Publications by authors named "Yu-Chun Lin"

245 Publications

Mimics of malignancy caused by concurrent imperforate hymen and transverse vaginal septum: an instructive case and review of the literature.

J Int Med Res 2021 May;49(5):3000605211014797

Department of Paediatrics, Tri-Service General Hospital, National Defense Medical Centre, Taipei.

The coexistence of imperforate hymen and vaginal septum is rare and their ability to mimic malignant manifestations have not been frequently reported. This current case report describes a 13-year-old girl that presented with cyclic abdominal pain for 6 months. She was found to have a huge mass via abdominal plain film X-ray and sonography, with inexplicably high levels of serum carcinoembryonic antigen, cancer antigen (CA)-19-9 and CA-125. Pelvic computed tomography imaging disclosed two huge cystic lesions in the uterine and upper vaginal cavities. Surgical intervention conformed the diagnosis of a concurrent imperforate hymen and transverse vaginal septum, echoing the imaging findings of haematocolpometra. Her tumour marker levels gradually returned to normal after surgery. This rare case of concomitant imperforate hymen and transverse vaginal septum highlights that haematocolpometra, a benign disease that might mimic malignancy, should be taken into consideration in any adolescent females with an abdominal mass and amenorrhoea to ensure an early diagnosis and timely appropriate management.
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http://dx.doi.org/10.1177/03000605211014797DOI Listing
May 2021

Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice.

Int J Mol Sci 2021 Apr 28;22(9). Epub 2021 Apr 28.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz-Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/β-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of β-catenin in the Pdx-1-Cre LKB1 β-catenin mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of β-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1 mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the β-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/β-catenin signaling in PC harboring LKB1 deficiency.
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http://dx.doi.org/10.3390/ijms22094649DOI Listing
April 2021

A novel platform for discovery of differentially expressed microRNAs in patients with repeated implantation failure.

Fertil Steril 2021 Apr 3. Epub 2021 Apr 3.

Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan; Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Objective: To identify predictor microRNAs (miRNAs) from patients with repeated implantation failure (RIF).

Design: Systemic analysis of miRNA profiles from the endometrium of patients undergoing in vitro fertilization (IVF).

Setting: University research institute, private IVF center, and molecular testing laboratory.

Patient(s): Twenty five infertile patients in the discovery cohort and 11 patients in the validation cohort.

Interventions(s): None.

Main Outcome Measure(s): A signature set of miRNA associated with the risk of RIF.

Result(s): We designed a reproductive disease-related PanelChip to access endometrium miRNA profiles in patients undergoing IVF. Three major miRNA signatures, including hsa-miR-20b-5p, hsa-miR-155-5p, and hsa-miR-718, were identified using infinite combination signature search algorithm analysis from 25 patients in the discovery cohort undergoing IVF. These miRNAs were used as biomarkers in the validation cohort of 11 patients. Finally, the 3-miRNA signature was capable of predicting patients with RIF with an accuracy >90%.

Conclusion(s): Our findings indicated that specific endometrial miRNAs can be applied as diagnostic biomarkers to predict RIF. Such information will definitely help to increase the success rate of implantation practice.
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http://dx.doi.org/10.1016/j.fertnstert.2021.01.055DOI Listing
April 2021

Fixel-Based Analysis of White Matter Degeneration in Patients With Progressive Supranuclear Palsy or Multiple System Atrophy, as Compared to Parkinson's Disease.

Front Aging Neurosci 2021 16;13:625874. Epub 2021 Mar 16.

Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Keelung, Taiwan.

White matter degeneration may contribute to clinical symptoms of parkinsonism. We used fixel-based analysis (FBA) to compare the extent and patterns of white matter degeneration in different parkinsonian syndromes-including idiopathic Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). This is a retrospective interpretation of prospectively acquired data of patients recruited in previous studies during 2008 and 2019. Diffusion-weighted images were acquired on a 3-Tesla scanner (diffusion weighting b = 1000 s/mm-applied along either 64 or 30 non-collinear directions) from 53 patients with PD (men/women: 29/24; mean age: 65.06 ± 5.51 years), 47 with MSA (men/women: 20/27; mean age: 63.00 ± 7.19 years), and 50 with PSP men/women: 20/30; mean age: 65.96 ± 3.14 years). Non-parametric permutation tests were used to detect intergroup differences in fixel-related indices-including fiber density, fiber cross-section, and their combination. Patterns of white matter degeneration were significantly different between PD and atypical parkinsonisms (MSA and PSP). Compared with patients with PD, those with MSA and PSP showed a more extensive white matter involvement-noticeably descending tracts from primary motor cortex to corona radiata and cerebral peduncle. Lesions of corpus callosum were specific to PSP and absent in both MSA and PD. FBA identified specific patterns of white matter changes in MSA and PSP patients compared to PD. Our results proved the utility of FBA in evaluation of implied biological processes of white matter changes in parkinsonism. Our study set the stage for future applications of this technique in patients with parkinsonian syndromes.
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http://dx.doi.org/10.3389/fnagi.2021.625874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018443PMC
March 2021

Oscillatory behavior of microbubbles impacts efficacy of cellular drug delivery.

J Control Release 2021 May 31;333:316-327. Epub 2021 Mar 31.

Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Drug-loaded microbubbles have been proven to be an effective strategy for non-invasive and local drug delivery when combined with ultrasound excitation for targeted drug release. Inertial cavitation is speculated to be a major mechanism for releasing drugs from drug-loaded microbubbles, but it results in lethal cellular pore damage that greatly limits its application. Thus, we investigated the cellular vesicle attachment and uptake to evaluate the efficiency of drug delivery by modulating the behaviors of targeted microbubble oscillation. The efficiency of vesicle attachment on the targeted cell membrane was 36.5 ± 15.9% and 3.8 ± 2.3% under stable and inertial cavitation, respectively. Further, stable cavitation enhanced cell permeability (26.8 ± 3.2%), maintained cell viability (90.8 ± 2.1%), and showed 7.9 ± 1.9-fold enhancement of in vivo vesicle release on tumor vessels. Therefore, our results reveal the ability to improve drug delivery via stable cavitation induced by targeted microbubbles. We propose that this strategy might be suitable for tissue repair or neuromodulation.
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http://dx.doi.org/10.1016/j.jconrel.2021.03.044DOI Listing
May 2021

Computer-Aided Segmentation and Machine Learning of Integrated Clinical and Diffusion-Weighted Imaging Parameters for Predicting Lymph Node Metastasis in Endometrial Cancer.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou and Chang Gung University, 5 Fuhsing St., Guishan, Taoyuan 33382, Taiwan.

Precise risk stratification in lymphadenectomy is important for patients with endometrial cancer (EC), to balance the therapeutic benefit against the operation-related morbidity and mortality. We aimed to investigate added values of computer-aided segmentation and machine learning based on clinical parameters and diffusion-weighted imaging radiomics for predicting lymph node (LN) metastasis in EC. This prospective observational study included 236 women with EC (mean age ± standard deviation, 51.2 ± 11.6 years) who underwent magnetic resonance (MR) imaging before surgery during July 2010-July 2018, randomly split into training ( = 165) and test sets ( = 71). A decision-tree model was constructed based on mean apparent diffusion coefficient (ADC) value of the tumor (cutoff, 1.1 × 10 mm/s), skewness of the relative ADC value (cutoff, 1.2), short-axis diameter of LN (cutoff, 1.7 mm) and skewness ADC value of the LN (cutoff, 7.2 × 10), as well as tumor grade (1 vs. 2 and 3), and clinical tumor size (cutoff, 20 mm). The sensitivity and specificity of the model were 94% and 80% for the training set and 86%, 78% for the independent testing set, respectively. The areas under the receiver operating characteristics curve (AUCs) of the decision-tree was 0.85-significantly higher than the mean ADC model (AUC = 0.54) and LN short-axis diameter criteria (AUC = 0.62) (both < 0.0001). We concluded that a combination of clinical and MR radiomics generates a prediction model for LN metastasis in EC, with diagnostic performance surpassing the conventional ADC and size criteria.
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http://dx.doi.org/10.3390/cancers13061406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003367PMC
March 2021

Aril Ameliorates Diet-Induced Metabolic Dysfunction and Non-Alcoholic Fatty Liver by Modulating Gut Microbiota.

Int J Mol Sci 2021 Mar 5;22(5). Epub 2021 Mar 5.

Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei City 112, Taiwan.

Obesity and its associated conditions, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are a particular worldwide health problem at present. (MC) is consumed widely in Southeast Asia. However, whether it has functional effects on fat-induced metabolic syndrome remains unclear. This study was conducted to examine the prevention effect of aril (MCA) on obesity, non-alcoholic fatty liver and insulin resistance in mice. MCA protected the mice against high-fat diet (HFD)-induced body weight gain, hyperlipidemia and hyperglycemia, compared with mice that were not treated. MCA inhibited the expansion of adipose tissue and adipocyte hypertrophy. In addition, the insulin sensitivity-associated index that evaluates insulin function was also significantly restored. MCA also regulated the secretion of adipokines in HFD-induced obese mice. Moreover, hepatic fat accumulation and liver damage were reduced, which suggested that fatty liver was prevented by MCA. Furthermore, MCA supplementation suppressed hepatic lipid accumulation by activation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) signaling pathway in the human fatty liver HuS-E/2 cell model. Our data indicate that MCA altered the microbial contents of the gut and modulated microbial dysbiosis in the host, and consequently is involved in the prevention of HFD-induced adiposity, insulin resistance and non-alcoholic fatty liver disease.
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http://dx.doi.org/10.3390/ijms22052640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961723PMC
March 2021

Transplantation of 3D MSC/HUVEC spheroids with neuroprotective and proangiogenic potentials ameliorates ischemic stroke brain injury.

Biomaterials 2021 May 24;272:120765. Epub 2021 Mar 24.

Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan. Electronic address:

Ischemic stroke, and the consequent brain cell death, is a common cause of death and disability worldwide. Current treatments that primarily aim to relieve symptoms are relatively inefficient in achieving brain tissue regeneration and functional recovery, and thus novel therapeutic options are urgently needed. Although cell-based therapies have shown promise for treating the infarcted brain, a recurring challenge is the inadequate retention and engraftment of transplanted cells at the target tissue, thereby limiting the ultimate therapeutic efficacy. Here, we show that transplantation of preassembled three-dimensional (3D) spheroids of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs) results in significantly improved cell retention and survival compared with conventional mixed-cell suspensions. The transplanted 3D spheroids exhibit notable neuroprotective, proneurogenic, proangiogenic and anti-scarring potential as evidenced by clear extracellular matrix structure formation and paracrine factor expression and secretion; this ultimately results in increased structural and motor function recovery in the brain of an ischemic stroke mouse model. Therefore, transplantation of MSCs and ECs using the 3D cell spheroid configuration not only reduces cell loss during cell harvesting/administration but also enhances the resultant therapeutic benefit, thus providing important proof-of-concept for future clinical translation.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120765DOI Listing
May 2021

The Emerging Roles of Axonemal Glutamylation in Regulation of Cilia Architecture and Functions.

Front Cell Dev Biol 2021 4;9:622302. Epub 2021 Mar 4.

Institute of Molecular Medicine, National Tsing Hua University, HsinChu City, Taiwan.

Cilia, which either generate coordinated motion or sense environmental cues and transmit corresponding signals to the cell body, are highly conserved hair-like structures that protrude from the cell surface among diverse species. Disruption of ciliary functions leads to numerous human disorders, collectively referred to as ciliopathies. Cilia are mechanically supported by axonemes, which are composed of microtubule doublets. It has been recognized for several decades that tubulins in axonemes undergo glutamylation, a post-translational polymodification, that conjugates glutamic acid chains onto the C-terminal tail of tubulins. However, the physiological roles of axonemal glutamylation were not uncovered until recently. This review will focus on how cells modulate glutamylation on ciliary axonemes and how axonemal glutamylation regulates cilia architecture and functions, as well as its physiological importance in human health. We will also discuss the conventional and emerging new strategies used to manipulate glutamylation in cilia.
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http://dx.doi.org/10.3389/fcell.2021.622302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970040PMC
March 2021

Effect of adalimumab interventions on general infection among adults: a systematic review and meta-analysis of randomized controlled trials.

Expert Rev Anti Infect Ther 2021 Apr 13:1-17. Epub 2021 Apr 13.

Evidence-based Medicine Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang China.

Background: This study assessed the safety of adalimumab in different dosages and durations of treatment.

Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to explore the infection risk in people who received adalimumab. We searched the Cochrane Library, PubMed, and EMBASE from inception to December 8, 2020. Summary estimates were obtained  using meta-analysis with a random-effects model.

Results: Twenty-one RCTs, considered to be of high quality, were analyzed. We found that there was a risk of infection (RR: 1.10, 95% CI: 1.02-1.18). In the stratified analysis, we found an increase in infection among those that received normal dosage (RR: 1.13, 95% CI: 1.04-1.23), and in patients with psoriasis (RR: 1.13, 95% CI: 1.00-1.35) and rheumatoid arthritis (RR: 1.23, 95% CI: 1.06-1.41), but not in those that received high doses and other criteria. In the meta-regressions, intervention duration was not related to changes in incidence risk.

Conclusions: Trials that have a longer treatment duration and higher doses are needed to clarify whether patients that received adalimumab had an elevated risk of general infection.
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http://dx.doi.org/10.1080/14787210.2021.1902804DOI Listing
April 2021

Improved Stabilities of Labeling Probes for the Selective Modification of Endogenous Proteins in Living Cells and In Vivo.

Chem Asian J 2021 Apr 9;16(8):937-948. Epub 2021 Mar 9.

Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu, 30013, Taiwan.

To date, various affinity-based protein labeling probes have been developed and applied in biological research to modify endogenous proteins in cell lysates and on the cell surface. However, the reactive groups on the labeling probes are also the cause of probe instability and nonselective labeling in a more complex environment, e. g., intracellular and in vivo. Here, we show that labeling probes composed of a sterically stabilized difluorophenyl pivalate can achieve efficient and selective labeling of endogenous proteins on the cell surface, inside living cells and in vivo. As compared with the existing protein labeling probes, probes with the difluorophenyl pivalate exhibit several advantages, including long-term stability in stock solutions, resistance to enzymatic hydrolysis and can be customized easily with diverse fluorophores and protein ligands. With this probe design, endogenous hypoxia biomarker in living cells and nude mice were successfully labeled and validated by in vivo, ex vivo, and immunohistochemistry imaging.
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http://dx.doi.org/10.1002/asia.202100060DOI Listing
April 2021

Comparison of the accuracy of diagnoses of oral potentially malignant disorders with dysplasia by a general dental clinician and a specialist using the Taiwanese Nationwide Oral Mucosal Screening Program.

PLoS One 2021 11;16(1):e0244740. Epub 2021 Jan 11.

Division of Oral and Maxillofacial Surgery, Tri-Service General Hospital, Taipei, Taiwan, R.O.C.

Screening for oral potentially malignant disorders (OPMDs) with dysplasia in high-risk groups is suggested in countries with a high prevalence of the disorders. This study aimed to compare the accuracy of diagnoses of OPMDs with dysplasia made by a primary examiner (general dental clinician) and a specialist (oral and maxillofacial surgeon) using the current Taiwanese Nationwide Oral Mucosal Screening Program (TNOMSP). A total of 134 high-risk participants were enrolled for oral mucosal screening via the TNOMSP. A primary examiner and a specialist examined each participant. Mucosal biopsies were obtained and subjected to histopathological analysis. The OPMD most frequently diagnosed by the primary examiner was thin homogeneous leukoplakia (48/134; 35.8%), and in 39/134 participants (29.1%) the diagnosis was uncertain, but abnormalities were suggested. The OPMDs most frequently diagnosed by the specialist were erythroleukoplakia (23/134; 17.2%) and thin homogeneous leukoplakia (21/134; 15.7%), and 51/134 participants (38.1%) were diagnosed with other diseases. Via histopathology, 70/134 participants (52.3%) were diagnosed with dysplasia, and 58/134 (43.3%) were diagnosed with benign conditions. The specialist's diagnoses exhibited a higher specificity, positive predictive value, and accuracy than the primary examiners. A specialist using the current TNOMSP for high-risk participants diagnosed OPMDs with dysplasia more accurately than a primary examiner. Early diagnosis of high-risk OPMDs is crucial in countries with a high prevalence of the disorders. Proficient examination via the current TNOMSP by trained clinician is effective for the management of OPMDs with dysplasia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244740PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799778PMC
May 2021

Urinary incontinence and its association with socioeconomic status among middle-aged and older persons in Taiwan: A population-based study.

Geriatr Gerontol Int 2021 Feb 15;21(2):245-253. Epub 2020 Dec 15.

Department of Public Health, China Medical University, Taichung, Taiwan.

Aim: This study aimed to explore the association between socioeconomic status and urinary incontinence (UI).

Methods: We used data from the three waves of the Taiwan Longitudinal Study on Aging. This study included 2458 women and 2866 men aged ≥50 years. We used logistic random effects models to examine the associations of interest, adjusting for demographics, health-related behaviors, disability, number of health conditions and prostate problems for men and numbers of children for women.

Results: In adjusted analysis, women with secondary education least frequently reported UI compared with women with no formal education (adjusted odds ratio [AOR] 0.41, 95% confidence interval [95% CI] 0.22-0.79). Those with severe economic hardships (vs those with no economic hardships) had an increased risk of UI among men and women (AOR 2.71, 95% CI 1.72-4.25 and AOR 1.94, 95% CI 1.31-2.88, respectively). Compared with men doing mentally demanding jobs, service workers/salesperson and retired men were more prone to UI (AOR 2.67, 95% CI 1.14-6.36 and AOR 2.41, 95% CI 1.19-4.87, respectively). Further analysis showed that the associations of economic hardship with UI were attenuated when adjusting for access to healthcare.

Conclusion: No formal education in women and severe economic hardship in both the sexes were associated with an increased risk of UI among middle-aged and older persons. The disparities should be taken into account in interventions for prevention, treatment and management of UI. Geriatr Gerontol Int 2021; 21: 245-253.
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http://dx.doi.org/10.1111/ggi.14115DOI Listing
February 2021

Add-on therapy of interfascial hydrodissection to trigger point injection for myofascial pain?

J Chin Med Assoc 2021 Apr;84(4):453

Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.

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http://dx.doi.org/10.1097/JCMA.0000000000000472DOI Listing
April 2021

Purple-leaf tea (Camellia sinensis L.) ameliorates high-fat diet induced obesity and metabolic disorder through the modulation of the gut microbiota in mice.

BMC Complement Med Ther 2020 Dec 10;20(1):376. Epub 2020 Dec 10.

Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou District, Taipei, 11221, Taiwan.

Background: Obesity and its associated diseases have become a major world-wide health problem. Purple-leaf Tea (Camellia sinensis L.) (PLT), that is rich of anthocyanins, has been shown to have preventive effects on obesity and metabolic disorders. The intestinal microbiota has been shown to contribute to inflammation, obesity, and several metabolic disorders. However, whether PLT consumption could prevent obesity and diet-induced metabolic diseases by modulating the gut microbiota, is not clearly understood.

Methods: In this study, six-week-old male C57BL/6 J mice were fed a normal diet (ND) or a high fat diet (HFD) without or with PLT for 10 weeks.

Results: PLT modulated the gut microbiota in mice and alleviated the symptoms of HFD-induced metabolic disorders, such as insulin resistance, adipocyte hypertrophy, and hepatic steatosis. PLT increased the diversity of the microbiota and the ratio of Firmicutes to Bacteroidetes. f_Barnesiellaceae, g_Barnesiella, f_Ruminococcaceae, and f_Lachnospiraceae were discriminating faecal bacterial communities of the PLT mice that differed from the HFD mice.

Conclusions: These data indicate that PLT altered the microbial contents of the gut and prevented microbial dysbiosis in the host, and consequently is involved in the modulation of susceptibility to insulin resistance, hepatic diseases, and obesity that are linked to an HFD.
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http://dx.doi.org/10.1186/s12906-020-03171-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727182PMC
December 2020

Poor Appetite and Eating Difficulties Can Predict the Long-Term Risk of Falling: A Longitudinal Study in Middle-Aged and Older Adults.

J Appl Gerontol 2020 Dec 2:733464820976439. Epub 2020 Dec 2.

China Medical University, Taichung City, Taiwan.

Objectives: This study investigates whether self-reported nutritional status affects falling among middle-aged and older adults.

Method: We used 8-year follow-up data from the Taiwan Longitudinal Study on Aging. At baseline, respondents' appetite, changes in amount of food intake, and eating difficulties were assessed in a questionnaire-based survey in addition to anthropometric measurements (body mass index, mid-arm circumferences, and involuntary body weight loss). Their associations with falls in the follow-up were examined using multivariable log-binomial regression.

Results: The study included 2,519 respondents aged 50 years and older. Poor appetite (prevalence ratio [PR] = 1.25, 95% confidence interval [CI] = [1.07, 1.46]) and eating difficulties (PR = 1.16, 95% CI = [1.02, 1.32]) significantly predicted falling 8 years later with adjustments for sociodemographics, health behaviors, comorbidities, and anthropometric measures by taking into account probabilities of follow-up.

Conclusion: Poor appetite and eating difficulties can predict falling in the long-term independent of anthropometric measurements among middle-aged and older adults.
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http://dx.doi.org/10.1177/0733464820976439DOI Listing
December 2020

Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity.

Chemosphere 2021 Jan 6;262:127878. Epub 2020 Aug 6.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, China. Electronic address:

Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrices and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces, and whether Cd destabilizes, the ER-mitochondria crosstalk to have a toxic effect on the nervous system. Herein, in our present study, bioinformatics analysis revealed an important role of protein interaction and mitochondrial machinery in brain samples from Alzheimer's disease (AD) patients. Furthermore, we established a neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl). We demonstrated that CdCl exposure disrupts the balance in mitochondrial redox represented by enhanced mitochondrial ROS (mitoROS) levels, which enhance mitofusin 2 (Mfn2) S-glutathionylation and interrupt the mitochondria-associated ER membranes (MAMs) for crosstalk between the ER and mitochondria to induce neuronal necroptosis. Mechanistically, it was shown that CdCl exposure significantly enhances the mitochondria-associated degradation (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (a key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation, and necroptosis in neurons induced by CdCl exposure in vitro. Moreover, the intervention with antioxidants to reduce mitochondrial redox, such as N-acetyl-l-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, reduced the S-glutathionylation of Mfn2 involved in the antagonism of CdCl-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results are the first time to demonstrate that S-glutathionylation of Mfn2 promotes neuronal necroptosis via disruption of ER-mitochondria crosstalk in CdCl-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chemical-induced adverse effects in various organs and tissues could be interpreted by intraorganellar pathways under the control of MAMs components in neurons.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127878DOI Listing
January 2021

Self-Immolative Difluorophenyl Ester Linker for Affinity-Based Fluorescence Turn-on Protein Detection.

Anal Chem 2020 12 12;92(23):15463-15471. Epub 2020 Nov 12.

Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan, Republic of China.

Currently most fluorogenic probes are developed for the analysis of enzymes, where a bond breaking or rearrangement reaction is required to transform a nonfluorescent enzymatic substrate into a fluorescent product. However, this approach cannot be used for proteins that do not possess enzymatic activities. In this article, we show that fluorogenic probes with a self-immolative difluorophenyl ester linker can mimic the bond disassembly processes of fluorogenic enzyme substrates for the rapid analysis of nonenzymatic proteins. Although numerous self-immolative reagents have shown promising applications in sensors, drug delivery systems, and material chemistry, all of them are triggered by either enzymes or small reactive molecules. In our strategy, the probe binds to the protein via a specific protein-ligand interaction, inducing a chemical reaction between the self-immolative linker and an amino acid of the protein, thereby triggering a cascade reaction that leads to the activation and release of the fluorogenic reporter. In contrast, a phenyl ester linker without the difluoro substituent cannot be triggered to release the fluorogenic reporter. With this probe design, live-cell imaging of extracellular and intracellular endogenous tumor marker proteins can be achieved with high selectivity and sensitivity.
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http://dx.doi.org/10.1021/acs.analchem.0c03178DOI Listing
December 2020

Lipopolysaccharide-Mediated Chronic Inflammation Promotes Tobacco Carcinogen-Induced Lung Cancer and Determines the Efficacy of Immunotherapy.

Cancer Res 2021 01 29;81(1):144-157. Epub 2020 Oct 29.

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that is associated with increased risk of lung cancer. (PA) infections are frequent in patients with COPD, which increase lung inflammation and acute exacerbations. However, the influences of PA-induced inflammation on lung tumorigenesis and the efficacy of immune checkpoint blockade remain unknown. In this study, we initiated a murine model of lung cancer by treating FVB/NJ female mice with tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) alone or in combination with PA-lipopolysaccharide (LPS). LPS-mediated chronic inflammation induced T-cell exhaustion, increased the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, and enhanced NNK-induced lung tumorigenesis through an immunosuppressive microenvironment characterized by accumulation of myeloid-derived suppressive cells (MDSC) and regulatory T cells. Anti-PD-1 antibody treatment reduced tumors in NNK/LPS-treated mice with a 10-week LPS treatment but failed to inhibit tumor growth when LPS exposure was prolonged to 16 weeks. Anti-Ly6G antibody treatment coupled with depletion of MDSC alone reduced tumor growth; when combined with anti-PD-1 antibody, this treatment further enhanced antitumor activity in 16-week NNK/LPS-treated mice. Immune gene signatures from a human lung cancer dataset of PD-1 blockade were identified, which predicted treatment responses and survival outcome and overlapped with those from the mouse model. This study demonstrated that LPS-mediated chronic inflammation creates a favorable immunosuppressive microenvironment for tumor progression and correlates with the efficacy of anti-PD-1 treatment in mice. Immune gene signatures overlap with human and mouse lung tumors, providing potentially predictive markers for patients undergoing immunotherapy. SIGNIFICANCE: This study identifies an immune gene signature that predicts treatment responses and survival in patients with tobacco carcinogen-induced lung cancer receiving immune checkpoint blockade therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878420PMC
January 2021

mRNA expression and functional analysis of chicken IFIT5 after infected with Newcastle disease virus.

Infect Genet Evol 2020 12 6;86:104585. Epub 2020 Oct 6.

Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu Campus, Chengdu 611130, China. Electronic address:

Innate immunity is the first line against the invasion of pathogenic microorganisms. Over the past several years, the antiviral activity and mechanisms of the IFIT5 gene have been confirmed in mammals. However, more information is needed on the role of IFIT5 in response to viral infection in chickens. In this study, we examined the mRNA expression profile of chicken IFIT5 (chIFIT5) in different tissues and explored how chIFIT5 transduces upstream signaling to the downstream adaptor. Relative mRNA expression level of chIFIT5 was the highest in spleen and expression level of chIFIT5 was significantly up-regulated following Newcastle disease virus (NDV) infection, and polyinosinic:polycytidylic acid [poly (I:C)]- and poly(deoxyadenylic-thymidylic) [poly (dA:dT)]-triggered antiviral immune responses. Chicken MDA5, MAVS, and IRF7 positively regulated the mRNA expression of chIFIT5. Overexpression of chIFIT5 could promote IRF7- and NF-κB-mediated gene expression following NDV infection or transfection with poly (I:C). These results suggested that chIFIT5 is an important enhancer of the innate immunity response.
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http://dx.doi.org/10.1016/j.meegid.2020.104585DOI Listing
December 2020

Effect of increasing occlusal vertical dimension on lower facial form and perceived facial esthetics: A digital evaluation.

J Prosthet Dent 2020 Sep 24. Epub 2020 Sep 24.

Assistant Professor, Advanced Graduate Prosthodontics, Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, Mass. Electronic address:

Statement Of Problem: Increasing occlusal vertical dimension (OVD) is often indicated in complex prosthodontic rehabilitations to gain restorative space and improve the occlusal relationship and esthetics. The effect of increasing occlusal vertical dimension on lower facial height (distance from subnasale to soft-tissue menton) and perceived facial esthetics is not well understood.

Purpose: The purpose of this clinical study was to investigate the effect of incremental increases in the occlusal vertical dimension on lower facial height and perceived facial esthetics by using a digital approach.

Material And Methods: Twenty-five participants with Class I jaw relationship and no loss of OVD participated in the study. Custom mandibular devices were digitally designed and 3-dimensionally printed to increase the OVD by 3, 6, and 9 mm in each participant. Three-dimensional facial scans and frontal photographs were made with the participants wearing a specific device to achieve the desired OVD increase. The lower facial height, total facial height (distance between nasion to soft-tissue menton), nasolabial angle, lip width, and lip height were digitally measured on facial scans. All measurements were recorded in a computer-aided design (CAD) software program and were repeated 3 times. Subsequently, frontal photographs of 10 participants were randomly selected for survey. Three groups each of 10 prosthodontists, general dentists, or laypersons participated in the survey and were asked to detect OVD difference in 2 photographs of the same participant and to rank facial esthetics at varying OVDs. One-way repeated measures ANOVA (α=.05) for the facial measurements and descriptive statistics for the survey results were used.

Results: Lower facial height, the ratio of lower facial height to total facial height, lip height, and nasolabial angle increased with an OVD increase, whereas lip width decreased (P<.001). Bonferroni corrected paired t tests revealed all groups of OVD increase to be significantly different from each other (P<.001) except for an OVD increase to 6 mm versus 9 mm in lip height (P=.540) and lip width (P=.019), respectively. Prosthodontists, general dentists, and laypersons could detect a +3 mm OVD increase 63.9%, 62.5%, and 56.5% of the time, respectively. The participants' original OVD was considered the most esthetic (60.0%, 45.0%, and 68.0%) by prosthodontists, general dentists, and laypersons, respectively.

Conclusions: Increased OVD increases lower facial height, the ratio of lower facial height to total facial height, lip height, and nasolabial angle but decreases lip width. Prosthodontists are more sensitive to a smaller increase in OVD, closely followed by general dentists and then laypersons. In case of no loss of OVD, a vertical increase as small as 3 mm can be detected by both dentists and the general public and perceived as less esthetic. The larger the increase in OVD, the more detectable the difference and the less the faces are perceived as esthetic.
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http://dx.doi.org/10.1016/j.prosdent.2020.07.013DOI Listing
September 2020

Development of a High-Resolution Single-Nucleotide Polymorphism Strain-Typing Assay Using Whole Genome-Based Analyses for the Probiotic Strain.

Microorganisms 2020 Sep 21;8(9). Epub 2020 Sep 21.

Bioresource Collection and Research Center, Food Industry Research and Development Institute, 331 Shih-Pin Rd, Hsinchu 30062, Taiwan.

is one of the most commonly used industrial products worldwide. Since its probiotic efficacy is strain-specific, the identification of probiotics at both the species and strain levels is necessary. However, neither phenotypic nor conventional genotypic methods have enabled the effective differentiation of strains. In this study, a whole-genome sequence-based analysis was carried out to establish high-resolution strain typing of 41 strains (including commercial isolates and reference strains) using the cano-wgMLST_BacCompare analytics platform; consequently, a strain-specific discrimination method for the probiotic strain LA1063 was developed. Using a core-genome multilocus sequence-typing (cgMLST) scheme based on 1390 highly conserved genes, 41 strains could be assigned to 34 sequence types. Subsequently, we screened a set of 92 loci with a discriminatory power equal to that of the 1390 loci cgMLST scheme. A strain-specific polymerase chain reaction combined with a multiplex minisequencing method was developed based on four (, , , and 1) out of 21 loci, which could be discriminated between LA1063 and other strains using the cgMLST data. We confirmed that the strain-specific single-nucleotide polymorphisms method could be used to quickly and accurately identify the probiotic strain LA1063 in commercial products.
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http://dx.doi.org/10.3390/microorganisms8091445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564606PMC
September 2020

Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver.

Tissue Eng Regen Med 2020 10 3;17(5):671-682. Epub 2020 Sep 3.

Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan.

Background: This study investigated whether xenotransplantation of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouse liver fibrosis and the underlying molecular mechanism.

Methods: Recipient NOD/SCID mice were injected intraperitoneally with TAA twice weekly for 6 weeks before initial administration of WJ-MSCs. Expression of regenerative and pro-fibrogenic markers in mouse fibrotic livers were monitored post cytotherapy. A hepatic stallate cell line HSC-T6 and isolated WJ-MSCs were used for in vitro adhesion, migration and mechanistic studies.

Results: WJ-MSCs were isolated from human umbilical cords by an explant method and characterized by flow cytometry. A single infusion of WJ-MSCs to TAA-treated mice significantly reduced collagen deposition and ameliorated liver fibrosis after 2-week therapy. In addition to enhanced expression of hepatic regenerative factor, hepatocyte growth factor, and PCNA proliferative marker, WJ-MSC therapy significantly blunted pro-fibrogenic signals, including Smad2, RhoA, ERK. Intriguingly, reduction of plasma fibronectin (pFN) in fibrotic livers was noted in MSC-treated mice. In vitro studies further demonstrated that suspending MSCs triggered pFN degradation, soluble pFN conversely retarded adhesion of suspending MSCs onto type I collagen-coated surface, whereas pFN coating enhanced WJ-MSC migration across mimicked wound bed. Moreover, pretreatment with soluble pFN and conditioned medium from MSCs with pFN strikingly attenuated the response of HSC-T6 cells to TGF-β1-stimulation in Smad2 phosphorylation and RhoA upregulation.

Conclusion: These findings suggest that cytotherapy using WJ-MSCs may modulate hepatic pFN deposition for a better regenerative niche in the fibrotic livers and may constitute a useful anti-fibrogenic intervention in chronic liver diseases.
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http://dx.doi.org/10.1007/s13770-020-00274-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524930PMC
October 2020

Arthropod Bite-Like Eruption as Rare Presentation of Secondary Syphilis in an HIV-Infected Patient.

Indian J Dermatol 2020 Jul-Aug;65(4):307-309

Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Secondary syphilis represents a diagnostic challenge due to its varied clinical manifestations. Co-infection with human immunodeficiency virus (HIV) adds to the diversity of the clinical presentation of syphilis. We herein report a case of secondary syphilis as an arthropod bite-like eruption in a previously undiagnosed HIV-coinfected patient. A 24-year-old homosexual male presented with multiple corticosteroid-resistant insect bite-like nodules on his trunk and bilateral arms. Skin biopsy disclosed plasma cell infiltration and positive staining. His symptoms got dramatic remission after benzathine penicillin G therapy. The presented case extends the clinical spectrum of secondary syphilis in HIV patient.
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http://dx.doi.org/10.4103/ijd.IJD_522_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423235PMC
August 2020

MicroRNA-101 inhibits cadmium-induced angiogenesis by targeting cyclooxygenase-2 in primary human umbilical vein endothelial cells.

Biochem Pharmacol 2020 Aug 9:114192. Epub 2020 Aug 9.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address:

Exposure to toxic metal contaminants, such as cadmium compounds (Cd), has been shown to induce adverse effects on various organs and tissues. In particular, blood vessels are severely impacted by Cd exposure, which may lead to cardiovascular diseases (CVDs). According to previous studies, CVDs are associated with increased cyclooxygenase 2 (COX-2) levels. However, the mechanisms by which CdCl-induced COX-2 overexpression leads to cardiovascular dysfunction remain unclear. Herein, we show that the relative gene expressions of VEGF and PTGS2 (COX-2 encoding gene) are positively correlated in CVDs patients. Moreover, we demonstrate that the in vitro administration of CdCl induces cytotoxicity and endoplasmic reticulum (ER) stress in primary human umbilical vein endothelial cells (HUVECs). The induction of ER stress and the overexpression of COX-2 in CdCl-treated cells alters the protein level of vascular endothelial growth factor (VEGF), resulting in abnormal angiogenesis and increased cytotoxicity. At the pre-transcription level, the inhibition of ER stress by siGRP78 (a key mediator of ER stress) can restore normal angiogenesis in the CdCl-exposed cells. Meanwhile, at the transcription level, the adverse effects of CdCl exposure may be reversed via genetic modification with siRNA (siPTGS2) or by using phytochemical inhibitors (parthenolide, PN) of COX-2. Finally, at the post-transcription level, COX-2 expression may be restricted by the binding of microRNA-101 (miR-101) to the 3'-UTR of PTGS2 mRNA. The use of mimic miR-101 (mi101) to induce the expression of miR-101 eventually leads to reduced COX-2 protein levels, relieved ER stress, and less abnormal angiogenesis and cytotoxicity of CdCl-exposed primary HUVECs. Overall, our results suggest that CdCl-induced abnormal angiogenesis is mediated by miR-101/COX-2/VEGF-axis-dependent ER stress, and that cardiovascular dysfunction may be controlled by manipulating COX-2 at the pre-transcription, transcription, and post-transcription levels.
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http://dx.doi.org/10.1016/j.bcp.2020.114192DOI Listing
August 2020

Principles and treatment strategies for the use of Chinese herbal medicine in patients at different stages of coronavirus infection.

Am J Cancer Res 2020 1;10(7):2010-2031. Epub 2020 Jul 1.

Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University Taichung, Taiwan.

Coronavirus disease 2019 (COVID-19) is a novel, human-infecting β-coronavirus enveloped, positive-sense single-stranded RNA viruses, similar to the severe acute respiratory syndrome (SARS) infection that emerged in November 2002. In traditional Chinese medicine (TCM), the epidemic disease concepts of "febrile epidemics" (wenyi) or "warm diseases" (wenbing) are based on geographic and cultural aspects, and Chinese herbal medicine (CHM) played an important role in the treatment of epidemic diseases. CHM was widely used to treat patients suffered with SARS almost two decades ago during outbreak of SARS, with proven safety and potential benefits. TCM has also been widely used to treat cancer patients for a long history and much of them associate with immunomodulatory activity and are used to treat coronavirus-related diseases. We propose the use of CHM treatment principles for clinical practice, based on four main stages of COVID-19 infection: early, intermediate, severe, and convalescence. We suggest corresponding decoctions that exhibit antiviral activity and anti-inflammatory effects in the early stage of infection; preventing the disease from progressing from an intermediate to severe stage of infection; restoring normal lung function and improving consciousness in the severe stage; and ameliorating pulmonary and vascular injury in the convalescent stage. We summarize the pharmaceutical mechanisms of CHM for treating coronavirus via antiviral, anti-inflammatory and immunomodulatory effects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407358PMC
July 2020

Investigating the Mechanistic Differences of Obesity-Inducing M1 and Anti-obesity APS1 by Microbolomics and Metabolomics.

Front Microbiol 2020 8;11:1454. Epub 2020 Jul 8.

Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.

Many studies have investigated the anti-obesity effects of probiotics in animal models and humans. However, few studies have focused on the mechanisms of obesity-inducing probiotics. In a previous study, we demonstrated that specific bacterial strains isolated from kefir, M1 and APS1, possess obesity and anti-obesity effects, respectively, in high-fat diet (HFD)-induced obese mice. Thus, in the present study, we systematically investigated whether APS1 and M1 affect energy homeostasis and lipid metabolism in HFD-induced obese mice and how this might be achieved. We observed that the M1/APS1 intervention influenced fat accumulation by regulating adipogenesis and inflammation-related marker expression both and in a HFD induced C57BL/6J mice model. We also observed putative links between key taxa and possible metabolic processes of the gut microbiota. Notably, families and were negatively correlated with body weight gain through increase in the essential esterized carnitine for energy expenditure. These results suggest the importance of specific probiotic interventions affecting leanness and obesity of subjects under a HFD, which are operated by modulating the tripartite relationship among the host, microbiota, and metabolites.
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http://dx.doi.org/10.3389/fmicb.2020.01454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360855PMC
July 2020

Is trade a blessing or a curse? A panel data analysis of the determinants of depressive disorders.

Int J Public Health 2020 Sep 25;65(7):1113-1121. Epub 2020 Jul 25.

Department of Government, University of Essex, Colchester, UK.

Objectives: Given the speculation of the market economy causing an epidemic of depression, this study aimed to examine the influence of international trade on the prevalence of depressive disorders.

Methods: We used panel data from 1993 to 2015 covering 170 countries (n = 3787) and applied fixed effects regression models. We modeled the prevalence of depressive disorders as a function of international trade, adjusting for economic development, economic growth, and population size. Regime types, media freedom, and capital-labor ratio were included as moderators.

Results: A 100% point increase in the value of international trade indicated a 0.09% point decrease in the prevalence of depressive disorders (- 0.09, confidence interval [CI] - 0.01 to - 0.18). However, this effect existed only for democratic countries (- 0.15, CI - 0.03 to - 0.28). The effect was more prevalent when the governments allowed the media more freedom (score of 100, - 0.31, CI - 0.17 to - 0.45) or when a country's capital-labor ratio of endowments was high (50,000, - 0.22, CI - 0.08 to - 0.35).

Conclusions: Trade brings about positive mental health outcomes in democracies, countries having free media, or capital-abundant economies.
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http://dx.doi.org/10.1007/s00038-020-01410-6DOI Listing
September 2020

sp. nov., isolated from human faeces.

Int J Syst Evol Microbiol 2020 Aug;70(8):4767-4773

PRIME, Japan Agency for Medical Research and Development (AMED), Tsukuba, Ibaraki 305-0074, Japan.

A strictly anaerobic predominant bacterium, designated as strain gm001, was isolated from a freshly voided faecal sample collected from a healthy Taiwanese adult. Cells were Gram-stain-negative rods, non-motile and non-spore-forming. Strain gm001 was identified as a member of the genus , and a comparison of 16S rRNA and gene sequences revealed sequence similarities of 98.5 and 93.3 %, respectively, demonstrating that it was most closely related to the type strain of . Phylogenomic tree analysis indicated that the gm001 cluster is an independent lineage of DSM 18205. The average nucleotide identity, digital DNA‒DNA hybridization and average amino acid identity values between strain gm001 and DSM 18205 were 80.9, 28.6 and 83.8 %, respectively, which were clearly lower than the species delineation thresholds. The species-specific genes of this novel species were also identified on the basis of pan-genomic analysis. The predominant menaquinones were MK-11 and MK-12, and the predominant fatty acids were anteiso-C, C and iso-C. Acetate and succinate were produced from glucose as metabolic end products. Taken together, the results indicate that strain gm001 represents a novel species of the genus , for which the name sp. nov. is proposed. The type strain is gm001 (=BCRC 81118=JCM 33280).
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http://dx.doi.org/10.1099/ijsem.0.004342DOI Listing
August 2020

Inactivation of APC Induces CD34 Upregulation to Promote Epithelial-Mesenchymal Transition and Cancer Stem Cell Traits in Pancreatic Cancer.

Int J Mol Sci 2020 Jun 23;21(12). Epub 2020 Jun 23.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.

Pancreatic cancer (PC) is a highly lethal malignancy due to the cancer routinely being diagnosed late and having a limited response to chemotherapy. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic malignant tumor, representing more than 85% of all pancreatic cancers. In the present study, we characterized the phenotypes of concomitant P53 and APC mutations in pancreatic neoplasms driven by the oncogene KRAS in genetically modified mice (GEMM). In this GEMM setting, APC haploinsufficiency coupled with P53 deletion and KRAS activation resulted in an earlier appearance of pancreatic intraepithelial neoplasia (PanIN) lesions and progressed rapidly to highly invasive and metastatic PDAC. Through a microarray analysis of murine PDAC cells derived from our APC-deficient PDAC model, we observed that APC loss leads to upregulated CD34 expression in PDAC. CD34 is a member of a family of single-pass transmembrane proteins and is selectively expressed in hematopoietic progenitor cells, vascular endothelial cells, interstitial precursor cells, and various interstitial tumor cells. However, the functional roles of CD34 in pancreatic cancer remain unclear. Thus, in this study, we explored the mechanisms regarding how CD34 promotes the deterioration of pancreatic malignancy. Our results demonstrated that the increased expression of CD34 induced by APC inactivation promotes the invasion and migration of PDAC cells, which may relate to PDAC metastasis in vivo. Collectively, our study provides first-line evidence to delineate the association between CD34 and the APC/Wnt pathway in PDAC, and reveals the potential roles of CD34 in PDAC progression.
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http://dx.doi.org/10.3390/ijms21124473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352299PMC
June 2020