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Identification of specific leukemia subtypes is a key to successful risk-directed therapy in childhood acute lymphoblastic leukemia (ALL). Although RNA sequencing (RNA-seq) is the best approach to identify virtually all specific leukemia subtypes, the routine use of this method is too costly for patients in resource-limited countries. This study enrolled 295 patients with pediatric ALL from 2010 to 2020. Routine screening could identify major cytogenetic alterations in approximately 69% of B-cell ALL (B-ALL) cases by RT-PCR, DNA index, and multiplex ligation-dependent probe amplification. STIL-TAL1 was present in 33% of T-cell ALL (T-ALL) cases. The remaining samples were submitted for RNA-seq. More than 96% of B-ALL cases and 74% of T-ALL cases could be identified based on the current molecular classification using this sequential approach. Patients with Philadelphia chromosome-like ALL constituted only 2.4% of the entire cohort, a rate even lower than those with ZNF384-rearranged (4.8%), DUX4-rearranged (6%), and Philadelphia chromosome-positive (4.4%) ALL. Patients with ETV6-RUNX1, high hyperdiploidy, PAX5 alteration, and DUX4 rearrangement had favorable prognosis, whereas those with hypodiploid and KMT2A and MEF2D rearrangement ALL had unfavorable outcomes. With the use of multiplex ligation-dependent probe amplification, DNA index, and RT-PCR in B-ALL and RT-PCR in T-ALL followed by RNA-seq, childhood ALL can be better classified to improve clinical assessments.

Background Little is known about the associations between healthy dietary patterns and metabolic dysfunction-associated fatty liver disease (MAFLD) in less-developed ethnic minority regions (LEMRs), where the prevalence of MAFLD is increasing rapidly and dietary habits are quite different from those in developed countries. Moreover, a significant subset of MAFLD individuals in LEMRs are nonobese, but the efficacy of dietary patterns on MAFLD individuals with different obese statuses is also unclear. We aimed to test the associations of two wildly recommended a priori dietary patterns—Alternate Mediterranean diet (AMED) and Dietary Approaches to Stop Hypertension (DASH)—with the risk of MAFLD in the total population, and further in nonobese and obese individuals. Methods We recruited 99,556 participants in the China Multi-Ethnic Cohort Study, an ongoing cohort study in less-developed southwest China. Using validated food frequency questionnaire, each participant was assigned an AMED score and a DASH score. MAFLD was ascertained as hepatic steatosis on ultrasound together with diabetes, overweight/obesity, or two other metabolic risk factors. We performed logistic regression with inverse probability of exposure weighting (IPEW) to examine associations between two dietary patterns and MAFLD, adjusting for potential confounders under the guidance of directed acyclic graphs. Further, analyses were stratified by body mass index. Results We included 66,526 participants (age 49.5±11.0; 62.6% women), and the prevalence of MAFLD was 16.1%. Participants in the highest quintile of DASH score showed strong inverse associations with risks of MAFLD (OR = 0.85; 95% CI, 0.80-0.91; Ptrend OR = 0.69; 95% CI, 0.61-0.78; Ptrend I2 = 78.5 % ; Pheterogeneity = 0.001) than that with obese MAFLD (OR = 0.90; 95% CI, 0.83-0.98; Ptrend = 0.002). There was a null association between AMED and MAFLD risk. Conclusions In LEMRs, a DASH diet but not AMED was associated with MAFLD. The relationship appeared to be more pronounced in nonobese MAFLD individuals than in obese MAFLD individuals.

Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer. Graphical abstract: SENTI-101 schematic and mechanism of action SENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow–derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.

Fibrosis-related disorders account for an enormous burden of disease-associated morbidity and mortality worldwide. Fibrosis is defined by excessive extracellular matrix deposition at fibrotic foci in the organ tissue following injury, resulting in abnormal architecture, impaired function and ultimately, organ failure. To date, there lacks effective pharmacological therapy to target fibrosis per se, highlighting the urgent need to identify novel drug targets against organ fibrosis. Recently, we have discovered the critical role of a fibroblasts-enriched endoplasmic reticulum protein disulfide isomerase (PDI), thioredoxin domain containing 5 (TXNDC5), in cardiac, pulmonary, renal and liver fibrosis, showing TXNDC5 is required for the activation of fibrogenic transforming growth factor-β signaling cascades depending on its catalytic activity as a PDI. Moreover, deletion of TXNDC5 in fibroblasts ameliorates organ fibrosis and preserves organ function by inhibiting myofibroblasts activation, proliferation and extracellular matrix production. In this review, we detailed the molecular and cellular mechanisms by which TXNDC5 promotes fibrogenesis in various tissue types and summarized potential therapeutic strategies targeting TXNDC5 to treat organ fibrosis.

Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown induced cell death programmes in melanoma cells, an activity blocked by inhibition of the upstream lysine catabolism enzyme DHTKD1. The transcription factor NRF2 mediates GCDH-dependent melanoma cell death programmes. Mechanistically, GCDH knockdown induces NRF2 glutarylation, increasing its stability and DNA binding activity, with a concomitant transcriptional upregulation of ATF4, ATF3, DDIT3 and CHAC1, resulting in cell death. In vivo, inducible inactivation of GCDH effectively inhibited melanoma tumour growth. Correspondingly, reduced GCDH expression correlated with improved survival of patients with melanoma. These findings identify melanoma cell addiction to GCDH, limiting apoptotic signalling by controlling NRF2 glutarylation. Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma.

ObjectiveWith the demand for rehabilitation has been increasing faster for the aging of China's population, the equity of rehabilitation resource has aroused great concern. This study aimed to analyze the spatial distribution and evolution of the human resources of rehabilitation institutions and propose targeted countermeasures and suggestions to promote optimal allocation.MethodsA total of 31 provinces in China Mainland were identified and geocoded. The spatial weight matrix was introduced to analyze the spatial correlation. Spatial autocorrelation analysis and tests were used to analyze the spatial distribution and evolution characteristics of rehabilitation institutions' human resources in China from 2016 to 2019.ResultsThe average density of rehabilitation staff from 2016 to 2019 has been rising yearly (From 1.60 to 1.88). From 2018 to 2019, the proportion of rehabilitation professionals was higher than 75% in only 5 provinces, and no provinces met 75% from 2016 to 2017. Global Moran's I index from 2016 to 2019 showed no apparent aggregation phenomenon in the allocation of management personnel resources (P > 0.05). Three provinces in western China belonged to the Low-Low area and a province in northeastern China fitted to the Low–High area, with statistically significant differences. In addition, the changes in the spatial distribution and evolution trend of the human resources of rehabilitation institutions in different periods were affected by health policies.ConclusionsAlthough the overall spatial distribution gap of human resource allocation of rehabilitation institutions is shrinking, there are still internal structural defects and a maldistribution at the provincial level. It is necessary to improve the overall number of staff in rehabilitation institutions and to ameliorate the proportion of different types of staffing.

BackgroundThe Coronavirus disease 2019 (COVID-19) has presented a major challenge to the health, economic, and social sectors of the entire world. This study aimed to investigate the mental health and academic performance of medical postgraduates during the COVID-19 pandemic in China.MethodsA cross-sectional online survey was conducted from March 20 to April 20, 2022 at the Zhejiang University School of Medicine in China. The questionnaire consisted of three parts: general information, mental health and academic performance. Mental health outcomes were assessed according to the Generalized Anxiety Scale (GAD-7) and the Patient Health Questionnaire-9 Scale (PHQ-9).ResultsA total of 153 valid questionnaires were obtained. Of the medical postgraduates in this study, (1) 41.8% had no anxiety symptoms. In addition, 51.0% had mild anxiety symptoms during the COVID-19 pandemic. None of the participants had a severe anxiety or depression disorder; (2) Females experienced significantly more symptoms in mental health measure scores than the males (P < 0.01); (3) 78.4% believed that the COVID-19 pandemic had varying degrees of impact on their academics. Doctoral postgraduates showed greater academic stress, and they were more worried about not meeting graduation standards than the master's postgraduates (P < 0.05). There were no significant differences between the surgical postgraduates and internal postgraduates in either mental health or academic performance.ConclusionsOur study found that the COVID-19 pandemic has had a mild impact on the mental health and academic performance of medical postgraduates in China. Females experienced significantly more symptoms on mental health measure scores than the males. Doctoral postgraduates showed greater academic stress than the master's postgraduates. There is uncertainty regarding how long this COVID-19 situation will persist and increasing recognition that there may be periods of recurrence in the future. We need more active curricular innovation and transformation to maintain and improve medical postgraduates' mental health and academic performance.

Aims Atrial fibrillation (AF) is a preventable cause of ischaemic stroke but it is often undiagnosed and undertreated. The utility of smartphone electrocardiogram (ECG) for the detection of AF after ischaemic stroke is unknown. The aim of this study is to determine the diagnostic yield of 30-day smartphone ECG recording compared with 24-h Holter monitoring for detecting AF ≥30 s. Methods and results In this multicentre, open-label study, we randomly assigned 203 participants to undergo one additional 24-h Holter monitoring (control group, n = 98) vs. 30-day smartphone ECG monitoring (intervention group, n = 105) using KardiaMobile (AliveCor®, Mountain View, CA, USA). Major inclusion criteria included age ≥55 years old, without known AF, and ischaemic stroke or transient ischaemic attack (TIA) within the preceding 12 months. Baseline characteristics were similar between the two groups. The index event was ischaemic stroke in 88.5% in the intervention group and 88.8% in the control group (P = 0.852). AF lasting ≥30 s was detected in 10 of 105 patients in the intervention group and 2 of 98 patients in the control group (9.5% vs. 2.0%; absolute difference 7.5%; P = 0.024). The number needed to screen to detect one AF was 13. After the 30-day smartphone monitoring, there was a significantly higher proportion of patients on oral anticoagulation therapy at 3 months compared with baseline in the intervention group (9.5% vs. 0%, P = 0.002). Conclusions Among patients ≥55 years of age with a recent cryptogenic stroke or TIA, 30-day smartphone ECG recording significantly improved the detection of AF when compared with the standard repeat 24-h Holter monitoring.

Background Patients with recurrent implantation failure (RIF) may have more uterine contractions. Several observational studies suggested that atosiban administration around embryo transfer resulted in higher pregnancy rates in RIF patients. This study aimed to evaluate the effect of atosiban given before fresh embryo transfer on pregnancy outcomes of women with RIF. Methods A prospective, randomized, double-blind controlled clinical trial was performed in IVF center of Shanghai First Maternity and Infant Hospital. According to a computer-generated randomization list, 194 infertile women with RIF received fresh embryo transfer between July 2017 and December 2019 were randomly allocated into the atosiban (n = 97) and the placebo (n = 97) groups. Women in the treatment group received atosiban intravenously about 30 min before embryo transfer with a bolus dose of 6.75 mg over one minute. Those in the placebo group received only normal saline infusion for the same duration. Results There was no significant difference in the live birth rate between the atosiban and placebo groups (42.3% vs 35.1%, P = 0.302, RR = 1.206 (0.844–1.723)). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and implantation rates. Similar results were found when stratified by the number of embryos previously transferred, number of previous failed embryo transfers, frequency of endometrial peristalsis on embryo transfer day (≥ 3 waves/min) or serum estradiol (E2) on the day of hCG above the median level. And, there was no correlation between the serum E2 level on the day of hCG and the frequency of endometrial peristalsis on embryo transfer day. The frequency of endometrial peristalsis on embryo transfer day, total FSH/HMG dosage and duration were the significant factors which independently predicted the likelihood of a live birth. Conclusions These results suggested that atosiban treatment before fresh embryo transfer might not improve the live birth rate in RIF patients. Trial registration The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722.

IntroductionThe aim of this prospective study is to evaluate the effects of combining topical airway anaesthesia with intravenous induction on haemodynamic variables during the induction period in patients undergoing cardiac surgery.Methods and analysisThis randomised, double-blind, controlled, parallel-group, superiority study from 1 March 2021 to 31 December 2021 will include 96 participants scheduled for cardiac surgery. Participants will be screened into three blocks (ASA II, ASA III, ASA IV) according to the American Society of Anesthesiologists (ASA) grade and then randomly allocated into two groups within the block in a 1:1 ratio. Concealment of allocation will be maintained using opaque, sealed envelopes generated by a nurse according to a computer-generated randomisation schedule. In addition to general intravenous anaesthetics, participants will receive supraglottic and subglottic topical anaesthesia. Changes in arterial blood pressure and heart rate in both groups will be recorded by an independent investigator at the start of anaesthesia induction until the skin incision. If vasopressors are used during this period, the frequency, dosage and types of vasopressors will be recorded. The incidence and severity of participants’ postoperative hoarseness and sore throat will also be assessed.Ethics and disseminationThis study was approved by the Ethics Committee of Qianfoshan Hospital of Shandong Province (registration number: YXLL-KY-2021(003)). The results will be disseminated through a peer-reviewed publication and in conferences or congresses.Trial registration numberNCT04744480.

Chia-Yih Wang,1,2,* Shih-Wei Tsai,3,* Han-Hsiang Chien,1 Ting-Yu Chen,2,4 Shi-Yuan Sheu,5,6 Edmund Cheung So,7,8 Bu-Miin Huang1,9 1Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Obstetrics and Gynecology, An Nan Hospital, China Medical University, Tainan, Taiwan; 4Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; 5School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan; 6Department of Chinese Medicine, E-Da Cancer Hospital, Kaohsiung, Taiwan; 7Department of Anesthesia & Medical Research, An Nan Hospital, China Medical University, Tainan, Taiwan; 8Graduate Institute of Medical Sciences, Chang Jung Christian University Tainan, Tainan, Taiwan; 9Institute of Medical Research, China Medical University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Edmund Cheung So; Bu-Miin Huang Tel +886-6-3553111 ext.1517; +886-6-2353535 ext. 5337Fax +886-6-3553111; +886-6-2093007Email edmundsotw@gmail.com; bumiin@mail.ncku.edu.twIntroduction: Human gestational choriocarcinoma, a type of gestational trophoblastic disease, occurs after miscarriage, abortion, ectopic pregnancy, or molar pregnancy. Despite recent advances in the mechanism of anticancer drugs that induce human gestational choriocarcinoma apoptosis or block its growth, new therapeutic approaches are needed to be established. Cordycepin is an active anti-cancer component extracted from Cordyceps sinensis. It prevents cell proliferation both in vitro and in vivo.Materials and Methods: Here, we examined cell growth by counting cell numbers, and performing a flow cytometry assay and EdU incorporation assay. Centrosome and cytoskeleton-related structures were observed by immunofluorescence assay. The DNA damage-related signaling was examined by Western blot assay.Results: Here, we showed that cordycepin inhibited human gestational choriocarcinoma cell proliferation and induced cell death. In addition, treatment with cordycepin activated DNA-PK and ERK, thus inducing centrosome amplification and aberrant mitosis. These amplified centrosomes also disrupted microtubule arrays and actin networks, thus leading to defective cell adhesion. Furthermore, cordycepin induced autophagy for triggering cell death.Conclusion: Thus, our study demonstrates that cordycepin inhibits cell proliferation and disrupts the cytoskeleton by triggering centrosome amplification.Keywords: human gestational choriocarcinoma, cordycepin, centrosome, cell growth, microtubule

Background Stearoyl-coenzyme A desaturase-1 (SCD1) can inhibit the development of diabetic bone disease by promoting osteogenesis. In this study, we examined whether this regulation by SCD1 is achieved by regulating the expression of related miRNAs. Methods SCD1 expression levels were observed in human bone-marrow mesenchymal stem cells (BM-MSCs) of patients with type 2 diabetes mellitus (T2DM), and the effect of SCD1 on osteogenesis was observed in human adipose-derived MSCs transfected with the SCD1 lentiviral system. We designed a bioinformatics prediction model to select important differentially expressed miRNAs, and established protein-protein interaction and miRNA-mRNA networks. miRNAs and mRNAs were extracted and their differential expression was detected. The SCD1-miRNA-mRNA network was validated. Findings SCD1 expression in bone marrow was downregulated in patients with T2DM and low-energy fracture, and SCD1 expression promotes BM-MSC osteogenic differentiation. The predictors in the nomogram were seven microRNAs, including hsa-miR-1908 and hsa-miR-203a. SCD1 inhibited the expression of CDKN1A and FOS, but promoted the expression of EXO1 and PLS1. miR-1908 was a regulator of EXO1 expression, and miR-203a was a regulator of FOS expression. Interpretation The regulation of BM-MSCs by SCD1 is a necessary condition for osteogenesis through the miR-203a/FOS and miR-1908/EXO1 regulatory pathways.

Inflammatory cytokines are important protagonists in the formation of atherosclerotic plaques, triggering effects throughout the atherosclerotic vessels due to the destruction in proliferation, migration and angiogenesis of endothelial cells. In this study, we found SNHG1 is upregulated in TNF-α-treated HUVECs. We silenced SNHG1 and found it inhibited vascular endothelial cell proliferation and angiogenesis. In the other hand, exogenetic overexpression of SNHG1 promotes proliferation, migration and angiogenesis. Then we demonstrated that SNHG1 may interact directly with miR-196a to act as a miR-196a sponge. Further, MAPK6 were predicted to be the target of miR-196a. So we blocked miR-196a, which increased expression level of MAPK6, enhanced cell proliferation, migration and angiogenesis. These data indicated that SNHG1/miR-196a/MAPK6 axis may take a part in autophagy regulation in TNF-α-treated HUVECs. The subsequent rescue experiments come to the results ascertained the specificity of SNHG1/miR-196a/MAPK6 axis in regulating MAPK6. Overall, our findings demonstrate a novel mechanism by which SNHG1 overexpression protects the function of HUVECs, which may delay the progression of AS. SNHG1/miR-196a/MAPK6 axis may be of therapeutic significance in AS.

Emerging adults often increase problematic drinking during college. Although they generally do not seek help for problematic drinking, college students discuss their drinking on social media. This study followed college students’ Facebook profiles from the inception of their attendance at a university and identified alcohol-related posts. Within 28 days of their first alcohol-related Facebook post, participants were interviewed to assess problematic drinking (binge drinking episodes and number of drinks). Linguistic analysis of alcohol-related Facebook posts found that use of negative emotion language and swear words were related to problematic drinking, in support of proposed hypotheses. Results are situated within alcohol use disorder and health research examining the link between problematic drinking and anxiety, deviant behavior, and negative emotions.

Health-based aerosol sampling should reflect how particles penetrate and deposit in various regions of the human respiratory system. Therefore, size-selective sampling should be adopted when monitoring aerosol concentration in the atmosphere. However, cyclone samplers, the most commonly used respirable sampler type in the workplace, show specific particle size-dependent bias toward the international respirable convention. Additionally, cyclone samplers are vulnerable to the dust loading effect resulting in an underestimation of respirable particulate matter. In the previous study, a virtual cyclone has been employed to overcome the dust loading effect, but still had the disadvantage of high aerosol penetration of large particle sizes. Therefore, in this work, the effects of key dimensions of virtual cyclones including chamber width (or inlet width), chamber size and inlet height on the separation performance were further studied and the configurations of virtual cyclones were modified to best fit the ISO/CEN/ACGIH respirable convention. Experimental results demonstrated that a better match with the ISO/CEN/ACGIH respirable convention curve can be achieved by increasing the chamber width to over 20 mm. Moreover, the new virtual cyclones can operate at a flow rate up to 21.5 L/min to collect more respirable particulate matter for the increasingly stringent respirable dust standards. The new virtual cyclones demonstrate accurate and constant measurement of the respirable dust for exposure assessment.

This study examined if creating intimacy in a group discussion is more effective toward reaching consensus about climate change than a focus on information. Participants were randomly assigned to either a group that spent the first part of an online discussion engaging in self-disclosure and focusing on shared values (intimacy condition) or discussing information from an article about climate change (information condition). Afterward, all groups were given the same instructions to try to come to group consensus on their opinions about climate change. Participants in the intimacy condition had higher ratings of social cohesion, group attraction, task interdependence, and collective engagement and lower ratings of ostracism than the information condition. Intimacy groups were more likely to reach consensus, with ostracism and the emotional tone of discussion mediating this effect. Participants were more likely to change their opinion to reflect that climate change is real in the intimacy than information condition.

BACKGROUND A green emission up-conversion carbon-based polymer dots (CPDs) owned excellent photophysical properties and good solubility. While most of the photosensitizers (PS) are hydrophobic thus limits the application of PSs in biomedicine. Herein we synthesized and integrated green emitting CPDs into pyropheophorbide-α (PPa) to improve the overall properties of the PS. MATERIAL AND METHODS The nano-agent was incorporated through amide condensation and electrostatic interaction. The structure, size and morphology of the prepared conjugates were determined by FTIR, TEM, DLS, TGA, 1HNMR, Uv-vis, and fluorescence spectrophotometry. The dark and light toxicity, as well as cellular uptake, was also monitored on the human esophageal cancer cell line (Eca-109). RESULTS Our results illustrate that the conjugation improved the PDT efficacy by increasing the ROS generation. The nano-hybrids showed pH sensitivity as well as good hemocompatibility as the hemolysis ratio was decreased when treated with nano-conjugates. PPa-CPD1 and PPa-CPD2 had the pH response and stronger ability to absorb light and produce fluorescence in an acidic environment (pH 4.0 and pH 5.0) The synthesized nano-hybrids doesnot affect the clotting time. An increase in the absorbance wavelengths was observed. The results of MTT assay showed that dark toxicity was reduced after conjugation. CONCLUSION Thus, this CPDs-based drug enhanced tumor-inhibition efficiency as well as low dark toxicity in vitro, showing significant application potential in the PDT-based treatment.

Background and objectivesLiver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF.DesignHistological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg, Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses.ResultsTXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice.ConclusionsER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.

Rationale: Cardiac arrest caused by water intoxication syndrome following hysteroscopic surgery is a rare but life-threatening occurrence. Extracorporeal membrane oxygenation (ECMO) is rarely used to treat water intoxication syndrome in hysteroscopic surgery. Here, we successfully treated a patient with water intoxication syndrome following hysteroscopic surgery with ECMO. Patient concerns: We report a rare case of cardiac arrest during hysteroscopic surgery treated with veno-venous (VV) ECMO. Diagnosis: Water poisoning syndrome was diagnosed by electrolyte examination, the lowest value of serum sodium was 110.7 mmol/L. Interventions: VV-ECMO was prescribed as a measure after traditional cardiopulmonary resuscitation. Results: ECMO was successfully evacuated on day 5 and the patient was discharged on day 45. Conclusion: Mastering the hysteroscopic operative techniques and using a bipolar hysteroscopic generator, isotonic fluid, perfusion pressures less than 100 mm Hg, and local anesthesia may reduce the risk of hysteroscopic water intoxication syndrome. During hysteroscopic surgery, patients may experience cardiac arrest and fatal water intoxication syndrome. Even when traditional cardiopulmonary resuscitation is successful, VV ECMO may contribute to the recovery of brain function if oxygenation is not maintained.

Inhibition of ubiquitin ligases with small molecule remains a very challenging task, given the lack of catalytic activity of the target and the requirement of disruption of its interactions with other proteins. Siah1/2, which are E3 ubiquitin ligases, are implicated in melanoma and prostate cancer and represent high-value drug targets. We utilized three independent screening approaches in our efforts to identify small-molecule Siah1/2 inhibitors: Affinity Selection-Mass Spectrometry, a protein thermal shift-based assay and an in silico based screen. Inhibitors were assessed for their effect on viability of melanoma and prostate cancer cultures, colony formation, prolyl-hydroxylase-HIF1α signaling, expression of selected Siah2-related transcripts, and Siah2 ubiquitin ligase activity. Several analogs were further characterized, demonstrating improved efficacy. Combination of the top hits identified in the different assays demonstrated an additive effect, pointing to complementing mechanisms that underlie each of these Siah1/2 inhibitors.

C6orf141 (Chromosome 6 open reading frame 141) is a novel gene, and its role in oral cancer progression remains unclear. C6orf141 expression in oral squamous cell carcinoma (OSCC) and adjacent normal tissues from 428 patients was examined through immunohistochemistry (IHC). Our results revealed that C6orf141 expression was significantly reduced in OSCC compared with adjacent normal tissues. Low C6orf141 expression was significantly associated with a poor American Joint Committee on Cancer pathological stage (P P = 0.002), and pN stage (P = 0.032). Kaplan–Meier curves revealed that low C6orf141 expression was significantly associated with shorter disease-specific survival (DSS) in patients with OSCC (log-rank P = 0.007). Multivariate analysis indicated that low C6orf141 expression was an independent prognostic biomarker for DSS (adjusted hazard ratio = 1.34; 95% confidence interval = 1.10–1.81; P = 0.05). Additionally, ectopic C6orf141 expression could significantly suppress oral cancer cell proliferation, colony formation, and migratory and invasive abilities. Xenograft tumor growth assay revealed that C6orf141 could significantly suppress oral tumor growth in vivo. Our results suggest that C6orf141 plays a novel tumor-suppressive role in oral cancer cell growth and motility. Furthermore, C6orf141 dysfunction could be a potential prognostic biomarker for OSCC and provide new therapeutic strategies in the future.

Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity affects invadopodia formation. Among the top hits selected for further analysis was TAO3, an STE20-like kinase of the GCK subfamily. TAO3 was overexpressed in many human cancers and regulated invadopodia formation in melanoma, breast, and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in three-dimensional matrices and in vivo. A novel, potent catalytic inhibitor of TAO3 was developed that inhibited invadopodia formation and function as well as tumor cell extravasation and growth. Treatment with this inhibitor demonstrated that TAO3 activity is required for endosomal trafficking of TKS5α, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein subunit protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation. Thus, TAO3 is a new therapeutic target with a distinct mechanism of action. Significance: An unbiased screening approach identifies TAO3 as a regulator of invadopodia formation and function, supporting clinical development of this class of target.

Background: While irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal diseases in clinical practice, it has diverse pathogenesis. Because of its sudden and lingering intractable symptoms, it seriously affects patients work and life. Opioid receptors are G protein-coupled receptors distributed across the brain, spinal cord, skin, and gastrointestinal tract, and each of the subtypes has a unique role and specific distribution. They play a role in regulating gastrointestinal motility, secretion, and visceral sensations in the gastrointestinal tract. Therefore, this meta-analysis aims to evaluate the effects of opioid receptor modulators on improving the symptoms of IBS. Methods: Searching the key words (Irritable Bowel Syndromes or Syndrome, Irritable Bowel OR Syndromes, Irritable Bowel OR Colon, Irritable OR Irritable Colon OR Colitis, Mucous OR Colitides, Mucous OR Mucous Colitides OR Mucous Colitis) AND (opioid receptor modulators OR eluxadoline OR Viberzi OR asimadoline OR loperamide), a preliminary search on PubMed (English), EMBASE (English), Cochrane Library (English), China National Knowledge Infrastructure Database (CNKI, Chinese), WanFang (Chinese), VIP citation databases (Chinese) and SinoMed (Chinese) databases yielded 1023 papers published in English and Chinese from inception to July 1, 2019. Nine studies were included in the final meta-analysis. Because this is a systematic review and meta-analysis, ethical approval is not necessary. Results: The random-effects meta-analysis based on these 9 studies and their 4156 patients found that opioid receptor modulators have a statistically significant beneficial effect on IBS global symptoms (RR = 0.85, 95%CI = 0.79–0.92, P

The optimal duration of dual antiplatelet therapy (DAPT) as a routine treatment in stroke patients is still controversial. The efficacy and safety of DAPT may vary with different regiments, initiating treatment time and race. Our study assessed the efficacy and safety of DAPT in patients with stroke and to determine the factors influencing the efficacy and safety of DAPT. Relevant studies published up to May 2019 from PubMed, Embase, Web of Science and the Cochrane Library. Randomized controlled trials comparing DAPT with mono antiplatelet therapy (MAPT) for stroke secondary prevention were included. The primary endpoints were stroke recurrence, ischemic stroke recurrence and all-cause death. Subgroup analysis was made according to regiment, initiating treatment time and race. Eighteen studies (n=33353) were included. Comparing with MAPT, short-term DAPT reduced stroke recurrence (RR = 0.68, 95% CI = 0.60-0.77) and ischemic stroke recurrence (RR = 0.67, 95% CI = 0.59-0.77) but increased major bleeding (RR = 1.82, 95% CI = 1.11-2.98). Long-term DAPT had no superiority compared with MAPT. Aspirin plus clopidogrel comparing with aspirin and early initiating treatment time comparing with MAPT decreased stroke recurrence (RR = 0.74, 95% CI = 0.67-0.83; RR = 0.69, 95% CI = 0.61-0.78) and ischemic stroke recurrence ( RR = 0.71, 95% CI = 0.64-0.79; RR = 0.68, 95% CI = 0.59-0.77) but also increased major bleeding (RR = 1.70, 95% CI = 1.38-2.09; RR = 1.75, 95% CI = 1.07-2.85). DAPT reduced stroke and ischemic stroke recurrence in non-Asian group but only reduced ischemic stroke recurrence in Asian group. As stroke secondary prevention, short-term DAPT rather than long-term DAPT could be a better choice. Patients could benefit more from aspirin plus clopidogrel or given DAPT within 72 h after symptoms onset. Race may be a factor influencing the efficacy of DAPT.

Background: Creating and maintaining a functioning arteriovenous access is essential for long-term hemodialysis patients. Transposed brachiobasilic fistula (BBF) or arteriovenous graft (AVG) becomes an option when radiocephalic or brachiocephalic fistula cannot be created or fails. This study compared the patency and complications between BBFs and AVGs among patients on hemodialysis. Methods: A retrospective study was performed in Shuang Ho Hospital, Taiwan, from November 2015 to May 2020. All the operations were done by a single surgeon. Primary outcomes were primary patency, primary-assisted patency, and secondary patency of the BBF and AVG groups. Secondary outcomes were incidence of complications and reinterventions. Results: Of the 144 consecutive patients, 20 and 124 patients underwent BBF and AVG creation, respectively. Median follow-up time was 19.2 months. Primary patency at 1 and 2 years were 67% and 19% in the BBF group and 44% and 16% in the AVG group (P = 0.126). Primary-assisted patency at 1 and 2 years were 82% and 54% in the BBF group and 54% and 30% in the AVG group (P = 0.012). Secondary patency at 1 and 2 years were 100% and 82% in the BBF group and 81% and 67% in the AVG group (P = 0.078). The incidence of complication was significantly higher in the AVG than in the BBF group (1.7 per patient-year vs 0.93, P < 0.001). Conclusion: Compared with the AVG group, BBF group showed better primary-assisted patency, less complication and intervention rates. Therefore, BBF is a reliable option for patients with exhausted cephalic veins if basilic vein is available for reconstruction.

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF., Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis.

Monitoring nicotine concentrations in human fluids is extremely crucial owing to the harmful effect of nicotine on human health. Herein, it is shown that nicotine could quench the cathodic electrochemiluminescence (ECL) of gold nanoclusters (AuNCs) with high efficiency. The ECL quenching mechanism of nicotine was studied in detail using various experimental tools and theoretical calculations. It was concluded that the strongly oxidizing intermediate SO

The association between implanted stent types and heart failure in patients with non-ST-elevation myocardial infarction (NSTEMI) remains unknown. The current study aimed to investigate whether the implantation of a newer-generation drug-eluting stent (NG-DES) compared with that of a bare-metal stent (BMS) in patients with NSTEMI who receive an undefined duration of dual antiplatelet therapy (DAPT) reduces the risk of hospitalization for heart failure (HHF).In this nationwide, population-based retrospective cohort study, propensity score matching was used on the Taiwan's National Health Insurance Research Database to select 8,644 pairs of patients with NSTEMI and similar baseline characteristics receiving NG-DES or BMS implantation between January 1, 2007 and December 31, 2016. A competing risk model was constructed to evaluate the risk of HHF in the NG-DES and BMS groups. Death was considered a competing risk.Rates of cumulative incidence competing risk for HHF at 1, 2, 3, 4, and 5-year follow-ups were lower in the NG-DES group (4.11%, 5.63%, 6.72%, 7.65%, and 8.89%, respectively) than in the BMS group (5.89%, 7.81%, 9.25%, 10.8%, and 11.9%, respectively). After adjustment for all clinical variables, NG-DES implantation was associated with a lower risk of HHF than BMS implantation after 5 years, with an adjusted subdistribution hazard ratio of 0.71 (95% CI = 0.64-0.79, p 0.001). These results are in agreement with those of patients who received DAPT for6 months.NG-DESs may reduce HHF risk in patients with NSTEMI who receive an undefined duration of DAPT.

Rationale: Metformin-associated lactic acidosis (MALA) is rarely encountered, but has a high mortality rate, Conventional treatments include hemodialysis or continuous renal replacement therapy (CRRT); however, when the disease progresses to end-stage, cardiac function is significantly inhibited, circulation cannot be maintained, CRRT cannot be tolerated, V-A extracorporeal membrane oxygenation (ECMO) may be the last treatment. Patient concerns: The study report a rare case of MALA in an elderly female patient at the age of 72 who was admitted to hospital because of nausea for 2 days, complicated with systemic fatigue. Diagnosis: MALA was cofirmed because of patient have increased lactic acid levels, blood pH

Supplemental Digital Content is available in the text, This study explored the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT). Between January 2006 and December 2016, 184 patients with newly-diagnosed rectal cancer receiving neoadjuvant CCRT were enrolled. Risk of overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method and Cox proportional hazard models. Stratified survival analyses were also performed between post-neoadjuvant pathological (yp) stage. The mean follow-up time was 72.73 ± 36.82 months. High- and low-NLR patients differed significantly in both 5-year DFS (P = .026) and OS (P = .016). High- and low-PLR patients differed significantly in 5-year DFS (P = .011) but not OS (P = .185). Multivariate analyses revealed worse 5-year DFS (adjusted HR [aHR] = 2.8; 95% CI: 1.473–5.41; P = .002) and 5-year OS (aHR = 1.871; 95%CI: 1.029–3.4; P = .04) in the high-NLR group after adjusting for covariates. After adjustments, the high-PLR group had inferior 5-year DFS (aHR = 2.274; 95%CI: 1.473–5.419; P = .038) but not 5-year OS (aHR = 1.156; 95%CI: 0.650–2.056; P = .622). Further stratified analysis indicated that yp stage II and III patients with high NLR had worse 5-year DFS (aHR = 2.334; 95% CI: 1.158–4.725; P = .018) and OS (aHR = 2.226; 95% CI: 1.165–4.251; P = .015). Additionally, yp stage II and III patients with high PLR had inferior 5-year DFS (aHR = 2.012; 95% CI: 1.049–3.861; P = .036). Pre-CCRT NLR and PLR are independent prognostic factors for rectal cancer patients and could be used as a potential biomarker to identify high-risk patients for more intense treatment and care.

Background Transbronchial needle aspiration (TBNA) is a minimally invasive procedure performed to diagnose lymph node (LN) adenopathy. TBNA with and without endobronchial ultrasound (EBUS) guidance has a high diagnostic yield for malignant LN enlargement, but the value for diagnosing benign LN enlargement has been less thoroughly investigated. Methods We retrospectively evaluated 3540 patients with mediastinal LN enlargement who received TBNA. One hundred sixty-six patients with benign mediastinal lymphadenopathy were included and 293 LNs were biopsied. A positive result was defined as a specific histological abnormality. Conventional TBNA (cTBNA) and EBUS-TBNA, as well as cTBNA and transbronchial forceps biopsy (TBFB), were compared. The subgroup analysis was stratified by disease type and LN size. Results A diagnosis was made in 76.84% of the EBUS-TBNA and 61.31% of the cTBNA (P P P P 20 mm the difference was marginal. These findings were confirmed in a group of independent patients who received cTBNA plus EBUS-TBNA. The diagnostic yield did not differ between cTBNA and TBFB, but significantly increased to 76.67% when both modalities were employed. Conclusions EBUS-TBNA is the preferred minimally invasive diagnostic method for benign mediastinal LN disease. Combined cTBNA and TBFB is a safe and feasible alternative when EBUS is unavailable.

Bullying at workplaces is a growing problem associated with several antecedents and outcomes of psychological disorders. Extant literature shows the relationship of victimization with the owning-up curriculum to confront bullying, but so far there is little research to cure the issue of bullying through ethics and there is no study to check the impact of ethical lessons and exercises in training materials to curb bullying at workplace. The current paper is based on a literature review of aggression and bullying, and chiefly addresses the HR practices in rescuing the people from peer victimization. Conceptually segregating supervisor-subordinate (vertical) and peer-peer (horizontal) bullying psychology, this paper attempts to see what possible corrective steps can be taken by senior managers, supervisors and psychologists to resolve this critical problem through interior capacities. In this paper, we have developed three propositions for conducting a future empirical investigation in connection to a cohort study. By addressing the counterproductive/deviant behavior, the present report is likely to be beneficial for psychology scientists and HR practitioners in noticing and resolving the bullying issues at the workplace for the well-being of employees.

Background Synovial fluid proteins had been applied as diagnostic biomarkers for periprosthetic joint infection (PJI) in recent research papers. Thus, this meta-analysis aimed to estimate the diagnostic efficiency of synovial fluid α-defensin and leukocyte esterase (LE) for PJI. Methods We conducted our systematic review by searching the keywords in online databases such as PubMed, Embase, Cochrane, Elsevier, Springer, and Web of Science from the time of database inception to October 2018. Inclusion criteria were as follows: patients who have undergone knee, hip, or shoulder joint replacements; α-defensin or leukocyte esterase (LE strip) of synovial fluid was detected as the biomarker for PJI diagnosis; and Musculoskeletal Infection Society (MSIS) or utilizing a combination of clinical data was considered as the gold standard. Diagnostic parameters including sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary of receiver operating characteristics curve (AUSROC) were calculated for the included studies to evaluate the synovial fluid α-defensin and LE for PJI diagnosis. Results After full-text review, 28 studies were qualified for this systematic review, 16 studies used α-defensin and the other 12 were conducted using LE strip. The pooled sensitivity, specificity, and DOR of LE strip were 87% (95% CI 84–90%), 96% (95% CI 95–97%), and 170.09 (95% CI 97.63–296.32), respectively, while the pooled sensitivity, specificity, and DOR of α-defensin were 87% (95% CI 83–90%), 97% (95% CI 96–98%), and 158.18 (95% CI 74.26–336.91), respectively. The AUSROC for LE strip and α-defensin were 0.9818 and 0.9685, respectively. Conclusion Both LE strip and α-defensin of synovial fluid provide rapid and convenient diagnosis for PJI. Sensitivity of α-defensin and LE strip are the same, while both these two methods have high specificity in clinical practice.