hospitalizations, emergency department visits, institutionalization, and falls. Results: Data of 728 eligible elderly participants (73.4 ± 5.4 years; 52.9% males) were analyzed. The prevalence of FNIH-diagnosed sarcopenia was 9.5%: 11.9% males; 6.7% females. Participants having FNIH-defined sarcopenia were considerably older, frailer, more obese, with poorer physical performance than nonsarcopenic subjects (All p < .001); during mean follow-up of 32.9 ± 8.8 months, they also had 3.8 times higher risk of dying, independent of age, sex, multimorbidity, cognitive function, and nutritional status (hazard ratio = 3.8; 95% confidence interval = 1.26-11.45; p = .018). Moreover, sarcopenia defined by grip strength-BMI ratio (WeakBMI) showed stronger association with composite adverse outcomes than traditional handgrip strength (hazard ratio = 1.99; 95% confidence interval = 1.01-3.93; p = .047 vs hazard ratio = 1.80; 95% confidence interval = 0.89-3.62; p = .102 in fully-adjusted model). Conclusion: Among community-dwelling older people in Taiwan, participants with FNIH-defined sarcopenia had a significantly greater risk of all-cause mortality and composite falls, emergency department visits, institutionalization, and hospitalization.

The Association of MMP-8 Genotypes with Pterygium.

BACKGROUND/AIM: Pterygium is composed of proliferating fibrovascular tissue, and its formation and progression are closely related to the homeostasis of the extracellular microenvironment. However, few studies have examined the contribution of matrix metalloproteinases (MMP) to either diagnostic or prognostic potential in pterygium. In this study, we investigated the contribution of a polymorphism in the promoter region of MMP-8 (-799C/T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to pterygium. MATERIALS AND METHODS: In this study, 134 patients with pterygium and 268 non-cancer controls patients were collected and the MMP-8 -799C/T, Val436Ala and Lys460Thr polymorphic genotypes of each subject were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The results showed that the three polymorphisms investigated were not significantly associated with risk of pterygium. In addition, the stratified analysis showed that there was no interaction between MMP-8 genotype with age or gender on pterygium risk determination. CONCLUSION: Polymorphisms at MMP-8 -799C/T, Val436Ala and Lys460Thr may not mainly contribute to determining personal susceptibility to pterygium in the Taiwanese examined.

Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2.

Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 µM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 µM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.

The Association of Flap Endonuclease 1 Genotypes with the Susceptibility of Endometriosis.

BACKGROUND/AIM: Flap endonuclease 1 (FEN1), a protein with multiple functions in genome stability maintenance, is important in cancer prevention. The two functional germline variants of FEN1, rs174538 and rs4246215, regarding cancer susceptibility have been reported in lung, breast, liver, esophageal, gastric, colorectal cancer, glioma and leukemia, but not endometriosis. In this study, we firstly aimed at evaluating the contribution of FEN1 genotypes to endometriosis risk in a representative Taiwan population. MATERIALS AND METHODS: In total, 153 patients with endometriosis and 636 non-cancer healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: The genotypes of FEN1 rs174538, but not those of rs4246215, were differently distributed between the endometriosis and control groups. In detail, the AA of FEN1 rs174538 genotypes were significantly less frequently found among endometriosis patients than among controls (odds ratio [OR]=0.43, 95% confidence interval [CI]=0.24-0.78, p=0.0125). The A allele at FEN1 rs174538 was also significantly less frequent among cases than controls (OR=0.65, 95%CI=0.50-0.86, p=0.0021). As for age of first menarche, those with first menarche at the age >12.8 carrying the FEN1 rs174538 AA genotype conferred lower OR of 0.29 (95%CI=0.11-0.78, p=0.0381) for endometriosis. Regarding the full pregnancy status, those without having had a full-term pregnancy carrying the FEN1 rs174538 AA genotype were of lower risk (ORs=0.12, 95%CI=0.03-0.53, p=0.0050). CONCLUSION: The FEN1 rs174538 A allele is a novel protective biomarker for endometriosis and this genotype may have interactions with age- and hormone-related factors on the development of endometriosis.

Compounds isolated from Eriobotrya deflexa leaves protect against ultraviolet radiation B-induced photoaging in human fibroblasts.

Ultraviolet (UV) irradiation leads to skin photoaging because of the upregulation of matrix metalloproteinase (MMP)-1 and downregulation of type I collagen and tissue inhibitor of metalloproteinase (TIMP)-1. Eriobotrya deflexa (Hemsl.) Nakai (Rosaceae) is a flowering plant endemic to Taiwan, and its leaves have been used as an expectorant and in antitussive folk remedy. Our previous studies have demonstrated that an E. deflexa leaf extract functions as a free radical scavenger. The current evaluated the antiphotoaging effect of partitioned fractions and specific compounds from the leaves of E. deflexa by using bioguided isolation, compound identification, and biological activity testing with UVB-irradiated human fibroblasts (WS-1 cells). E. deflexa leaves were extracted with 95% ethanol and then partitioned using a sequential treatment of n-hexane, ethyl acetate, and n-butanol (n-BuOH). The bioactive n-BuOH fraction was used for isolation and purification through chromatography. The compounds were identified by analyzing their physical and spectroscopic properties. We identified eight compounds from this fraction; of these compounds, 3-O-α-l-rhamnopyranosyl-(1‴→6″)-ß-d-galactopyranoside (1), hyperin (2), afzelin (5), and cryptochlorogenic acid methyl ester (7) were isolated from E. deflexa for the first time, and they exhibited MMP-1 inhibition activity. The IC50 values were 96.5, 89.5, 93.4, and 92.8µM for 1, 2, 5, and 7, respectively. These compounds also enhanced the expression of procollagen type I, and TIMP-1 and hyperin (2) were found to be most effective with IC50 values of 56.7 and 70.3µM, respectively. Hyperin (2) could reduce intracellular reactive oxygen species production in UVB-irradiated WS-1 cells, with the corresponding IC50 value being 80.7µM. Liquid chromatography triple-quadrupole mass spectrometry was used for the quantitative and chemical fingerprint analysis of active compounds. Quercetin 3-O-α-l-rhamnopyranosyl-(1‴→6″)-ß-d-galactopyranoside (1), hyperin (2), afzelin (5), and cryptochlorogenic acid methyl ester (7) constituted 24.2±3.9, 5.5±1.0, 3.4±0.3, and 67.1±8.1mg/g of dry weight in the active n-BuOH fraction, respectively. Our results demonstrate that the extract and the isolated active compounds from E. deflexa leaves possess the potential for protection against skin photoaging.

Predictive factors for dementia and cognitive impairment among residents living in the veterans' retirement communities in Taiwan: Implications for cognitive health promotion activities.

AIM: To identify potentially modifiable risk factors for cognitive decline among veterans' home residents in Taiwan METHODS: The present retrospective cohort study was part of the Veteran Affairs-Comprehensive Geriatric Assessment study that retrieved data of the comprehensive geriatric assessment for 946 residents living at four veterans' homes in Taiwan. The study participants were interviewed every 3-6 months from January 2012 and December 2014. Demographic characteristics,multimorbidity by Charlson's Comorbidities Index, physical function by the Barthel Index, cognition by the Mini-Mental State Examination (MMSE), depression by the five-item Geriatric Depression Scale and nutritional status by the Mini-Nutrition Assessment-Short Form were collected for analysis. A generalized estimating equation model was used after it was adjusted for age, educational level, five-item Geriatric Depression Scale, and problem of communication difficulty to identify potential modifiable risk factors for cognitive decline. RESULTS: The mean age of the participants was 85.7 ± 5.2 years, with a mean follow-up period of 41 ± 21.6 weeks. The prevalence of cognitive impairment (defined by MMSE <24) was 65.6%, whereas 34% of the study participants were positive for depressive symptoms. Approximately one-fifth of the study participants were using psychotropic agents, which was higher among participants with cognitive impairment (23.6% vs 15.6%, P < 0.05) than those without. In the generalized estimating equation model, physical function, nutritional status, depressive symptoms, ex-drinker, multimorbidity and stool incontinence were positively correlated with MMSE score; whereas advanced age, low educational level (<6 years), presence of communication difficulty and use of psychotropic agents were inversely associated with the MMSE score. CONCLUSIONS: Physical function and nutritional status were positively associated with the MMSE score, and use of psychotropic agents was negatively correlated with cognitive function. Further intervention study is required to improve the cognitive health of older adults living in the veterans' retirement communities. Geriatr Gerontol Int 2017: 17 (Suppl. 1): 7-13.