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Endoscopy artifacts are widespread in real capsule endoscopy (CE) images but not in high-quality standard datasets.To improve the segmentation performance of polyps from CE images with artifacts based on ensemble learning.We collected 277 polyp images with CE artifacts from 5760 h of videos from 480 patients at Guangzhou First People's Hospital from January 2016 to December 2019. Two public high-quality standard external datasets were retrieved and used for the comparison experiments. For each dataset, we randomly segmented the data into training, validation, and testing sets for model training, selection, and testing. We compared the performance of the base models and the ensemble model in segmenting polyps from images with artifacts.The performance of the semantic segmentation model was affected by artifacts in the sample images, which also affected the results of polyp detection by CE using a single model. The evaluation based on real datasets with artifacts and standard datasets showed that the ensemble model of all state-of-the-art models performed better than the best corresponding base learner on the real dataset with artifacts. Compared with the corresponding optimal base learners, the intersection over union (IoU) and dice of the ensemble learning model increased to different degrees, ranging from 0.08% to 7.01% and 0.61% to 4.93%, respectively. Moreover, in the standard datasets without artifacts, most of the ensemble models were slightly better than the base learner, as demonstrated by the IoU and dice increases ranging from -0.28% to 1.20% and -0.61% to 0.76%, respectively.Ensemble learning can improve the segmentation accuracy of polyps from CE images with artifacts. Our results demonstrated an improvement in the detection rate of polyps with interference from artifacts.

Studies are trying to add immunotherapy to gemcitabine and cisplatin (GP) induction chemotherapy, the standard therapy, in nasopharyngeal carcinoma (NPC) patients with locoregionally advanced disease. However, how the immune system responds to GP remains unknown.We examined the dynamic changes of circulating immune cells and plasma cytokines in NPC patients administered with GP.After GP administration, immunosuppressive myeloid cells, including CD11b+CD14+ monocytes, CD33+ myeloid cells, CD33+CD11+ myeloid cells, total MDSCs (CD33+CD11+HLA-DR-/low), monocytic MDSCs, and granulocytic MDSCs decreased significantly. The regulatory T cells and B cells, two important suppressive lymphocyte subpopulations, also decreased. On the other hand, the levels of CD3+ T cells, total B cells, central memory CD4+ T cells, and pro-inflammatory cytokines (including Interleukin [IL]-1β, IL-6, IL-2, IL-5, and IL-8) increased significantly after GP administration. Besides, GP chemotherapy did not weaken the cytotoxic activity and proliferative capacity of T cells.Our results showed the immune modulation effect of GP induction chemotherapy in locoregionally advanced NPC, providing a solid basis for its combination with immunotherapy.

Periostin, as an emerging biomarker, is involved in multiple steps in bone metabolism. This study aimed to investigate the correlation between periostin levels and bone mineral density as well as bone turnover markers in postmenopausal women with type 2 diabetes (T2DM).This study was a cross-sectional study that included 164 postmenopausal women with T2DM as study subjects and 32 age-matched nondiabetic postmenopausal women with normal bone mineral density (BMD) as healthy control subjects. A total of 164 subjects with T2DM were then divided into three groups according to BMD: the normal BMD group (n = 29), the osteopenia group (n = 70), and the osteoporosis group (n = 65). The clinical data of all subjects along with the relevant biochemical parameter data were collected. Plasma periostin was detected using an enzyme-linked immunosorbent assay (ELISA).Plasma periostin levels were significantly increased in T2DM patients with normal BMD compared with healthy controls (p 0.05). In the diabetic group, plasma periostin levels were significantly elevated with decreased BMD, were positively correlated with osteocalcin levels (r = 0.162, p = 0.039) and were inversely associated with femoral neck BMD (r = - 0.308, p 0.001) and total femur BMD (r = - 0.295, p 0.001). In the case of chronic complications, periostin levels were slightly increased in individuals with complications of diabetic retinopathy, diabetic nephropathy and fracture (p 0.05).The current study demonstrated that plasma periostin levels were significantly associated with BMD in patients with T2DM, and periostin might act as a novel biochemical marker of osteoporosis in postmenopausal women with type 2 diabetes.

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)–MAPK–MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR–ACLY–PADI1–MAPK–MMP2/9 axis as a potential therapeutic target in NPC. Significance: TINCR-mediated regulation of a PADI1–MAPK–MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.

Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT–qPCR validation and selection using a machine learning method in the training cohort (n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal (n = 177) and Guilin external (n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.

Background Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC). However, the epigenetic mechanisms underlying NPC metastasis remains poorly understood. We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment. Methods Bisulfite pyrosequencing was used to analyze zinc finger protein 582 (ZNF582) methylation in NPC tissues and cell lines. Quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) and Western blotting were used to determine the expression of ZNF582. In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC. ZNF582‐targeting genes were identified by chromatin immunoprecipitation sequencing (ChIP‐seq) and were confirmed by ChIP‐qPCR and luciferase assay. Results ZNF582 promoter was hypermethylated in NPC, and both the mRNA and protein levels of ZNF582 were down‐regulated in NPC tissues and cell lines. The restoration of ZNF582 inhibited NPC migration, invasion, and metastasis, while the knockdown of ZNF582 promoted NPC migration, invasion, and metastasis in vitro and in vivo. ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin‐3 and NRXN3. Both Nectin‐3 and NRXN3 were identified as functional targets of ZNF582, and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis. Conclusions ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin‐3 and NRXN3, which may provide novel therapeutic targets for NPC treatment.

Rationale: Currently, for locoregionally advanced nasopharyngeal carcinoma (LA-NPC), there is no effective blood-based method to predict distant metastasis. We aimed to detect plasma protein profiles to identify biomarkers that could distinguish patients with NPC who are at high risk of posttreatment distant metastasis. Methods: A high-throughput antibody array was initially applied to detect 1000 proteins in pretreatment plasma from 16 matched LA-NPC patients with or without distant metastasis after radical treatment. Differentially expressed proteins were further examined using a low-throughput array to construct a plasma protein-based signature for distant metastasis (PSDM) in a cohort of 226 patients. Results: Fifty circulating proteins were differentially expressed between metastatic and non-metastatic patients and 18 were proven to be strongly correlated with distant metastasis-free survival (DMFS) in NPC. A PSDM signature consisting of five proteins (SLAMF5, ESM-1, MMP-8, INSR, and Serpin A5) was established to assign patients with NPC into a high-risk group and a low-risk group. Patients in the high-risk group had shorter DMFS (P < 0.001), disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001). Moreover, the PSDM performed better than N stage and Epstein-Barr virus (EBV) DNA load at effectively identifying patients with NPC at high risk of metastasis. For patients in the high-risk group, induction chemotherapy significantly improved DMFS, DFS, and OS. Conclusions: The PSDM could be a useful liquid biopsy tool to effectively predict distant metastasis and the benefit of induction chemotherapy in patients with LA-NPC.

Previous studies have investigated influencing factors of early discontinuation of breastfeeding, but few studies have developed an easy-to-use tool to identify risk of breastfeeding cessation at 6 months after birth. This research team aimed to develop and validate an exclusive breastfeeding duration risk nomogram in Chinese mothers. A longitudinal cohort survey was conducted. Data were collected from 394 postpartum women in three hospitals in Hubei Province, China from December 2017 to December 2018. The LASSO regression model was used to screen for optimized factors in an exclusive breastfeeding duration model. Multivariable logistic regression was applied to construct a prediction model. Discrimination and calibration were assessed using a C-index and calibration curve, and internal validity was established using bootstrapping validation. Factors integrated in the prediction risk nomogram were monthly household income (odds ratio [OR] = 1.31, 95% confidence interval [CI]: [0.95, 1.80]), experiences of breastfeeding (OR = 1.23, 95% CI: [0.92, 1.63]), attitude (OR = 1.72, 95% CI: [0.94, 3.16]), self-efficacy (OR = 2.45, 95% CI: [1.40, 4.29]), perceived insufficient milk supply (OR = 0.12, 95% CI: [0.06, 0.25]) and postpartum depression (OR = 0.06, 95% CI: [0.02, 0.17]). The model displayed good discrimination with a C-index of 0.87 (95% CI: [0.84, 0.91]) and good calibration. The C-index interval validation was confirmed to be 0.86. This study resulted in the development of a novel nomogram with good accuracy to aid healthcare professionals in assessing the probability of a mother discontinuing exclusive breastfeeding at the breast before 6 months.

ImportanceMicrobiota-tumor interactions have qualified microbiota as a promising prognostic biomarker in various types of cancers. Although the nasopharynx acts as a crucial niche of the upper respiratory tract microbiome, whether the intratumoral microbiota exists and its clinical significance in nasopharyngeal carcinoma (NPC) remain uncertain.ObjectiveTo evaluate the clinical significance of intratumoral microbiota for individual prognostication in patients with NPC.Design, Setting, and ParticipantsThis retrospective cohort study included NPC biopsy samples from 2 hospitals: Sun Yat-sen University Cancer Center (Guangzhou, China) and Zhejiang Cancer Hospital (Hangzhou, China) between January 2004 and November 2016, with follow-up through November 2020. A total of 802 patients were included according to the following criteria: with histologically proven NPC, without distant metastasis at initial diagnosis, had not received antitumor treatment before biopsy sampling, aged between 18 and 70 years, with complete medical records and regular follow-up, without a history of cancer, and successfully extracted enough DNA for experiments.Main Outcomes and MeasuresThe primary end point was disease-free survival, and the secondary end points included distant metastasis–free survival and overall survival. To assess the existence and load of intratumoral microbiota in 96 patients with NPC with or without tumor relapse, 16S rRNA sequencing and quantitative polymerase chain reaction were used. The associations between intratumoral bacterial load and clinical outcome were evaluated in 241 fresh-frozen NPC samples (training cohort) and validated in paraffin-embedded NPC samples of internal (n = 233) and external (n = 232) validation cohorts. Metagenomic and transcriptome analyses were performed to ascertain the origin and underlying mechanism of intratumoral bacteria.ResultsA total of 802 patients with NPC (mean [SD] age, 46.2 [10.6] years; 594 [74.1%] male) were enrolled. Microbiota presented within NPC tumor tissues, among which Corynebacterium and Staphylococcus predominated. Patients with a high bacterial load in the training cohort had inferior rates of disease-free survival (hazard ratio [HR], 2.90; 95% CI, 1.72-4.90; P P P Conclusions and RelevanceIntratumoral bacterial load was a robust prognostic tool for patients with NPC in this cohort study, indicating potential guidance for treatment decisions in patients at different levels of risk of malignant progression.

Introduction Aneurysmal subarachnoid hemorrhage (aSAH), caused by rupture of an intracranial aneurysm and bleeding into the subarachnoid space, is a life‐threatening cerebrovascular disease. Because of improvements in clinical interventions, the mortality rate of aSAH is gradually decreasing. Thus, many survivors recover from aSAH but still have sequelae. Working memory (WM) deficit is one of the most common and severe sequelae after aSAH. Interestingly, the severity of WM deficit is not identical to the extent or localization of brain damage, which implies an underlying mechanism of WM deficit other than direct hemorrhagic brain damage. Previous studies have revealed altered neural activity of several brain regions during stimulus tasks. However, the behaviors and functional organization of these corresponding areas in the resting state remain unclear. Insights into the organization of the WM network could reveal novel information about the mechanism of WM deficits, which will be of great value in developing new therapeutic strategies. Methods In this study, we recruited 50 aSAH patients consisting of survivors with either impaired or intact WM (two groups). Independent component analysis was performed on resting state data to extract the WM network. Dynamic causal modeling was then performed to assess the intrinsic coupling between key regions of the WM network. A model describing the neural activity and functional organization of the WM network was established, although some connections were not consistent in the resting state. Results We found that effective connectivity of the precuneus (PCUN)‐middle temporal gyrus (MTG), MTG‐PCUN, and middle frontal gyrus‐inferior parietal lobule was significantly decreased in the impaired WM group, which suggests a vital and central role of affected regions or connections and provides new targets for brain stimulation. Conclusions The results of this study may contribute to new therapeutic or rehabilitation strategies for aSAH patients with WM deficits., 1. Our study suggests a vital and central role of affected regions or connections and provides new targets for brain stimulus. 2. We hope new therapeutic strategy or rehabilitation for aneurysmal subarachnoid hemorrhage patients with working memory deficit could benefit from this study.

Recent phase 1–2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1–5/3–5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1–5 AEs whereas camrelizumab and nivolumab regarding grade 3–5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1–positive and PD-L1–negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.

Macrophages are paramount to the initiation and procession of atherosclerosis, thus targeting macrophages in the progress of atherosclerosis is indispensable. Therefore, we perform in vitro experiments to investigate the effects of FGF-21 on macrophages in the progress of atherosclerosis. First, we use phorbol-12-myristate-13-acetate (PMA), a phorbol ester, to induce THP-1 cells into macrophages as macrophages model. After that we use Ox-LDL to induce macrophages into foam cells and simultaneously administrate with FGF-21 or not to determine whether FGF-21 has effects on foam cells formation and related inflammatory response. Wound healing results show that FGF-21 can inhibit macrophage migration. Oil Red-O stain, immunofluorescence and flow cytometer results show that FGF-21 can repress cholesterol accumulation in macrophages thereby inhibit foam cells formation and these effects can be abolished by FGFR inhibitor. Moreover, real-time PCR results showed that FGF-21 significantly reduces expression of inflammatory factors including IL-1α, IL-6 and TNF-α and this effect can be abolished by FGFR inhibitor. Furthermore, to determine the mechanism of FGF-21 regulates inflammatory response in Ox-LDL-induced THP-1 macrophages, western blotting results show that after treatment of Ox-LDL in macrophages, NF-κB signaling pathway is activated but FGF-21 can significantly inhibit this pathway. In addition, FGF-21 also regulates some regulators of lipid metabolism after treatment of Ox-LDL in macrophages. Above all, our findings demonstrate that FGF-21 can regulate foam cells formation, macrophage migration, inflammatory response and lipid metabolism in Ox-LDL-induced THP-1 macrophages.

Background and aims The relationship between prior breastfeeding experience and the duration of exclusive breastfeeding is of significant interest, but few studies have explored the mechanisms underlying this relationship. The purpose of this study is to address two hypotheses: (a) that attitude and self-efficacy mediate the relationship between previous breastfeeding experience and the duration of exclusive breastfeeding; and (b) that attitude and self-efficacy have serial mediation functions in this relationship. Methods The data collection process was divided into two stages. The original stage included 394 women hospitalized after delivery who completed socio-demographic questionnaires (including previous breastfeeding experience), the Iowa Infant Feeding Attitude Scale (IIFAS), and the Breastfeeding Self-efficacy Short-Form Scale (BSES-SF). Follow-up data about duration of exclusive breastfeeding were obtained at six months postpartum. Results Mediation analysis indicated that previous breastfeeding experience directly affected the duration of exclusive breastfeeding and that the rate of the total indirect effect was 22.878%. Self-efficacy mediated previous breastfeeding experience and duration of exclusive breastfeeding, whereas attitude and self-efficacy played the series mediational role between previous breastfeeding experience and duration of exclusive breastfeeding. Cluster analysis supported these results. Conclusions The duration of exclusive breastfeeding can be promoted by improving breastfeeding attitude and self-efficacy in women without breastfeeding experience.

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in the tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in nasopharyngeal carcinoma (NPC) are still largely unknown. Our previous lncRNA expression profiles identified that LINC01503 was overexpressed in NPC. Here, we verified that LINC01503 was highly expressed in NPC and correlated with poor prognosis. LINC01503 promoted NPC cell proliferation, migration, and invasion in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, LINC01503 recruited splicing factor proline-and glutamine-rich (SFPQ) to activate Fos like 1 (FOSL1) transcription, and ectopic expression of FOSL1 reversed the suppressive effect of LINC01503 knockdown on NPC progression. Moreover, androgen receptor (AR)-mediated transcription activation was responsible for the overexpression of LINC01503, and AR ligand-dependent cell growth, migration, and invasion in NPC cells. Taken together, our findings reveal that AR-induced LINC01503 can promote NPC progression through the SFPQ-FOSL1 axis, which represents a novel prognostic biomarker and therapeutic target for NPC patients.

The development of immune checkpoint blockade (ICB)-based immunotherapy has dramatically changed methods of cancer treatment. This approach triggers a durable treatment response and prolongs patients' survival; however, not all patients can benefit. Accumulating evidence demonstrated that the efficacy of ICB is dependent on a robust antitumor immune response that is usually damaged in most tumors. Conventional chemotherapy and targeted therapy promote the antitumor immune response by increasing the immunogenicity of tumor cells, improving CD8+ T cell infiltration, or inhibiting immunosuppressive cells in the tumor microenvironment. Such immunomodulation provides a convincing rationale for the combination therapy of chemotherapeutics and ICBs, and both preclinical and clinical investigations have shown encouraging results. However, the optimal drug combinations, doses, timing, and sequence of administration, all of which affect the immunomodulatory effect of chemotherapeutics, as well as the benefit of combination therapy, are not yet determined. Future studies should focus on these issues and help to develop the optimal combination regimen for each cancer.

Background Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the mainstay treatment for patients with locoregionally advanced nasopharyngeal carcinoma. However, some patients obtain little benefit and experience unnecessary toxicities from IC. We intended to develop a gene-expression signature that can identify beneficiaries of IC. Methods We screened chemosensitivity-related genes by comparing gene-expression profiles of patients with short-term tumor response or nonresponse to IC (n = 95) using microarray analysis. Chemosensitivity-related genes were quantified by digital expression profiling in a training cohort (n = 342) to obtain a gene signature. We then validated this gene signature in the clinical trial cohort (n = 187) and an external independent cohort (n = 240). Tests of statistical significance are 2-sided. Results We identified 43 chemosensitivity-related genes associated with the short-term tumor response to IC. In the training cohort, a 6-gene signature was developed that was highly accurate at predicting the short-term tumor response to IC (area under the curve [AUC] = 0.87, sensitivity = 87.5%, specificity = 75.6%). We further found that IC conferred failure-free survival benefits only in patients in the benefit group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.34 to 0.87; P = .01) and not on those in the no-benefit group (HR = 1.25, 95% CI = 0.62 to 2.51; P = .53). In the clinical trial cohort, the 6-gene signature was also highly accurate at predicting the tumor response (AUC = 0.82, sensitivity = 87.5%, specificity = 71.8%) and indicated failure-free survival benefits. In the external independent cohort, similar results were observed. Conclusions The 6-gene signature can help select beneficiaries of IC and lay a foundation for a more individualized therapeutic strategy for locoregionally advanced nasopharyngeal carcinoma patients.

Fibroblast growth factor 21 (FGF-21) has been previously judged as a major metabolic regulator. In this paper, we show that FGF-21 has a potential role in anti-inflammation and immunoregulation. In vivo, treatment with exogenous FGF-21 can alleviate LPS-induced inflammation. In vitro, FGF-21 inhibited LPS-induced IL-1β expression in THP-1 cells. Furthermore, besides the NF-κB pathway, the mechanism of action of FGF-21 was observed to involve the elevation of IL-10 in the ERK1/2 pathway. This study clearly indicates that FGF21 can be used as an attractive target for the management of inflammatory disorders. This piece of research indicates that FGF-21 could have much value in the management of inflammatory disorders.

Monocytes display a gradual change in metabolism during inflammation. When activated, the increase in glucose utilization is important for monocytes to participate in immune and inflammatory responses. Further studies on the mechanism underlying this biological phenomenon may provide a new understanding of the relationship between immune response and metabolism. The THP-1 cells were used as a monocyte model. The cells were activated with lipopolysaccharide (LPS). Glucose uptake was measured using flow cytometry. The expression of fibroblast growth factor 21 (FGF-21), glucose transporter 1 (GLUT-1), and other FGF-21 signaling pathway-related factor mRNAs was determined by real-time polymerase chain reaction. Further, the relationship between FGF-21 expression in monocytes and phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signaling pathway was determined by Western blotting. LPS elevated FGF-21 expression in monocytic THP-1 cells in vitro. Functional assays showed that the phenomenon in which LPS and FGF-21 stimulated glucose uptake in monocytic THP-1 cells could be inhibited by FGFR inhibitor. The mechanism of elevation of FGF-21 was found to involve the PI3K/Akt signaling pathway. This study indicated that FGF-21 could regulate the immune response indirectly by influencing the glucose uptake of activated monocytes cells.

Fibroblast growth factor 21 (FGF21) is a member of the FGF family and acts as a potent regulator of glucose and lipid homeostasis, but its effect on renal fibrosis and the underlying mechanisms are totally unknown. The purpose of this study was designed to investigate whether FGF21 has effect on high glucose-induced fibrogenesis in human mesangial cells (HMCs) and the underlying mechanism. High glucose is well known to stimulate the expression of extracelluar matrix (ECM) in human mesangial cells. In humans, overexpression and deposition of ECM lead to renal fibrosis. Thus, in this study, HMCs were incubated in high glucose with or without various concentrations of FGF21. Results demonstrated that the expression of FN, Col, TGF β1 and α-SMA were significantly up-regulated in HMCs. Whereas, treatment with FGF21 down-regulated the expression of FN, Col, TGF β1 and α-SMA. In addition, growth factors are considered to be an important driving force for the pathogenesis of renal fibrosis. Significantly increased PDGF, VEGF and CTGF expression were found in HMCs induced by high glucose. FGF21 treatments significantly decreased these growth factors expression by down-regulating the phosphorylation level of STAT5. Here, we reported for the first time that FGF21 decreases ECM expression by inhibiting STAT5 signal pathway and consequently decreasing the expression of PDGF, VEGF and CTGF.

Uterine fibroids, also known as uterine leiomyomas, are a benign tumor of the human uterus and the commonest estrogen-dependent benign tumor found in women. Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. The role of myocardin and its relationship with ERα in uterine fibroids have barely been addressed. We noticed that the expression of myocardin was markedly reduced in human uterine fibroid tissue compared with corresponding normal or adjacent myometrium tissue. Here we reported that myocardin induced the transcription and expression of differentiation markers SM22α and alpha smooth muscle actin (α-SMA) in rat primary uterine smooth muscle cells (USMCs) and this effect was inhibited by ERα. Notably, we showed that, ERα induced expression of proliferation markers PCNA and ki-67 in rat primary USMCs. We also found ERα interacted with myocardin and formed complex to bind to CArG box and inhibit the SM22α promoter activity. Furthermore, ERα inhibited the transcription and expression of myocardin, and reduced the levels of transcription and expression of downstream target SM22α, a SMC differentiation marker. Our data thus provided important and novel insights into how ERα and myocardin interact to control the cell differentiation and proliferation of USMCs. Thus, it may provide potential therapeutic target for uterine fibroids.

Background Immunotherapy, especially immune checkpoint inhibition, has provided powerful tools against cancer. We aimed to detect the expression of common immune checkpoints and evaluate their prognostic values in nasopharyngeal carcinoma (NPC). Methods The expression of 9 immune checkpoints consistent with 13 features was detected in the training cohort (n = 208) by immunohistochemistry and quantified by computational pathology. Then, the LASSO cox regression model was used to construct an immune checkpoint-based signature (ICS), which was validated in a validation cohort containing 125 patients. Results High positive expression of PD-L1 and B7-H4 was observed in tumour cells (TCs), whereas PD-L1, B7-H3, B7-H4, IDO-1, VISTA, ICOS and OX40 were highly expressed in tumour-associated immune cells (TAICs). Eight of the 13 immune features were associated with patient overall survival, and an ICS classifier consisting of 5 features (B7-H3TAIC, IDO-1TAIC, VISTATAIC, ICOSTAIC, and LAG3TAIC) was established. Patients with high-risk scores in the training cohort had shorter overall (P

Background Circular RNAs (circRNAs), a new type of noncoding RNA (ncRNA), have been identified as significant gene expression regulators and are involved in cancer progression. However, the roles of circRNAs in nasopharyngeal carcinoma (NPC) remain largely unknown. Methods Here, the expression profile of circRNAs in a pair of NPC cell lines with different metastatic abilities (S18 and S26 cells) was analyzed by RNA-sequencing. Quantitative reverse transcription PCR was used to detect the expression level of circCRIM1 in NPC cells and tissues. Then, function experiments in vitro and in vivo were performed to evaluate the effects of circCRIM1 on NPC metastasis and EMT. Mechanistically, RNA immunoprecipitation, luciferase reporter assay, pull-down assay with biotinylated miRNA, fluorescent in situ hybridization were performed to confirm the interaction between circCRIM1 and miR-422a in NPC. The clinical value of circCRIM1 was evaluated in NPC metastasis and chemosensitivity. Results We identified that circCRIM1 was upregulated in highly metastatic NPC cells. CircCRIM1 was also overexpressed in NPC tissues with distant metastasis, and its overexpression promoted NPC cell metastasis and EMT. Mechanistically, circCRIM1 competitively bound to miR-422a and prevented the suppressive effects of miR-422a on its target gene FOXQ1, which finally led to NPC metastasis, EMT and docetaxel chemoresistance. Furthermore, high circCRIM1 expression was associated with unfavorable survival in NPC patients. We established a prognostic model based on circCRIM1 expression and N stage that effectively predicted the risk of distant metastasis and treatment response to docetaxel-containing induction chemotherapy in NPC patients. Conclusions Our findings reveal the critical role of circCRIM1 specifically in promoting NPC metastasis and chemoresistance via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for prognosis and treatment resistance in NPC patients.

The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0–2 and T1–4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0–2 and T1–4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). We included 3107 patients with stage IVa NPC disease (1871 with T4N0–2 and 1236 with T1–4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0–2 and T1–4N3 patients were compared. T1–4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis–free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse–free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0–2 patients. Multivariate analysis showed that T1–4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274–1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100–1.572, p = 0.003), whereas T4N0–2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158–2.158, p = 0.004). In terms of the OS, T4N0–2 patients had better prognosis compared with T1–4N3 patients, and the patterns of failure differed between T4N0–2 and T1–4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0–2 from T1–4N3. • In nasopharyngeal carcinoma, T4N0–2 patients tended to develop local relapse, whereas T1–4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0–2 patients had better prognosis than T1–4N3 patients. • T4N0–2 should be separated from T1–4N3 in the UICC/AJCC staging system.

Five new phloroglucinol derivatives, eucalyptins C-G (1-5), together with 13 known analogues (6-18) were isolated from the fruits of Eucalyptus globulus. The structures and absolute configurations of 1-5 were established by means of spectroscopic data analysis, computational calculation methods, and single-crystal X-ray diffraction. Compounds 1-18 were investigated for their immunosuppressive effects in vitro, and 1, 2, 6, and 7 displayed moderate inhibitory activities with IC50 values of 11.8, 10.2, 18.2, and 19.1 μM, respectively. The stimulation index (SI) of 1 was 64.2 and was compared to that of cyclosporine A (SI = 149.57). Further study demonstrated that 1 exhibited an immunosuppressive effect through inducing apoptosis and inhibiting cytokine secretion.

Cynaroside is a flavonoid compound proved to possess antioxidant activity, but its protective effect on age-related macular degeneration still remains unclear. In this study, the protective effects of cynaroside on oxidative stress and apoptosis in retinal pigment epithelial (RPE) cells induced by hydrogen peroxide (H2 O2 ) were investigated. Results showed that cynaroside effectively attenuated the decrease of cell activity induced by H2 O2 . The total reactive oxygen species can be remitted by decreasing malondialdehyde level, as well as increasing glutathione level, and superoxide dismutase and catalase activities. In addition, Western blot analysis indicated that cynaroside protected ARPE-19 cells from apoptosis through downregulation of caspase-3 protein activation which was controlled by the upstream proteins Bcl-2 and Bax. It was finally proved that cynaroside could enhance the antioxidant and antiapoptotic ability in ARPE-19 cells by promoting the expression of p-Akt.

Although the prevalence of brucellosis in Inner Mongolia Autonomous Region currently remains high, data available on the epidemiological of circulating Brucella abortus strains were limited. A total of 75 isolates obtained from cattle, sheep, and humans were analysed using both the classical method and multiple locus variable-number tandem repeat analysis (MLVA). There are at least three B. abortus biovars (1, 3 and 6) in this region, and B. abortus biovar 3 is the predominant one. Ten known MLVA-11 genotypes were identified, of which five genotypes (72, 75, 78, 82 and 210) were shared among strains from this study and others previously collected in two to seven different nations, suggesting that this population has multiple geographic origins. An MLVA-16 assay sorted the 75 B. abortus strains into two groups (I and II), 5 clusters (A-E) and 44 genotypes (GT1-44), with 26 unique genotypes represented by single isolates, indicating that these B. abortus brucellosis cases were not directly epidemiologically related. The remaining 18 shared genotypes (among a total of 47 isolates) were represented by two to eight isolates, suggesting that there were epidemiologically related pathogens from each shared genotype among the cases. Importantly, the cluster B1 branch including 22 cluster isolates with identical or similar genotypes confirmed the occurrence of a concentrated outbreak epidemic in the eastern region during 1988-1995. This work will contribute to better understanding of B. abortus brucellosis epidemiology in Inner Mongolia.

Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo. Importantly, we found that UCHL1 interacts with CTTN, and may function as a ligase promoting CTTN degradation by increasing K48-linked ubiquitination of CTTN. Additionally, restoration of CTTN in NPC cells that overexpressed UCHL1 rescued UCHL1 suppressive effects on NPC cell migration and invasion, which indicated that CTTN is a functional target of UCHL1 in NPC. Our findings revealed that UCHL1 acts as a tumor suppressor gene in NPC and thus provided a novel therapeutic target for NPC treatment.

The intricate molecular network shared between diabetes mellitus (DM) and cancer has been broadly understood. DM has been associated with several hormone-dependent malignancies, including breast, pancreatic, and colorectal cancer (CRC). Insulin resistance, hyperglycemia, and inflammation are the main pathophysiological mechanisms linking DM to cancer. Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are widely appreciated as pervasive regulators of gene expression, governing the evolution of metabolic disorders, including DM and cancer. The ways ncRNAs affect the development of DM complicated with cancer have only started to be revealed in recent years. Insulin-like growth factor 1 receptor (IGF-1R) signaling is a master regulator of pathophysiological processes directing DM and cancer. In this review, we briefly summarize a number of well-known miRNAs and lncRNAs that regulate the IGF-1R in DM and cancer, respectively, and further discuss the potential underlying molecular pathogenesis of this disease association.

Although previous studies have shown the potential of FGF21 to regulate blood glucose in animal and humans, the precise mechanisms of the action have not been well explored. The kidney plays a crucial role for glucose homeostasis. The purpose of this study is to explore the effect of FGF21 on renal glucose reabsorption. Administration of type 2 and type 1 diabetic mice with FGF21 reduced the transport maximum of glucose in the kidney and enhanced urinary glucose excretion in a dose-dependent manner. The inhibition of glucose reabsorption results showed little change in diabetic mice treated with Insulin. In physiological state, both FGF21 and insulin had no effect on glucose reabsorption and urinary glucose excretion. Next, we examined the expression of SGLT2 in the kidney, which is an important molecule for renal glucose reabsorption. SGLT2 was highly expressed in the kidneys of diabetic mice. Administration of FGF21 reduced SGLT2 expression in the kidney of diabetic mice. In contrast, the expression of SGLT2 had little change in diabetic mice treated with Insulin. FGF21 and Insulin did not promote SGLT2 expression in physiological state. To explore the mechanism which drives these changes, we detected the expression of PPARδ in mice and HK-2 cells, which plays a major role in regulating SGLT2 expression. Treatment with FGF21 promoted PPARδ expression in diabetic mice, whereas Insulin had no effect on PPARδ expression. At dose of 2 mg/kg FGF21 treatment promoted PPARδ expression in physiological state, whereas at dose of 1 mg/kg FGF21 did not. In HK-2 cells, treatment with FGF21 enhanced PPARδ expression, whereas Insulin treatment had no effect on PPARδ expression. Importantly, the expression of SGLT2 and PPARδ showed little change in HK-2 cells when β-klotho was knocked down. In conclusion, we discovered for the first time that FGF21 ameliorates hyperglycemia in part via reducing renal glucose reabsorption through PPARδ mediated SGLT2 pathway.

Background: Genome-wide association studies have validated the RAS guanyl nucleotide-releasing protein 1 (RASGRP1) gene as a type 2 diabetes (T2D) susceptibility locus. Aims: This study aimed to replicate and verify the association of RASGRP1 tag single-nucleotide polymorphisms with T2D in a Chinese Han population. Methods: Eleven common variants of RASGRP1 were detected using TaqMan technology in 1272 healthy controls and 1234 T2D patients. All study participants were unrelated members of the Han ethnic group in China. In this study, the rs7403531 genotype frequency differed significantly between T2D patients and controls (allele: adjusted p=8.30×10−6, genotype: adjusted p=2.50×10−5, OR=1.366 [95% CI=1.206–1.546]). The rs4465567–rs4567661 C-A and C-C haplotypes were also significant risk factors for T2D (adjusted p=0.0002 and p=0.0006, respectively) with a global p-value of 6.46×10−5. These results indicate that in a Chinese Han population, RASGRP1 variants, particularly rs7403531, confer a risk for deve...

Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. Our previous study has shown that MRTF-A promote the migration of MDA-MB-231 cells and WDR1 promotes breast cancer cell migration. But the exact molecular mechanism on metastasis is still not fully understood, we now report that WDR1 enhanced the effect of MRTF-A induced-MDA-MB-231 cell migration by promoting the expression of the EMT markers and migration markers via RhoA-MRTF-A signaling pathway. Importantly, WDR1 promoted the nuclear importion of MRTF-A by affecting the expression of nuclear transport protein importin. But WDR1 did not affect the expression of MRTF-A. Interestingly, MRTF-A promoted the expression of miR-206 via its promoter CArG box but miR-206 inhibits the migration of breast cancer cells through suppressing the expression of WDR1 and MRTF-A via targeted their 3'UTR. Our data thus provide important and novel insights into MRTF-A-miR-206-WDR1 form feedback loop to regulate breast cancer cell migration.

We have grafted temperature-responsive tethered poly(N-isopropylacrylamide) (PNIPAAm) onto silicon surfaces through atom transfer radical polymerization (ATRP) as a medium to extract human genomic DNA molecules from a biological specimen, namely human blood incorporating target DNA (hgDNA584) and control DNA (hgDNA528) at concentrations of 0.5, 1, and 50 ng μL(-1). The variable adhesion forces of the tethered PNIPAAm brushes on the surfaces were used to capture and release DNA molecules through changes in temperature. After amplifying the signal of the hgDNA584 and hgDNA528 strands released from the tethered PNIPAAm on the substrate using the polymerase chain reaction (PCR), we identified these DNA macromolecules using agarose gel electrophoresis. The accuracy of the detection of hgDNA584 and hgDNA528 was controlled through the design of specific primers in the PCR process. The quantities of these two DNA molecules obtained through the capture and release from tethered PNIPAAm brushes under temperature tuning conditions were sufficient for them to be amplified recognizably, suggesting that this approach could be used in miniaturized lab-on-a-chip cartridges for rapid disease diagnosis.

Impaired antioxidant defense increases the oxidative stress and contributes to the development of type 2 diabetes mellitus (T2DM). MnSOD and eNOS are important antioxidant enzymes. This aim of this study was to verify the association of MnSOD and eNOS tagSNPs with T2DM in a Chinese Han population. Four tagSNPs of MnSOD and eight tagSNPs of eNOS were detected using TaqMan technology in 1272 healthy controls and 1234 T2DM patients. All study participants were unrelated members of the Han ethnic group in China. In this study, the frequency of the rs4880 MnSOD single nucleotide polymorphisms (SNP) genotype differed significantly between T2DM patients and controls [allele: P = 0.03, genotype: P = 0.04, odd's ratio (OR) = 1.26; 95% confidence interval (CI) = 1.07-1.49]. The A-T haplotype and G-T haplotype remained significant in T2DM after Bonferroni correction (P = 1.58 x 10(-6) and 8.00 x 10(-4), respectively) with a global p-value of 7.25 x 10(-8). The rs1799983 and rs891512 SNPs of eNOS differed significantly between T2DM patients and controls [rs1799983: corrected allele: P = 2.10 x 10(-3), corrected genotype: P = 6.30 x 10(-3), OR = 1.43 (95%CI = 1.18-1.73); rs891512, corrected allele: P = 3.50 x 10(-3), corrected genotype: P = 9.10 x 10(-3), OR = 1.70 (95%CI = 1.26-2.30)]. Following Bonferroni correction, none of the haplotypes of eNOS were significant in T2DM. These results indicate that common variants in MnSOD and eNOS increased the risk of T2DM in the Chinese Han population.

Diabetic nephropathy (DN) is one of the most serious chronic complications of diabetes mellitus. The observed incidence patterns in different ethnics and familial clustering have suggested that the genetic factor plays an important role in the development and progression of DN. This paper reviews the recent advances on genetics of DN, including candidate genes association studies, linkage studies and genome-wide association studies (GWASs). Candidate genes association studies and meta-analysis showed that a few candidate genes have been reproducibly associated with DN, such as ACE, AGT and PPARG genes. Linkage studies and genome-wide linkage studies have also identified susceptibility chromosomal loci. With the development of high-throughput sequencing and chip techniques, GWAS has become an important strategy to identify variants responsible for DN. The genetic factor has been the significant contribution to the pathobiology of DN. However, it is not the only cause of the pathobiology of DN, because the environment factor also influences the pathobiology of DN. Nonetheless, genetic studies may provide valuable information for the pathobiology of nephropathy and potential targets of its treatment.

A strain of Flavobacterium lindanitolerans isolated from a sick child's ascites was described. The 16S rRNA gene of the strain was 100% identical to that of Flavobacterium lindanitolerans which was first identified in India in 2008. It was first described that the isolate required X factor (Hemin) for growth in the optimal conditions of 37 °C with 5% CO(2). The isolate produced indole and H(2)S. It did not present hemolytic feature on blood agar.

Hereditary hypotrichosis simplex (MIM 146520, HHS) is a rare form of nonsyndromic alopecia. The locus for autosomal dominant HHS was mapped to 18p11.32-p11.23 and 6p21.3, respectively, suggestive of genetic heterogeneity.To identify the disease-causing gene for a four-generation Chinese family with dominant transmission of a form of HHS. The work was carried out at State Key Laboratory of Medical Genomics.Genome-wide screening was carried out in a Chinese family with HHS using microsatellite markers, and linkage analysis was performed using the MLINK program.The highest two-point logarithm of the odds (LOD) score was obtained with the microsatellite marker D13S217 (LOD score of 4.041 at theta = 0.00). After fine mapping and haplotype analysis, we defined a critical region of about 9.57 cM flanked by markers D13S1243 and D13S1299. The disease-causing gene was mapped to 13q12.12 approximately 12.3 in this family.A novel locus for HHS maps to chromosome 13q12.12 approximately 12.3 in a Chinese family.

To study the malignant transformation of human bronchial epithelial cells induced by glycidyl methacrylate (GMA).16HBE cells were treated multiple times with GMA at concentrations of 1, 2, 4 and 8 microg/ml. Cellular biological characteristics of malignant transformation were identified by the tests of conA, colony forming frequency on soft agar, scanning electron microscope and tumorigenesis in nude mice. Test of immunocytochemical detection was also applied to confirm the derivation of cell and tumor. Groups of solvent control (DMSO) and positive control (MCA) were also performed at the same time.Transformed foci could be observed after the cells were treated by GMA at concentrations from 1 to 8 microg/ml. The number of transformation foci increased with the concentration of GMA. Transforming rate in 8 microg/ml group (8.48 x 10(-6)) was significantly higher (P0.01) than that of solvent control group (4.5 x 10(-7)). The transformed cells lost contact inhibition and exhibited a crossover growth in culture dish. They also could grow in semi-solid agar and showed dose-reaction relations with the concentration of GMA. The colony forming frequency in 2, 4 and 8 microg/ml group was 1.20 per thousand, 2.35 per thousand and 5.70 per thousand respectively, which were higher than that of solvent control group (P0.01). The transformed cells could be agglutinated by low concentration of conA. Microvilli on the surface of transformed cells increased and became strong and long under scanning electron microscope. The transformed cells could form subcutaneous tumor in nude mice which was diagnosed as squamous cell carcinoma in morphology. Expression of cytokeratin (CK) was detected in both 16HBE cells and tumor formed in nude mice.GMA could induce the malignant transformation of 16HBE cells. This research system might provide a potential tool and lay a foundation for the study of the molecular mechanism of carcinogenesis induced by GMA.