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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are serious neurodegenerative diseases. Although their pathogenesis is unclear, the abnormal accumulation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological feature that exists in almost all patients. Thus far, there is no drug that can cure ALS/FTLD. Tetramethylpyrazine nitrone (TBN) is a derivative of tetramethylapyrazine, derived from the traditional Chinese medicine Ligusticum chuanxiong, which has been widely proven to have therapeutic effects on models of various neurodegenerative diseases. TBN is currently under clinical investigation for several indications including a Phase II trial of ALS. Here, we explored the therapeutic effect of TBN in an ALS/FTLD mouse model. We injected the TDP-43 M337V virus into the striatum of mice unilaterally and bilaterally, and then administered 30 mg/kg TBN intragastrically to observe changes in behavior and survival rate of mice. The results showed that in mice with unilateral injection of TDP-43M337V into the striatum, TBN improved motor deficits and cognitive impairment in the early stages of disease progression. In mice with bilateral injection of TDP-43M337V into the striatum, TBN not only improved motor function but also prolonged survival rate. Moreover, we show that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3β and AMPK/PGC-1α/Nrf2 signaling pathways. In summary, TBN is a promising agent for the treatment of ALS/FTLD.

Depression is the most frequent psychiatric disorder among the older adults, the purpose of this study is to explore the mediation effect of health promoting lifestyle on the relationship between Socioeconomic Status (SES) and depression, so as to provide practical reference for effectively preventing and alleviating depression of the older adults.A multi-stage random sampling method was conducted in Shanxi Province. A total 8526 older adults were included in the analysis. Regression analysis was used to explore the relationship between the socioeconomic status, health promoting lifestyle and depression, and the mediation effect test process was used to verify the mediating mechanism of health promoting lifestyle on this relationship.62.1% of the older adults had depression symptoms in this study, and there were significant differences in depression scores among the older adults with gender, age, residence, marital status, endowment pattern, self-care ability, exercise frequency, physical examination frequency, daily diet rules(P0.05). The results of mediating effect analysis showed that health promoting lifestyle as mediation effect between social economic status and depression was established, and the mediating effect was accounted for (a*b/c) 63.1%.Given the cross-sectional study, it is not possible to make causal inferences.There were different degrees of depression in the older adults. The lower the SES is, the higher the risk of depression is. This result once again confirms the social causation theory. Combined with the theory of health risk behavior, the study further confirmed the applicability of lifestyle mechanism in the intermediate mechanism of the relationship between SES and depression in the elderly. Thus, in addition to providing material support and financial assistance, helping the elderly develop a healthy lifestyle is also effective measure to improve their depression.

Objective This study was aimed at exploring whether miR-30a enhanced sensitivity of non-small-cell lung cancer (NSCLC) cells against neoadjuvant chemotherapy through an autophagy-dependent way. Methods We totally recruited 304 NSCLC patients who have underwent chemotherapy, as well as 185 NSCLC patients who did not receive chemotherapy. NSCLC cell lines (i.e. H1299 and H460) were also purchased, and they were transfected by miR-30a mimic/inhibitor. Furthermore, cisplatin (DDP)/pemetrexed (PEM) resistance of NSCLC cells was assessed utilizing MTT assay, and autophagic proteins isolated from NSCLC tissues and cells were quantitated by western blotting. Results Lowly expressed miR-30a was reflective of lymph node metastasis, advanced TNM stage and poor 5-year survival among NSCLC patients treated by neoadjuvant chemotherapy (i.e. combined treatment of DDP and PEM) (P Conclusions Intentionally elevating miR-30a expression was conducive to improving NSCLC prognosis after neoadjuvant chemotherapy, for its depressing drug-caused autophagy and resistance.

Melanoma differentiation-associated gene 5 (MDA5) is a key cytoplasmic dsRNA sensor. Upon binding to invading viral RNA, activated MDA5 is recruited to mitochondria and interacts with mitochondrial antiviral signaling gene (MAVS) to initiate innate antiviral immune responses. The elegant regulation of this process remains elusive. In this study, using the Chinese tree shrew (Tupaia belangeri chinensis), which is genetically close to primates, we identified the Tupaia oligoadenylate synthetases-like 1 (tOASL1) as a positive regulator of the Tupaia MDA5 (tMDA5) and Tupaia MAVS (tMAVS)–mediated IFN signaling. Overexpression of tOASL1 significantly potentiated the RNA virus-triggered induction of the type I IFNs and downstream antiviral genes. Conversely, knockdown of tOASL1 had an impaired antiviral immune response. Mechanistically, tOASL1 was associated with mitochondria and directly interacted with tMDA5 and tMAVS. Upon RNA virus infection, tOASL1 enhanced the interaction between tMDA5 and tMAVS via its OAS and UBL domains. Our results revealed a novel mechanism by which tOASL1 contributes to host antiviral responses via enhancing tMDA5 and tMAVS interaction.

Host-microbiota interactions are vital for diverse pathophysiological events and may be targeted for innovative therapeutics. Nuclear receptors (NRs) are versatile host sensors of microbial signals that coordinate diverse environmental cues with local and remote adaptions. Harnessing NR-mediated sensory machinery could provide an alternative lynchpin for gut microbiota-oriented drug discovery strategy.

Accompanying with diabetes mellitus-induced osteoporosis (DM-OS), diabetic patients show poor peri-implant osteogenesis after implantation for dentition defect. Berberine (BBR), a candidate oral hypoglycemic agent, is a promising agent for treating DM-OS. In this study, BBR was applied on DM rats and high-glucose-cultured bone mesenchymal stem cells (BMSCs) to investigate its therapeutic mechanism on DM-OS, thus laying a theoretical basis for the future application of BBR in implant restoration. Phenotypes were assessed in the DM rats after 4 w of gavage with BBR. Furthermore, BMSCs were cultured with high glucose and BBR. Cell Counting Kit-8, 2',7'-dichlorofluorescin diacetate (H2 DCF-DA), quantitative real-time PCR (qRT-PCR), and western blot were performed to estimate the cell proliferation, oxidative stress, and osteogenic differentiation. Moreover, the DM rats treated with BBR and insulin receptor substrate-1 anti-sense oligonucleotide (IRS-1-ASO) underwent a 4-w implant-healing period and then micro computed tomography (Micro-CT) and histology were performed to verify the mechanism. Results showed that the 4-w administration of BBR markedly improved the glucose metabolism and bone metabolism in the DM rats. in vitro experiments revealed that BBR alleviated high-glucose-inhibited osteogenesis of the BMSCs by upregulating reactive oxygen species (ROS)-mediated IRS-1 signaling. Besides, injection of IRS-1-ASO abolished the BBR promotion of implant osseointegration in the DM rats. In conclusion, targeting ROS-mediated IRS-1 signaling, BBR acted as an efficient agent to advance osseointegration in DM, which indicated that BBR use is a good strategy for future implants restoration in diabetic patients.

Gut microbial metabolism is intimately coupled with host health and disease. Aromatic amino acid (AAA) catabolism by the gut microbiome yields numerous metabolites that may regulate immune, metabolic, and neuronal responses at local and distant sites. Such a chemical dialog between host cells and the gut microbiome is shaped by environmental cues, and may become dysregulated in gastrointestinal and systems diseases. Increasing knowledge of the bacterial pathway and signaling basis may shed additional light on metabolic host-microbiome crosstalk that remains untapped for drug discovery. Here, we update our understanding of microbial AAA metabolism and its impacts on host physiology and disease. We also consider open questions related to therapeutically mining these signaling metabolites and how recent concepts and tools may drive this area forward.

Hepatitis C virus (HCV) infection is the cause of severe liver disease in many people. The restricted species tropism of HCV hinders the research and development of drugs and vaccines. The Chinese tree shrew (Tupaia belangeri chinensis) is a close relative of primates and can be infected by HCV, but the underlying mechanisms are unknown. In this study, we have characterized the functions of tree shrew MAVS (tMAVS) in response to HCV infection and defined the capacity of HCV replication. HCV was shown to be colocalized with tMAVS in primary tree shrew hepatocytes and cleaved tMAVS at site Cys508 via its NS3/4A protease, with a modulating effect by site Glu506 of tMAVS. The tMAVS cleavage by HCV NS3/4A impaired the IRF3-mediated induction of IFN-β but maintained the activated NF-κB signaling in the tree shrew primary cells. Activation of the tMAVS-dependent NF-κB signaling inversely inhibited HCV replication and might limit the establishment of persistent infection. Overall, our study has revealed an elegant example of the balance between the host defenses and HCV infection via the MAVS-mediated antiviral signaling and has provided an insight into the mechanisms underpinning HCV infection in the Chinese tree shrew.

Lung cancer (LC), is the most common and lethal cancer worldwide. It affects both sexes and in its early stages is clinically silent, until it reaches a more advanced stage, when it becomes highly incurable. In order to improve the high mortality associated with LC there has been an urgent need for screening high risk patients by low dose CT scan (LDCT) for the early detection of small resectable malignant tumors. However, while highly sensitive to detect small lung nodules, LDCT is non-specific, resulting in a compelling need for a complementary diagnostic tool. For example, a non-invasive blood test or liquid biopsy, (LB), could prove quite useful to confirm a diagnosis of malignancy prior to definitive therapy. With the advent of LB becoming increasingly clinically accepted in the diagnosis and management of LC, there has been an explosion of publications highlighting new technologies for the isolation of and detection of circulating tumor cells (CTCs) and cell free tumor DNA (cfDNA). The enormous potential for LB to play an important role in the diagnosis and management of LC to obtain valuable diagnostic information via an approach that may yield equivalent information to a surgical biopsy, regarding the presence of cancer and its molecular landscape is described.

The clinical use of FDA-approved bone morphogenetic proteins (BMPs) are impeded by high costs, super-high dosage requirement, short half-life, and other undesirable side effects. Therefore, designing a biomaterial that can promote new bone formation without using exogenous BMPs is highly desirable in clinical applications. In the present work, a new kind of nanofibrous scaffold composed of gelatin and 45S5 bioglass (GF/45S5 BG) was prepared through thermally induced phase separation method together with the particle leach technique (TIPS&P). In addition to the significantly higher mechanical strength, the composite scaffolds (GF/45S5 BG) significantly increased osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro compared with the neat scaffold (GF) without adding other biological agents, for example, BMPs or hormones. Most importantly, our in vivo studies also indicated that GF/45S5 BG scaffolds could directly promote ectopic bone regeneration in SD rats without exogenous BMP2. In summary, both in vitro and in vivo results indicated that the novel 45S5 bioglass functionalized GF nanofibrous scaffold is a promising alternative for bone tissue engineering.

The presence of tumor infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) in tumor tissues are of great prognostic significance in several types of human cancer. The present study investigated the density of TILs and TLSs in gastric cancer (GC) tissues and their association with pathological parameters. Moreover, the clinical significance of follicular CD8+ cytotoxic T cells present within the germinal centers of the tumor-associated TLSs was investigated. Immunohistochemistry and H&E staining were used to examine the infiltration and distribution patterns of TILs, TLSs and germinal center (gc) CD8+ TILs in tumor tissues obtained from 63 patients with GC. The number of TILs, TLSs, combination of TILs and TLSs (TILs-TLSs) and gcCD8+ TILs were used to define tumoral immune parameters, and the prognostic value of these parameters was assessed. The analysis revealed that patients with GC with increased levels of TILs, TLSs, or gcCD8+ TILs exhibited improved overall survival. In addition, gcCD8+ TILs levels were significantly associated with patient age, histological grade and pTN stage. Increased levels of TILs-TLSs were positively associated with nerve invasion, tumor thrombus, nodal metastasis and histological grade. Multivariate Cox regression analysis revealed that TILs-TLSs and gcCD8+ TILs were independent prognostic factors. The data obtained in the present study demonstrated that high levels of tumoral immune parameters are important independent prognostic predictors for human GC. The results also suggested a possible role of gcCD8+ TILs in tumor immune surveillance.

Background Gallbladder torsion is a rare acute abdominal condition that requires emergency surgery. It occurs more commonly in elderly people and in women in the adult population. Diagnosis is a challenge as non-specific symptoms and signs have been reported on ultrasonography, computed tomography and magnetic resonance imaging. Prompt cholecystectomy can decrease the mortality and morbidity of perforation due to gallbladder torsion. Case summary An 82-year-old woman with upper-right quadrant pain and associated nausea and vomiting was diagnosed with ectopic acute calculus cholecystitis. Magnetic resonance cholangiopancreatography (MRCP) showed a V-shaped distortion of the extrahepatic bile ducts and a particularly extended twisted cystic duct, which indicated the presence of gallbladder torsion. Emergency laparoscopic cholecystectomy confirmed the diagnosis and the patient recovered without incident. Conclusion Gallbladder torsion can be diagnosed pre-operatively by MRCP. The specific signs are a V-shaped distortion of the extrahepatic bile ducts and a particularly extended twisted cystic duct which can be called twisting signs.

Purpose Hepatocellular carcinoma (HCC) is one of the most malignant cancers around the world. HCC is less sensitive to conventional cytotoxic agents and easily develops into systemic metastases. However, the molecular mechanisms of the metastasis of HCC are poorly understood and need elucidation. Materials and methods Transwell system of the chemotherapy-challenged and unchallenged HepG2 cells was established. Adhesion assay and scratch-wound assay were utilized to analyze the adhesion and migration of HepG2 cells. iPLA2 and LOX-5 expression were analyzed by Western blot. LTB4 level was analyzed by ELISA. Results Chemotherapeutics are traditionally regarded as a way of killing tumor cells; on the other hand, we proved that the chemotherapeutics-induced tumor cell apoptosis can also change the tumor microenvironment by activating the LOX pathway and subsequently release inflammatory factors such as LTB4 which can stimulate the adhesion and migration of the small number of surviving cells. Berberine can reverse the adhesion and migration of HepG2 cells by inhibiting the expression of LOX-5 and reducing the LTB4 production in the tumor microenvironment. Conclusion Our study sheds light on a novel anti-metastasis strategy that the combination of Berberine and chemotherapy may prevent the chemotherapy-induced metastasis in HCC.

Background: Lung cancer is the leading cause of cancer-related deaths worldwide, imposing an enormous economic burden on society. Several studies have identified a link between the genetic polymorp...

Background Despite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years. Methods Using multiple human ovarian cancer cell lines, a transwell co-culture system of the carboplatin or VP-16-challenged feeder and receptor cells was established to demonstrate the chemotherapy-exacerbated migration. The migration and cancer stem cell (CSC)-like characteristics were determined by wound healing, transwell migration, flow cytometry and sphere formation. mRNA and protein expression were identified by qPCR and western blot. Bioinformatics analysis was used to investigate the differentially expressed genes. GLI1 expression in tissue samples was analysed by immunohistochemistry. Results Chemotherapy was found to not only kill tumour cells, but also trigger the induction of CSC-like traits and the migration of ovarian cancer cells. EMT markers Vimentin and Snail in receptor cells were upregulated in the microenvironment of chemotherapy-challenged feeder cells. The transcription factor GLI1 was upregulated by chemotherapy in both clinical samples and cell lines. Follow-up functional experiments illustrated that inhibiting GLI1 reversed the chemotherapy-exacerbated CSC-like traits, including CD44 and CD133, as well as prevented the migration of ovarian cancer cells. Conclusions Targeting GLI1 may improve clinical benefits in the chemotherapy-exacerbated metastasis in ovarian cancer treatment.

Background The Goto-Kakizaki (GK) rat, developed from repeated inbreeding of glucose-intolerant Wistar rats, has been widely used to explore the development of spontaneous type-2 diabetes mellitus (T2DM). However, the gastric microbiota of GK and Wistar rats are still unclear. This study aimed to understand the gastric microbiota characteristics of GK rats by comparing it with non-diabetic Wistar rats. Materials and Methods Male Wistar rats and GK rats were housed in specific pathogen-free (SPF) environment for 12 weeks with free access to sterilized food and water. Body weight and random blood glucose (BG) levels were determined. At the end of the experiment, the gastric contents of the rats were collected for the identification of gastric microbiota using 16S rRNA gene sequencing. Results The richness of gastric microbiota in GK rats was similar to that of Wistar rats (P > 0.05). The results of Shannon, Simpson, beta diversity indices, and ANOSIM analysis showed that alpha and beta diversity of gastric microbiota in GK rats were significantly lower than that of Wistar rats (P < 0.01). Firmicutes (96.0%), Proteobacteria (1.9%) and Cyanobacteria (0.8%) were the dominant gastric microbiota in GK rats accounting for 72.9%, 14.7% and 10.9%, respectively. Linear discriminant analysis effect size (LEfSe) revealed that phylum Firmicutes and four genera (Anaerovibrio, Collinsella, Prevotellaceae_UCG_001, and Lactobacillus) were significantly abundant in the stomachs of GK rats. In contrast, seven genera (unidentified_Chloroplast, Porphyromonas, Neisseria, Rubrobacter, Veillonella, Lachnospiraceae_UCG_005, and unidentified_Erysipelotrichaceae) were significantly abundant in the stomachs of Wistar rats. Blood glucose was positively correlated with Anaerobibrio and Lactobacillus, and negatively correlated with four genera (Porphyromonas, Rubrobacter, Lachnospiraceae_UCG_005, and unidentified_Erysipelotrichaceae). In addition, chemoheterotrophy and fermentation were the most important functions of gastric microbiota. Conclusion The gastric microbiota of GK rats with spontaneous T2DM showed the typical characteristics of low diversity and significant enrichment of Firmicutes phylum and four genera (Anaerovibrio, Collinsella, Prevotellaceae_UCG_001, and Lactobacillus) compared with gastric microbiota of Wistar rats.

Acute myeloid leukemia (AML) is a highly aggressive disease that causes high mortality. Long noncoding RNA (lncRNA) have studied in recent years that could be a potential biomarker and therapeutic target. Therefore, it is urgently necessary to explore the novel lncRNAs in AML. Microarray analysis was performed to determine the differentially expressed lncRNAs between mononuclear cells of AML and normal samples. The biological function of lncRNA on cell proliferation and migration was measured in vitro. The predicted downstream target of lncRNA was validated by dual-luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, and rescue experiments. The tumor formation and metastasis study were conducted in vivo. The expression of lncRNA in clinical samples was determined by a quantitative reverse transcription-polymerase chain reaction. LINC00449 was one of the most differentially expressed lncRNA which is mainly located in the cytoplasm. We found that overexpression of LINC00449 could inhibit the cell proliferation and invasion of AML cells in vitro and in vivo. Besides, miR-150 was identified as the downstream target gene that was negatively regulated by LINC00449 and FOXD3 was targeted by miR-150. The results were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, rescue experiments, and in vivo assays. Patients with AML with high expression of LINC0049 may characterize a favorable survival. All the above-mentioned findings indicated that the LINC00449/miR-150/FOXD3 signaling pathway might represent a novel prognostic biomarker or therapeutic target for the treatment of AML.

Objectives: We aimed to observe the relationship between serum 25-hydroxyvitamin D (25-[OH] D) and different cognitive domains, and to evaluate the predictive value of 25-(OH) D level for cognitive impairment in patients with white matter lesions (WML). Methods: The differences in clinical data including 25-(OH) D were analyzed between cognitive normality (n = 87) and impairment (n = 139) groups, and variant cognitive domains were analyzed between groups of different levels of serum 25-(OH) D. Risk factors for cognitive impairments were evaluated with multivariate logistic regression analysis; a receiver operating characteristic (ROC) curve of 25-(OH) D levels was used to examine the association between 25-(OH) D and WML with cognitive dysfunction. Results: As the severity of WML increased, the proportion of patients with a low level of serum 25-(OH) D increased (p < 0.05). The total MoCA (Montreal Cognitive Assessment) scores and all domain scores except naming were significantly lower in patients with low levels of serum 25-(OH) D than in patients with high levels of serum 25-(OH) D (p < 0.05). Multivariate logistic regression analyses showed that serum 25-(OH) D levels were independently correlated with cognitive impairment. In the ROC analysis, the optimal cut-off value for 25-(OH) D was 17.53 with 76% sensitivity and 70% specificity (AUC =0.751, 95% CI: 0.674–0.819, p < 0.05). Conclusion: We observed that vitamin D deficiency is associated with multiple areas of cognitive impairment and that it is an independent risk factor for cognitive impairment in WML.

Background: Ginsenoside Rb1 (Rb1), one of the most abundant protopanaxadiol-type ginsenosides, exerts excellent neuroprotective effects even though it has low intracephalic exposure. Purpose: The present study aimed to elucidate the apparent contradiction between the pharmacokinetics and pharmacodynamics of Rb1 by studying the mechanisms underlying neuroprotective effects of Rb1 based on regulation of microflora. Methods: A pseudo germ-free (PGF) rat model was established, and neuroprotective effects of Rb1 were compared between conventional and PGF rats. The relative abundances of common probiotics were quantified to reveal the authentic probiotics that dominate in the neuroprotection of Rb1. The expressions of the gamma-aminobutyric acid (GABA) receptors, including GABAA receptors (α2, β2, and γ2) and GABAB receptors (1b and 2), in the normal, ischemia/reperfusion (I/R), and I/R+Rb1 rat hippocampus and striatum were assessed to reveal the neuroprotective mechanism of Rb1. Results: The results showed that microbiota plays a key role in neuroprotection of Rb1. The relative abundance of Lactobacillus helveticus (Lac.H) increased 15.26 fold after pretreatment with Rb1. I/R surgery induced effects on infarct size, neurological deficit score, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were prevented by colonizing the rat gastrointestinal tract with Lac.H (1 × 109 CFU) by gavage 15 d before I/R surgery. Both Rb1 and Lac.H upregulated expression of GABA receptors in I/R rats. Coadministration of a GABAA receptor antagonist significantly attenuated neuroprotective effects of Rb1 and Lac.H. Conclusion: In sum, Rb1 exerts neuroprotective effects by regulating Lac.H and GABA receptors rather than through direct distribution to the target sites. Keywords: Gamma-aminobutyric acid receptor, Ginsenoside Rb1, Lactobacillus helveticus, Microbiota, Neuroprotective effects

Single-cell RNA-sequencing (scRNA-seq) data provide opportunities to reveal new insights into many biological problems such as elucidating cell types. An effective approach to elucidate cell types in complex tissues is to partition the cells into several separated subgroups via clustering techniques, where the cells in a specific cluster belong to the same cell type based on gene expression patterns. In this work, we present a novel multiple kernel clustering framework for scRNA-seq data clustering via locality preserving kernel alignment. Specifically, we first generate a series of similarity kernel matrices by using different kernel functions. Then we transfer the clustering task to a multiple kernel k-means problem with the kernels aligned in a local manner, i.e., the similarity of a sample to its k-nearest neighbours are aligned with the ideal similarity matrix. In our method, the clustering process focuses on closer sample pairs that shall stay together, and avoids involving unreliable similarity evaluation for farther sample pairs. In addition, we construct a local Laplacian matrix for each sample to constrain that closer samples should be allocated similar labels. In such a manner, the local structure of the data can be well preserved and utilized to produce better alignment for clustering. An alternate updating algorithm with theoretical analysis is developed to solve the proposed problem. We evaluate the performance of the proposed method on various real scRNA-seq data, and the results show that our method can obtain superior results when compared with other state-of-the-art approaches.

Objective To determine the prognostic impact of pathologic lymph node (LN) status and investigate risk factors of recurrence in esophageal squamous cell carcinoma (ESCC) patients with pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT). Summary background data There are no large-scale prospective study data regarding ypN status and recurrence after pCR in ESCC patients receiving NCRT. Methods The NEOCRTEC5010 trial was a prospective multicenter trial that compared the survival and safety of NCRT plus surgery (S) with S in patients with locally advanced ESCC. The relationships between survival and cN, pN, and ypN status were assessed. Potential prognostic factors in patients with ypN+ and pCR were identified. Results A total of 389 ESCC patients (NCRT: 182; S: 207) were included. Patients with pN+ in the S group and ypN+ in the NCRT group had decreased overall survival (OS) and disease-free survival (DFS) compared with pN0 and ypN0 patients, respectively. Partial response at the primary site [hazard ratio (HR), 2.09] and stable disease in the LNs (HR, 3.26) were independent risk factors for lower DFS, but not OS. For patients with pCR, the recurrence rate was 13.9%. Patients with distant LN metastasis had a median OS and DFS of 16.1 months and 14.4 months, respectively. Failure to achieve the median total dose of chemotherapy was a significant risk factor of recurrence and metastasis after pCR (HR, 44.27). Conclusions Persistent pathologic LN metastasis after NCRT is a strong poor prognostic factor in ESCC. Additionally, pCR does not guarantee a cure; patients with pCR should undergo an active strategy of surveillance and adjuvant therapy.

Background IFIT2 (interferon-induced proteins with tetratricopeptide repeats 2), also known as ISG54, is an important interferon-stimulated gene family protein, which has been confirmed to play a crucial role in anti-cancer as well as anti-virus process. In the present study, we aimed to investigate the IFIT2 expression in human non-small-cell cancer (NSCLC) tissues and its clinical implications. Methods The immunohistochemistry assay was used to identify the clinical significance and prognostic value of IFIT2 expression in NSCLC tissues. The depletion of IFIT2 was achieved using RNAi approach to assess the role of IFIT2 in the regulation of biological behaviors in human lung cancer cell lines. Results Decreased IFIT2 expression was found in human NSCLC tissues (both in lung adenocarcinoma and lung squamous cell carcinoma) in contrast to the adjacent normal tissues (both P

Health promoting lifestyle (HPL) may be a facilitator for empty nesters' active aging against depression. Social support (SS) may improve their HPL. This study aimed to examine moderating effect of SS and its three sources of SS on relationship between depression and HPL among empty nesters. The compensating role of socioeconomic status (SES) for lack of SS was examined, too.A cross-sectional survey of empty nesters (n = 1593) was conducted in six districts of Taiyuan, China, using a stratified random cluster sampling method. Hierarchical multiple linear regression analyses were performed to assess moderation models by SS and its three sources.The findings indicated that low depression (p 0.001) and sufficient perceived SS (p 0.001) could directly predict better HPL among empty nesters. The effect of SS on HPL declined with the raise of educational level (p 0.001). Family support (β = 0.083, p 0.001), friends support (β = 0.085, p 0.001) and others support (β = 0.098, p 0.001) expressed significant negative buffer effects on depression and HPL individually.There was a cross-sectional study that limited the moderating effect of SS on depression and HPL just for empty nesters in Taiyuan, China. The results cannot explain the causal relationships among the study variables.SS might be a protective factor of empty nesters' health in China. Three sources of SS all showed moderating effect on the relationship between depression and HPL among empty nesters, and should be integrated to achieve maximum utility. Friends support/ others support could play complement role for lack of family support. SES expressed partial compensatory for lack of SS.

Background As China’s aging trend intensifies and the proportion of empty nests increases, the health-related quality of life of the elderly is the focus of social attention. Previous studies focused on the quality of life of the elderly, rather than empty nesters, and lacked the discussion of the mechanism of influencing factors. Thus, this study aimed to explore the influencing factors of the quality of life (QOL) and interaction mechanisms among empty nesters in Shanxi Province, China, so as to provide practical reference for improving the QOL of empty nesters. Methods A total of 4901 empty nesters in Shanxi Province, China, were selected using multi-stage random cluster sampling method in this cross-sectional study. The quality of life was assessed with the Short Form 36 Health Survey (SF-36). Multiple linear regression analysis (stepwise) was performed to examine the factor associated with QOL. Structural equation model (SEM) approach was conducted to test the direct and indirect association between QOL influencing factors with QOL. Results The average QOL score of empty nesters was 63.34 (SD = 17.23). The multiple linear regression revealed that gender, age, education, monthly income, drinking status, exercise frequency, physical examination frequency, attention to daily nutritional health, relationship with a spouse and relationship with children were significant predictors of the empty nester’s QOL (P R2 = 0.128). SEM showed that behavioral lifestyle had a direct effect on QOL (β = 0.446, P β = 0.288, P β = 0.115, P Conclusion Behavioral lifestyle was the strongest influencing factor in the quality of life among empty nesters, followed by socio-economic status and family relationships. Thus, maintaining a healthy behavioral lifestyle was important to improve the QOL of the empty nesters. Our findings provide a concrete and strong reference for the formulation of targeted intervention strategies.

The positive roles of earthworms on soil functionality has been extensively documented. The capacity of the earthworm gut microbiota on decomposition and nutrient cycling under long-term fertilization in field conditions has rarely been studied. Here, we report the structural, taxonomic, and functional responses of Eisenia foetida and Pheretima guillelmi gut microbiota to different fertilization regimes and durations using 16S rRNA gene-based Illumina sequencing and high-throughput quantitative PCR techniques. Our results revealed that the core gut microbiota, especially the fermentative bacteria were mainly sourced from the soil, but strongly stimulated with species-specificity, potential benefits for the host and soil health. The functional compositions of gut microbiota were altered by fertilization with fertilization duration being more influential than fertilization regimes. Moreover, the combination of organic and inorganic fertilization with the longer duration resulted in a higher richness and connectivity in the gut microbiota, and also their functional potential related to carbon (C), nitrogen, and phosphorus cycling, particularly the labile C decomposition, denitrification, and phosphate mobilization. We also found that long-term inorganic fertilization increased the abundance of pathogenic bacteria in the P. guillelmi gut. This study demonstrates that understanding earthworm gut microbiota can provide insights into how agricultural practices can potentially alter soil ecosystem functions through the interactions between soil and earthworm gut microbiotas.

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal malignancies of the digestive system, and shows an especially high incidence in some regions of China. Octamer transcription factors are a family of transcription factors whose DNA-binding domain is a POU domain. OCT transcription factors (OCT-TFs) mediate maintenance of the pluripotency of embryonic stem cells. We measured expression of OCT-TFs in ESCC clinical specimens. Among the OCTs tested, OCT1 showed the highest expression in ESCC tissues. Using molecular docking, we discovered a small-molecule inhibitor, which we named "novel inhibitor of OCT1" (NIO-1), for OCT1. Treatment with NIO-1 inhibited recruitment of OCT1 to the promoter region of its downstream genes and, consequently, repressed OCT1 activation. Treatment with NIO-1 enhanced the susceptibility of ESCC cells to chemotherapeutic agents. Therefore, OCT1 may be a valuable target for ESCC treatment, and NIO-1 could be a promising therapeutic agent.

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI &lt, 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p &lt, 0.05), and increased the expression of E-cadherin (p &lt, 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p &lt, 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health threat since December 2019, and there is still no highly effective drug to control the pandemic. To facilitate drug target identification for drug development, studies on molecular mechanisms, such as SARS-CoV-2 protein interactions, are urgently needed. In this study, we focused on Nsp2, a non-structural protein with largely unknown function and mechanism. The interactome of Nsp2 was revealed through the combination of affinity purification mass spectrometry (AP-MS) and stable isotope labeling by amino acids in cell culture (SILAC), and 84 proteins of high-confidence were identified. Gene ontology analysis demonstrated that Nsp2-interacting proteins are involved in several biological processes such as endosome transport and translation. Network analysis generated two clusters, including ribosome assembly and vesicular transport. Bio-layer interferometry (BLI) assay confirmed the bindings between Nsp2- and 4-interacting proteins, i.e. STAU2 (Staufen2), HNRNPLL, ATP6V1B2, and RAP1GDS1 (SmgGDS), which were randomly selected from the list of 84 proteins. Our findings provide insights into the Nsp2-host interplay and indicate that Nsp2 may play important roles in SARS-CoV-2 infection and serve as a potential drug target for anti-SARS-CoV-2 drug development.

Droplet size distribution of dispersed oil in deep-water is critical to the transport and biodegradation of spilled oil in deep-sea. Few studies have focused on the effects of pressure on chemically dispersed oil through experiments. This study thus simulated how the crude oil homogenously pre-dispersed by Corexit 9500A using baffled flasks would behave after being exposed to deep-water conditions. Key factors included dispersant-to-oil ratio (DOR), mixing energy (energy dissipation rate and Kolmogorov microscale), and pressure (up to 150 bar). The variations of pressure were demonstrated to have insignificant effects on the size distribution of pre-dispersed oil. Both the average and medium droplet sizes were correlated negatively with DOR and mixing energy in an established model with a p-value ≤ 0.0011. The log-normal and log-logistic distributions provided a reasonable fit to simulate the droplet size distribution. The two parameters of log-logistic distribution were dependent on DOR and mixing energy with a p-value < 0.005. The results would be valuable to advance the understanding of the behaviours and trajectories of chemically dispersed oil under deep-water conditions. The research helped provide more scientific evidence to improve the understanding of dispersed oil behaviours under high pressure and support deep-sea oil spill research and potential extension of the existing results from shallow water to deep water conditions., marine oil spill; chemically dispersed oil; droplet size distribution; deep-water; high pressure; mixing energy

We, at first, fully characterized the complete chloroplast genome of the woody bamboo Acidosasa gigantea using genome skimming and focused on comparative analyses among Acidosasa and Indosasa. This...

Intrathyroidal thymic carcinoma is a malignant epithelial tumor of the thyroid gland with thymic epithelial differentiation; it is the malignant counterpart of ectopic thymoma of the thyroid gland and histologically resembles thymic carcinoma. Given its favorable prognostic course, preoperative cytological diagnosis is important to distinguish this neoplasm from other more aggressive thyroid neoplasms that can have similar or overlapping cytomorphological features. However, there is little information about the cytology of this disease available in the literature, even in the latest fourth edition of World Health Organization classification of tumors of endocrine organs. Here, we report a case of intrathyroidal thymic carcinoma exhibiting neuroendocrine differentiation in a 33-year-old woman and present a review of the literature.

The prognostic significance and clinical implications of resident CD103+CD8+T cells in human colorectal cancer tissues still remains largely unexplored. In our present study, we aimed to characterize the resident CD8+T cells in human colorectal cancer tissues by using double staining of CD103 and CD8, and further evaluated the prognostic significance of resident CD8+T cells in colorectal cancer. We found that the OS rate of the colorectal cancer patients with higher infiltration of CD8+T cells, or with higher numbers of resident CD103+CD8+T cells, or with higher ratio of CD103+CD8+T cells over total CD8+T cells in cancer tissues was significantly better than that of the patients with lower infiltration of CD8+T cells, or with lower numbers of resident CD103+CD8+T cells, or with higher ratio of CD103+CD8+T cells over total CD8+T cells in cancer tissues, respectively. Moreover, higher infiltration of CD8+T cells in colorectal cancer tissues was significantly and inversely correlated with advanced TNM stage. Higher numbers of resident CD103+CD8+T cells in colorectal cancer tissues were significantly and inversely correlated with distant metastasis status. Higher ratio of CD103+CD8+T cells over total CD8+T cells in colorectal cancer tissues was significantly and inversely correlated with age status. The COX model analysis demonstrated that higher infiltration of CD8+T cells, higher numbers of resident CD103+CD8+T cells, or higher ratio of CD103+CD8+T cells over total CD8+T cells in colorectal cancer tissues, could serve as independent prognostic predictors for colorectal cancer patients. Taken together, our present study demonstrated the density of tumor infiltrating CD8+T cells or the numbers of resident CD103+CD8+T cells in colorectal tissues could be used as an important prognostic predictor for this malignancy.

Loss of biodiversity is a major threat to the ecosystem processes upon which society depends. Natural ecosystems differ in their resistance to invasion by alien species, and this resistance can depend on the diversity in the system. Little is known, however, about the barriers that microbial diversity provides against microbial invasion. The increasing prevalence of antibiotic-resistant bacteria is a serious threat to public health in the 21st century. We explored the consequences of the reduction in soil microbial diversity for the dissemination of antibiotic resistance. The relationship between this diversity and the invasion of antibiotic resistance was investigated using a dilution-to-extinction approach coupled with high-capacity quantitative PCR. Microbial diversity was negatively correlated with the abundance of antibiotic-resistance genes, and this correlation was maintained after accounting for other potential drivers such as incubation time and microbial abundance. Our results demonstrate that high microbial diversity can act as a biological barrier resist the spread of antibiotic resistance. These results fill a critical gap in our understanding of the role of soil microbial diversity in the health of ecosystems.

Circular RNA (circRNA) plays an important role in the development of human malignant tumors. Recently, an increasing number of circRNAs have been identified and investigated in various tumors. However, the expression pattern and biological function of circRNAs in colorectal cancer (CRC) still remain largely unexplored. In the present study, hsa_circ_0009361 was significantly down-regulated in CRC tissues and cells. Low expression level of hsa_circ_0009361 promoted the proliferation, epithelial–mesenchymal transition (EMT), migration, and invasion of CRC cells. Hsa_circ_0009361 was identified as the sponge of miR-582 by fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), and luciferase reporter assays. Overexpression of hsa_circ_0009361 up-regulated the expression of adenomatous polyposis coli 2 (APC2) and inhibited the activity of the Wnt/β-catenin pathway by competitively combining with miR-582. Exogenous miR-582 and APC2 interventions could reverse the multiple biological functions mediated by hsa_circ_0009361 in CRC cells. In vivo experiments also confirmed that hsa_circ_0009361 inhibited the growth and metastasis of CRC. Hsa_circ_0009361 acted as a tumor suppressive sponge of miR-582, which could up-regulate the expression of APC2, inhibit the Wnt/β-catenin signaling, and suppress the growth and metastasis of CRC. Collectively, the hsa_circ_0009361/miR-582/APC2 network could be employed as a potential therapeutic target for CRC patients.

Background: Classification of the pulmonary neuroendocrine tumor (pNET) categories is a step-wise process identified by the presence of necrosis and number of mitoses per 2 mm2. In neuroendocrine tumor pathology, Ki-67 was first described as a prognostic factor in the pancreas and incorporated into the grading system of digestive tract neuroendocrine neoplasms in the 2010 WHO classification. However, the significance of Ki-67 in pNETs was still a controversial issue. This study was to investigate the potentially diagnostic value of Ki-67 in pNETs. Methods: We retrieved 159 surgical specimens of pNETs, including 35 typical carcinoids (TCs), 2 atypical carcinoid (ACs), 28 large-cell neuroendocrine carcinomas (LCNECs), 94 small-cell lung cancers (SCLCs). Manual conventional method (MCM) and computer-assisted image analysis method (CIAM) were used to calculate the Ki-67 proliferative index. In CIAM, 6 equivalent fields (500 × 500 μm) at 10× magnification were manually annotated for digital image analysis. Results: The Ki-67 index among the 4 groups with ranges of 0.38% to 12.66% for TC, 4.34% to 29.48% for AC, 30.67% to 93.74% for LCNEC, and 40.71% to 96.87% for SCLC. The cutoff value of Ki-67 index to distinguish low grade with high grade was 30.07%. For the univariate survival analyses in pNETs, both the overall survival and progression-free survival correlated with Ki-67 index. In addition, the Ki-67 index performed by CIAM was proved to be of great positive correlation with MCM. Conclusions: Ki-67 index counted by CIAM is a reliable method and can be a useful adjunct to classify the low- and high-grade NETs. Key words: Antigen Ki-67; Computer-assisted numerical analysis; Neuroendocrine tumor; Prognostic factor

Background It has been well established that circular RNAs (circRNAs) play an important regulatory role during tumor progression. Recent studies have indicated that even though circRNAs generally regulate gene expression through miRNA sponges, they may encode small peptides in tumor pathogenesis. However, it remains largely unexplored whether circRNAs are involved in the tumorigenesis of colon cancer (CC). Methods The expression profiles of circRNAs in CC tissues were assessed by circRNA microarray. Quantitative real-time PCR, RNase R digestion assay and tissue microarray were used to confirm the existence and expression pattern of circPPP1R12A. The subcellular distribution of circPPP1R12A was analyzed by nuclear mass separation assay and fluorescence in situ hybridization (FISH). SDS-PAGE and LC/MS were employed to evaluate the protein-coding ability of circPPP1R12A. CC cells were stably transfected with lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPPP1R12A and its encoded protein circPPP1R12A-73aa. RNA-sequencing and Western blotting analysis were furthered employed to identify the critical signaling pathway regulated by circPPP1R12A-73aa. Results We firstly screened the expression profiles of human circRNAs in CC tissues and found that the expression of hsa_circ_0000423 (termed as circPPP1R12A) was significantly increased in CC tissues. We also found that circPPP1R12A was mostly localized in the cytoplasm of CC cells. Kaplan–Meier analysis showed that patients with higher levels of circPPP1R12A had a significantly shorter overall survival. By gain- and loss-of-function approaches, the results suggested that circPPP1R12A played a critical role in proliferation, migration and invasion of CC cells. Furthermore, we showed that circPPP1R12A carried an open reading frame (ORF), which encoded a functional protein (termed as circPPP1R12A-73aa). Next, we found that PPP1R12A-C, not circPPP1R12A, promoted the proliferation, migration and invasion abilities of CC in vitro and in vivo. Finally, we identified that circPPP1R12A-73aa promoted the growth and metastasis of CC via activating Hippo-YAP signaling pathway. In addition, the YAP specific inhibitor Peptide 17 dramatically alleviated the promotive effect of circPPP1R12A-73aa on CC cells. Conclusions In the present study, we illustrated the coding-potential of circRNA circPPP1R12A in the progression of CC. Moreover, we identified that circPPP1R12A-73aa promoted the tumor pathogenesis and metastasis of CC via activating Hippo-YAP signaling pathway. Our findings might provide valuable insights into the development of novel potential therapeutic targets for CC.

Background In China, aging has become a serious social problem, and the number of empty-nest elderly is on the rise. The aim of this study is to clarify the prevalence of depressive symptoms among empty-nest elderly in Shanxi province and evaluate the effects of sociodemographic factors and health-promoting lifestyles so as to provide a scientific reference for preventing and intervening their depression. Methods A cross-sectional study, which used a multi-stage random cluster sampling way, was conducted among 4901 empty-nest elderly in Shanxi. An independent t-test and a chi square test were used to compare the sociodemographic factors, depression scores, and health-promoting lifestyle scores of the empty-nest elderly. Multinomial logistic regression was used to analyze the potential influencing factors for depression. Results The prevalence of depressive symptoms in the population was 64.2%. Among all participants 1,776 (36.2%) had mild depression, 1,236 (25.2%) had moderate depression, and 135 (2.8%) had severe depression. The health-promoting lifestyle of the empty nesters in this study was at the medium level (2.51 ± 0.47). Gender, education level, old-age provision model, exercise frequency, chronic disease, relationships with children, self-care ability, and health-promoting lifestyles were found to be influencing factors of depression and all variables had different effects on different degrees of depression. Limitations This was a cross-sectional study, so the results cannot establish causal relationships among the study variables. Conclusions Depression was prevalent among the empty-nest elderly in Shanxi. Maintaining good interpersonal relationships, developing extensive interests, and maintaining healthy lifestyles including good nutrition habits and regular exercises can reduce the incidence of depression among empty nesters.

Circular RNAs (circRNAs) were recently reported to be involved in the pathogenesis of Non-small cell lung cancer (NSCLC), however, the molecular mechanisms of circRNAs in cell proliferation, invasion and TKI drug resistance remain largely undetermined. Here, we identified hsa_circ_0004015 was upregulated in NSCLC tissues, and was associated with the poor overall survival rate of NSCLC patients. Knockdown of hsa_circ_0004015 significantly decreased cell viability, proliferation, and invasion, whereas overexpression exhibited opposed effects in vivo and in vitro. Furthermore, hsa_circ_0004015 could enhance the resistance of HCC827 to gefitinib. In mechanism, hsa_circ_0004015 acted as a sponge for miR-1183, and PDPK1 was revealed to be target gene of miR-1183. Subsequently, functional assays illustrated that the oncogenic effects of hsa_circ_0004015 was attributed to the regulation of miR-1183/PDPK1 axis. In conclusion, circ_0016760/miR-1183/PDPK1 signaling pathway might play vital roles in the tumorigenesis of NSCLC.

Background: Circular RNAs (circRNAs) are a new class of RNAs that play a significant role in regulating gene expression and biological function. However, the expression profile and function of circRNAs in gastric cancer (GC) remain mostly uncertain. In the present study, we researched the expression profile of circRNAs in human GC tissues and explored the role of circCACTIN (hsa_circ_0092303). Methods: Circular RNA microarray assays were performed to detect circular RNA expression profiles of GC and circCACTIN was identified for further investigation. Quantitative real-time PCR was used to detect the expression of circCACTIN, miR-331-3p and TGFBR1 in GC specimens and cell lines. CircCACTIN was stably silenced and overexpressed in GC cells, and cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), as well as tumorigenesis in nude mice were performed to assess the effect of circCACTIN on GC. Results: CircCACTIN expression was obviously up-regulated in GC tissues and cell lines. Knockdown of circCACTIN inhibited GC cells proliferation, migration, invasion and EMT. Enforced-expression of circCACTIN promoted GC cells migration, invasion and EMT, but had no effect on GC cells proliferation. Moreover, in vivo experiments, circCACTIN up-regulation promoted GC tumor growth and EMT, and circCACTIN down-regulation inhibited GC tumor growth and EMT. Binding interactions were detected between circCACTIN and miR-331-3p, and between miR-331-3p and TGFBR1 by Dual-luciferase reporter assays. Mechanistically, we demonstrated that circCACTIN promoted gastric cancer progression by sponging miRNA-331-3p and regulating TGFBR1 mRNA expression. Conclusion: The circCACTIN/miR-331-3p/TGFBR1 axis affected the proliferation, migration, invasion and EMT of GC through the mechanism of competing endogenous RNAs (ceRNA). Furthermore, our results identified circCACTIN as a novel oncogenic circRNA in GC.

Objectives This study aimed to investigate anxiety status and its relationship with body mass index (BMI) among empty nesters in China, so as to improve their quality of life and provide direction for further research. Methods A cross-sectional survey was conducted among 4901 empty nesters in Shanxi, China. Anxiety, weight, height, depression, socio-demographic variables, attention to daily nutritional health, social activities, and self-care ability were evaluated in the study. T-tests and chi-square tests were used to compare differences in categorical and continuous variables. Binary logistic regression was performed to explore the association between anxiety and BMI among male and female empty nesters. Results The results showed that 44.5% of empty nesters reported anxiety, of which, 43.2% were male participants and 45.9% were female participants. After adjusting for other variables, overweight empty nesters odds ratio (OR; 95% confidence interval [CI]) = 0.813 (0.692-0.954) were less likely to be anxious, compared with their normal-weight counterparts. Gender was a significant factor in the relationship, with the negative association between overweight and anxiety only found in female empty nesters OR (95%CI) = 0.718 (0.572-0.901). Income, education, complete self-care ability, and depression showed significant associations with anxiety. Conclusion The prevalence of anxiety was high in the study population. Gender is a significant factor in the relationship between anxiety and BMI among empty nesters. The results intend to inform the government and media that overweight is a protective factor for anxiety among female empty nesters, necessitating a move toward eliminating weight bias.

Metabolic disturbance is commonly observed in schizophrenia patients, and the metabolic impacts of atypical antipsychotics such as olanzapine (OLA) have received much attention. Drug naive schizophrenia patients display metabolic abnormality to varying degrees, but how this shapes the metabolic responses to chronic OLA exposure is unknown. Using high-fat diet (HFD, 8 weeks) induced obesity, here we explored the metabolic outcome of chronic OLA exposure in conditions of pre-existing metabolic disturbance. OLA treatment (2 mg/kg) for 4 weeks led to markedly reduced body weight and adiposity in obese mice, concomitant with reduced adipose inflammation and hepatic steatosis. No significant change was observed on insulin sensitivity or energy expenditure after OLA exposure. Mechanistically, OLA restored autophagic clearance in the subcutaneous adipose tissue of obese mice, in line with its potentiation of lysosomal function in adipocytes. The metabolic phenotypes induced by OLA were partially reversed by chemical suppression of autolysosome. Together, these data uncover distinct metabolic effects of OLA in obesity involving the regulation of adipose tissue autophagy, and suggest a complicated link between OLA therapy and metabolic disturbance in schizophrenia.

Phyllosphere contains various microorganisms that may harbor diverse antibiotic resistance genes (ARGs). However, we know little about the composition of antibiotic resistome and the factors influencing the diversity and abundance of ARGs in the phyllosphere. In this study, 16S rRNA gene amplicon sequencing and high-throughput quantitative PCR approaches were employed to investigate the effects of long-term (over 10 years) organic fertilization on the phyllosphere bacterial communities and antibiotic resistome. Proteobacteria, Bacteroidetes, Actinobacteria and Firmicutes dominated in the phyllosphere bacterial communities. Long-term application of sewage sludge and chicken manure altered the phyllosphere bacterial community composition, with a remarkable decrease in bacterial alpha-diversity. A total of 124 unique ARGs were detected in the phyllosphere. The application of sewage sludge and chicken manure significantly increased the abundance of ARGs, with a maximum 2638-fold enrichment. Variation partitioning analysis (VPA) together with network analysis indicated that the profile of ARGs is strongly correlated with bacterial community compositions. These results improve the knowledge about the diversity of plant-associated antibiotic resistome and factors influencing the profile of ARGs in the phyllosphere.

Single nucleotide polymorphisms (SNPs) in 3′UTR of key DNA repair enzyme genes are associated with inter‐individual differences of DNA repair capacity (DRC) and susceptibility to a variety of human malignancies such as lung cancer. In this study, seven candidate SNPs in 3′UTR of DRC‐related genes including ERCC1 (rs3212986, rs2336219, and rs735482), OGG1 (rs1052133), MLH3 (rs108621), CD3EAP (rs1007616), and PPP1R13L (rs6966) were analyzed in 300 lung cancer patients and controls from the northeast of China. Furthermore, we introduced ERCC1 (CDS+3′UTR) or CD3EAP (CDS) cDNA clone to transfect HEK293T and 16HBE cells. Cell viability between different genotypes of transfected cells exposed to BPDE was detected by CCK‐8 assay, while DNA damage was visualized using γH2AX immunofluorescence and the modified comet assay. We found that minor A‐allele of rs3212986 could reflect a linkage with increasing risk of NSCLC. Compared with CC genotype, AA genotype of ERCC1 rs3212986 was a high‐risk factor for NSCLC (OR = 3.246; 95%CI: 1.375‐7.663). Particularly stratified by smoking status in cases and controls, A allele of ERCC1 rs3212986 also exhibited an enhanced risk to develop lung cancer in smokers only (P

Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m2 IV day 1, or 25 mg/m2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.

Objective To compare the effect differences of electroacupuncture (EA) at Jiājĭ (夹脊 EX-B2) and conventional acupoints for lumbar intervertebral disc herniation (LIDH) and the factors influenced the effect during the way of data mining. Methods A total of 160 patients of LIDH were randomly assigned into the EX-B2 group and the conventional acupoints group, 80 cases in each one. The patients in the EX-B2 group received EA at the symmetrical 2 acupoints of the bilateral EX-B2 on the lesion part. The patients in the conventional acupoints group received EA at the tender point of the lesion part, Zhibiān( 秩边BL54), Huantiao(环跳 GB30), Weǐzhōng(委中BL40), Chengshān(承山BL57) and Fuyang (跗阳BL59) on the affected side. The retain time of the needles is both 45 min. The treatment of the two groups is 3 times a week and for a connective 20 times. The modified Assessment Criteria for Low Lumbar Pain of Japanese Orthopedic Association (JOA), Visual Analogue Scale (VAS) were evaluated before and after the treatment and at the 6-month follow up. Results (1) Effective outcomes. JOA score: The JOA score of the patients in the EX-B2 group after treatment was (20.89 ± 3.43), and was (19.35 ± 4.02) on the follow-up. Compared with the JOA score (12.35 ± 4.42) in the same group before the treatment, there were statistical significant higher (both P 0.05). (2)Related results from data mining: The middle-aged people and disease duration less than six months, their effect of the immediate treatment was the best. According to JOA score, EA at EX-B2 was better than EA conventional acupoints, either in the process of treatment effect, or in pertinence of the treatment, which were superior to EA conventional acupoints therapy; The best curative effect time of EA at EX-B2 was the first treatment after 24 h, and the best curative effect of the conventional acupoints was after the first treatment. The age and disease duration also affected curative effect. Conclusion The effect of EA at EX-B2 was superior to the conventional acupoints in treating LIDH.

Berberine, a widely used isoquinoline alkaloid in traditional Chinese medicine, has been proved to be a potential candidate in liver cancer therapy. However, the low therapeutic dose in the tumor target which is due to the poor solubility and oral bioavailability has limited its clinical application. In this study, fluorescent self-carried Berberine microrods (Ber-MRs) were prepared in gram-scale through a facile and cheap antisolvent precipitation method. Ber-MRs exhibited good optical properties, pH-responsive drug release behavior and selective and safe antitumor performance in vitro and in vivo without obvious toxicity. These findings have demonstrated that Ber-MRs are promising for efficient and safe liver cancer therapy. © 2018 BioFactors, 44(5):496-502, 2018.

Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure–activity relationships for the newly identified quinoline-based PPARα agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid transposition and deconstruction of the Y-0452 quinoline system would enhance ligand–protein interactions and better complement the nature of the binding pocket. A focused subset of analogs was designed, synthesized, and assessed for PPARα agonism. Two key observations arose from this work 1) contrary to other PPARα agonists, incorporation of the fibrate “head-group” decreases PPARα selectivity and instead provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic pocket in PPARα that provides new opportunities for the development of novel agonists. As an example, compound 10 exhibits more potent PPARα agonism (EC50 = ∼6 µM) than Y-0452 (EC50 = ∼50 µM) and manifests >20-fold selectivity for PPARα over the PPARγ and PPARδ isoforms. More detailed biochemical analysis of 10 confirms typical downstream responses of PPARα agonism including PPARα upregulation, induction of target genes, and inhibition of cell migration.

Background: Interleukin-1 receptor type II (IL-1R2), also known as CD121b, is a member of the IL-1 receptor family. IL-1R2 acts as negative regulator of the IL-1 system, modulating IL-1 availability for the signaling receptor. IL-1R2 is abnormally expressed in many human inflammatory diseases and cancers, and has important clinical significance. The present study was designed to investigate IL-1R2 expression in human gastric cancer (GC) tissues and the associated clinical implications. Methods: Immunohistochemistry was used to identify the clinical significance and prognostic value of IL-1R2 expression in GC tissues. We investigated IL-1R2 expression in GC tissues, cells, and serum using real-time PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) assays. Results: IL-1R2 was highly expressed in GC tissues, and the overall survival in patients with advanced GC and high IL-1R2 expression was significantly poorer than that in patients with advanced GC and low IL-1R2 expression. Moreover, IL-1R2 mRNA levels in GC tissues and most GC cells were higher than those in para-cancer tissues and GES1 human gastric mucosal epithelial cells. The level of plasma-soluble IL-1R2 in GC patients was higher than that of the healthy control group. Conclusion: Increased IL-1R2 levels are involved in the initiation and progression of human GC, and IL-1R2 might be employed to develop immunotherapeutic approaches targeting GC.

Dietary patterns and psychosocial factors, ubiquitous part of modern lifestyle, critically shape the gut microbiota and human health. However, it remains obscure how dietary and psychosocial inputs coordinately modulate the gut microbiota and host impact. Here, we show that dietary raffinose metabolism to fructose couples stress-induced gut microbial remodeling to intestinal stem cells (ISC) renewal and epithelial homeostasis. Chow diet (CD) and purified diet (PD) confer distinct vulnerability to gut epithelial injury, microbial alternation and ISC dysfunction in chronically restrained mice. CD preferably enriches Lactobacillus reuteri, and its colonization is sufficient to rescue stress-triggered epithelial injury. Mechanistically, dietary raffinose sustains Lactobacillus reuteri growth, which in turn metabolizes raffinose to fructose and thereby constituting a feedforward metabolic loop favoring ISC maintenance during stress. Fructose augments and engages glycolysis to fuel ISC proliferation. Our data reveal a diet-stress interplay that dictates microbial metabolism-shaped ISC turnover and is exploitable for alleviating gut disorders., Here, using a mouse model of chronic stress, the authors investigate how diet impacts stress and gut microbial structure and epithelial integrity and show that dietary raffinose metabolism to fructose couples stress-induced gut microbial remodeling to intestinal stem cell renewal and epithelial homeostasis.