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ImportanceMild thyroid-associated ophthalmopathy (TAO) negatively impacts quality of life, yet no clinical guidelines for its treatment are available. Existing evidence supports the use of doxycycline in treating mild TAO.ObjectiveTo evaluate the short-term (12 weeks) efficacy of doxycycline in treating mild TAO.Design, Setting, and ParticipantsIn this placebo-controlled multicenter randomized double-masked trial, 148 patients were assessed for eligibility. After exclusions (patients who were pregnant or lactating, had an allergy to tetracyclines, or had uncontrolled systematic diseases), 100 patients with mild TAO (orbital soft tissue affected mildly) at 5 centers in China were enrolled from July 2013 to December 2019 and monitored for 12 weeks.InterventionsParticipants were randomly assigned 1:1 to receive doxycycline (50 mg) or placebo once daily for 12 weeks.Main Outcomes and MeasuresThe primary outcome was the rate of improvement at 12 weeks compared with baseline assessed by a composite indicator of eyelid aperture (reduction ≥2 mm), proptosis (reduction ≥2 mm), ocular motility (increase ≥8°), and Graves ophthalmopathy-specific quality-of-life (GO-QOL) scale score (increase ≥6 points). Adverse events were recorded.ResultsA total of 50 participants were assigned to doxycycline and 50 to placebo. The mean (SD) age was 36.7 (9.1) years; 75 participants (75.0%) were female and 100 (100.0%) were Asian. Medication compliance was checked during participant interviews and by counting excess tablets. At week 12, the improvement rate was 38.0% (19 of 50) in the doxycycline group and 16.0% (8 of 50) in the placebo group (difference, 22.0%; 95% CI, 5.0-39.0; P = .01) in the intention-to-treat population. The per-protocol sensitivity analysis showed similar results (39.6% [19 of 48] vs 16.0% [8 of 50]; difference, 23.6%; 95% CI, 6.4-40.8; P = .009). No adverse events other than 1 case of mild gastric acid regurgitation was recorded in either group.Conclusions and RelevanceThe results of this study indicate that oral doxycycline, 50 mg daily, resulted in greater improvement of TAO-related symptoms at 12 weeks compared with placebo in patients with mild TAO. These findings support the consideration of doxycycline for mild TAO but should be tempered by recognizing the relatively short follow-up and the size of the cohort.Trial RegistrationClinicalTrials.gov Identifier: NCT02203682

BACKGROUND: Arteriosclerosis is one of the diseases that endanger human health. There is a large amount of information in pulse wave signals to reflect the degree of arteriosclerosis. OBJECTIVE: The degree of arteriosclerosis is assessed by analyzing pulse wave signal and calculating multi-scale entropy values. METHODS: A method based on the multiscale cross-approximate entropy of the pulse wave of the human finger is proposed to assess the degree of arteriosclerosis. A total of 86 subjects were divided into three groups. The data of 1000 pulse cycles were selected in the experiment, and the multiscale cross-approximate entropy was calculated for the climb time and pulse wave peak interval. Independent sample t-test analysis gives the small-scale cross-approximate entropy of the two time series of climb time and pulse wave peak interval as p< 0.001 in Groups 1 and 2. The large-scale cross-approximate entropy of the two time series of climb time and pulse wave peak interval is p< 0.017 in Groups 2 and 3. RESULTS: Using the proposed algorithm, the results showed that the small-scale cross-approximate entropy of climb time and pulse wave peak interval could reflect the degree of arteriosclerosis in the human body from the perspective of autonomic nerve function. The large-scale cross-approximate entropy of climb time and pulse wave peak interval confirmed the effect of diabetes on the degree of arteriosclerosis. CONCLUSIONS: The results demonstrate the multiscale cross-approximate entropy is a comprehensive index to evaluate the degree of human arteriosclerosis.

PURPOSE: To explore novel role and molecular mechanism of a natural anti-inflammatory cytokine interleukin (IL) 37 in preventing corneal epithelial barrier disruption from hyperosmolar stress as can occur in dry eye disease. METHODS: Primary human corneal epithelial cells (HCECs) were cultured from fresh donor limbal explants. An in vitro dry eye model with hyperosmolar stress was established by switching HCECs from isosmolar (312mOsM) to hyperosmolar medium (350–500 mOsM), and some cells were treated with rhIL-37 or rhTNF-α, for different periods (2–48 h). The expression of cytokines and cathepsin S, and barrier protein integrity were evaluated by RT-qPCR, ELISA, and immunofluorescent staining with confocal microscopy. RESULTS: The integrity of epithelial barrier was significantly disrupted in HCECs exposed to hyperosmolar medium, as shown by immunofluorescent images of tight junction (TJ, ZO-1, occludin and claudin-1) and adheren junction (E-cadherin) proteins. TNF-α accentuated hyperosmolar-induced disruption of TJ barrier functional integrity whereas exposure to IL-37 blunted or even reversed these changes. Cathepsin S, encoded by CTSS gene, was found to directly disrupt epithelial barrier integrity. Interestingly, CTSS expression was significantly induced by TNF-α and hyperosmolarity, while exogenous rhIL-37 inhibited TNF-α and CTSS expression at mRNA and protein levels following hyperosmolar stress. Furthermore, rhIL-37 restored barrier protein integrity, observed in 2D and 3D confocal immunofluorescent images, in HCECs under hyperosmolar stress. CONCLUSION: Our findings demonstrate a novel signaling pathway by which anti-inflammatory cytokine IL-37 prevents corneal epithelial barrier disruption under hyperosmotic stress via suppressing TNF-α and CTSS expression. This study provides new insight into mechanisms protecting corneal barrier in dry eye disease.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM. Published version The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supported the meta-analysis—Project-ID 387509280—SFB1350 (Subproject C6 to I.M.H.). A.M.H., B.R., and R.T. were supported by VACSR&D MVP grant CX001897. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VACSR&D MVP grant CX001897 (A.M.H.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We conducted this research using the UK Biobank resource under the application number 20272.

Breast cancer is prone to relapse and metastasize to many vital organs, contributing to most of the breast cancer-related death and accentuating the importance of systematic identification of key factors regulating the metastasis of breast cancer. In this study, we performed a genome-wide CRISPR/Cas9 knock out screen in an orthotopic murine model of breast cancer for essential genes monitoring the progression and metastasis of breast cancer. We found one member of the zinc finger protein (ZNF) family, i.e., ZNF319, was among the top candidate genes. We further confirmed the lower expression of ZNF319 in the tumor tissue of breast cancer patients by analyzing tissue sections with IHC staining and TCGA database. Consistently, higher expression of ZNF319 correlates with better clinical outcome in almost all subtypes of breast cancer. Moreover, knocking down or overexpressing ZNF319 in breast cancer cells dramatically affects the breast cancer growth and metastasis capacity both in vitro and in vivo, suggesting ZNF319 functions as a strong suppressor of breast cancer progression. Lastly, the transcriptome analysis on ZNF319-silenced breast cancer cells shows that ZNF319 is involved in multiple crucial signaling pathways and biological processes, especially in cell cycle and proliferation. GO and KEGG analyses of our RNA-seq results reveal the up-regulation of E2F and G2/M related genes in ZNF319-silenced cells, suggesting that ZNF319 monitors the cell cycle during the breast cancer progression through the regulation of the E2F target genes and G2/M checkpoint. In summary, our study identifies ZNF319 as a novel metastasis suppressor gene arresting tumor cell cycle in breast cancer and thus presents a novel potential therapeutic target for breast cancer treatment.

Cancer-associated fibroblasts (CAFs) represent one of the main components in the tumor stroma and play a key role in breast cancer progression. Transforming growth factor-β (TGF-β) has been established to mediate breast cancer metastasis by regulating the epithelial-mesenchymal transition (EMT) and stemness of cancer cells. Caveolin-1 (CAV-1) is a scaffold protein of caveolae that is related to the proliferation and metabolism of cancer cells. It is now well demonstrated that CAV-1 deficiency in the tumor stroma is positively correlated with distant metastasis, but the mechanism remains unclear. Here, we explore whether CAV-1-deficient fibroblasts play an essential role in the EMT and stemness of breast cancer cells (BCCs) through TGF-β signaling. We establish a specific small interfering RNA (siRNA) to inhibit CAV-1 expression in fibroblasts and coculture them with BCCs to investigate the effect of CAV‑1-deficient fibroblasts and the tumor microenvironment on breast cancer progression. This study refreshingly points out that CAV-1 deficiency in fibroblasts enhances TGF-β1 secretion and then activates the TGF-β1/Smad signaling pathway of BCCs, thus promoting the metastasis and stemness of BCCs. Collectively, our findings indicate an unexpected role of CAV-1 deficiency in fibroblasts and the tumor microenvironment as a permissive factor, which is regulated by the TGF-β1 signaling pathway in BCCs.

Purpose This study aimed to combine plasma netrin-1 and clinical parameters to construct a diagnostic model for bladder pain syndrome/interstitial cystitis (BPS/IC). Methods We analyzed the independent diagnostic value of netrin-1 and the correlation with clinical symptom scores of BPS/IC. Clinical parameters were selected using LASSO regression, and a multivariate logistic regression model based on netrin-1 was established, and then a nomogram of BPS/IC prevalence was constructed. The nomogram was evaluated using calibration curves, the C-index, and decision curve analysis (DCA). Finally, the model was validated using an internal validation method. Results The area under the curve for the ability of netrin-1 to independently predict BPS/IC diagnosis was 0.858 (p Conclusion Netrin-1 can be used as a diagnostic marker for BPS/IC and is associated with pain. The nomogram constructed by combining netrin-1 and clinical parameters was able to predict BPS/IC with great accuracy. In addition, Netrin-1 may also serve as a novel therapeutic target for BPS/IC.

Purpose: Phase I results of this phase I/II study showed that pamiparib 60 mg twice a day had antitumor activity and an acceptable safety profile in Chinese patients with advanced cancer, including epithelial ovarian cancer. Patients and Methods: This open-label phase II study was conducted in China and enrolled adult (≥18 years) patients with platinum-sensitive ovarian cancer (PSOC; disease progression occurring ≥6 months after last platinum treatment) or platinum-resistant ovarian cancer (PROC; disease progression occurring Results: In the total patient population (N = 113; PSOC, n = 90; PROC, n = 23), median age was 54 years (range, 34–79) and 25.6% of patients received ≥4 prior systemic chemotherapy lines. Median study follow-up was 12.2 months (range, 0.2–21.5). Eighty-two patients with PSOC and 19 patients with PROC were evaluable for efficacy. In patients with PSOC, 8 achieved a complete response (CR) and 45 achieved a partial response (PR); ORR was 64.6% [95% confidence interval (CI), 53.3–74.9]. In patients with PROC, 6 achieved a PR; ORR was 31.6% (95% CI, 12.6–56.6). Frequently reported grade ≥3 adverse events were hematologic toxicities, including anemia and decreased neutrophil count. Conclusions: Pamiparib 60 mg twice a day showed antitumor activity with durable responses in patients with PSOC or PROC with gBRCAmut, and had a manageable safety profile.

Vision impairment (VI) is associated with poor quality of life and increased risk of falls. Few prospective data are available on Asians. This study investigates the longitudinal impact of VI and the major eye diseases on mortality risk in Asians.Prospective cohort study with meta-analysis.We conducted a multi-ethnic prospective study of adults (40-80 years old) in the Singapore Epidemiology of Eye Diseases Study (baseline: 2004-2011). All-cause mortality was obtained from the National Death Registry until May 2017. VI was defined by best-corrected visual acuity (BCVA)20/40 in the better eye. Major eye diseases were assessed using standard protocols. We examined associations using multivariate-adjusted Cox proportional hazards regression models. Finally, we conducted a meta-analysis of the associations between VI and mortality.Of 9,986 participants, 1,210 deaths occurred (12.1%) over a median follow-up of 8.8 years. Compared to participants with normal vision, persons with VI had increased risk of mortality (hazards ratio [HR]: 1.53; 95% confidence interval [CI:] 1.30-1.81) in multivariate models. In ethnicity-specific analyses, this association was significant across Chinese (HR: 1.63; 95% CI: 1.08-2.48); Malays (HR: 1.31; 95% CI: 1.06-1.62); and Indians (HR: 2.25; 95% CI: 1.61-3.15). Cataract, under-corrected refractive errors (URE), and diabetic retinopathy (DR) were significantly associated with mortality (HRs: 1.30, 1.22, and 1.54, respectively). In a meta-analysis of 12 studies including 58,034 persons, VI was associated with 30% increased risk of mortality (HR: 1.3; 95% CI: 1.2-1.5).In this multi-ethnic Asian population, VI and preventable eye conditions (cataract, URE, and DR) were associated with mortality, emphasizing the need for early detection and intervention to prevent and treat VI and major eye diseases.

ObjectiveThe aim of the current study was to investigate the contributing role of gene variation and transcription levels among the m6A methyltransferases METTL3, METTL14, and WTAP in pulmonary tuberculosis (PTB).MethodsA case-control study including 461 PTB patients and 467 normal controls was designed for genotyping. Three SNPs in METTL3 (rs1061027, rs1139130, rs1061026), three SNPs in METTL14 (rs62328061, rs4834698, rs1064034), and two SNPs in WTAP (rs1853259, rs11752345) were genotyped via the SNPscan™ technique. METTL3, METTL14, and WTAP transcription levels were determined in 78 PTB patients and 86 controls via quantitative real-time reverse-transcription PCR.ResultsFrequencies of the METTL14 rs62328061 GG genotype, WTAP rs11752345 CT genotype, and T allele were significantly increased in PTB patients compared to controls. An increased risk of rs62328061 was detected in a recessive model, and a decreased risk of rs11752345 was detected in a dominant model in the PTB group. METTL3 gene variation was not associated with PTB risk. The METTL3 rs1139130 GG genotype was significantly increased with drug resistance, and the G allele was significantly decreased with drug-induced liver injury in PTB patients. A reduced frequency of the METTL14 rs62328061 G allele was associated with leukopenia, a reduced frequency of the WTAP rs11752345 T allele was associated with sputum smear positivity, and a higher frequency of the METTL14 rs4834698 TC genotype was evident in PTB patients with hypoproteinemia. Compared to controls, METTL3, METTL14, and WTAP transcription levels in PTB patients were significantly decreased, and the level of WTAP was increased in PTB patients with drug resistance. METTL3 level was negatively associated with erythrocyte sedimentation rate and aspartate aminotransferase, and METTL14 level was negatively correlated with alanine aminotransferase and aspartate aminotransferase.ConclusionMETTL14 rs62328061 and WTAP rs11752345 variants were associated with the genetic background of PTB, and METTL3, METTL14, and WTAP levels were abnormally decreased, suggesting that these m6A methyltransferases may play important roles in PTB.

Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals, and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete cytokines and chemokines to recruit immune cells and initiate innate and/or adaptive immune responses. However, whether chemokines affect viral replication in nonimmune cells is rarely clear. In this study, we detected that chemokine CCL5 was highly expressed, while expression of its receptor, CCR1, was downregulated in respiratory epithelial cells after RSV infection. When we overexpressed CCR1 on respiratory epithelial cells

BackgroundCurrently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC.MethodsOf 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors.ResultsAfter adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (PConclusionFor patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.

Aims This study was designed to confirm the hypothesis that thiopurines is a better option for preventing postoperative recurrence of Crohn's disease in patients with ≥2 risk factors. Methods Eighty-seven consecutive Crohn's disease patients with curative ileocolonic resection and ileocolic anastomosis were recruited for retrospective analysis: 43 prescribed thiopurines and 44 prescribed mesalamine. We had pre-defined 4 risk factors for subgroup analyses: smoking, penetrating disease, perianal disease and previous resection. Endpoints included clinical (CDAI>200) and endoscopic (Rutgeerts score ≥i2) recurrence during 52 weeks. Results By week 52, no significant differences of clinical recurrence (37.2%; 16/43 in thiopurines vs. 54.5%; 24/44 in mesalamine, p=0.105) and endoscopic recurrence (55.8%; 24/43 vs. 75.0%; 33/44, p=0.060) were found between two groups. In subgroup patients with ≥2 risk factors, clinical recurrence (35.7%; 5/14 vs. 81.8%; 9/11, p=0.042) and endoscopic recurrence (64.3%; 9/14 vs. 100.0%, 11/11, p=0.046) were less frequent in thiopurines compared with mesalamine. Patients added one more risk factor, the risk of endoscopic recurrence increased 2.201 folds (95%CI: 1.178-4.115) adjusted for treatment intervention. Patients with mesalamine added one more risk factor, the risk of clinical and endoscopic recurrence increased 3.383 (95%CI: 1.260-9.081) and 5.884 (95%CI: 1.598-21.662) folds. Three patients with thiopurines withdrew due to adverse effects, which was comparable to mesalamine (0, p=0.232). Conclusions Thiopurines may be superior to mesalamine for preventing postoperative clinical and endoscopic recurrence of CD in patients with ≥2 risk factors, but caution should be taken in the adverse events caused by thiopurines. This article is protected by copyright. All rights reserved.

PURPOSE: Without a standard test for pancreatic carcinomas, this highly lethal disease is normally diagnosed at its advanced stage, leading to a low survival rate of patients. Trophoblast cell-surface antigen 2 (Trop-2), a transmembrane glycoprotein, is associated with cell proliferation and highly expressed in most of solid epithelial tumors, including pancreatic cancer. A non-invasive method of imaging Trop-2 would greatly benefit clinical diagnosis and monitoring of pancreatic cancer. In the current study, (89)Zr-labeled anti-Trop-2 antibody (AF650) was recruited for the systemic evaluation of Trop-2 as an immunoPET target for pancreatic cancer imaging. METHODS: AF650 was conjugated with desferrioxamine (DFO) and then radiolabeled with (89)Zr. Trop-2 expression levels were determined in three pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and AsPC-1) via western blot, flow cytometry, saturation binding assay, and immunofluorescence staining. The targeting capacity of (89)Zr-DFO-AF650 was evaluated in mouse models with subcutaneous xenograft of pancreatic cancers via PET imaging and bio-distribution studies. In addition, a Trop-2-positive orthotopic cancer model was recruited for further validating the targeting specificity of (89)Zr-DFO-AF650. RESULTS: BxPC-3 cells expressed high levels of Trop-2, while AsPC-1 and MIA PaCa-2 cells expressed low levels of Trop-2. Additionally, (89)Zr-DFO-AF650 exhibited high specificity to Trop-2 in BxPC-3 cells (K(d) = 22.34 ± 2.509 nM). In subcutaneous xenograft models, about 28.8 ± 7.63%ID/g tracer accumulated in the BxPC-3 tumors at 120 h post injection, which was much higher than those reaching MIA PaCa-2 (6.76 ± 2.08%ID/g) and AsPC-1 (3.51 ± 0.69%ID/g) tumors (n = 4). More importantly, (89)Zr-DFO-AF650 could efficiently distinguish primary tumors in the orthotopic BxPC-3 cancer model, showing high correlation between PET imaging and bio-distribution and sensitivity. CONCLUSIONS: (89)Zr-DFO-AF650 can be effectively used to detect pancreatic cancer via Trop-2-mediated immunoPET in vivo, clearly revealing the great potential of Trop-2-based non-invasive imaging in pancreatic cancer detection and treatment monitoring.

Colorectal cancer (CRC) is the third most malignant tumour worldwide, with high mortality and recurrence. Chemoresistance is one of the main factors leading to metastasis and poor prognosis in advanced CRC patients. By analysing the Gene Expression Omnibus data set, we found higher hexokinase 2 (HK2) expression levels in patients with metastatic CRC than in those with primary CRC. Moreover, we observed higher enrichment in oxaliplatin resistance‐related gene sets in metastatic CRC than in primary CRC. However, the underlying relationship has not yet been elucidated. In our study, HK2 expression was significantly elevated in CRC patients. Gene set enrichment analysis (GSEA) revealed multi‐drug resistance and epithelial‐mesenchymal transition (EMT) pathways related to high HK2 expression. Our results showed that knockdown of HK2 significantly inhibited vimentin and Twist1 expression and promoted TJP1 and E‐cadherin expression in CRC cells. Additionally, transcriptional and enzymatic inhibition of HK2 by 3‐bromopyruvate (3‐bp) impaired oxaliplatin resistance in vitro and in vivo. Mechanistically, HK2 interacts with and stabilized Twist1 by preventing its ubiquitin‐mediated degradation, which is related to oxaliplatin resistance, in CRC cells. Overexpression of Twist1 reduced the apoptosis rate by HK2 knockdown in CRC cells. Collectively, we discovered that HK2 is a crucial regulator that mediates oxaliplatin resistance through Twist1. These findings identify HK2 and Twist1 as promising drug targets for CRC chemoresistance.

Translational regulation plays a critical role during the oocyte-to-embryo transition (OET) and zygotic genome activation (ZGA). Here, we integrated ultra-low-input ribosome profiling (Ribo-lite) with messenger RNA sequencing to co-profile the translatome and transcriptome in human oocytes and early embryos. Comparison with mouse counterparts identified widespread differentially translated gene functioning in epigenetic reprogramming, transposon defense, and small RNA biogenesis, in part driven by species-specific regulatory elements in 3′ untranslated regions. Moreover, PRD-like homeobox transcription factors, including TPRXL , TPRX1 , and TPRX2 , are highly translated around ZGA. TPRX1/2/L knockdown leads to defective ZGA and preimplantation development. Ectopically expressed TPRXs bind and activate key ZGA genes in human embryonic stem cells. These data reveal the conservation and divergence of translation landscapes during OET and identify critical regulators of human ZGA.

The aim of this study was to assess the association of vitamin B12 level and single nucleotide polymorphisms (SNPs) in vitamin B12 metabolic genes with pulmonary tuberculosis (PTB) in Chinese Han population. The plasma vitamin B12 expression level was detected using ELISA. Ten SNPs in six key genes (TCN1, TCN2, CUBN, MMACHC, FUT6, and MUT) of vitamin B12 metabolic pathway were included for genotyping by the SNPscan technique among 454 PTB patients and 467 controls. Our results found that vitamin B12 level was significantly reduced in PTB patients when compared with controls. There was no significant association between TCN1 rs526934, TCN2 rs1801198, CUBN rs7906242, rs10904861, rs1801222, MMACHC rs10789465, FUT6 rs3760776, rs3760775, MUT rs9473555, rs9381784 variants, and PTB susceptibility. TCN2 rs1801198 CC genotype, C allele was significantly associated with hypoproteinemia in PTB patients. In CUBN, rs7906242 GG genotype, G allele, rs10904861 TT genotype, and T allele were significantly related to the decreased frequency of sputum smear-positive, and rs10904861 variant affected the occurrence of drug resistance in PTB patients. In addition, the increased frequency of CUBN rs1801222 AA genotype was significantly associated with leukopenia. The decreased frequency of MUT rs9473555 CC genotype was found in the PTB patients with hypoproteinemia. However, vitamin B12 expression was not associated with the genotype distribution of above SNPs. In conclusion, vitamin B12 level was significantly decreased in PTB patients and genetic variants in vitamin B12 metabolic genes were not contributed to PTB susceptibility. Several SNPs in TCN2, CUBN, and MUT gene might associate with multiple clinical manifestations in PTB.

This study evaluated and compared the efficacy, safety and economy of four Chinese patent medicines(CPMs) in the treatment of functional dyspepsia(FD) using the method of rapid health technology assessment. It aims to provide decision-makers with rapid decision-making information. The eight Chinese and English databases were comprehensively and systematically searched for the relevant clinical research. Studies were screened and evaluated. A total of 110 studies were identified, including 95 randomized controlled trials(RCTs), 7 controlled clinical trials(CCTs), 7 systematic review/Meta-analysis and 1 economic evaluation, among which 28 were Dalitong Granules, 49 were Zhizhu Kuanzhong Capsules, 3 were Biling Weitong Granules and 30 were Qizhi Weitong Granules(Tablets/Capsules). The quality of the included literature was generally low. The efficacy of four CPMs alone or combined with western medicine in the treatment of FD is different. Dalitong Granules was used to treat motility disorder in FD. Zhizhu Kuanzhong Capsules and Qizhi Weitong Granules(Tablets/Capsules) can treat FD patients with anxiety and depression. Qizhi Weitong Granules(Tablets/Capsules) were mainly used in FD for perimenopausal patients. There were no serious adverse reactions in the clinical study of four CPMs in the treatment of FD. Dalitong Granules has better effects than mosapride in the treatment of FD, but the cost is slightly higher. The cost-effectiveness ratio of Zhizhu Kuanzhong Capsules in the treatment of FD patients with anxiety and depression was lower than that of Domperidone. In terms of average daily price, Qizhi Weitong Tablets has the highest price(27.00 yuan per day), Qizhi Weitong Granules has the lowest price(5.04 yuan per day), Biling Weitong Granules has a relatively high price(15.53 yuan per day), followed by Dalitong Granules(13.03 yuan per day). The evidence of Dalitong Granules covered the efficacy, safety and economy, which is relatively complete compared with the other three drugs. It has effective potential in the treatment of motility disorder in FD. Further research in this field in the future is needed.

This study analyzed and reported the basic information and clinical evidence of Chinese patent medicines for digestive system diseases in children in a scoping review manner. Based on the drug instructions, the basic information of Chinese patent medicines for digestive system diseases in children was obtained by searching the three lists of national medicines. At the same time, the relevant clinical literatures from the first day of establishment to March 7, 2022 were obtained from Chinese and English databases. According to the screening criteria, 39 Chinese patent medicines were included, involving 8 dosage forms. Eight Chinese medicines including Crataegi Fructus, Poria, Citri Reticulatae Pericarpium, Hordei Fructus Germinatus, Arecae Semen, Massa Medicata Fermentata, Dioscoreae Rhizoma, and Atractylodis Macrocephalae Rhizoma were frequently used, and the main effects were invigorating spleen, checking diarrhea, promoting digestion, clearing heat, and harmonizing stomach. The indications for Chinese patent medicines were mainly diarrhea, anorexia, food accumulation, dyspepsia, and rotavirus enteritis in children. Among all drug instructions, only 4 mentioned adverse reactions and 6 mentioned contraindications. Ninety-two clinical studies were included ultimately, including 84 randomized controlled studies, 2 systematic reviews/Meta-analysis, 1 retrospective study, and 5 case series. The literatures only covered 21 kinds of Chinese patent medicines, with the most studies related to Xingpi Yanger Granules, accounting for 32.6% of the total literature volume. The sample size in the literatures was mainly focused on 51-200 cases, and 51-100 cases were selected by the most literatures, accounting for 34.45%. The interventions of the experimental group were mainly Chinese patent medicines or Chinese patent medicines combined with western medicines. The literatures with treatment course of 0-7 d accounted for the largest proportion(51.10%). The effective rate and symptom improvement time were used as the indexes to evaluate the results. The main adverse reactions were vomiting, constipation, nausea, rash, cold, diarrhea, redness of the skin around the umbilicus, or red itchy skin. The analysis of this study found that Chinese patent medicines have good curative effect and research prospects in the treatment of digestive system diseases in children. However, most clinical evidence has problems, such as limited indexes to evaluate the results, lack of traditional Chinese medicine characteristics, uneven quantity and low quality of Chinese patent medicine literatures, and insufficient specification of instructions. In the future, high-quality clinical studies on this field should be actively carried out, and economic studies and clinical comprehensive evaluation of Chinese patent medicines should be strengthened to explore the characteristics and advantages of its treatment, so as to provide decision-making basis for finding the accurate clinical positioning and promoting the rational clinical application of Chinese patent medicines for treating digestive system diseases in children.

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ObjectiveTo study the effects of liraglutide or lifestyle interventions combined with other antidiabetic drugs on glucose metabolism and abdominal fat distribution in patients with obesity and type 2 diabetes mellitus (T2DM).MethodsFrom April 30, 2020, to April 30, 2022, a prospective randomized controlled study was carried out at the Endocrinology Department of Beijing Hospital, the National Center of Gerontology. According to the in- and exclusion criteria and by the random table method, revisited T2DM patients were selected as the research subjects and were allocated into a Study group (taking liraglutide) and a Control group (underwent lifestyle interventions). All patients received continuous 12-weeks interventions to the endpoint, and the changes of value [Δ=(endpoint)-(baseline)] of physical measurements, blood tests, the energy spectrum CT examination results, and body composition analysis results were analyzed and compared.ResultsA total of 85 people completed this study, and among them, 47 were in the Study group and 38 were in the Control group. Compared with the Control group, the changes of hemoglobin A1c (HbA1c) level (-0.78 ± 1.03% vs. -1.57 ± 2.00%, P=0.025), visceral fat area (0.91 ± 16.59 cm2 vs. -7.1 ± 10.17 cm2, P=0.011), and subcutaneous fat area of abdomen [0 (-18.75, 15.5) cm2 vs. -16.5 (-41.75, -2.25) cm2, P=0.014] were all greater in the Study group. The adverse events caused by liraglutide were mainly concentrated in the gastrointestinal system and all of them were minor adverse events.ConclusionLiraglutide can be the drug of choice for weight management and reduction of abdominal fat distribution in patients with obesity and T2DM.

Piwi-interacting RNAs (piRNAs/piRs) are small non-coding RNAs that play important roles in stablizing genome through silencing transposable genetic elements. The piR-651 was reported to be dysregulated in several human solid cancer tissues, such as gastric and lung cancers. However, the role of piRNA-651 in carcinogenesis of breast cancer has not been defined. We found that piR-651 was highly expressed in breast cancer tissues and cell lines. Overexpression of piR-651 facilitated cell proliferation and invasion, restrained cell apoptosis and the percentage of arrested cells in G0/G1 phase, accompanied by upregulated expression of oncogenes (MDM2, CDK4 and Cyclin D1), whereas piR-651 downregulation showed the opposite effects. Additionally, piR-651 could promote phosphatase and tensin homolog (PTEN) methylation and its downregulated expression by recruiting DNA methyltransferase 1 (DNMT1) to the PTEN promoter region through complex formation with PIWIL2. PTEN overexpression reversed the effects of upregulated piR-651 on cell functions. This study reveals that piR-651 promotes proliferation and migration and induces apoptosis of breast cancer cells by facilitating DNMT1-mediated PTEN promoter methylation, which may provide a potential therapeutic mechanism for breast cancer.

This study examined (a) the identification of various reading groups across languages in Chinese (L1) adolescents learning English as a second language (ESL), in terms of their word-reading and reading comprehension skills, (b) overlap in reading group membership across languages, and (c) the performance of the various reading groups on reading-related language comprehension measures in English. The participants were 246 eighth-grade students from an English-immersion program in a middle school in China. Latent profile analysis identified three reading groups in each language: (a) a typically developing reader group with average or above-average word-reading and reading comprehension, (b) a group with poor decoding/word-reading skills and weak reading comprehension, and (c) a group with poor reading comprehension in the absence of poor decoding/word reading. The overlap in profile characteristics across languages for typically developing readers and poor decoders was high (about 68% for typically developing readers and 54% for poor decoders), whereas the overlap for being poor comprehenders in each language was moderate (about 37%). Furthermore, poor decoders in either language performed more poorly than the typically developing and poor comprehender groups on word reading in the other language, while poor comprehenders in either language performed more poorly than the typically developing and poor decoder groups on reading comprehension in the other language. The comparison of the reading groups’ performance on English reading-related language comprehension measures showed that poor comprehenders and poor decoders performed worse than typically developing readers. Implications for identification and instruction of ESL children with reading difficulties are discussed.

Objective This study aimed to investigate the clinical effects of surgically treating lumbosacral tuberculosis with a modified posterior unilateral limited laminectomy method for debridement. Methods This retrospective study enrolled a total of 26 patients who were administered in our institution from January 2010 to December 2016, diagnosed with lumbosacral tuberculosis at the L5/S1 level, and underwent one‐stage posterior unilateral limited laminectomy as surgical treatment for debridement, allograft of cortical bone grafting, and fixation. The erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP) level, visual analog scale (VAS) score, Oswestry Disability Index (ODI), and lumbosacral angle (LA, Cobb's method) were statistically compared, and the American Spinal Injury Association Impairment (ASIA) Scale was compared between the preoperative and postoperative time points to evaluate the clinical outcomes. Results All 26 patients were observed during the follow‐up period, and the mean follow‐up time was 1.3 ± 0.42 years. The mean age was 56 ± 7.4 years old. The average operation time was 118.1 ± 17.5 min, and the mean bleeding volume was 513.0 ± 79.6 mL. There were no intraoperative complications or tuberculous sinus, and two cases experienced hypostatic pneumonia during hospitalization, which resolved with responsive antibiotics and symptomatic supportive treatment. At the final follow‐up, there was no recurrence of tuberculosis, and the ESR (11.8 ± 1.8 mm/h) and CRP (3.0 ± 1.0 mg/L) levels in all patients had returned to normal. The patients with neurologic deficits had improved, and the mean ODI was 79.9 ± 10.6 (87–62) preoperatively and significantly decreased to 20.5 ± 5.7 (11–29) at the final follow‐up (P, One‐stage posterior unilateral limited laminectomy for debridement, internal fixation, and bone graft fusion could reserve the posterior appurtenances of the lumbosacral spine, and serve as an effective procedure to treat short‐segment lumbosacral tuberculosis without extensive anterior sacral abscesses and gravitation abscesses.

Kinesin family member 18B (KIF18B) is a new tumor-associated protein that contributes to the carcinogenesis of multiple malignancies. However, the detailed relevance of KIF18B in breast cancer has not been fully elucidated. This work aimed was to evaluate a possible relationship between KIF18B and breast cancer progression. Our findings show KIF18B is increased in breast cancer and demonstrate that high KIF18B level predicts a reduced survival rate. Cellular functional studies revealed that knockdown of KIF18B markedly reduces the proliferation, invasion, and epithelial-mesenchymal transition of breast cancer cells and enhances their chemosensitivity toward doxorubicin. Further studies showed that KIF18B modulates the level of phospho-Akt, phospho-glycogen synthase kinase-3β, and β-catenin. Notably, suppression of Akt abolished KIF18B-overexpression-induced increases in activation of Wnt/β-catenin pathway. In addition, re-expression of β-catenin reversed KIF18B-silencing-induced cancer-promoting effect. In vivo animal experiments elucidated that knockdown of KIF18B significantly weakened the tumorigenicity of breast cancer cells. Taken together, data of this study illustrate that KIF18B exerts a potential cancer-promoting function in breast cancer via enhancement of Wnt/β-catenin pathway through modulation of the Akt/GSK-3β axis.

This study evaluated the safety, efficacy, and cost effectiveness of Biantong Capsules(Tablets), Maren Runchang Pills, Qirong Runchang Oral Liquid, and Qihuang Tongmi Soft Capsules in the treatment of constipation by the rapid health technology assessment(RHTA) to provide evidence for clinical decision and references for rapid evaluation of Chinese patent medicine(CPM). CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Web of Science, and Cochrane Library were searched for research articles from database inception to February 2022. Two reviewers conducted literature screening, data extraction, and quality evaluation according to the predetermined standards. Descriptive analysis of the results combined with visual charts was performed. Sixty research articles were included, involving 44 randomized controlled trials(RCTs), 7 clinical controlled trials(CCTs), 4 systematic reviews/Meta-analyses, and 5 economic analysis studies. As revealed by the results, Biantong Capsules(Tablets) could be used for postoperative and senile constipation, in which some studies reported Biantong Capsules(Tablets) were superior to Maren Runchang Pills and Qirong Runchang Oral Liquid. Maren Runchang Pills were mainly used for senile constipation, and the efficacy was similar to that of conventional wes-tern medicine, but the cost was low and the compliance of patients was good. Qirong Runchang Oral Liquid was indicated for disease-derived or drug-induced constipation, chronic constipation, and senile constipation with fewer adverse reactions. Qihuang Tongmi Soft Capsules had good efficacy and safety in the treatment of functional constipation. Overall, compared with western medicine glycerine enema and lactulose, the number of clinical studies of the four CMPs was small, but they targeted constipation patients with different subtypes. In conclusion, the four CMPs have their advantages and characteristics in the treatment of constipation, but they are restric-ted by sparse existing evidence, low quality of evidence, and insufficient economic research. In the future, more high-quality and long-term follow-up studies should be carried out to obtain reliable evidence. Meanwhile, it is called for strengthening the economic evaluation of CMPs to provide evidence for decision-making.

Th17 cells play a key role in immunity against Mycobacterium tuberculosis (MTB), and this study aimed to explore the association of Th17 pathway gene polymorphisms with pulmonary tuberculosis (PTB) susceptibility in a Chinese population. A total of 10 single nucleotide polymorphisms in Th17 pathway genes (IL-17A gene rs2275913, rs3748067, rs8193036, rs3819024, IL-17F gene rs7741835, rs763780, IL-21 gene rs907715, rs2055979, IL-23R gene rs11805303, and rs7518660) were genotyped in 456 PTB patients and 466 controls using SNPscan technique. The IL-23R rs11805303 CC genotype, C allele frequencies were significantly lower in PTB patients than in controls, and the rs11805303 variant was significantly associated with the reduced risk of PTB in a recessive model. There were no significant associations between IL-17A, IL-17F, and IL-21 gene variations and PTB risk. In IL-17A gene, rs2275913, rs3748067, and rs3819024 variants were associated with drug resistance in PTB patients. In IL-17F gene, rs7741835 variant affected drug resistance, and rs763780 variant was associated with hypoproteinemia in PTB patients. In addition, the lower frequencies of the TT genotype, T allele of rs2055979 were found in PTB patients with drug-induced liver injury. Haplotype analysis showed that IL-23R CG haplotype frequency was significantly lower in PTB patients than in controls, while the TG haplotype frequency was higher. In conclusion, IL-23R rs11805303 polymorphism may contribute to the genetic underpinnings of PTB in the Chinese population, and the IL-17A, IL-17F, and IL-21 genetic variations are associated with several clinical manifestations of PTB patients.

NOD-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptotic cell death and inflammation contribute to the pathogenesis of bronchial asthma, and it is reported that Substance P (SP) plays important role in the process, however, the detailed molecular mechanisms by which SP participates in the aggravation of bronchial asthma have not been fully studied. Here, our clinical data showed that SP and its receptor Neurokinin-1 receptor (NK1R) were significantly elevated in the plasma and peripheral blood mononuclear cell (PBMC) collected from patients with bronchial asthma, and further pre-clinical experiments evidenced that SP suppressed cell viability, accelerated lactate dehydrogenase (LDH) release, and upregulated ASC, Caspase-1, NLRP3, IL-1β and IL-18 to promote pyroptotic cell death and cellular inflammation in the human bronchial epithelial cells and asthmatic mice modelsiin vitro/iandiin vivo/i. Interestingly, SP-induced pyroptotic cell death was reversed by NK1R inhibitor L732138. Then, we uncovered the underlying mechanisms, and found that SP activated the downstream PI3K/AKT/NF-κB signal pathway in a NK1R-dependent manner, and blockage of this pathway by both PI3K inhibitor (LY294002) and NF-κB inhibitor (MG132) reversed SP-induced pyroptotic cell death and recovered cell viability in bronchial epithelial cells. Collectively, we concluded that SP interacted with its receptor NK1R to activate the PI3K/AKT/NF-κB pathway, which further triggered NLRP3-mediated pyroptotic cell death in the bronchial epithelial cells, resulting in the aggravation of bronchial asthma.

Despite integrin being highlighted as a stiffness-sensor molecule in matrix stiffness-driven angiogenesis, other stiffness-sensor molecules and their mechanosensory pathways related to angiogenesis in hepatocellular carcinoma (HCC) remain obscure. Here, we explored the interplay between Piezo1 and integrin β1 in the mechanosensory pathway and their effects on HCC angiogenesis to better understand matrix stiffness-induced angiogenesis.The role of Piezo1 in matrix stiffness-induced angiogenesis was investigated using orthotopic liver cancer SD rat models with high liver stiffness background, and its clinical significance was evaluated in human HCC tissues. Matrix stiffness-mediated Piezo1 upregulation and activation were assayed using an in vitro fibronectin (FN)-coated cell culture system with different stiffness, Western blotting and CaIncreased matrix stiffness significantly upregulated Piezo1 expression at both cellular and tissue levels, and high expression of Piezo1 indicated an unfavorable prognosis. High matrix stiffness also noticeably enhanced the activation level of Piezo1, similar to its expression level. Piezo1 knockdown significantly suppressed tumor growth, angiogenesis, and lung metastasis of HCC rat models with high liver stiffness background. shPiezo1-CM from HCC cells attenuated tube formation and migration abilities of vascular endothelial cells remarkably, and analysis of differentially expressed pro-angiogenic factors revealed that Piezo1 promoted the expression and secretion of vascular endothelial growth factor (VEGF), CXC chemokine ligand 16 (CXCL16) and insulin-like growth factor binding protein 2 (IGFBP2). Matrix stiffness-caused Piezo1 upregulation/activation restrained hypoxia inducible factor-1α (HIF-1α) ubiquitination, subsequently enhanced the expression of downstream pro-angiogenic factors to accelerate HCC angiogenesis. Besides, collagen 1 (COL1)-reinforced tissue stiffening resulted in more expression of Piezo1 via miR-625-5p.This study unravels a new mechanism by which the integrin β1/Piezo1 activation/Ca

Small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) is a cysteine protease that catalyzes the cleavage of the C-terminus of SUMO1 for the processing of SUMO precursors and deSUMOylation of target proteins. SENP1 is considered to be a promising target for the treatment of hepatocellular carcinoma (HCC) and prostate cancer. SENP1 Gln597 is located at the unstructured loop connecting the helices α4 to α5. The Q597A mutation of SENP1 allosterically disrupts the hydrolytic reaction of SUMO1 through an unknown mechanism. Here, extensive multiple replicates of microsecond molecular dynamics (MD) simulations, coupled with principal component analysis, dynamic cross-correlation analysis, community network analysis, and binding free energy calculations, were performed to elucidate the detailed mechanism. Our MD simulations showed that the Q597A mutation induced marked dynamic conformational changes in SENP1, especially in the unstructured loop connecting the helices α4 to α5 which the mutation site occupies. Moreover, the Q597A mutation caused conformational changes to catalytic Cys603 and His533 at the active site, which might impair the catalytic activity of SENP1 in processing SUMO1. Moreover, binding free energy calculations revealed that the Q597A mutation had a minor effect on the binding affinity of SUMO1 to SENP1. Together, these results may broaden our understanding of the allosteric modulation of the SENP1−SUMO1 complex.

Thiopurine dose optimization by thiopurine-S-methyltransferase (TPMT) or nudix hydrolase-15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence ( 2 months). Although laboratory monitoring of 6-thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA-thioguanine nucleotides (DNA-TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA-TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells 3.5 × 10

The blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), which remains a major challenge in clinical management. However, the underlying molecular mechanism driving blastic transformation remains unclear. Here, we show that ASF1A, an essential activator, enhanced the transformation to CML-BC by mediating cell differentiation arrest. ASF1A expression was aberrantly increased in bone marrow samples from CML-BC patients compared with newly diagnosed CML-chronic phase (CP) patients. ASF1A inhibited cell differentiation and promoted CML development in vivo. Mechanistically, we identified ASF1A as a coactivator of the Notch transcriptional complex that induces H3K56ac modification in the promoter regions of Notch target genes, and subsequently enhanced RBPJ binding to these promoter regions, thereby enhancing Notch signaling activation to mediate differentiation arrest in CML cells. Thus, our work suggests that targeting ASF1A might represent a promising therapeutic approach and a biomarker to detect disease progression in CML patients.

Background/aimsObesity is a well-known risk factor for diabetes, but its association with diabetic retinopathy (DR) is inconclusive, in particular in Asians. We aimed to assess whether body mass index (BMI) is associated with the presence and severity of DR in Asian populations with diabetes.MethodsPooled analysis of individual-level cross-sectional data from 10 010 adults with diabetes who participated in 12 population-based studies conducted in China, India, Japan, Russia (Asian), Singapore and South Korea that were part of the Asian Eye Epidemiology Consortium (AEEC). BMI was calculated as weight in kilograms divided by height in square metres and categorised into normal (2, reference), overweight (25–29.9 kg/m2) and obese (≥30 kg/m2). Any-DR (n=1669) and vision-threatening DR (VTDR, n=489) were assessed from digital retinal photographs and graded according to standard protocols. Each study was analysed separately using multivariable logistic regression models adjusted for age, sex, haemoglobin A1c%, systolic blood pressure and diabetes duration, and the estimated odds ratios (ORs) and 95% confidence interval (CIs) from all studies were then combined using random-effects models.ResultsIn multivariable models, obesity showed a significant inverse association with any-DR (pooled OR (95% CI) =0.74 (0.59 to 0.91)) and VTDR (0.75 (0.60 to 0.93)). Similarly, in continuous analysis, BMI showed a significant inverse association with both any-DR (0.93 (0.87 to 0.99)) and VTDR (0.79 (0.68 to 0.92) per SD increase). Overweight did not show a significant association with any-DR.ConclusionsAmong Asian adults with diabetes, both BMI and obesity showed an inverse association with DR. These findings warrant confirmation in further longitudinal studies.

Objectives To examine the validity and reliability of the Mandarin version of the Treatment Burden Questionnaire (TBQ) among stroke patients. Background Stroke patients need long-term management of symptoms and life situation, and treatment burden has recently emerged as a new concept that can influence the health outcomes during the rehabilitation process. Methods The convenience sampling method was used to recruit 187 cases of stroke patients in a tertiary grade hospital in Tianjin for a formal investigation. Item analysis, reliability and validity tests were carried out. The reliability test included internal consistency and test–retest reliability. And as well as content, structure and convergent validity were performed for the validity test. Results Of the 187 completed questionnaires, only 180 (96.3%) were suitable for analysis. According to the experts’ evaluation, the I-CVI of each item was from 0.833 to 1.000, and the S-CVI was 0.967. The exploratory factor analysis yielded three-factor components with a cumulative variation of 53.054%. Convergent validity was demonstrated using measures of Morisky’s Medication Adherence Scale 8 (r = –0.450, P < 0.01). All correlations between items and global scores ranged from 0.403 to 0.638. Internal consistency reliability and test–retest reliability were found to be acceptable, as indicated by a Cronbach’s α of 0.824 and an intraclass correlation coefficient of 0.846, respectively. Conclusions The Mandarin TBQ had acceptable validity and reliability. The use of TBQ in the assessment of treatment burden of stroke survivor may benefit health resources allocation and provide tailor therapeutic interventions to construct minimally disruptive care.

This study examined the sources of reading comprehension difficulties in English language learners (ELLs). The characteristics of ELL poor comprehenders were compared to their English as a first language (EL1) peers. Participants included 124 ELLs who spoke Chinese as an L1 and 79 EL1 students. Using a regression technique based on age, non-verbal reasoning, word reading accuracy, and word reading fluency, three types of comprehenders (poor, average, and good) were identified within each language group. The groups were then compared on measures of oral language skills (vocabulary breadth, vocabulary depth, and listening comprehension), metalinguistic skills (morphological awareness and syntactic awareness), working memory, and higher-level processing skills (inference, conjunction use, and comprehension monitoring). ELL poor comprehenders had significantly lower scores than ELL average and good comprehenders on vocabulary breadth, listening comprehension, and morphological awareness, whereas there were no significant differences between the average and good comprehender groups on these skills. Additionally, both ELL poor and average comprehenders had lower scores than ELL good comprehenders on all three higher-level skills. Finally, results showed that ELL poor comprehenders scored lower than EL1 poor comprehenders on vocabulary breadth, listening comprehension, and morphological awareness, but the two groups did not differ on higher-level skills. Theoretical and educational implications for the identification and instruction of ELL poor comprehenders are discussed.

Postoperative adhesive bowel obstruction (ABO) is a common complication especially in complicated appendicitis. This study aimed to analyze the risk factors for ABO following appendectomy in children with complicated appendicitis, and establish a scoring model for predicting postoperative ABO and treatment option to relieve the obstruction. From December 2014 to January 2020, all files of consecutive patients with complicated appendicitis underwent appendectomy were reviewed. Univariate and multivariate analyses were used to screen out the risk factors of postoperative ABO, and establish a scoring model for predicting postoperative ABO and surgical relief to relieve the obstruction. Of the 780 patients, 87 (11.2%) had ABO following appendectomy, including 27 who underwent surgical relief. Age ≤ 6 years, overweight and obesity, duration of symptoms ≥ 36 h, C-reactive protein ≥ 99 mg/L, duration of operation ≥ 60 min, intraoperative peritoneal lavage, and postoperative flatus time ≥ 20 h were independent risk factors for postoperative ABO. The final scoring model for postoperative ABO included factors above, and exhibited a high degree of discrimination (area under the curve [AUC]: 0.937; 95% confidence interval [CI] 0.913–0.960) corresponding to an optimal cut-off value of 6: 82.8% sensitivity, 92.6% specificity. Furthermore, the scoring model showed a sensitivity of 74.1% and a specificity of 91.7% for patients wo underwent surgical relief to relieve obstruction with the optimal cut-off value of 9. Risk factors for postoperative ABO should be taken seriously in children with complicated appendicitis. The scoring model is a novel but promising method to predict postoperative ABO and provide reference for clinical decision-making to relieve the obstruction.

It remains unknown for decades how some of the therapeutic fusion proteins positive in a small percentage of cancer cells account for patient outcome. Here, we report that osteosarcoma Rab22a-NeoF1 fusion protein, together with its binding partner PYK2, is sorted into exosomes by HSP90 via its KFERQ-like motif (RVLFLN142). The exosomal Rab22a-NeoF1 fusion protein facilitates the pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages. The exosomal PYK2 activates RhoA in its negative recipient osteosarcoma cells and induces signal transducer and activator of transcription 3 activation in its recipient macrophages to increase M2 phenotype. Consequently, lung metastases of its recipient osteosarcoma cells are promoted by this exosomal Rab22a-NeoF1 fusion protein, and this event can be targeted by disrupting its interaction with PYK2 using a designed internalizing RGD peptide.

Dynamic changes in intron sequences, with their loss and gain, are poorly detected due to the limited methods for the non-invasive monitoring of the pre-mRNA splicing process. Here, we describe the design of a two-step transcriptional activation (TSTA) reporter for the real-time imaging of the splicing process in living subjects. By taking advantage of the strong transactivating properties of the GAL4-VP16 fusion protein, which can target upstream activation sequence (UAS) elements to boost subsequent firefly luciferase reporter gene expression, we successfully and consistently detected the dynamic pre-mRNA splicing activity in response to exogenous splicing modulators in living cells and animals. Our findings provide a valuable tool for the high-throughput screening of splicing modulators, which could speed up the development of new drugs for the treatment of disordered splicing diseases.

Hyperlipidemia-induced retinal vascular dysfunction is a complex pathological process. circRNAs are important regulators of biological processes and disease progression. However, the expression pattern of circRNAs in hyperlipidemia-induced retinal vascular dysfunction remains unclear. Herein, we used a murine model of hyperlipidemia and identified 317 differentially expressed circRNAs between hyperlipidemic retinas and normolipidemic retinas by circRNA microarrays. GO analysis indicated that the host genes of dysregulated circRNAs were targeted to cell differentiation (ontology: biological process), cytoplasm (ontology: cellular component), and protein binding (ontology: molecular function). Pathway analysis revealed that circRNAs-mediated network was mostly enriched in focal adhesion signaling. Notably, circLDB1 was significantly up-regulated in the serum of coronary artery disease patients and aqueous humor of age-related macular degeneration patients. circLDB1 regulated endothelial cell viability, proliferation, and apoptosis in vitro. Thus, circRNAs are the promising targets for the prediction and diagnosis of hyperlipidemia-induced vascular diseases.

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer‑associated mortality worldwide. In the present study, a novel molecular therapeutic target for lung cancer was investigated. The protein expression level of fidgetin‑like 1 (FIGNL1) in human lung cancer tissues was determined and its potential functions in the H1299 and A549 lung cancer cell lines was subsequently studied. In addition, the protein expression level of FIGNL1 in 109 lung cancer samples and corresponding para‑cancerous tissues was investigated, using immunohistochemical staining. RNA interference and overexpression of FIGNL1 was used to determine the role of FIGNL1 in regulating cell proliferation, and cDNA microarray analysis was performed to identify the potential regulatory pathways. Lastly, the potential role of FIGNL1 in regulating tumorigenesis in lungs and also the proliferation of lung cancer cells was investigated. Firstly, lung cancer tissues were found to express higher protein levels of FIGNL1 and was significantly associated with decreased cell proliferation, migration and invasion abilities, and enhanced cell death. Overexpression of FIGNL1 significantly promoted cell proliferation, including decreased arrest at the G1 phase of the cell cycle and apoptosis, as well as increased ability for fission and migration. These in vitro findings were consistent with the results of the cell‑line derived xenografts in BALB/c nude mice, where tumor growth was decreased when injected with cells transfected with shFIGNL1. Collectively, these results provide suggest that FIGNL1 is involved in cell growth and tumorigenesis.

Lung cancer has the highest mortality of all cancers worldwide. To identify epigenetic markers for early diagnosis of lung adenocarcinoma (LUAD), we integrated genome‐wide DNA methylation and gene expression analyses. We identified methylation signatures in three genes (CMTM2, TBX4, and DPP6) for early diagnosis of LUAD. Our findings may contribute toward an earlier LUAD diagnosis, potentially improving outcomes for patients., Lung cancer has the highest mortality of all cancers worldwide. Epigenetic alterations have emerged as potential biomarkers for early diagnosis of various cancer tissue types. To identify methylation markers for early diagnosis of lung adenocarcinoma, we aimed to integrate genome‐wide DNA methylation and gene expression data from The Cancer Genome Atlas. To this end, we first examined the global DNA methylation pattern of lung adenocarcinoma and investigated the relationship between DNA methylation subtypes and clinical features. We then extracted differentially methylated and expressed genes, and adopted feature selection techniques to determine the final methylation markers. The performance of the markers in predicting lung adenocarcinoma was evaluated on three independent datasets from Gene Expression Omnibus. Protein levels of marker genes were validated by immunohistochemistry, and their biological function was further verified in vivo. We identified three novel methylation markers in lung adenocarcinoma including cg08032924, cg14823851, and cg19161124, mapping to CMTM2, TBX4, and DPP6, respectively. Validating these results on three independent datasets indicated that the three markers can achieve extremely high sensitivity and specificity in distinguishing lung adenocarcinoma from normal samples. Immunohistochemistry quantification results confirmed that markers are weakly expressed in human lung adenocarcinoma, and CMTM2 decreased tumor growth of mouse Lewis lung carcinoma in vivo. Overall, our study identified three novel methylation markers in lung adenocarcinoma which may contribute toward an improved diagnosis potentially leading to a better outcome for patients with lung adenocarcinoma.

N6-Methyladenosine (m6A) is associated with many biological processes and the development of multiple diseases. The aim of this study was to analyze the association of m6A readers' genes variation, as well as their expression levels, with pulmonary tuberculosis (PTB). A total of 11 single-nucleotide polymorphisms (SNPs) in m6A readers' genes (i.e., YTHDF1 rs6122103, rs6011668, YTHDF2 rs602345, rs3738067, YTHDF3 rs7464, rs12549833, YTHDC1 rs3813832, rs17592288, rs2293596, and YTHDC2 rs6594732, and rs2416282) were genotyped by SNPscan™ technique in 457 patients with PTB and 466 normal controls. The m6A readers' genes expression levels in peripheral blood mononuclear cells (PBMCs) from 78 patients with PTB and 86 normal controls were detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). There was no significant association between all SNPs in YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 genes and PTB susceptibility. The increased frequencies of YTHDF2 rs3738067 GG genotype and YTHDC1 rs3813832 CC genotype, C allele, were, respectively, found in PTB patients with hypoproteinemia and fever. YTHDC2 rs6594732 variant was significantly associated with drug-induced liver damage and sputum smear-positive, and the rs2416282 variant was significantly associated with fever in patients with PTB. Compared with controls, the YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 mRNA levels were significantly decreased in PTB. Moreover, YTHDF1 level was negatively associated with erythrocyte sedimentation rate (ESR), and YTHDF3 and YTHDC1 levels were negatively related to alanine aminotransferase (ALT) in patients with PTB. Our results demonstrated that YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 genes SNPs did not contribute to PTB susceptibility, while their decreased levels in patients with PTB suggested that these m6A readers might play significant roles in PTB.

Estrogen receptor α (ERα) plays a key role in the adaptive response of liver metabolism to energy demands, especially in controlling lipid metabolism. Tamoxifen (TMX), a main drug for the treatment of ER-positive breast cancer in clinical, is a selective ER modulator (SERM). However, accordingly, the long-term use of TMX would lead to nonalcoholic fatty liver (NAFLD) in clinical, which had no definite treatment up to now. Fatostatin (Fato), an inhibitor of sterol-regulatory element binding protein 2 (SREBP2), was reported as a synergistic inhibitor of ER-positive breast cancer with TMX, but the hepatic lipid regulation of this combination is still unknown. Herein, we aimed to explore the effect and mechanism of Fato against TMX-induced NAFLD. The results identified that hepatic cholesterol content increase was the main reason for TMX-induced NAFLD. It was caused by the upregulation of circulating cholesterol uptake mediated by low density lipoprotein receptor (LDLR) in liver, which resulted from the activation of SREBP2. Meanwhile, Fato could inhibit activation of SREBP2-LDLR pathway, alleviating TMX-induced hepatic cholesterol accumulation. In summary, these results provided a new insight into the mechanism of TMX-induced NAFLD. Moreover, it supported the combination of Fato and TMX for the treatment of ER-positive breast cancer to reduce the adverse effect of TMX in clinical.