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Abstract Background Radiomics provided opportunities to quantify the tumor phenotype non-invasively. This study extracted contrast-enhanced computed tomography (CECT) radiomic signatures and evaluated clinical features of bone metastasis in non-small-cell lung cancer (NSCLC). With the combination of the revealed radiomics and clinical features, the predictive modeling on bone metastasis in NSCLC was established. Methods A total of 318 patients with NSCLC at the Tianjin Medical University Cancer Institute & Hospital was enrolled between January 2009 and December 2019, which included a feature-learning cohort (n = 223) and a validation cohort (n = 95). We trained a radiomics model in 318 CECT images from feature-learning cohort to extract the radiomics features of bone metastasis in NSCLC. The Kruskal-Wallis and the least absolute shrinkage and selection operator regression (LASSO) were used to select bone metastasis-related features and construct the CT radiomics score (Rad-score). Multivariate logistic regression was performed with the combination of the Rad-score and clinical data. A predictive nomogram was subsequently developed. Results Radiomics models using CECT scans were significant on bone metastasis prediction in NSCLC. Model performance was enhanced with each information into the model. The radiomics nomogram achieved an AUC of 0.745 (95% confidence interval [CI]: 0.68,0.80) on predicting bone metastasis in the training set and an AUC of 0.808(95% confidence interval [CI]: 0.71,0.88) in the validation set. Conclusion The revealed invisible image features were of significance on guiding bone metastasis prediction in NSCLC. Based on the combination of the image features and clinical characteristics, the predictive nomogram was established. Such nomogram can be used for the auxiliary screening of bone metastasis in NSCLC.

Abstract Background Depression is a prevalent issue among older adults, affecting their quality of life and overall well-being. Exercise is an effective means of relieving depressive symptoms in older adults, but the optimal dose for different exercise types remains unclear. As such, the aim of this meta-analysis was to examine the dose–response relationship between overall and specific types of exercise with depression symptoms in older adults. Methods This systematic review and network meta-analysis included a search of PubMed, Medline, Embase, PsycINFO, Cochrane library, and Web of Science for randomized controlled trials of exercise in older adults with depression symptoms from inception to 15 July 2023. Comprehensive data extraction covered dose, treatment regimen, demographics and study duration. Dosage metrics, encompassing METs-min/week, were scrutinized in correlation with the Minimal Clinically Importance Difference (MCID). Results A total of 47 studies involving 2895 participants and 7 kinds of exercise were included in the review. Without considering the dose, the results of our network meta-analysis indicated that Walking was the most effective in alleviating depression in older adults, in addition to Aerobic exercise (AE), Yoga, Qigong, Resistance training (RT), and Tai Chi (TC), which were equally effective. However, the results of the dose–response analysis found that Aerobic exercise was most effective at a dose of 1000 METs-min/week. It is noteworthy that Walking is significantly effective in alleviating depressive symptoms in older adults at very low doses. In terms of clinical benefits, we found that overall exercise doses in the range of 600 ~ 970 METs-min/week were clinically effective. Considering the specific types of exercise, Aerobic exercise, Resistance training, Walking, and Yoga were found to be effective at doses ranging from 820 ~ 1000 METs-min/week, 520 ~ 1000 METs-min/week, 650 ~ 1000 METs-min/week, 680 ~ 1000 METs-min/week, respectively. At the same time, we found that when the age exceeded 81 years, even when participating in exercise, it did not achieve the effect of alleviating depressive symptoms in older adults. Conclusions In conclusion, including Walking, AE, Yoga, Qigong, RT, and TC, effectively alleviate depressive symptoms in older adults. Furthermore, we established statistically and clinically significant threshold doses for various exercise types. Early initiation of exercise is beneficial, but its efficacy diminishes from the age of 80, and beyond 81, exercise no longer significantly alleviates depressive symptoms.

Abstract Objective Clinically, it has been found that patients undergoing knee replacement have a high incidence of concomitant hallux valgus. In this study, we analyzed whether patients with osteoarthritis who underwent surgery and those patient who did not have surgery had an increased risk of hallux valgus by Mendelian randomization and performed reverse causal analysis. Design Genomewide association study (GWAS) data for osteoarthritis, categorized by knee arthritis with joint replacement, knee arthritis without joint replacement, hip arthritis with joint replacement, and hip arthritis without joint replacement.And acquired hallux valgus were downloaded for Mendelian randomized studies. MR analysis was performed using inverse variance-weighted (IVW), weighted median, and MR-Egger methods. MR-egger regression, MR pleiotropic residuals and outliers (MR-presso), and Cochran's Q statistical methods were used to evaluate heterogeneity and pleiotropy. Results The IVW results indicate that, compared to healthy individuals, patients who meet the criteria for knee osteoarthritis joint replacement surgery have a significantly higher risk of acquired hallux valgus. There were no significant causal relationships found for the remaining results. No significant heterogeneity or multiplicity was observed in all the Mr analyses. Conclusion Our study supports the increased risk of acquired hallux valgus in patients eligible for knee replacement. There is necessary for clinicians to be concerned about the hallux valgus status of patients undergoing knee arthroplasty.

Abstract Background The growth-regulating factor-interacting factor (GIF) gene family plays a vital role in regulating plant growth and development, particularly in controlling leaf, seed, and root meristem homeostasis. However, the regulatory mechanism of heteromorphic leaves by GIF genes in Populus euphratica as an important adaptative trait of heteromorphic leaves in response to desert environment remains unknown. Results This study aimed to identify and characterize the GIF genes in P. euphratica and other five Salicaceae species to investigate their role in regulating heteromorphic leaf development. A total of 27 GIF genes were identified and characterized across six Salicaceae species (P. euphratica, Populus pruinose, Populus deltoides, Populus trichocarpa, Salix sinopurpurea, and Salix suchowensis) at the genome-wide level. Comparative genomic analysis among these species suggested that the expansion of GIFs may be derived from the specific Salicaceae whole-genome duplication event after their divergence from Arabidopsis thaliana. Furthermore, the expression data of PeGIFs in heteromorphic leaves, combined with functional information on GIF genes in Arabidopsis, indicated the role of PeGIFs in regulating the leaf development of P. euphratica, especially PeGIFs containing several cis-acting elements associated with plant growth and development. By heterologous expression of the PeGIF3 gene in wild-type plants (Col-0) and atgif1 mutant of A. thaliana, a significant difference in leaf expansion along the medial-lateral axis, and an increased number of leaf cells, were observed between the overexpressed plants and the wild type. Conclusion PeGIF3 enhances leaf cell proliferation, thereby resulting in the expansion of the central-lateral region of the leaf. The findings not only provide global insights into the evolutionary features of Salicaceae GIFs but also reveal the regulatory mechanism of PeGIF3 in heteromorphic leaves of P. euphratica.

Abstract Bovine viral diarrhea virus (BVDV) belongs to the genus Pestivirus within the family Flaviviridae. Mitophagy plays important roles in virus-host interactions. Here, we provide evidence that non-cytopathic (NCP) BVDV shifts the balance of mitochondrial dynamics toward fission and induces mitophagy to inhibit innate immune responses. Mechanistically, NCP BVDV triggers the translocation of dynamin-related protein (Drp1) to mitochondria and stimulates its phosphorylation at Ser616, leading to mitochondrial fission. In parallel, NCP BVDV-induced complete mitophagy via Parkin-dependent pathway contributes to eliminating damaged mitochondria to inhibit MAVS- and mtDNA-cGAS-mediated innate immunity responses, mtROS-mediated inflammatory responses and apoptosis initiation. Importantly, we demonstrate that the LIR motif of ERNS is essential for mitophagy induction. In conclusion, this study is the first to show that NCP BVDV-induced mitophagy plays a central role in promoting cell survival and inhibiting innate immune responses in vitro.

Abstract Background The labial salivary glands (LSGs) are important for the diagnosis, evaluation of therapeutic efficacy, and genetic analyses of primary Sjögren’s syndrome (pSS). In autoimmune diseases, the recognition of self nucleic acids and viral RNA and DNA through endogenous Toll-like receptor(TLR) triggers the production of type I IFN and pro-inflammatory cytokines, leading to the occurrence and progression of the disease. Here, we detected the expression of TLR7 in LSGs and analyse its correlation with clinical features and serum cytokines in pSS patients. Methods LSGs and serum samples were obtained from 56 pSS patients and 19 non-SS patients (non-pSS patients). The expression of TLR7 in the LSGs was evaluated with immunohistochemistry. The serum levels of interferon-α (IFN-α) and interleukin-6 (IL-6) were quantified by ELISA. Laboratory parameters were measured by clinical standard laboratory techniques. Results TLR7-positive cells in pSS were localized in the ductal epithelial cells and lymphocytes of LSGs. The expression of TLR7 was upregulated in pSS patients compared with controls. Patients with anti-Ro52 antibody positivity showed higher TLR7 levels than those who were negative but not those with anti-Ro60 and anti-SSB. TLR7 levels were positively associated with the levels of IgG, IgA, ANA, IL-6, IFN-α and serum globulin but were not associated with IgM, C3, C4, or rheumatoid factor (RF) in serum. Conclusion TLR7 may be involved in the inflammatory response and the production of antibodies in pSS and plays an important role in local and systemic pSS manifestations. This research showed that TLR7 is involved in pSS pathogenesis.

Abstract Background The relationship between aging and osteoporosis is well established. However, the relationship between the body's physiological age, i.e. epigenetic age, and osteoporosis is not known. Our goal is to analyze the bidirectional causal relationship between epigenetic clocks and osteoporosis using a bidirectional Mendelian randomization study. Methods We used SNPs closely associated with GrimAge, Hannum, PhenoAge, and HorvathAge in epigenetic age and SNPs closely associated with femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density as instrumental variables, respectively, using the inverse variance weighting method and several other MR methods to assess the bidirectional causal relationship between epigenetic age and osteoporosis. Result There was no evidence of a clear causal relationship of epigenetic age (GrimAge, Hannum, PhenoAge, and HorvathAge) on femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density. In reverse Mendelian randomization analysis showed a significant causal effect of lumbar spine bone mineral density on GrimAge: odds ratio (OR) = 0.692, 95% confidence interval (CI) = (0.538–0.890), p = 0.004. The results suggest that a decrease in lumbar spine bone mineral density promotes an acceleration of GrimAge. Conclusion There was no significant bidirectional causal relationship between epigenetic age and osteoporosis A decrease in lumbar spine bone density may lead to an acceleration of the epigenetic clock "GrimAge". Our study provides partial evidence for a bidirectional causal effect between epigenetic age and Osteoporosis.

Abstract Objective Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection. We aimed to evaluate the diagnostic accuracy of metagenomic next-generation sequencing (mNGS) for PJP. Methods A comprehensive electronic literature search of Web of Knowledge, PubMed, Cochrane Library, CNKI and Wanfang data was performed. Bivariate analysis was conducted to calculate the pooled sensitivity, specificity, diagnostic odds ratio (DOR), the area under the summary receiver operator characteristic (SROC) curve and the Q-point value (Q*). Results The literature search resulted in 9 studies with a total of 1343 patients, including 418 cases diagnosed with PJP and 925 controls. The pooled sensitivity of mNGS for diagnosis of PJP was 0.974 [95% confidence interval (CI), 0.953–0.987]. The pooled specificity was 0.943 (95% CI, 0.926–0.957), the DOR was 431.58 (95% CI, 186.77-997.27), the area under the SROC curve was 0.987, and the Q* was 0.951. The I 2 test indicated no heterogeneity between studies. The Deek funnel test suggested no potential publication bias. Subgroup analyses showed that the area under the SROC curve of mNGS for diagnosis of PJP in immunocompromised and non-HIV patients was 0.9852 and 0.979, respectively. Conclusions Current evidence indicates that mNGS exhibits excellent accuracy for the diagnosis of PJP. The mNGS is a promising tool for assessment of PJP in both immunocompromised and non-HIV patients.

Abstract Background Tumor necrosis (TN) was associated with poor prognosis. However, the traditional classification of TN ignored spatial intratumor heterogeneity, which may be associated with important prognosis. The purpose of this study was to propose a new method to reveal the hidden prognostic value of spatial heterogeneity of TN in invasive breast cancer (IBC). Methods Multiphoton microscopy (MPM) was used to obtain multiphoton images from 471 patients. According to the relative spatial positions of TN, tumor cells, collagen fibers and myoepithelium, four spatial heterogeneities of TN (TN1-4) were defined. Based on the frequency of individual TN, TN-score was obtained to investigate the prognostic value of TN. Results Patients with high-risk TN had worse 5-year disease-free survival (DFS) than patients with no necrosis (32.5% vs. 64.7%; P

Abstract Background Osteosarcoma is the most common primary malignant bone tumor. The current study was conducted to describe the general condition of patients with primary osteosarcoma in a single cancer center in Tianjin, China and to investigate the associated factors in osteosarcoma patients with lung metastasis. Methods From February 2009 to October 2020, patients from Tianjin Medical University Cancer Institute and Hospital, China were retrospectively analyzed. The Kaplan–Meier method was used to evaluate the overall survival of osteosarcoma patients. The Cox proportional hazard regression analysis was performed to analyze the prognostic factors of all osteosarcoma patients and those patients with lung metastasis, respectively. Furthermore, risk factors for developing lung metastasis were identified in synchronous lung metastasis (SLM) and metachronous lung metastasis (MLM) patients. Results A total of 203 patients were involved and 150 patients were successfully followed up for survival status. The 5-year survival rate of osteosarcoma was 70.0% and the survival months for patients with SLM and MLM were 33.3 ± 12.6 and 45.8 ± 7.4 months, respectively. The presence of lung metastasis was one of the independent prognostic factors for prognosis of osteosarcoma. In patients with lung metastasis, twenty-one (10.3%) showed lung metastasis at the diagnosis of osteosarcoma and 67 (33%) were diagnosed with lung metastases during the later course. T3 stage (OR = 11.415, 95%CI 1.362–95.677, P = 0.025) and bone metastasis (OR = 6.437, 95%CI 1.69–24.51, P = 0.006) were risk factors of SLM occurrence. Bone metastasis (OR = 1.842, 95%CI 1.053–3.224, P = 0.032), good necrosis (≥ 90%, OR = 0.032, 95%CI 0.050–0.412, P

Abstract Background Breast cancer has become the most common malignant tumour worldwide. Distant metastasis is one of the leading causes of breast cancer-related death. To verify the performance of clinicomics-guided distant metastasis risk prediction for breast cancer via artificial intelligence and to investigate the accuracy of the created prediction models for metachronous distant metastasis, bone metastasis and visceral metastasis. Methods We retrospectively enrolled 6703 breast cancer patients from 2011 to 2016 in our hospital. The figures of magnetic resonance imaging scanning and ultrasound were collected, and the figures features of distant metastasis in breast cancer were detected. Clinicomics-guided nomogram was proven to be with significant better ability on distant metastasis prediction than the nomogram constructed by only clinical or radiographic data. Results Three clinicomics-guided prediction nomograms on distant metastasis, bone metastasis and visceral metastasis were created and validated. These models can potentially guide metachronous distant metastasis screening and lead to the implementation of individualized prophylactic therapy for breast cancer patients. Conclusion Our study is the first study to make cliniomics a reality. Such cliniomics strategy possesses the development potential in artificial intelligence medicine.

Abstract Background Although men who have sex with men (MSM) and male sex workers (MSWs) both represent the high-risk groups for the transmission of HIV/AIDS and syphilis, the comparison between them have not yet been well studied in China. We aimed to evaluate the prevalence of HIV among MSM and MSW, and then identify the difference of risk factors of HIV infection. Methods A snowball sampling was employed to recruit patrons attending the Tianjin bathhouse from March 2011 to October 2018. A questionnaire covering sociodemographic characteristics, sexual behaviors, HIV-related and HIV awareness was completed by 5166 patrons from all parts of China. Bivariate analyses were done using the Chi-square test to investigate the association between factors and HIV infection among MSM and MSWs. Subsequently, we studied the different impact of risk factors on HIV infections among the two groups using multiple logistic regression with the adjusted odds ratio (aOR) being derived. Results From 2011 to 2018, 235 MSWs and 4931 MSM were included into our study. HIV prevalence among the MSWs was 17.8% (95%CI: 13.2% ~ 23.4%) while 6.5% (95%CI: 5.8% ~ 7.2%) for MSM (P

Abstract Background Subacute combined degeneration (SCD) is a neurological complication commonly associated with vitamin B12 deficiency. It can result from nitrous oxide (N2O) abuse and cause neuropsychiatric symptoms. However, there has been no literature regarding alterations of serum copper and cerebellum in SCD patients. Case presentation We reported two cases of young SCD patients with histories of N2O abuse. In these cases, elevated homocysteine, macrocytic anemia, spinal cord abnormalities, and peripheral nerve injuries were detected. In addition, decreased serum copper level and cerebellar atrophy were reported for the first time. The patients’ symptoms improved after withdrawal of N2O exposure and vitamin B12 supplements. Conclusion We reported two SCD cases with serum copper alteration and cerebellar atrophy after N2O abuse for the first time. These might be crucial complements to the diagnosis of SCD.

Abstracts Background In recent years, HIV testing has become one of the effective strategies to reduce the risk of the infection. Frequent quarterly HIV testing can be cost effective. Therefore, an in-depth study of factors related to the testing behavior of men who have sex with men (MSM) were analyzed to optimize intervention strategies. Methods From March 2011 to October 2018, the project was implemented in a Tianjin (China) bathhouse, and 5165 MSM were surveyed using snowball sampling. Factors related to HIV testing behavior were analyzed by ordinal logistic regression analysis after grouping according to testing frequency, and comprehensive analysis was performed. Results The multivariate logistic analysis showed that 6 variables including young MSM (OR = 0.67, 95% CI: 0.49–0.92, p = 0.01), low-educated MSM (OR = 0.60, 95% CI: 0.48–0.77, p

Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. Methods/design This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. Discussion Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20–35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. Trial registration ClinicalTrials.gov NCT 02936375 . Registered on October 18, 2016.

Abstract Background Autism spectrum disorder (ASD) is becoming increasingly prevalent of late. Methylenetetrahydrofolate reductase (MTHFR) has a significant role in folate metabolism. Owing to the inconsistencies and inconclusiveness on the association between MTHFR single nucleotide polymorphism (SNP) and ASD susceptibilities, a meta-analysis was conducted to settle the inconsistencies. Methods For this meta-analysis, a total of 15 manuscripts published up to January 26, 2020, were selected from PubMed, Google Scholar, Medline, WangFang, and CNKI databases using search terms “MTHFR” OR “methylenetetrahydrofolate reductase” AND “ASD” OR “Autism Spectrum Disorders” OR “Autism” AND “polymorphism” OR “susceptibility” OR “C677T” OR “A1298C”. Results The findings of the meta-analysis indicated that MTHFR C677T polymorphism is remarkably associated with ASD in the five genetic models, viz., allelic, dominant, recessive, heterozygote, and homozygote. However, the MTHFR A1298C polymorphism was not found to be significantly related to ASD in the five genetic models. Subgroup analyses revealed significant associations of ASD with the MTHFR (C677T and A1298C) polymorphism. Sensitivity analysis showed that this meta-analysis was stable and reliable. No publication bias was identified in the associations between MTHFRC677T polymorphisms and ASD in the five genetic models, except for the one with regard to the associations between MTHFRA1298C polymorphisms and ASD in the five genetic models. Conclusion This meta-analysis showed that MTHFR C677T polymorphism is a susceptibility factor for ASD, and MTHFR A1298C polymorphism is not associated with ASD susceptibility.

Abstract Background The objectives of this study were to assess the maintenance of effect of duloxetine 60 mg once-daily (QD) in Chinese patients with chronic pain due to osteoarthritis (OA) of the knee or hip and to provide additional long-term safety data. Methods This was an open-label, extension phase of a randomized, double-blind, placebo-controlled clinical trial. Eligible patients were outpatients who met the American College of Rheumatology clinical and radiographic criteria for OA with a rating ≥4 on Brief Pain Inventory (BPI) 24-h average pain. After completing the 13-week placebo-controlled phase, patients originally assigned to placebo were titrated to duloxetine 60 mg QD (PLA_DLX), whereas patients originally assigned to duloxetine 60 mg QD remained on the same dose of duloxetine (DLX_DLX) for another 13 weeks. The maintenance effect of duloxetine 60 mg QD during the extension phase was evaluated by a 1-sided 97.5% confidence interval (CI) of the baseline-to-endpoint change in the extension phase for patients who took duloxetine and reported ≥30% reduction in BPI average pain at the end of placebo-controlled phase (placebo-controlled phase duloxetine responders). Other BPI severity and interference items, as well as safety and tolerability, were assessed. Results Of 342 patients entering the extension phase, 162 (97.6%) DLX_DLX-treated patients and 157 (89.2%) PLA_DLX-treated patients completed this phase. Most patients (76.0%) were female. Mean age was 60.6 years. Mean BPI average pain was 5.5 at baseline of the placebo-controlled phase. Among 113 placebo-controlled phase duloxetine responders, mean change in BPI average pain during the extension phase was − 0.59 (from 2.47 to 1.88); the upper bound of the 1-sided 97.5% CI was − 0.31 and less than the pre-specified non-inferiority margin of a 1.5-point increase (p

Abstract Background lipopolysaccharide-binding protein (LBP) has been to be a surrogate marker of inflammation in OSA. This study aimed to test the hypothesis that the concentration of LBP is elevated in adult patients with obstructive sleep apnea (OSA). Methods A total of 90 patients were enrolled into the study, 50 subjects were divided into OSA groups and 40 in healthy control according to PSG examination. Subsequently, patients with apnea-hypopnea index (AHI) ≧ 5, were divided into different subgroups according to blood pressure, gender, body mass index (BMI) and AHI. Venous blood samples were collected for detection after polysomnography. The serum levels of LBP and proinflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α) were tested by ELISA. Results The present study demonstrated that the serum levels of both LBP and proinflammatory cytokines were elevated in OSA patients. A stratified analysis conducted to analyze differences among subgroups indicated that OSA patients with a higher AHI or BMI had an increased level of LBP and proinflammatory cytokines (all p < 0.05). Furthermore, a significant correlations were observed between LBP and inflammation and AHI. Multivariate regression analysis also demonstrated that AHI, LSaO2 and BMI had impact on the concentration of LBP. Conclusion The research showed that the serum level of LBP and proinflammatory cytokines were elevated in adult patients with OSA, and an association with severity of disease and BMI were established. Furthermore, sleep apnea and BMI had effect on the concentration of LBP.

Abstract Background and aims Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor with a high fatality rate. It was recently found that parathyroid hormone-like hormone (PTHLH) was frequently overexpressed in ICC compared with non-tumor tissue. This study aimed to elucidate the underlying mechanisms of PTHLH in ICC development. Methods The CCK-8 assay, colony formation assays, flow cytometry and a xenograft model were used to examine the role of PTHLH in ICC cells proliferation. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. Luciferase reporter, chromatin immunoprecipitation (ChIP) and DNA pull-down assays were used to verify the transcription regulation of activating transcription factor-2 (ATF2). Results PTHLH was significantly upregulated in ICC compared with adjacent and normal tissues. Upregulation of PTHLH indicated a poor pathological differentiation and intrahepatic metastasis. Functional study demonstrated that PTHLH silencing markedly suppressed ICC cells growth, while specific overexpression of PTHLH has the opposite effect. Mechanistically, secreted PTHLH could promote ICC cell growth by activating extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and subsequently upregulated ATF2 and cyclinD1 expression. Further study found that the promoter activity of PTHLH were negatively regulated by ATF2, indicating that a negative feedback loop exists. Conclusions Our findings demonstrated that the ICC-secreted PTHLH plays a characteristic growth-promoting role through activating the canonical ERK/JNK-ATF2-cyclinD1 signaling pathways in ICC development. We identified a negative feedback loop formed by ATF2 and PTHLH. In this study, we explored the therapeutic implication for ICC patients.

Abstract Background Oxidative stress (OS) is one of the major causes of ovarian aging and dysfunction. Indole-3-propionic acid (IPA) is an indole compound derived from tryptophan with free radical scavenging and antioxidant properties, and thus may have potential applications in protecting ovarian function, although the exact mechanisms are unknown. This study aims to preliminarily elucidate the potential mechanisms of IPA that benefit ovarian reserve function through network pharmacology, molecular docking, and experimental verification. Methods The related protein targets of IPA were searched on SwissTargetPrediction, TargetNet, BATMAN-TCM, and PharmMapper databases. The potential targets of diminished ovarian reserve (DOR) were identified from OMIM, GeneCards, DrugBank, and DisGeNET databases. The common targets were uploaded directly to the STRING database to construct PPI networks. We then performed GO and KEGG enrichment analysis on the targets. Subsequently, molecular docking and molecular dynamics simulation were used to validate the binding conformation of IPA to candidate targets. Furthermore, we carried out in vitro experiments to validate the prediction results of network pharmacology. Results We identified a total of 61 potential targets for the interaction of IPA with DOR. The PPI network topological parameter analysis yielded 13 hub genes for DOR treatment. The GO biological process enrichment analysis identified 293 entries, mainly enriched in aging, signal transduction, response to hypoxia, negative regulation of apoptotic process, and positive regulation of cell proliferation. The KEGG enrichment analysis mainly included lipid and atherosclerosis, progesterone-mediated oocyte maturation, AGE-RAGE, relaxin, estrogen, and other signaling pathways. The molecular docking further revealed the direct binding of IPA with six hub proteins including NOS3, AKT1, EGFR, PPARA, SRC, and TNF. In vitro experiments showed that IPA pretreatment attenuated H2O2-induced cellular oxidative stress damage, while IPA exerted cytoprotective and antioxidant damage effects by regulating the six hub genes and antioxidant proteins. Conclusion We systematically illustrated the potential protective effects of IPA against DOR through multiple targets and pathways using network pharmacology, and further verified the cytoprotective effect and antioxidant properties of IPA through in vitro experiments. These findings provide new insights into the targets and molecular mechanisms whereby IPA improves DOR.

Abstract Background In recent years, simultaneous or sequential occurrence of MOG antibody disease and anti-NMDAR encephalitis in the same patient has been reported with increasing frequency. Scholars refer to the overlapping occurrence of these two disorders as MOG antibody disease and anti-NMDAR encephalitis overlap syndrome (MNOS). Cortical T2-weighted fluid-attenuated inversion recovery (FLAIR) -hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES) is a rare clinical phenotype of MOGAD in which cortical FLAIR high-signal lesions are unilateral, with little spread to the cortex and meninges bilaterally. Although cases of FLAMES have been consistently reported. However, to our knowledge, such cases of FLAMES combined with NMDARE are rare. Case presentation Here, we describe a case of FLAMES combined with anti-NMDARE. The patient was a young male, 29 years old, admitted to our hospital with isolated seizures, whose MRI showed unilateral thalamic and bilateral frontal and parietal leptomeningeal involvement. Since we were unaware of the possibility of bilateral meningo-cortical MOGAD manifestations, the case was initially diagnosed as viral encephalitis and was given antiviral therapy. The diagnosis was not clarified until anti-NMDAR-IgG and MOG-IgG positivity was detected in the cerebrospinal fluid and serum. The patient was then treated with high-dose corticosteroids and his symptoms responded well to the steroids. Therefore, this case expands the clinical spectrum of MNOS overlap syndrome. In addition, we describe the clinical features of MNOS by summarizing the existing literature and exploring the possible mechanisms of its immune response. Conclusions Our case serves as a reminder to clinicians that when patients present with atypical clinical manifestations such as seizures, consideration should be given to MNOS and conduct testing for various relevant autoantibodies (including MOG abs) and viruses in both serum and cerebrospinal fluid, as it is easy to misdiagnose the disease as other CNS diseases, such as viral meningoencephalitis. This syndrome exhibits a high responsiveness to steroids, highlighting the critical importance of recognizing the clinical and neuroimaging features of this overlap syndrome for prompt diagnosis and treatment. Furthermore, it enriches the disease spectrum of MNOS.

Abstract Background Screen time and physical activity behaviors undergo development during early childhood and impact mental health. However, there is limited knowledge regarding the associations between physical activity, screen time, and mental health problems (MHP) in preschoolers. This study examines these associations using a large sample size and brief measures. Methods A multistage cluster stratified sampling method was used to conduct an observational cross-sectional study of 19,015 Chinese preschoolers in 2020. Information on physical activity, and screen time was collected by a self-administered questionnaire; MHP was assessed by the parent-reported Strengths and Difficulties Questionnaire (SDQ). Logistic regression models were used to obtain the odds ratios (ORs) and 95% confidence intervals (95% CIs) of preschoolers’ MHP associated with screen time, total physical activities, moderate to vigorous physical activity (MVPA), and outdoor physical activities. Results A total of 19,015 participants from the 19,548 recruited population were included in the analyses (missing rate: 2.73%), 52.60% were boys. 64.01%, 57.96%, 35.98%, and 82.64% of preschoolers were reported to meet total physical activities, MVPA, and outdoor activities with screen time recommendations level. The results of multivariable-adjusted ORs (95% CIs) of preschoolers’ MHP for comparisons of different levels of screen time (

Abstract Background Chest wall sinus with infection is a refractory disease caused by a variety of susceptible factors, and the treatment is still challenging. For clinically complex cases, although there are various surgical methods to choose from, it is still very difficult to achieve clinical cure, especially for patients with older age and many underlying diseases. Complete resection of chest wall sinus and application of repair and reconstruction technology may bring hope to refractory cases. Case presentation Herein, we report a case of a 67 year-old woman who had undergone breast cancer surgery and a history of multiple cycles of radiotherapy and chemotherapy. One year ago, she had a fistula in the left chest wall with yellow purulent fluid. After admission to our hospital, chest computed tomography (CT) showed the formation of the left chest wall sinus, accompanied by high-density images of the left clavicle, part of the ribs and part of the sternu. According to the patient's symptoms, signs and imaging examination, we preliminarily diagnosed the patient as chest wall sinus with infection and chronic osteomyelitis. Therefore, in the first-stage operation, the patient underwent left chest wall sinus resection, left partial rib resection, left partial clavicular resection and left partial sternal resection, After surgery, the wound surface was changed with gauze dressing with sensitive antibiotic solution every day until the wound surface was clean and new granulation was formed. In the second-stage operation, the wound surface was appropriately expanded, and the pedicled latissimus dorsi myocutaneous flap was transferred to the chest wall defect. Finally, the skin paddle was sutured without tension to the normal skin around the chest, and two drainage tubes were placed. Anti-infection, anti-spasm, anti-coagulation and other treatments were given after operation, and the survival of myocutaneous flap, wound healing and sinus disappearance were observed. Conclusion The application of pedicled latissimus dorsi myocutaneous flap in the treatment of intractable chronic chest wall sinus is an effective method. It does not change the shape of the thorax. The clinical effect is satisfactory in the near and medium term, which is worthy of clinical promotion.

Abstract Background To investigate the relationship between cyclin D2 (CCND2) and miR-206 expression in fine-needle aspiration cytology of thyroid carcinoma. Methods A total of 65 patients with thyroid carcinoma were selected as the subjects and 65 patients with benign thyroid nodules were in control group. The fine-needle aspiration cytology of thyroid nodules was performed. CCND2 and miR-206 levels were detected by PCR. Results Compared with the patients with benign thyroid nodules, the expression level of miR-206 in fine-needle aspiration cytology of thyroid cancer patients decreased significantly and the expression level of CCND2 increased significantly. CCND2 and miR-206 expression was negatively correlated in thyroid cancer tissues. Area under curve (AUC) of miR-206 level in the diagnosis of thyroid cancer was 0.889, and the sensitivity and specificity were 92.3% and 81.5%, respectively. AUC of CCND2 level in the diagnosis of thyroid cancer was 0.837, and the sensitivity and specificity were 67.7% and 89.2%, respectively. The AUC of combined detection of CCND2 and miR-206 in the diagnosis of thyroid cancer was 0.959, and the sensitivity and specificity were 93.8% and 87.7%, respectively. The levels of miR-206 and CCND2 were significantly correlated with TNM staging and lymph node metastasis. Conclusions miR-206 and CCND2 may become new biomarkers for clinical diagnosis of thyroid cancer based on the fine-needle aspiration cytology of thyroid nodules.

Abstract Background Esophageal cancer patients can experience co-occurring, related symptoms labeled symptom clusters. This study aimed to identify symptom clusters and explore which SCs independently affect the quality of life (QoL) among esophageal cancer patients. Methods This cross-sectional study was performed in Shenyang, China, from February 2021 to February 2022. Finally, 118 esophageal cancer patients effectively completed the survey. Questionnaires’ information included the Functional Assessment of Cancer Therapy-General (FACT-G), the MD Anderson Symptom Inventory Gastrointestinal Cancer Module (MDASI-GI), the Multidimensions Scale of Perceived Social Support, and demographic and clinical characteristics. Exploratory factor analysis with principal axis factoring was used to identify symptom clusters, and multiple regression analysis was employed to analyze the influencing factors of QoL. Results The mean score of FACT-G was 69.88 (SD = 17.85) among 118 esophageal cancer patients. Four symptom clusters were identified: psychological-somatic, dysphagia, fatigue-pain, and gastrointestinal symptom clusters. Results of regression analysis indicated a significant impact on QoL for chemotherapy (β = 0.140, P

Abstract Background Protein subcellular localization prediction plays an important role in biology research. Since traditional methods are laborious and time-consuming, many machine learning-based prediction methods have been proposed. However, most of the proposed methods ignore the evolution information of proteins. In order to improve the prediction accuracy, we present a deep learning-based method to predict protein subcellular locations. Results Our method utilizes not only amino acid compositions sequence but also evolution matrices of proteins. Our method uses a bidirectional long short-term memory network that processes the entire protein sequence and a convolutional neural network that extracts features from protein sequences. The position specific scoring matrix is used as a supplement to protein sequences. Our method was trained and tested on two benchmark datasets. The experiment results show that our method yields accurate results on the two datasets with an average precision of 0.7901, ranking loss of 0.0758 and coverage of 1.2848. Conclusion The experiment results show that our method outperforms five methods currently available. According to those experiments, we can see that our method is an acceptable alternative to predict protein subcellular location.

Abstract Background Bronchopleural fistula (BPF) refers to an abnormal channel between the pleural space and the bronchial tree. It is a potentially fatal postoperative complication after pulmonary resection and a complex challenge for thoracic surgeons because many patients with BPF ultimately develop refractory empyema, which is difficult to manage and has a major impact on quality of life and survival. Therefore, an operative intervention combined with conservative and endoscopic therapies may be required to control infection completely, to occlude BPF, and to obliterate the empyema cavity during treatment periods. Case presentation Two patients who suffered from BPF complicated with chronic empyema after lobectomy were treated in other hospitals for a long time and did not recover. In our department, we performed staged surgery and creatively combined an Amplatzer Septal Occluder (ASO) device (AGA Medical Corp, Golden Valley, MN, USA) with pedicled muscle flap transposition. First, open-window thoracostomy (OWT), or effective drainage, was performed according to the degree of contamination in the empyema cavity after the local infection was controlled. Second, Amplatzer device implantation and pedicled muscle flap transposition was performed at the same time, which achieved the purpose of obliterating the infection, closing the fistula, and tamponading the residual cavity. The patients recovered without complications and were discharged with short hospitalization stays. Conclusions We believe that the union of the Amplatzer device and pedicle muscle flap transposition seems to be a safe and effective treatment for BPF with chronic empyema and can shorten the length of the related hospital stay.

Abstract Background In the past decades, researchers have demonstrated the critical role of Toll-like receptors (TLRs) in the innate immune system. They recognize viral components and trigger immune signal cascades to subsequently promote the activation of the immune system. Main body Herpesviridae family members trigger TLRs to elicit cytokines in the process of infection to activate antiviral innate immune responses in host cells. This review aims to clarify the role of TLRs in the innate immunity defense against herpesviridae, and systematically describes the processes of TLR actions and herpesviridae recognition as well as the signal transduction pathways involved. Conclusions Future studies of the interactions between TLRs and herpesviridae infections, especially the subsequent signaling pathways, will not only contribute to the planning of effective antiviral therapies but also provide new molecular targets for the development of antiviral drugs.

Abstract Background The mortality rate from acute respiratory distress syndrome (ARDS) is high among hospitalized patients with coronavirus disease 2019 (COVID-19). Hence, risk evaluation tools are required to immediately identify high-risk patients upon admission for early intervention. Methods A cohort of 220 consecutive patients with COVID-19 were included in this study. To analyze the risk factors of ARDS, data obtained from approximately 70% of the participants were randomly selected and used as training dataset to establish a logistic regression model. Meanwhile, data obtained from the remaining 30% of the participants were used as test dataset to validate the effect of the model. Results Lactate dehydrogenase, blood urea nitrogen, D-dimer, procalcitonin, and ferritin levels were included in the risk score system and were assigned a score of 25, 15, 34, 20, and 24, respectively. The cutoff value for the total score was > 35, with a sensitivity of 100.00% and specificity of 81.20%. The area under the receiver operating characteristic curve and the Hosmer–Lemeshow test were 0.967 (95% confidence interval [CI]: 0.925–0.989) and 0.437(P Value = 0.437). The model had excellent discrimination and calibration during internal validation. Conclusions The novel risk score may be a valuable risk evaluation tool for screening patients with COVID-19 who are at high risk of ARDS.

Abstract Background Percutaneous renal biopsy (PRB) is the primary biopsy technique and it was used by 16G needles or 18G needles in China, but there is controversy about the effect and safety of the two different diameters. The study aims to compare the adequacy, complication rate and pathological classification when using 18G vs. 16G needles to perform renal biopsy with ultrasound-guidedance on native kidneys in Chinese individuals. Methods We retrospectively analyzed the number of glomeruli, adequate sample rates, complication rates and pathological classification in 270 patients with the use of 18G or 16G needles from January 2011 to May 2017 and verified whether the needle gauge affected the disease diagnosis. Results A total of 270 kidney biopsies were performed. Among them,72 were performed with 18G needles, and 198 were performed with 16G needles. There was no difference in the number of glomeruli under light microscope using 18G relative to 16G needles (24 ± 11 vs. 25 ± 11, p = 0.265), whereas more glomeruli were found in the 16G group than in the 16G group using immunofluorescence microscopy (3 ± 2 vs. 5 ± 3, p

Abstract Background MicroRNAs (miRNAs) are small non-coding RNAs about 22 nucleotides in length, which play an important role in gene regulation of both eukaryotes and viruses. They can promote RNA cleavage and repress translation via base-pairing with complementary sequences within mRNA molecules. Main body Human cytomegalovirus (HCMV) encodes a large number of miRNAs that regulate transcriptions of both host cells and themselves to favor viral infection and inhibit the host’s immune response. To date, ~ 26 mature HCMV miRNAs have been identified. Nevertheless, their roles in viral infection are ambiguous, and the mechanisms have not been fully revealed. Therefore, we discuss the methods used in HCMV miRNA research and summarize the important roles of HCMV miRNAs and their potential mechanisms in infection. Conclusions To study the miRNAs encoded by viruses and their roles in viral replication, expression, and infection will not only contribute to the planning of effective antiviral therapies, but also provide new molecular targets for the development of antiviral drugs.

Abstract Background Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. Methods Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis. Results BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1β in the SDH of our CYP-induced cystitis model. Conclusions In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1β, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.

Abstract Background Enteral nutrition should be implemented as early as possible in patients with moderate or severe acute pancreatitis. This study was designed to evaluate the feasibility and Deffectiveness of ultrasound-guided Freka-Trelumina tube placement for enteral nutrition in acute pancreatitis. Methods Patients with severe acute pancreatitis admitted to Shengjing Hospital of China Medical University who needed Freka-Trelumina tube placement for enteral nutrition and gastrointestinal decompression were included in the current study. The relevant evaluation indicators of tube placement included the success rate of tube placement, tube placement time, tube shift rate, and blocking rate. In addition, the evaluation indicators of ultrasound-guided tube placement (from 1 January 2018 to 31 July 2019) were compared with those of previous endoscope-guided placement (from 1 January 2015 to 31 December 2017) by analysing the data from the electronic medical record system. Results The success rate of ultrasound-guided tube placement was 90.7% (49/54). All 49 patients tolerated the Freka-Trelumina feeding tube. The average ultrasound-guided tube placement time for the 49 patients was 18.4 ± 12.8 min (range, 5–36 min). The Freka-Trelumina feeding tube had a shift rate of 10.2% (5/49). The blocking rate of the Freka-Trelumina feeding tube was 12.2% (6/49). The success rate of tube placement, tube shift rate and blocking rate for endoscope-guided tube placement were 100% (62/62), 11.3% (7/62), and 12.9% (8/62), respectively. The average endoscope-guided tube placement time for the 62 patients was 16.5 ± 5.7 min (range, 12–31 min). The comparison between the ultrasound-guided group and the endoscope-guided group showed that the success rate of tube placement, tube placement time, tube shift rate and blocking rate were similar. Conclusion The ultrasound-guided method can be done non-invasively at the bedside, which is safe and convenient, and the Freka-Trelumina feeding tube can be placed in time to achieve the goal of early enteral nutrition and gastrointestinal decompression.

Abstract Background Lipoprotein glomerulopathy (LPG) is a rare kidney disease with a poor prognosis that is related to mutation of the apoE gene. More than 10 variants of apoE associated with LPG have currently been identified. Case presentation A male and his mother presented with proteinuria during a health examination. They went to hospital for further examination. Renal biopsy was performed, and the diagnosis was lipoprotein glomerulopathy (LPG), which is a rare, inherited renal disease. Medical histories were collected from the 2 LPG patients and their family members. The patients and family members underwent a routine urine test, and their renal function, blood lipids, and lipoprotein levels were examined. Genomic DNA was extracted from the peripheral blood of 7 family members, and exon 2, exon 3 and exon 4 of apoE were amplified by polymerase chain reaction (PCR). The purified PCR products were sequenced. Sequence analysis identified a 15 bp deletion (GCGCAAGCTGCGTAA) in exon 4 of the apoE gene that results in a novel 5 amino acid deletion in apoE (143 K-147R → 0). No mutations were found in exon 2 and exon 3 of the apoE gene. Conclusions This family study suggests that a novel ApoE mutation (143 K-147R → 0) may be etiologically related to LPG, and other genetic or environmental factors may be associated with the occurrence of LPG.

Abstract Background Association of GSTM1- and GSTT1-null genotypes, GSTP1 A/G gene polymorphism with renal cell carcinoma (RCC) susceptibility was detected, and the relationship between the GSTM1/GSTT1-null genotype and clinical TNM stages of RCC was assessed, using meta-analysis method. Methods Association investigations according to eligibility criteria were searched and identified from the databases of Cochrane Library, PubMed, and Embase from establishment time of databases to July 1, 2017, and eligible reports were analyzed by meta-analysis. 95% confidence intervals (CI) were also detected, and odds ratios (OR) was used to express the results for dichotomous data. Results This meta-analysis indicated that there was no an association between GSTM1-null genotype, GSTT1-null genotype, GSTP1 A/G gene polymorphism and RCC risk in the overall population of Caucasians or Asians. The dual GSTM1–GSTT1-null genotype was also not associated with RCC in the overall population of Caucasians. Interestingly, there was an association between the dual GSTM1-GSTT1-null genotype and the susceptibility of RCC in Asians. Relationship of the GSTM1-null genotype with clinical TNM stage of RCC was not observed in the overall population of Asians or Caucasians. In this meta-analysis, no association between the GSTT1-null genotype and clinical TNM stage of RCC was observed in Caucasians or Asians. Interestingly, GSTT1-null genotype was detected to be associated with the clinical TNM stages in patients with RCC in the overall population. Conclusion The dual GSTM1-GSTT1-null genotype is detected to be associated with the onset of RCC in Asians, and there is an association between the GSTT1-null genotype and the clinical TNM stages in patients with RCC in the overall population.

Abstract Background Human cytomegalovirus (HCMV) infection is closely associated with coronary heart disease. Main body of the abstract In 1987, Adam et al. were the first to report an association between HCMV infection and atherosclerosis (AS), and later, many serum epidemiology and molecular biology studies showed that HCMV-infected endothelial cells play an important role in the development of AS. As patients with HCMV are generally susceptible to coronary heart disease, and with the increasing elderly population, a review of recent studies focusing on the relationships of HCMV infection and coronary heart disease is timely and necessary. Short conclusion The role of HCMV infection in the development of AS needs further study, since many remaining issues need to be explored and resolved. For example, whether HCMV promotes the development of coronary AS, and what the independent factors that lead to coronary artery AS by viral infection are. A comprehensive understanding of HCMV infection is needed in order to develop better strategies for preventing AS.

Abstract Background Malignant melanoma (MM) is one of the high degree of malignancy and early prone to blood and lymph node metastasis. There is not cured for MM. Tan II A has been reported to reduce cancer cell proliferation. But the mechanism by which Tan II A inhibited melanoma growth are not well characterized. We sought to explore the possible mechanism by which Tan II A regulated cell proliferation through autophagy signaling pathway in A375 cells. Methods We tested the effects of Tan II A on melanoma A375, MV3, M14, and other human cell lines including Hacat and HUVEC cells in cell culture model. Cell proliferation was assessed by using methyl thiazol tetrazolium (MTT) assay. Cell migration ability melanoma A375 was monitored by using cell scratch assay. Transwell chamber experimental was performed to assess the effect of Tan II A on A375 melanoma cell invasion ability. The autophagy body was examined by using flow cytometry. The expression of autophagy-associated protein beclin-1 and microtubule-associated protein 1 light chain 3(LC3)-II, as well as phosphatidylinositol 3-kinase(PI3K)、protein kinase B (Akt)、mammalian target of rapamycin (mTOR)、p70S6K1 signaling pathways were detected by using Western blotting. The effects of Tan II A on tumor progression was also examined in melanoma A375 induced tumor in mouse model. Results We found that Tan IIA inhibited melanoma A375, MV3, and M14 cell proliferation in dose and time dependent manner. Tan II A reduced CXCL12-induced A375 cell invasive ability and migration in a dose dependent manner. Tan IIA promoted autophagic body production and increased autophagy-associated protein beclin-1 and LC3-II expression in A375 cells. However, Tan IIA reduced the phosphorylation of PI3K, P-AKT, P-mTOR, and P-p7036k1. We also confirmed that Tan II A reduced melanoma A375 induced tumor volume and weight in mouse model. Conclusions We concluded that Tan II A reduced A375 cells proliferation by activation of autophagy production, blocked PI3K- Akt – mTOR - p70S6K1 signaling pathway, increased autophagic related gene beclin-1, LC3-II protein expressions and induced autophagocytosis. Tan II A inhibited melanoma A375 induced tumor development in mouse model.

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