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Background Hepatocellular carcinoma (HCC) ranks many tasks in clinical oncology due to possibly develop general tumor in men and, usually lead to malignant to death within years. Researches had reported about major factors for being HCC was male sex and HCC associated with cirrhosis in childhood was found more common in males than females. In certain mouse strains as studied, breeding with testosterone significantly increases the development of HCC. Furthermore, castration of male mice diminished the frequency of the development of liver tumors. Meanwhile Male hepatitis B virus transgenic mice have greater occurrence of HCC than females. Methods We apply degenerate priming PCR to observe the expression of various steroid receptors in livers. Yeast-two hybrid screening to search a novel RNA fragment helps to find a new full-length gene by RACE experiment. RT-PCR is applied to detect various of expression in tissues and cell lines. In situ hybridization detects DNA in Chromosome mapping. GFP-constructs transfection proves the gene localization in cells. Immunoprecipitation pulldown assay verifies protein interaction. Gene transfection followed with luciferase assay demonstrates interaction of genes within cellular signaling. Genomic alignment analysis for observing sequences data perform from NCBI database website (http://www.ncbi.nim.nih.gov/genebank/). Results The androgen receptor (AR) expression level is found at the highest level among the steroid receptors families detected in liver tumors. By yeast-two hybrid screening, we cloned an ARCAP (Androgen Receptor Complex Associated Protein), of 95 Kd in molecular weight and its cDNA. ARCAP locates at Chromosome 1. Our findings indicate ARCAP highly expresses in hepatoma cell lines and liver tumors and their adjacent tumors as observed. Yeast two-hybrid assay and in vitro immunoprecipitation assays demonstrated an interaction between AR and ARCAP. Conclusion Our aim is to search for different types and levels of steroid receptors expressed within human hepatocellular carcinomas and in the adjacent liver tissues. To verify possible molecular mechanisms by which AR might affect hepatoma cells, we had characterized a novel protein ARCAP which functions as a coregulator to interact with AR within liver. The ligand-dependent AR with its cofactor, ARCAP, can induce a signal cascade by transactivation.

Objective. To evaluate the effect of adding DPP4 inhibitor (DPP4-I) on glycemic variability (GV) in patients with type 2 diabetes mellitus (T2DM) treated with premixed human insulin (MHI). Methodology. We conducted a prospective study in patients with T2DM on twice-daily MHI with or without metformin therapy. Blinded continuous glucose monitoring was performed at baseline and following 6 weeks of Vildagliptin therapy. Results: Twelve patients with mean (SD) age of 55.8 (13.1) years and duration of disease of 14.0 (6.6) years were recruited. The addition of Vildagliptin significantly reduced GV indices (mmol/L): SD from 2.73 (IQR 2.12-3.66) to 2.11 (1.76-2.55), p=0.015; mean amplitude of glycemic excursions (MAGE) 6.94(2.61) to 5.72 (1.87), p=0.018 and CV 34.05 (8.76) to 28.19 (5.36), p=0.010. In addition, % time in range (3.9-10 mmol/l) improved from 61.17 (20.50) to 79.67 (15.33)%, p=0.001; % time above range reduced from 32.92 (23.99) to 18.50 (15.62)%, p=0.016; with reduction in AUC for hyperglycemia from 1.24 (1.31) to 0.47 (0.71) mmol/day, p=0.015. Hypoglycemic events were infrequent and the reduction in time below range and AUC for hypoglycemia did not reach statistical significance. Conclusion. The addition of DPP4-I to commonly prescribed twice-daily MHI in patients with T2DM improves GV and warrants further exploration.

Background Dopamine agonists such as bromocriptine and cabergoline have been found to be an effective treatment for hyperprolactinemia, not only inducing adenoma shrinkage but also lowering serum prolactin levels. Among known dopamine agonists, cabergoline is the drug of choice due to its enhanced tolerability compared with bromocriptine. This study aimed to evaluate cabergoline's effectiveness, along with transsphenoidal surgery, in the treatment of hyperprolactinemia. Methods We retrieved all patients with a diagnosis of prolactinoma who were treated in our hospital during 2000-2018. A total of 208 patients were enrolled in the analysis after applying exclusion criteria. Patients were divided into four groups according to the treatments received. The demographic data, dosage and duration of cabergoline, and serum prolactin levels at different time points were collected for analysis. Results Normalization was achieved in 59 patients (83.10%) within a short median duration of 2.80 months among those treated with cabergoline only. Although cabergoline alone was effective and well-tolerated, our data showed that long-term remission rates were more favorable when surgery was involved. The long-term remission rate of all patients enrolled was 53.8% (112 patients among 208 patients). The long-term remission rates for the different treatment groups were 17.8% (8 of 45 patients) in Group 1 (Operation→Drug), 83.3% (5 of 6 patients) in Group 2 (Drug→Operation), 79.0% (68 of 86 patients) in Group 3 (Operation only), and 43.7% (31 of 71 patients) in Group 4 (Drug only). Conclusion Cabergoline has been demonstrated to be effective and should be considered as a first-line treatment for hyperprolactinemia. In our study, transsphenoidal surgery was also demonstrated to achieve good results compared with medical treatment. Surgical intervention may resurface as an alternative first-line treatment. When used in combination with cabergoline, surgery offers a higher disease remission rate than either drug or operation alone.

Glioblastoma (GBM) is one of the most devastating cancers, with an approximate median survival of only 16 months. Although some new insights into the fantastic heterogeneity of this kind of brain tumor have been revealed in recent studies, all subclasses of GBM still demonstrate highly aggressive invasion properties to the surrounding parenchyma. This behavior has become the main obstruction to current curative therapies as invasive GBM cells migrate away from these foci after surgical therapies. Therefore, this review aimed to provide a relatively comprehensive study of GBM invasion mechanisms, which contains an intricate network of interactions and signaling pathways with the extracellular matrix (ECM). Among these related molecules, TGF-β, the ECM, Akt, and microRNAs are most significant in terms of cellular procedures related to GBM motility and invasion. Moreover, we also review data indicating that Musashi-1 (MSI1), a neural RNA-binding protein (RBP), regulates GBM motility and invasion, maintains stem cell populations in GBM, and promotes drug-resistant GBM phenotypes by stimulating necessary oncogenic signaling pathways through binding and regulating mRNA stability. Importantly, these necessary oncogenic signaling pathways have a close connection with TGF-β, ECM, and Akt. Thus, it appears promising to find MSI-specific inhibitors or RNA interference-based treatments to prevent the actions of these molecules despite using RBPs, which are known as hard therapeutic targets. In summary, this review aims to provide a better understanding of these signaling pathways to help in developing novel therapeutic approaches with better outcomes in preclinical studies.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues the pandemic spread of the coronavirus disease 2019 (COVID-19), over 60 million people confirmed infected and at least 1.8 million dead. One of the most known features of this RNA virus is its easiness to be mutated. In late 2020, almost no region of this SARS-CoV-2 genome can be found completely conserved within the original Wuhan coronavirus. Any information of the SARS-CoV-2 variants emerged through as time being will be evaluated for diagnosis, treatment, and prevention of COVID-19. METHODS: We extracted more than two million data of SARS-CoV-2 infected patients from the open COVID-19 dashboard. The sequences of the 38-amino acid putative open reading frame 10 (Orf10) protein within infected patients were gathered output through from National Center for Biotechnology Information and the mutation rates in each position were analyzed and presented in each month of 2020. The mutation rates of A8 and V30 within Orf10 are displayed in selected counties: United States, India, German, and Japan. RESULTS: The numbers of COVID-19 patients are correlated to the death numbers, but not with the death rates (stable and

Background Gene therapy is the advanced therapeutics for supplying or replacing the genetic material in patients with inherited disorders. Recent clinical studies have made some progress in a wide range of applications, including monogenic disorders, neurodegenerative diseases, malignant tumors, and congenital diseases. Heart diseases, especially myocardial ischemia, remain one of the leading causes of mortality worldwide and usually result in irreparable cardiomyocyte damage and severe heart failure. Methods Most advances in induced pluripotent stem cell (iPSC) technologies for promoting regenerative medicine and stem cell research. However, the driver molecules of myocardial-lineage differentiation and the functional reconstruction capacity of iPSC-derived cardiomyocytes are still an open question. Nanomedicine-based gene delivery provided a crucial platform to carry on the biogenomic materials for equipping functionalities and engineering the living organ environment. Nanodiamond (ND), a carbon-based nanomaterial, has been discovered and shown the high biocompatible and less toxicity for transporting protein, drug, and genomic plasmids. Results Here, we applied ND as a gene delivery vehicle to carry microRNA (miR-181a), and then transfected into iPS to promote cardiomyocyte-lineage differentiation. Notably, miR-181a plays a key role in iPS-derived cardiomyocyte differentiation which directly targets Hox-A11, leading to elevated MyoD expression and enhanced cardiomyocyte differentiation. Conclusion Our study demonstrated that miR-181a promotes iPSC differentiation into functional cardiomyocytes. Delivery of NANO-DIAMOND-miR-181a may host clinical potential to enhance the differentiation and recovery of the cardiogenic function in injured cardiomyocytes.

STUDY OBJECTIVES: We aimed (1) to investigate the effect of a 12-week exercise training on sleep quality and heart rate variability in middle-aged and older adults with poor sleep quality and (2) to examine the factors associated with the improvements in sleep quality and heart rate variability parameters. METHODS: Forty adults aged ≥ 40 years with poor sleep quality (mean age = 62 years; 82.5% female) participated in this study. They were randomized into the exercise group or control group. Each exercise training program consisted of 40 minutes of supervised aerobic exercise training and 10 minutes of stretching class, 3 times a week for 12 weeks. Outcome measures included both subjective (Pittsburgh Sleep Quality Index) and objective (actigraphy recordings) sleep quality assessments, a cardiopulmonary exercise test, and heart rate variability assessment. RESULTS: The exercise group showed significant improvements in the global score (P = .003), on all subscales of Pittsburgh Sleep Quality Index (P < .05), and in some heart rate variability parameters compared to the control group. Multiple regression analysis indicated that exercise participation was associated with either the sleep quality (β = −0.617, R(2) = .407; F = 6.226, P < .001) or heart rate monitor high frequency normalized units (β = 0.503, R(2) = .225; F = 3.200, P = .003) after adjustment for basic characteristics. However, the statistical significance between exercise participation and heart rate monitor high frequency normalized units diminished after controlling for the Pittsburgh Sleep Quality Index. CONCLUSIONS: Our results indicated that moderate-intensity exercise training had a beneficial effect on sleep quality and cardiac autonomic function. Middle-aged and older adults with poor sleep quality should be encouraged to engage in a moderate-intensity aerobic exercise training to improve their sleep quality and cardiac autonomic function. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: The Effects of Exercise Training in Community-dwelling Elderly With Sleep Disturbances With Follow-up; URL: https://clinicaltrials.gov/ct2/show/NCT03005990; Identifier: NCT03005990. CITATION: Tseng T-H, Chen H-C, Wang L-Y, Chien M-Y. Effects of exercise training on sleep quality and heart rate variability in middle-aged and older adults with poor sleep quality: a randomized controlled trial. J Clin Sleep Med. 2020;16(9):1483–1492.

Background Age-related macular degeneration (AMD) is one of the leading causes of vision loss. Once the retinal pigment epithelium (RPE) layers are destroyed, the poor visual acuity and recognition are generally irreversible. Cell therapy that possesses enormous potential in regenerative medicine may provide an alternative treatment for several incurable diseases such as AMD. In this study, we developed an innovative polydimethylsiloxane (PDMS)-based biomimetic scaffolds with cylinder micropillars for the cultivation of induced pluripotent stem cell-derived RPEs (iPSC-RPEs). RPEs were cultured on the PDMS-based biomimetic scaffolds and validated the cells gene expression. Methods The biomimetic PDMS scaffold was fabricated through spin coating and lithography method. It was further modified on surface with biomolecules to improve cell affinity and stability. The iPSC-RPEs were seeded on the scaffold and analyzed with characteristic gene expression. Results PDMS biomimetic scaffold was analyzed with Fourier transform infrared spectroscopy and proved its chemical composition. iPSC-RPEs demonstrated confluent cell monolayer on the scaffold and maintained RPE-specific gene expression, which proved the PDMS-based biomimetic scaffold to be supportive for iPSC-RPEs growth. Conclusion The PDMS interface allowed regular growth of iPSC-RPEs and the design of cylinder micropillars further provided the bioscaffold high motion resistance may improve the engraftment stability of iPSC-RPEs after transplantation. Taken together, this innovative PDMS-based biomimetic scaffold may serve as an ideal interface for in vitro iPSC-RPE cultivation and subsequent transplantation in vivo. This novel device exhibits better bioavailability than conventional injection of donor cells and may be an alternative option for the treatment of AMD.

BACKGROUND Heart diseases, especially myocardial ischemia, remain one of the leading causes of mortality worldwide and usually result in irreparable cardiomyocyte damage and severe heart failure. Recent advances in induced pluripotent stem cell (iPSC) technologies for applied regenerative medicine and stem cell research, especially for iPSC-derived cardiomyocytes have increased the hope for heart repair. However, the driver molecules of myocardial differentiation and the functional reconstruction capacity of iPSC-derived cardiomyocytes are still questionable. METHODS Herein, we established a rapid differentiated platform that is involved in cardiomyogenic differentiation and maturation from iPSCs in vitro. Functional analysis is performed in miR-181a-transfected iPSC-derived cardiomyocyte (iPSC-cardio/miR-181a) under a time-lapse microscope. In addition, we calculated the beating area and frequency of iPSC-cardio/miR-181a cells in the presence of HCN4 shRNA or miR-181a SPONGE. RESULTS miR-181a enhanced the beating area and maintained the beating frequency of iPSC-derived cardiomyocytes by enhancing HCN4 expression. CONCLUSION miR-181a would play a key role on maintaining proper beating function in iPSC-derived cardiomyocytes.

Background Traumatic brain injury (TBI) is a major cause of death and disability worldwide, and its treatment is potentially a heavy economic burden. Suicide is another global public health problem and the second leading cause of death in young adults. Patients with TBI are known to have higher than normal rates of non-fatal deliberate self-harm, suicide and all-cause mortality. The aim of this study was to explore the association between TBI and suicide risk in a Chinese cohort. Method This study analysed data contained in the Taiwan National Health Insurance Research Database for 17 504 subjects with TBI and for 70 016 subjects without TBI matched for age and gender at a ratio of 1 to 4. Cox proportional hazard regression analysis was used to estimate subsequent suicide attempts in the TBI group. Probability of attempted suicide was determined by Kaplan-Meier method. Results The overall risk of suicide attempts was 2.23 times higher in the TBI group compared with the non-TBI group (0.98 vs 0.29 per 1000 person-years, respectively) after adjustment for covariates. Regardless of gender, age or comorbidity, the TBI group tended to have more suicide attempts, and the risk attempted suicide increased with the severity of TBI. Depression and alcohol attributed disease also increased the risk of attempted suicide in the TBI group. Conclusion Suicide is preventable if risk factors are recognised. Hence, TBI patients require special attention to minimise their risk of attempted suicide.

Purpose An increasing number of studies have linked the severity of obstructive sleep apnea (OSA) with metabolic dysfunction. However, little is known about the lipid compartments (intramyocellular [IMCL] and extramyocellular [EMCL] lipids) inside the musculature in these patients. The present study was designed to investigate the IMCL and EMCL, biochemical data, and functional performance in patients with severe OSA, and to examine the correlations between intramuscular lipid contents and test variables. Participants and Methods Twenty patients with severe OSA (apnea-hypopnea index [AHI]: ≥30/h; body mass index [BMI]: 26.05±2.92) and 20 age- and BMI-matched controls (AHI

Hsi-Chung Chen,1,2 Nai-Wei Hsu,3– 5 Po-Jung Pan,6 Po-Hsiu Kuo,1,7 Meng-Yueh Chien,8 Pesus Chou9 1Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; 2Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan; 3Division of Cardiology, Department of Internal Medicine, National Yang-Ming Chiao Tung University Hospital, Yilan, Taiwan; 4Department of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; 5Public Health Bureau of Yilan County, Yilan, Taiwan; 6Department of Physical Medicine and Rehabilitation & Community Medicine Center, National Yang-Ming Chiao Tung University Hospital, Yilan, Taiwan; 7Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; 8College of Medicine, National Taiwan University and the Physical Therapy Center of National Taiwan University Hospital, Taipei, Taiwan; 9Community Medicine Research Center & Institute of Public Health, National Yang-Ming Chiao Tung University, Taipei, TaiwanCorrespondence: Hsi-Chung ChenDepartment of Psychiatry, National Taiwan University Hospital, No. 7 Chung San South Road, Taipei, 10002, TaiwanTel +886-2-2312-3456 ext. 66787Fax +886-2-2381-320Email hsichungchen@ntu.edu.twObjective: Poor sleep quality is prevailing, deleterious, but heterogeneous in older adults. This study aimed to develop a simplified instrument to screen and classify poor sleep quality in community-dwelling older adults, by which stepped care with needs-based interventions could be implemented.Methods: Cohorts of adults aged 65 years and older were used to develop the Rapid Classification Scale for Sleep Quality (RCSSQ). Poor sleep quality was defined with the Pittsburgh Sleep Quality Index (PSQI). Established subgroups of poor sleep quality in the development dataset (n = 2622) were used as the criterion standard. Two independent validation datasets (n = 964 and 193, respectively) were used to examine the external validity. Questions in the PSQI were examined by the stepwise multinomial logistic regressions to determine the optimal numbers of items in the RCSSQ. On the premise of item parsimony and instrument validity, the optimal combination of reduced items was determined.Results: In the development dataset, the 4-item RCSSQ (RCSSQ-4) was the optimal predictive model. In terms of internal validity, the accuracy rates to identify PSQI-defined poor sleep quality and its subgroups in the developmental dataset by the RCSSQ-4 were 89.0% and 79.9%, respectively. Meanwhile, the RCSSQ-4 also had good external validity in the validation datasets to detect PSQI-defined poor sleep quality (accuracy rates: 89.1– 90.7%). Furthermore, the profiles of PSQI component scores and comorbid conditions for the predicted subgroups in the validation dataset were comparable with the criterion standard.Conclusion: The RCSSQ-4 is a valid instrument for screening and subgrouping poor sleep quality in community-dwelling older adults. The RCSSQ-4 may help guide tailored interventions under the context of stepped care in the community.Keywords: older adults, screen, sleep quality, subgroup, scale, the Yilan study

Neuroblastoma is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. kynurenine treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of KISS1 levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. Significance: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.

Background: Pulmonary rehabilitation (PR) is now considered fundamental when managing patients with chronic respiratory disease. The individual variation in functional exercise capacity (FEC) response to PR within the cohort is unknown. The purpose of this study was to identify FEC patterns in response to PR in patients with chronic respiratory disease using the trajectory modeling method. Methods: The data of 67 patients with the chronic respiratory disease were retrospectively reviewed and analyzed in this study. All patients received once-weekly supervised training for 8 weeks. Six-minute walk distance (6MWD) was used to measure FEC. Muscle strength and 6MWD were assessed at baseline, Week 4, Week 8 and monthly for two months after PR completion. Group-based trajectory modeling (GBTM) was used to identify patterns in 6MWD in response to PR. The generalized estimating equation method was then used to detect the differences within and between the trajectories of identified groups across time. Results: Patients were grouped into low- (n=13), moderate- (n=34) and high- (n=20) FEC group based on GBTM analysis. All groups demonstrated significant improvements in 6MWD and leg muscle strength after 8-week PR. Compared to the high-FEC group, a greater proportion of the patients in the low-FEC group required oxygen supplementation during training and had worse baseline leg muscle strength. Conclusions: Patients showed distinct patterns of 6MWD changes in response to 8-week PR. Distinct characteristics for the low-FEC group included poor lower extremity strength and a greater proportion of required oxygen use at home and during training.

Osteoarthritis (OA) is a common degenerative disease; however, its exact pathophysiology and early diagnosis are still a challenge. Growing attention to the exosomes may inspire innovations that would make the current management of OA more effective. The exosomes in synovial fluid are relatively stable, and they can be easily isolated by the relatively noninvasive procedure of liquid biopsy to provide diagnostic and monitoring value. Some miRNAs (miR-504, miR-146a, miR-26a, miR-200c, and miR-210) have been known to be secreted in exosomes of OA patients. On the other hand, intraarticular injection of platelet-rich plasma (PRP) is becoming a popular therapy for OA patients. PRP is also a source of exosomes and their numerous contents. It is evident from the literature that PRP-derived exosomes can induce chondrogenic gene expression in OA chondrocytes. Here, we review the latest findings on the roles of exosomes in OA with the emphasis on PRP-derived exosomes and their potential applications for treating OA.

Lung cancer is one of the most prevalent human cancers, and single-cell RNA sequencing (scRNA-seq) has been widely used to study human lung cancer at the cellular, genetic, and molecular level. Even though there are published reviews, which summarized the applications of scRNA-seq in human cancers like breast cancer, there is lack of a comprehensive review, which could effectively highlight the broad use of scRNA-seq in studying lung cancer. This review, therefore, was aimed to summarize the various applications of scRNA-seq in human lung cancer research based on the findings from different published in vitro, in vivo, and clinical studies. The review would first briefly outline the concept and principle of scRNA-seq, followed by the discussion on the applications of scRNA-seq in studying human lung cancer. Finally, the challenges faced when using scRNA-seq to study human lung cancer would be discussed, and the potential applications and challenges of scRNA-seq to facilitate the development of personalized cancer therapy in the future would be explored.

BACKGROUND Plate and locked intramedullary nailing for humeral fractures are golden standard procedure, but the humerus is a nonweight-bearing bone and can tolerate a larger range of acceptable alignment. We believe the elastic stable intramedullary nails (ESINs) can provide enough relative stability for humeral shaft fractures in certain adult patients. METHODS There are four new indications for using ESINs: (1) patient could not tolerate a sugar-tong splint but was a high risk for general anesthesia, (2) intramedullary canal narrowing (

The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has brought an unprecedented impact upon the global economy and public health. Although the SARS-CoV-2 virology has been gradually investigated, measures to combat this new threat in public health are still absent. To date, no certificated drug or vaccine has been developed for the treatment or prevention of coronavirus disease Extensive researches and international coordination has been conducted to rapidly develop novel vaccines against SARS-CoV-2 pandemic. Several major breakthroughs have been made through the identification of the genetic sequence and structural/non-structural proteins of SARS-CoV-2, which enabled the development of RNA-, DNA-based vaccines, subunit vaccines, and attenuated viral vaccines. In this review article, we present an overview of the recent advances of SARS-CoV-2 vaccines and the challenges that may be encountered in the development process, highlighting the advantages and disadvantages of these approaches that may help in effectively countering COVID-19.

Background Cardiotocography is a common method of electronic fetal monitoring (EFM) for fetal well-being. Data-driven analyses have shown potential for automated EFM assessment. For this preliminary study, we used a novel artificial intelligence method based on fully convolutional networks (FCNs), with deep learning for EFM evaluation and correct recognition, and its possible role in evaluation of nonreassuring fetal status. Methods We retrospectively collected 3239 EFM labor records from 292 deliveries and neonatal Apgar scores between December 2018 and July 2019 at a single medical center. We analyzed these data using an FCN model and compared the results with clinical practice. Results The FCN model recognized EFM traces like physicians, with an average Cohen's kappa coefficient of agreement of 0.525 and average area under the receiver operating characteristic curve of 0.892 for six fetal heart rate (FHR) categories. The FCN model showed higher sensitivity for predicting fetal compromise (0.528 vs 0.132) but a higher false-positive rate (0.632 vs 0.012) compared with clinical practice. Conclusion FCN is a modern technique that may be useful for EFM trace recognition based on its multiconvolutional layered analysis. Our model showed a competitive ability to identify FHR patterns and the potential for evaluation of nonreassuring fetal status.

Background Various upper limb activities were speculated to be associated with the development of carpal tunnel syndrome (CTS). Nonetheless, there are currently no standardization on the uses of parameters in CTS assessments, nor are there any conclusive findings regarding the usefulness of various sonographic measurements in studies of different upper limb activities. In this review, we intend to evaluate the methodology of assessing Carpal Tunnel Syndrome (CTS) induced by upper limb activities with ultrasonographic technique and provide corresponding suggestions. Methods Clinical studies on the association between upper limb activities and prevalence of CTS using ultrasonography were recruited in a database research on the basis of a procedural selection criteria and reviewed. The following qualitative items were extracted: characteristics of studies, scanning methods, selection of sonographic parameters and related article findings. Results Eleven studies were qualified for this review. Three studies were computer keyboard typing-related, five studies were electronic device-related, and three studies were wheelchair-related. All sampled articles included cross-sectional area (CSA) at the pisiform level. The swelling ratio (SR) and flattening ratio (FR) at the hamate level are also used in most studies in addition to the CSA at the pisiform level. The effectiveness of such parameters are subjected to various confounding factors such as age, weight, BMI and wrist anthropometrics, suggesting CSA and SR with sufficient levels had significant values as sonographic parameters. Values of parameters were found affecting symptomatic signs and hand dominance. Conclusion Ultrasound scan is a suitable tool to assess the relationship between upper limb activity and CTS. CSA at the pisiform level, SR and the FR at the hamate levels are generally suitable in upper limb associated-CTS investigations. Specific study designs are required to eliminate different confounding factors accordingly.

Lung cancer (LC) causes the majority of cancer-related deaths. Circular RNAs (circRNAs) were reported to play roles in cancers by targeting pro- and anti-oncogenic miRNAs. However, the mechanisms of circRNAs in LC progression and their prognostic value of treatment response remain unclear. By using next generation sequencing (NGS) of LC cell lines&rsquo, transcriptomes, we identified highly overexpressed hsa_circ_0000190 and hsa_circ_000164 as potential biomarkers. By using the highly sensitive RT-ddPCR method, these circRNAs were shown to be secreted by cell lines and were detected in human blood. Clinical validation by RT-ddPCR was carried out on 272 (231 LC patients and 41 controls) blood samples. Higher hsa_circ_0000190 levels were associated with larger tumor size (p &lt, 0.0001), worse histological type of adenocarcinoma (p = 0.0028), later stage (p &lt, 0.0001), more distant metastatic organs (p = 0.0039), extrathoracic metastasis (p = 0.0004), and poor survival (p = 0.047) and prognosis. Using liquid biopsy-based RT-ddPCR, we discovered the correlation between increased hsa_circ_0000190 plasma level (p &lt, 0.0001) and higher programmed death-ligand 1 (PD-L1) level in tumor (p = 0.0283). Notably, long-term follow-up of the immunotherapy treated cases showed that upregulated plasma hsa_circ_0000190 level correlated with poor response to systemic therapy and immunotherapy (p = 0.0002, 0.0058, respectively). Secretory circRNAs are detectable in blood by LB-based RT-ddPCR and may serve as blood-based biomarkers to monitor disease progression and treatment efficacy.

Glycemic variability (GV) is emerging as an exciting therapeutic target for diabetes mellitus (DM) with recent evidences showing association of GV with hypoglycemia risk as well as chronic complications.(1,2) Twice daily human premixed insulin is commonly used in developing countries and Asia for treatment of type 2 DM (T2DM). (3) While more convenient and cost saving, human premixed insulin regime may increase GV due to lesser flexibility and less physiological pharmacokinetic profile. Dipeptidyl peptidase IV inhibitors (DPPIV-I) have been shown to improve GV when used for treatment of T2DM but the effects of DPPIV-I when added on human premixed insulin is limited. We therefore evaluated the changes in GV following addition of DPP IV-I among T2DM patients treated with premixed human insulin with or without metformin therapy. This was a prospective study involving adult patients with T2DM on stable doses of premixed human insulin with or without metformin for at least 3 months from two state hospitals in Malaysia. Blinded continuous glucose monitoring (CGM) were performed at baseline and following 6 weeks of adding Vildagliptin to their insulin regime. A total of 12 patients were recruited (50% male). Mean (SD) age was 55.8 (13) years with mean duration of disease of 14 (6.6) years. The addition of Vildagliptin significantly reduced GV indexes including SD 2.98 (1.17) to 2.33 (0.82), p=0.017; MAGE 6.94 (2.61) to 5.72 (1.87), p=0.018; MAG 1.60 (0.76) to 1.23 (0.48), p=0.009 and M Value 13.96 (13.01) to 6.52 (7.45), p=0.037. In addition there were improvements in terms of parameters for glycemic control. Time spent in optimal glycemic range (4-8 mmol/l) improved from 38.33 (19.69) to 58.17 (5.95) %, p=0.001 with reduction in AUC for hyperglycemia from 2.09 (1.73) to 1.06 (1.09) mmol/day, p=0.010. Hypoglycemia events were infrequent and the reduction in time spent in hypoglycemia [5.92(9.74) to 1.91 (2.54)%, p=0.191] as well as AUC for hypoglycemia [0.03(0.54) to 0.01(0.02) mmol/day, p=0.163] were found although these did not reach statistical significance. We concluded that addition of DPP IV-I to commonly prescribed twice daily premixed human insulin regime in patients with T2DM may improve GV and glycemic control and warrant further exploration. References (1) Gerry Rayman. Glycaemic control, glucose variability and the triangle of diabetes care. Br J Diabetes 2016;16(Suppl1):S3-S6 (2) Boris P. Kovatchev. Metrics for glycaemic control - from HbA1c to continuous glucose monitoring. Nat Rev Endocrinol. 2017 Jul;13(7):425-436 (3) Kalra S, Balhara YP, Sahay BK, Ganapathy B, Das AK. Why is premixed insulin the preferred insulin? Novel answers to a decade-old question. J Assoc Physicians India. 2013 Jan;61(1 Suppl):9-11

The prevalence of mediastinal parathyroid adenoma is unknown. Embryological origin and more extensive aberrant migration of the parathyroid glands result in ectopic glands found in the mediastinum. We report herein 4 cases of ectopic parathyroid adenoma causing primary hyperparathyroidism from three public hospitals in MalaysiaCase 1.A 70 year old lady with underlying diabetes mellitus, hypertension, chronic immune thrombocytopenic purpura and liver cirrhosis presented with incidental asymptomatic hypercalcemia during an admission for pneumonia. Her blood results revealed high corrected calcium of 2.93 mmol/L (2.02-2.60) and a low phosphate of 0.66 (0.81-1.45) mmol/L with an unsuppressed intact parathyroid hormone (iPTH) of 14.56 pmol/L (1.6-6.9). She had an equivocal urinary calcium excretion ratio of 0.01. Her bone mineral density confirmed severe osteoporosis at distal radius and neck of femur with a Tscore of -3.6 and -3.1 respectively. A hyperfunctioning ectopic parathyroid gland was seen in the Technetium Sestamibi scan which corelates with a mediastinal lymphadenopathy on CECT. The largest node measured 1.6 x 1.2 cm. Parathyroid gland was confirmed on HPE of the video-assisted-thoracoscopic surgical (VATS) excision of the mediastinal mass. Intraoperative iPTH (ioPTH) serially reduced from 8.87 to 1.94 to 1.03 pmol/L and she maintained a serum calcium levels of 2.4 mmol/L post surgery. She did not require any calcium or vitamin D supplementation. Case 2. A 36 year old male presented with generalized body weakness secondary to hypokalemia. His calcium was 3.07 mmol/l, phosphate 0.64 mmol/l and iPTH 11.53 pmol/L. Increase Technetium uptake seen at mediastinum. Post operatively, calcium normalized and remained stable 1 year later. Case 3.47 year old female presented with acute gallstone pancreatitis complicated with a pancreatic pseudocyst. She was found to have hypercalcemia of 2.77 mmol/L, phosphate 0.70 mmol/l and iPTH 21.87 pmol/L. Sestamibi scan revealed hyperfunctiong parathyroid tissue posterior to the left thyroid lobe and in the mediastinum. She is awaiting surgery. Case 4.Another asymptomatic 47 year old male who has history of post Radioactive-iodine hypothyroidism had an incidental finding of serum calcium of 2.69-2.84 mmol/L, phosphate 0.71-0.91 mmol/L and iPTH 9.89 pmol/L with urinary calcium excretion ratio of 0.019. His Sestamibi scan showed uptake at the superior mediastinum. Ectopic parathyroid gland is rarely encountered. With the advent of Technetium-Sestamibi scintigraphy, ectopic parathyroid adenoma can be localized easily. However, surgery poses a challenge due the location of the adenoma which may occasionally be near large vascular structures in the mediastinum. The availability of intraoperative PTH aids the decision for surgical exploration and completion.

Parkinson's disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem cells derived from human exfoliated deciduous teeth (SHED), mesenchymal stem cells derived from dental pulp, may have promising potential in regenerative medicine. In this study, we examine the therapeutic effect of SHED-derived conditioned medium (SHED-CM) in a rotenone-induced PD rat model. Intravenous administration of SHED-CM generated by standardized procedures significantly improved the PD symptoms accompanied with increased tyrosine hydroxylase amounts in the striatum, and decreased &alpha, synuclein levels in both the nigra and striatum, from rotenone-treated rats. In addition, this SHED-CM treatment decreased both Iba-1 and CD4 levels in these brain areas. Gene ontology analysis indicated that the biological process of genes affected by SHED-CM was primarily implicated in neurodevelopment and nerve regeneration. The major constituents of SHED-CM included insulin-like growth factor binding protein-6 (IGFBP-6), tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-1, and transforming growth factor 1 (TGF-1). RNA-sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) revealed that these factors may ameliorate PD symptoms through modulating the cholinergic synapses, calcium signaling pathways, serotoninergic synapses, and axon guidance. In conclusion, our data indicate that SHED-CM contains active constituents that may have promising efficacy to alleviate PD.

Dopamine agonist monotherapy is first line therapy in giant prolactinomas even when visual field defect is present. The costlier cabergoline is often preferred over bromocriptine due to higher efficacy and tolerability profile. Described herein combined cabergoline and bromocriptine therapy in 6 cases of giant prolactinomas. Retrospective records review of 6 patients with giant prolactinoma (3 males: M1-M3, 3 females: F1-F3) in a single tertiary centre was performed. Mean age at diagnosis: 29 years (range 17-39). Mean duration of follow up: 7 years (range 3-11). Headache and visual field defect were the presenting symptoms in all cases. Basal prolactin concentration: 100000 to 468851 mIU/L (

The prevalence of nonalcoholic fatty liver disease (NAFLD) is usually increased with age. Non-alcoholic steatohepatitis (NASH), a serious form of NAFLD, may lead to cirrhosis and end-stage liver diseases. Induced pluripotent stem cells (iPSCs) hold promising potential in personalized medicine. Although obviation of c-Myc reduces tumorigenic risk, it also largely reduced the generation of iPSCs. Recently, Poly(ADP-ribose) polymerase 1 (Parp1) has been reported to enhance cell reprogramming. In this study, we demonstrated that forced expression of Oct4/Sox2/Klf4/Parp1 (OSKP) effectively promoted iPSC generation from senescent somatic cells from 18-month-old mouse. The iPSCs presented regular pluripotent properties, ability to form smaller teratoma with smaller size, and the potential for tridermal differentiation including hepatocyte-like cells (OSKP-iPSC-Heps). Resembled to fetal hepatocytes but not senescent hepatocytes, these OSKP-iPSC-Heps possessed antioxidant ability and were resistant to oxidative insult induced by H2O2 or exogenous fatty acid. Intrasplenic transplantation of OSKP-iPSC-Heps ameliorated the triglyceride over-accumulation and hepatitis, prevented the production of inflammatory cytokines and oxidative substances, and reduced apoptotic cells in methionine/choline-deficient diet (MCDD)-fed mice. In conclusion, we demonstrated that Parp-1 promoted iPSC generation from senescent cells, which can be used for the treatment of NASH after hepatic-specific differentiation. These findings indicated that patient-derived iPSC-Heps may offer an alternative option for treatment of NASH and NASH-associated end-stage liver diseases.

Introduction: The Malaysian government implemented MCO or lockdown for nearly 3 months from 18 Mar to 9 Jun 2020 in response to the Covid-19 pandemic. This restricted access to usual food, workplace, and leisure sports, and also led to reduced clinic attendance. The effects of MCO on patients with chronic lifestyle diseases like DM is unknown. Methodology: This is a cross-sectional study exploring effects of MCO on adult (>18 years) DM patients (both Type 1 and Type 2) attending endocrinologist-run DM clinics in 3 tertiary centres in Malaysia. Glycaemic and metabolic parameters were collected through medical record review while data on healthcare utilisation, dietary and lifestyle habits before MCO (17 Nov 2019 to 17 Mar 2020) and during MCO were collected by investigator-administered questionnaires during routine clinic follow-up after the MCO period (10 Jun to 30 Oct 2020). Results: From a total of 207 patients (56.5% female, 73.4% T2D and 80% on insulin) no significant difference between mean (SD) A1c [8.6(2.39) % vs 8.4(2.14) %; p=0.073] or BMI [29.2(7.57) vs 29.4(9.23)kg/m2; p=0.968] were seen before and during MCO respectively. More than 95% of the patients attended clinic before MCO and at least 20.3% saw either the DM nurse educator, DM pharmacist or dietitian. In contrast, during MCO only 31.4% of patients attended clinic and less than 10% had face-to-face consultation with the DM support team. More patients also reported missing insulin (11.6% vs 7.7%) and not checking blood glucose (17.9% vs 15.5%) during MCO. Before MCO, 61.8% of patients had home-cooked food daily. During MCO this increased to 83.1%. However, there was a trend towards unhealthy eating during MCO. Patients reported eating more frequently with those eating more than 4 meals a day nearly tripled during MCO (18.4% vs 6.8%). In addition, 22% of patients recalled consuming more confectionary; a similar percentage also reported higher consumption of processed food like dry snacks, canned food and instant noodles during MCO. Mean (SD) hours of sleep [6.8 (1.35) vs 7.2 (1.73) hours; p

Decreased anabolism because of alterations in the insulin-like growth factor 1 (IGF-1)/growth hormone (GH) axis and increased catabolism induced by proinflammatory cytokines like tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) have been reported to contribute to muscle wasting in chronic heart failure (CHF). However, it is unclear whether exercise training could modulate anabolic and catabolic markers in CHF patients. The purpose of this study was to investigate the effects of exercise intervention on anabolic and catabolic markers for patients with CHF. Literatures were systematically searched in electronic databases and relevant references. Only published randomized controlled trials (RCTs) focusing on exercise training for CHF were eligible for inclusion. Outcome measurements included serum level and muscle biopsy of TNF-α, IL-6, GH, and IGF-I. Of the six included studies, four showed no significant difference between exercise group and control group in the serum levels of TNF-α, IL-6, GH, and IGF-I. However, two studies showed significant reduction in TNF-α and IL-6 and increase in IGF-I by local skeletal muscle biopsy. We conclude that the decreases in catabolic markers and increases in anabolic after exercise training were evident only by local skeletal muscle biopsy. More RCTs on dose-response relation of exercise programs are needed to further optimize anabolic and anti-inflammatory benefits of exercise training in patients with CHF.

The level of 8-hydroxy-2-deoxyguanosise (8-OHdG) is a marker of oxidative stress. The objective of this study was to evaluate the effect of enzyme replacement therapy (ERT) on the level of 8-OHdG in patients with Fabry cardiomyopathy and the clinical evolution of Fabry cardiomyopathy.We measured the serum levels of 8-OHdG in 20 healthy control and 22 patients with Fabry cardiomyopathy before and after ERT.The mean lysoGb3 and 8-OHdG levels was significantly increased in patients with Fabry cardiomyopathy compared with that of control subjects (lysoGb3, 3.6 ± 1.1 nM vs. 0.4 ± 0.1 nM, p 0.01; 8-OHdG, 4.5 ± 0.5 ng/mL vs. 3.4 ± 0.4 ng/mL, P 0.05). The mean lysoGb3 and 8-OHdG levels was significantly reduced after ERT for 14.2 months (lysoGb3, 3.6 ± 1.1 nM vs. 2.9 ± 1.1 nM, P 0.05; 8-OHdG, 4.5 ± 0.5 ng/mL to 4 ± 0.4 ng/mL, P 0.05). These changes were accompanied by decreases in LVM and LVMI.We demonstrated that the serum 8-OHdG levels is increased in patients with Fabry cardiomyopathy (FC) and that successful management of FC with ERT is associated with a decrease in this oxidative stress marker. Serum 8-OHdG levels can be used not only as a noninvasive biomarker of oxidative stress in patients with FC but also an objective and quantitative parameter in the follow-up of patients during ERT.

The liver is an essential organ that is primarily responsible for digestion and eliminating toxic substances from the body. After the industrial revolution, Western diet and lifestyle changes have increased the incidence of several liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). NAFLD and NASH are mostly asymptomatic at early stages, and the disease progression from NAFLD to life-threatening HCC remains not fully understood. Circular RNA (circRNA) is consist of a circular structure, and the circRNA-microRNA(miRNA)-mRNA axes have been shown to be involved in several cellular events, including apoptosis, vascularization, metastasis, etc. The highly stable structure of circRNAs has enabled themselves to be used as putative biomarkers of several diseases. Here, we conducted a literature review and discussed the identified roles of circRNAs in NAFLD, NASH, liver cirrhosis, and HCC. For example, deficiency of circRNA_0046366 and circRNA_0046367 has been shown as the characteristics of NAFLD, and restoration of these circRNAs ameliorates the oxidative stress, lipotoxicity, and disease severity in NAFLD. Silencing of circ_0071410 was shown to alleviate hepatic stellate activation, the key step of liver cirrhosis. CDR1 and circ_0067934 can facilitate the invasion and metastasis of HCC, while circMTO1 negatively regulates the progression of HCC. Although several research works have been conducted, the whole picture of circRNA-related underlying mechanisms is unclear. Future works using high-throughput bioinformatic approaches will be needed to delineate the role of circRNAs in liver diseases and to further develop novel diagnostics and therapeutics.

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation, partially through IGF-1-dependent mechanisms.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye’s accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.

Elevated homocysteine levels have been proposed as a risk factor for cardiovascular disease. The aim of this study was to evaluate factors associated with hyperhomocysteinemia in relatively healthy Taiwanese adults.A retrospective cross-sectional study was conducted using data from the health examination database in a medical center located in southern Taiwan. Hyperhomocysteinemia was defined as a plasma homocysteinemia level >15 μmol/L. Factors associated with hyperhomocysteinemia were evaluated using univariate and multiple stepwise logistic regression analyses.A total of 817 adults with a mean age of 55.5 years were included in the present study, and of them, 67 (8.2%) had hyperhomocysteinemia. Results from multiple logistic regression analysis showed that male sex (Odd ratio [OR] = 12.28, 95% CI = 2.94-51.27, P = .001), advanced age (OR = 1.37 per 10 years, 95% CI = 1.06-1.77, P = .017), triglycerides (OR = 1.02 per 10 mg/dL, 95% CI = 1.01-1.04, P = .010), and uric acid (OR = 1.27, 95% CI = 1.09-1.49, P = .004) were significantly and independently associated with hyperhomocysteinemia.In this retrospective medical record study, male sex, advanced age, higher plasma level of triglyceride, and uric acid were significantly associated with hyperhomocysteinemia in relatively healthy Taiwanese adults.

// Yueh Chien 1, 7, * , Chian-Shiu Chien 1, 7, * , Huai-Chih Chiang 1, 7, * , Wei-Lin Huang 1, 9 , Shih-Jie Chou 1, 7 , Wei-Chao Chang 4 , Yuh-Lih Chang 2, 7 , Hsin-Bang Leu 3, 8 , Kuan-Hsuan Chen 2, 8 , Kang-Ling Wang 3, 8 , Ying-Hsiu Lai 8 , Yung-Yang Liu 1, 8 , Kai-Hsi Lu 5 , Hsin-Yang Li 1, 9 , Yen-Jen Sung 9 , Yuh-Jyh Jong 6 , Yann-Jang Chen 10 , Chung-Hsuan Chen 11, 12 , Wen-Chung Yu 3, 13 1 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan 2 Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan 3 Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 4 Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University and Department of Biotechnology, Asia University, Taichung, Taiwan 5 Department of Medical Research, Cheng-Hsin Hospital, Taipei, Taiwan 6 College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan 7 Institute of Pharmacology, Taipei, Taiwan 8 Institute of Clinical Medicine, Taipei, Taiwan 9 Institute of Anatomy and Cell Biology, Taipei, Taiwan 10 Department of Life Sciences and Institute of Genome Sciences, Taipei, Taiwan 11 Genomics Research Center, Academia Sinica, Taipei, Taiwan 12 Department of Chemistry, National Taiwan University, Taipei, Taiwan 13 Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Wen-Chung Yu, email: wcyu@vghtpe.gov.tw Keywords: fabry cardiomyopathy, iPSC, enzyme replacement therapy, IL-18 Received: May 11, 2016 Accepted: November 07, 2016 Published: November 24, 2016 ABSTRACT Rationale: A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown. Objective: Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC. Results and methods: The iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients’ sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs. Conclusion: Our data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation.

(1) To compare the frailty status between community-dwelling older adults with and without atrial fibrillation (AF) in Taiwan and (2) to test the hypothesis that AF is associated with frailty in community-dwelling older adults.We conducted a cross-sectional study in several communities in Taipei. AF was confirmed by electrocardiogram recordings or medical diagnosis. Frailty status was assessed using both the Cardiovascular Health Study (CHS) frailty phenotype and Edmonton Frail Scale (EFS).A total of 207 community-dwelling older adults voluntarily participated in this study, and 38 had AF. There was a significantly higher percentage of frailer (prefrail and frailty) older adults in the AF group (69 % vs. 36 %, p0.001) according to CHS phenotype, but no significant difference was detected by EFS criteria (92 % vs. 92 %, p = 0.966). The AF group showed significantly lower grip strength in men (26.8 ± 8.3 vs. 33.0 ± 6.9 kg, p = 0.006), walking speed (1.1 ± 0.3 vs. 1.2 ± 0.3 m/s, p = 0.003), and Timed Up and Go performance (8.8 ± 2.4 vs. 7.0 ± 1.9 s, p 0.001) than the control group. The multiple logistic regression model showed that AF was an independent factor associated with frailer community-dwelling older adults after adjusted for covariates (odds ratio, 3.02; 95 % confidence interval, 1.32-6.89, p = 0.009).Community-dwelling older adults with AF showed a significantly higher percentage of frailer individuals and lower physical function than those without AF. Furthermore, AF was an independent predictor of frailer community-dwelling older adults.

We report the characteristics of reflectance spectra of the 15- and 20-period ZnTe/ZnSe distributed Bragg reflector grown on GaAs (001) substrates by molecular beam epitaxy. The reflectance spectra measured at various incident angles and polarizations were investigated by the theoretical curves simulated using transfer matrix method. The wavelength variation of the refractive indices described by Sellmeier equation and random thickness model were also considered for the interpretation of the experimentally observed curves. An omnidirectional reflection range defined from the edge of incident-angle-dependent reflection band with TE and TM polarizations is about 15 nm, and is consistent with the observed experimental curves. The results showed that the selected ZnTe and ZnSe materials are suitable for constructing multilayer structures having omnidirectional reflection band.

Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.

Aims: The purposes of this study were (1) to compare body composition, physical function, and quality of life (QOL) between patients after coronary artery bypass grafting (CABG) with and without chronic kidney disease (CKD) and (2) to analyze the factors associated with physical function and QOL domains in these patients. Methods: Thirty male post-CABG patients with CKD and 30 matched controls were recruited. All subjects underwent dual-energy X-ray absorptiometry for body composition evaluation. Physical function tests included the grip strength test, 30-second chair stand test (30CST), and 6-min walk test (6MWT). Physical activity and QOL were assessed using the long form of the International Physical Activity Questionnaire and the World Health Organization Quality of Life Instrument (WHOQOL)-BREF, respectively. Results: Post-CABG patients with CKD exhibited a lower arm lean mass and higher percent leg fat mass than those without CKD (p < 0.05). The patients with CKD also had lower 30CST scores, 6MWT distances, and QOL domain of social relationships scores than those without CKD after adjusting for covariates (p < 0.05). If NYHA class was considered in the model, NYHA class became the most important factor associated with 6MWT distances (β = -0.647, p < 0.001) and the QOL domains of psychological health (β = -0.285, p = 0.027) and environment (β = -0.406, p = 0.001). Conclusion: Post-CABG patients with CKD had worse body composition, physical function, and QOL than those without CKD, and this might be associated with a worse NYHA class.

Neuroblastoma (NB) is a childhood cancer with a low survival rate and great metastatic potential. Vascular endothelial growth factor (VEGF), an angiogenesis factor, has been found to be involved in CRT-related neuronal differentiation of NB cells. In this study, we further confirmed the role VEGF in NB through mouse xenograft model and clinical analysis from NB patients. In xenograft experiments, CRT overexpression effectively inhibited the tumor growth. In addition, the mRNA and protein levels of VEGF and differentiation marker GAP-43 were upregulated by induced CRT expression. However, no significant correlation between the expression level of VEGF and microvessel density was observed in human NB tumors, suggesting a novel mechanism of VEGF participating in NB tumorigenesis through an angiogenesis-independent pathway. In NB patients’ samples, mRNA expression levels of CRT and VEGF were positively correlated. Furthermore, positive VEGF expression by immunostaining of NB tumors was found to correlate well with histological grade of differentiation and predicted a favorable prognosis. In conclusion, our findings suggest that VEGF is a favorable prognostic factor of NB and might affect NB tumor behavior through CRT-driven neuronal differentiation rather than angiogenesis that might shed light on a novel therapeutic strategy to improve the outcome of NB.

We present the incident-angle-dependent reflectance spectra of the 10-period ZnO/MgO multilayer films deposited on Si by sputtering technique. As increasing the incident angle, the resonant wavelength and bandwidth of the measured reflectance spectra exhibit redshift and narrower, respectively. The theoretical curves using transfer matrix method taken account of transverse electric (TE) and transverse magnetic (TM) polarizations are calculated to well describe the variations in the behavior of the experimental spectra. The simulated TE- and TM-reflection band at different angles can evaluate the bandwidth of the resonance band and provide valuable parameters to design an omnidirectional-reflection band in selected multilayer structure.

The optical properties of In x Ga 1− x N epitaxial layers ( x = 0.02, 0.04, 0.11, 0.15, 0.30 and 0.33) grown by metalorganic chemical vapor deposition (MOCVD) have been investigated by temperature-dependent photoluminescence (PL) measurement. The surface morphologies of InGaN samples are studied by scanning electron microscopy (SEM) images. The PL feature at 12 K has shown an increase in full-width at half-maximum (FWHM) with increasing In content. An anomalous S-shaped temperature dependence of the PL peak energy exhibited by InGaN films with higher In content enabled the evaluation of the exciton localization energy. The broadened FWHM and S-shaped emission shift are attributed to larger compositional fluctuation due to compositional inhomogeneity of In. Additionally, the luminescence mechanism relating to the phase separation has to be considered for the much larger FWHM value and the pronounced S-shaped behavior for the InGaN samples with In content of 0.30 and 0.33.

Introduction In patients with obstructive sleep apnea (OSA), intermittent apnea and hypopnea might cause different adaptations in inspiratory and peripheral muscles. In this study we aimed to determine the changes that occur in muscle activation characteristics during incremental exercise testing in patients with severe OSA. Surface electromyography of inspiratory muscles and knee extensors was performed. Methods Eleven men with severe OSA and 11 matched controls were recruited. Changes in muscle activity were compared by determining root mean square (RMS) and median power frequency (MPF) values obtained at different exercise intensities. Results The ratios of RMS to oxygen consumption in inspiratory muscles and vastus lateralis increased significantly at peak workload in the control group (P < 0.05), but not in the OSA group. Conclusions Patients with severe OSA demonstrated an inability to increase motor unit recruitment of inspiratory muscles and knee extensors during incremental exercise. Muscle Nerve, 48: 212–218, 2013

Mechanical ventilation in patients may increase the risk of an acute lung injury (ALI), termed ventilator-induced lung injury (VILI). Induced pluripotent stem cells (iPSCs) have previously been shown to improve tissue repair in different disease models, including ALI. However, the therapeutic efficacy of iPSCs-derived conditioned medium (iPSC-CM) on ALI or VILI remains unknown. Here, we demonstrated that both iPSCs and iPSC-CM effectively decrease high-tidal-volume-induced VILI-related inflammatory processes and HMGB1 and PAI-1 production, predominantly through suppressing PI3K/Akt signaling. Notably, iPSC-CM suppressed production of macrophage inflammatory protein-2, malondialdehyde, and increased total glutathione content. Transmission electron microscopy revealed that iPSC-CM potentially restored the bronchial microstructure. This iPSC-CM efficacy could be mimicked by PI3K inhibitor LY294002 or Akt heterozygous knockout, and either treatment showed no further improvement on VILI in iPSC-CM recipients. Furthermore, iPSC-CM increased interferon gamma-induced protein 10 (IP-10) production in injured lungs. Administration of IP-10-neutralizing antibodies increased neutrophil infiltration, impaired lung oxygenation and deteriorated the protective effects mediated by iPSC-CM. Our data provide a preclinical indication regarding the therapeutic potential of iPSC-CM in VILI and suggest that inhibiting PI3K/Akt pathway or increasing IP-10 is a prospective diagnostic and therapeutic target for VILI patients.

Background Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. Objectives We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. Methods Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. Results The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. Conclusion This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease.

To explore the mechanism, breakthrough the current bottleneck and overcome the efficiency droop from green InGaN/GaN multiple quantum wells (MQWs) light-emitting diodes (LEDs). The photoluminescence properties and carrier dynamics of green InGaN/GaN MQW LEDs are investigated by temperature-dependent photoluminescence (PL) from 10 K to 300 K and time-resolved PL (TRPL) measurements at 10 K in our new-built lab. With increasing temperature, a blue shift of PL behavior is attributed to band-tail states formed in local potential minima resembling In-rich clusters. The energy-dependent TRPL experiments are measured at 10 K to study the carrier dynamics in the MQWs. The results show that the PL slow decays for the low-energy side are much slower than the high-energy side. The depth of carrier localization is obtained by fitting the reduced slow decay time with the emission energy increasing. All the results indicate that the PL peak is related to localized radiative recombination.

Two ultraviolet InGaN/GaN light emitting diodes (LEDs) with and without InGaN underlying layer beneath the multiple quantum wells (MQWs) were grown by metal-organic vapor phase epitaxy. Based on the photoluminescence excitation measurements, it was found that the Stokes shift of the sample with a 10-nm-thick In0.1Ga0.9N underlying layer was about 64 meV, which was smaller than that of the reference sample without InGaN underlying layer, indicating a reduced quantum-confined Stark effect (QCSE) due to the decrease of the piezoelectric polarization field in the MQWs. In addition, by fitting the photon energy dependence of carrier lifetime values, the radiative recombination lifetime of the sample with and without InGaN underlying layer were obtained about 1.22 and 1.58 ns at 10 K, respectively. The shorter carrier lifetime also confirmed that the QCSE in the MQWs was weakened after inserting the InGaN underlying layer. In addition, although the depth of carrier localization in the sample with InGaN underlying layer became smaller, the nonradiative recombination centers (NRCs) inside it decreased, and thus suppressed the nonradiative recombination process significantly according to the electroluminescence measurement results. Compared to the reference sample, the efficiency droop behavior was delayed in the sample with InGaN underlying layer and the droop effect was also effectively alleviated. Therefore, the enhanced light-emission efficiency of ultraviolet InGaN/GaN MQW LEDs could be attributed to the decrease of QCSE and NRCs.