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We aimed to explore the effect of chaetocin on atherosclerosis and its possible mechanism. In vitro, we observed that chaetocin treatment significantly inhibited the proliferation of VSMCs in concentration- and time-dependent manner. We also found that chaetocin suppressed the migration of VSMCs. Moreover, chaetocin treatment induced a contractile phenotype in VSMCs by increasing α-SMA and SM22α expression. In addition, chaetocin treatment attenuated the accumulation of H3K9me3 on VSMCs contractile gene promoters, which promoted the expression of α-SMA and SM22α. In vivo, chaetocin treatment decreased the H3K9me3 expression, diminished atherosclerotic plaque formation, and increased plaque stability by decreasing necrotic core area and lipid accumulation and increasing collagen content and contractile VSMC phenotype. We demonstrated a new function of chaetocin in inhibiting atherosclerosis progression and increasing plaque stability partly by inhibiting pathological phenotypic switching of VSMCs. These newly identified roles of chaetocin might provide a novel therapeutic target in atherosclerosis.

Yu-Jie Wang,1,&ast; Chun-Hua Jin,2,&ast; Jiang-Feng Ke,1 Jun-Wei Wang,1 Yi-Lin Ma,1 Jun-Xi Lu,1 Mei-Fang Li,3 Lian-Xi Li1 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China; 2Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Preparatory Stage), Shanghai, People’s Republic of China; 3Department of Emergency, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mei-Fang Li, Department of Emergency, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People’s Republic of China, Tel +86 18930170426, Email 15821955054@126.com Lian-Xi Li, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600 Yishan Road, Shanghai, 200233, People’s Republic of China, Tel +86 21 64369181x58337, Email lilx@sjtu.edu.cnPurpose: The association between serum osteocalcin (OCN) levels and metabolic dysfunction-associated fatty liver disease (MAFLD) is still controversial. Moreover, few studies have explored their relationship in type 2 diabetes mellitus (T2DM) patients so far. The present study aimed to investigate the association of serum OCN levels with MAFLD in Chinese T2DM patients.Methods: This cross-sectional, real-world study included 1889 Chinese T2DM inpatients. MAFLD was diagnosed by abdominal ultrasonography. Participants were divided into four groups according to serum OCN quartiles, among which the clinical characteristics were compared. The association of serum OCN levels with the presence of MAFLD was also analyzed in subjects.Results: After controlling for sex, age, and diabetes duration, the prevalence of MAFLD significantly decreased across the serum OCN quartiles (55.3%, 52.0%, 48.6%, and 42.1% for the first, second, third, and fourth quartiles, respectively, P < 0.001 for trend). A fully adjusted multiple logistic regression analysis showed that serum OCN levels were independently and negatively associated with the presence of MAFLD in T2DM patients (odds ratio, 0.832; 95% confidence interval, 0.719– 0.962; P = 0.013). Furthermore, there were significant decreases in HOMA-IR (P = 0.001 for trend) and C-reactive protein (P < 0.001 for trend) levels across the serum OCN quartiles after controlling for sex, age, and diabetes duration.Conclusion: Serum OCN levels were independently and negatively associated with the presence of MAFLD in Chinese T2DM patients, partially due to the improvement of insulin resistance and inflammation mediated by OCN. Serum OCN may be used as a biomarker to assess the risk of MAFLD in T2DM patients.Keywords: diabetes mellitus, type 2, metabolic dysfunction-associated fatty liver disease, osteocalcin, insulin resistance, inflammation

Two new chromone derivatives (

Chemical investigation of an EtOAc extract of the endophytic fungus

Background and aims Vascular smooth muscle cells (VSMCs) play a critical role in atherosclerosis. The family with sequence similarity 172, member A (FAM172A) is a novel protein and its role in atherosclerosis has not been explored so far. Therefore, our aim is to investigate whether FAM172A affects atheroprogression through VSMCs and its possible mechanism. Methods Fam172a−/− mice were generated using CRISPR/Cas9 technology. Fam172a−/− and Apoe−/− double knockout (Fam172a−/−/Apoe−/−) mice and their littermates (Fam172a+/+/Apoe−/−) were fed with a Western diet for 18 weeks to induce advanced atherosclerotic lesions. The role and mechanism of Fam172a in phenotypic switching, proliferation and migration of VSMCs were investigated through in vivo and in vitro experiments. Results Compared with Fam172a+/+/Apoe−/− mice, Fam172a−/−/Apoe−/− mice showed increased atherosclerotic lesion size and plaque instability such as increased necrotic core area and decreased fiber deposition. Additionally, knockout of Fam172a promoted expression of CD68 and KLF4 and decreased expression of α-SMA and SM22α in atherosclerotic lesions. Furthermore, overexpression of Fam172a promoted Movas cells proliferation and migration, increased expression of α-SMA and SM22α and decreased expression of KLF4. Meanwhile, knockdown of Fam172a in Movas cells and deletion of Fam172a in VSMCs from Fam172a−/−/Apoe−/− mice showed opposite phenotypes. Similar phenotypes were also observed in human aortic smooth muscle cells. Conclusions Our results provide the first direct evidence that Fam172a has a protective role in advanced atherosclerosis by increasing atherosclerotic plaque stability and inhibiting transition of VSMCs from contractile to synthetic phenotype, which may be through KLF4-dependent pathway.

Jinghui Lin, Meifang Li, Shijie Chen, Lihong Weng, Zhiyong He Department of Thoracic Medical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou City, Fujian Province, 350014, People’s Republic of ChinaCorrespondence: Zhiyong HeDepartment of Thoracic Medical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou City, Fujian Province, 350014, People’s Republic of ChinaEmail zhiyonghecn@sina.comPurpose: This single-center, open-label, single-arm, phase II clinical trial aimed to examine the efficacy and safety of the first-generation EGFR-TKIs combined with chemotherapy among treatment-naïve advanced non-small-cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations.Materials and Methods: Patients with advanced EGFR-mutant NSCLC were given concurrent gefitinib (250 mg orally daily) and 3-week cycle of carboplatin plus pemetrexed for 4 to 6 cycles, followed by gefitinib maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This trial was registered at ClinicalTrials.gov (NCT02886195).Results: Of the 21 patients enrolled in this study, a 76.2% ORR and 100% DCR were observed and a higher ORR was seen in patients with EGFR 21L858R mutations than in those with 19del mutations (P = 0.012). The subjects had a median PFS of 15.0 months and a median OS of 26.0 months, and numerically longer PFS was seen in patients with EGFR 21L858R mutations than in those with 19del mutations (P = 0.281). There were 15 NSCLC patients without cerebral metastases at baseline, with 4 cases developing cerebral metastases during the treatment, and the 6-, 12- and 24-month cumulative incidence rates of the central nervous system metastasis were 6.67%, 13.3% and 26.7%, respectively. There were 17 subjects with progressive diseases tested for EGFR T790M mutations, and 11 cases were positive for T790M mutations. Grade 3 toxicity included neutropenia (9.5%), leukopenia (4.8%), liver dysfunction (9.5%) and diarrhea (4.8%), and no grade 4 adverse events or treatment-related death occurred.Conclusion: The combination of first-generation EGFR-TKIs and chemotherapy achieves a satisfactory PFS, ORR and DCR and well-tolerated toxicity in advanced NSCLC patients with EGFR mutations, notably in patients with EGFR L858R mutations.Keywords: non-small-cell lung cancer, EGFR-TKIs, chemotherapy, combination strategy, clinical efficacy, toxicity

Chemical investigation of an EtOAc extract of the endophytic fungus Pseudocercospora sp. TSS-1 led to the isolation of three new polyketide derivatives, including one benzophenon derivative (1), two spirocyclic polyketides (4 and 5), along with four known compounds (2, 3, 6 and 7). Their structures and the absolute configurations were characterized by means of NMR, HRESIMS, 13C NMR and theoretical electronic circular dichroism calculations. Furthermore, all compounds were evaluated for their antibacterial activity against four microbial pathogens (Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Escherichia coli), and compounds 1, 2, 3 and 5 displayed significant selective antibacterial activity against S. aureus with MIC values ranging from 3.9 to 7.8 µg/mL.

Background: The associations between serum free triiodothyronine (FT3) and diabetic peripheral neuropatprohy (DPN) / carotid atherosclerotic lesions in type 2 diabetic patients with normal thyroid function is still unclear. The purpose of our study was to explore the relationships of FT3 with DPN and carotid atherosclerotic lesions in Chinese type 2 diabetes inpatients with euthyroid function.Methods: A total of 2477 type 2 diabetes inpatients with euthyroid function were recruited in this cross-sectional study, and they were stratified into quartiles by FT3 levels. Peripheral neuropathy was assessed by neurological symptoms and signs as well as nerve conduction velocity tests. Carotid atherosclerotic lesions, including carotid intima-media thickness, plaque and stenosis, were evaluated by Doppler ultrasound. Results: After adjusting for potential confounders, there was a significant decrease in the prevalence of DPN in the patients with type 2 diabetes across the FT3 quartiles (23.5%, 20.9%, 18.9%, and 11.2%, respectively, p < 0.001). Logistical regression analysis further revealed that FT3 quartiles were significantly and inversely associated with DPN. Compared with the subjects in the highest FT3 quartile, the adjusted odds ratios (95% confidence interval) of DPN in the first to third FT3 quartile were successively 2.338 (1.407-3.884), 1.903 (1.134-3.194) and 1.598 (0.960-1.125). The patients with DPN had significantly higher prevalence of carotid plaques (55.8%) and carotid stenosis (1.3%) than non-DPN patients (44.8%; 0.5%). However, no statistical association was observed between FT3 quartiles and carotid atherosclerotic lesions.Conclusions: Lower FT3 within the normal range was independently associated with DPN, but not with carotid atherosclerotic lesions in Chinese type 2 diabetes inpatients with euthyroid function.

Background Primary familial brain calcification (PFBC) is a rare degenerative disease characterized by symmetrical bilateral calcinosis in the basal ganglia and other brain regions. It has an autosomal dominant inheritance pattern in most cases and exhibits genetic heterogeneity. Previous studies reported that SLC20A2, PDGFRB, PDGFB, XPR1 and MYORG are associated with PFBC, with SLC20A2 the main culprit. However, other mutations may also cause PFBC. Here, we performed a study to reveal the contributing mutations that gave rise to PFBC in a Chinese PFBC family. Methods We recruited a PFBC family consisting of eight patients and eight healthy family members across three generations. Whole-exome sequencing, Sanger sequencing and RT-PCR were used to detect the genetic mutations. Results Whole-exome sequencing revealed that c.730 + 1G > A of SLC20A2 was the candidate pathogenic mutation for the proband in this family. Genomic DNA PCR amplification and Sanger sequencing confirmed that all the patients from the family carried this mutation, while the healthy subjects in the family did not. Complementary DNA (cDNA) PCR amplification and Sanger sequencing confirmed that the patients had a mutation that caused exon 6 skipping in SLC20A2. Conclusion We identified a SLC20A2 splicing variant (c.730 + 1G > A) in a PFBC family. This mutation led to an alternative splicing event that skipped exon 6 in SLC20A2.

Background Non-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases. Patients and methods The medical records of 104 treatment-naive, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts. Results The baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526). Conclusion Our data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy.

Resistance to chemotherapy remains a significant problem in the treatment of breast cancer, especially for triple negative breast cancer (TNBC), in which standard systemic therapy is currently limited to chemotherapeutic agents. Our study aimed to better understand the molecular mechanisms that lead to failure of chemotherapy in TNBC. Herein, we observed elevated expression of Notch1 and major vault protein (MVP) in MDA-MB-231DDPR cells compared to their parental counterparts. We demonstrated that Notch1 could positively regulate the expression of MVP. Also, Notch1 intracellular domain (ICD) was capable of binding to CBF-1 on the promoter of MVP to drive its transcription, resulting in activation of AKT pathway and promoting the progress of epithelial to mesenchymal transition (EMT). Conversely, silencing of Notch1 and MVP suppressed AKT pathway, reduced EMT and enhanced the sensitivity of TNBC cells to cisplatin and doxorubicin. Survival analysis indicated that the MVP was closely related to shorter recurrence-free survival (RFS) in patients with TNBC. Collectively, this study provides evidence that Notch1 activates AKT pathway and promotes EMT partly through direct activation of MVP. Targeting Notch1/MVP pathway appears to have potential in overcoming chemoresistance in TNBC.

Background: Increasing evidence suggests that de novo T790M mutation occurs at a low frequency in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, the effects of this mutation on the formation of T790M resistant clones and efficacy of EGFR tyrosine kinase inhibitors (TKIs) remain unclear. Methods: Fifty-nine treatment-naïve in-patients with advanced EGFR-mutant NSCLC were enrolled in this study between 2017 and 2018. We dynamically monitored T790M mutation in ctDNA of patients before and during treatment with first-generation EGFR-TKIs, which were administered every 2 to 3 months until disease progression. Results: Among the patients, 28.81% (17/59) had a low-frequency de novo T790M mutation, 66.67% (10/15) of them retained T790M mutation and resistance in this group was defined as “selection” resistance. T790M mutation was detected after treatment in 42.3% (11/26) of patients without de novo T790M mutation who experienced disease progression and resistance in this group was defined as “acquisition” resistance. After treatment with third-generation EGFR-TKI, patients with the “selection” T790M resistance mutation had significantly better objective response rate (ORR) and longer progression-free survival (PFS) than those with the “acquisition” T790M resistance mutation. Conclusion: Our study provides evidence that low-frequency de novo T790M mutation is not rare in patients with advanced EGFR-mutant NSCLC. T790M resistance mutations can have two origins: the selection of low-frequency de novo T790M clones or the acquisition of the mutation in initially T790M-negative cells clinically. Since the origin of T790M resistance mutations can affect the efficacy of third-generation EGFR-TKIs, these EGFR-TKIs may be more effective for the treatment of NSCLC patients with “selection” T790M resistance mutations.

Aims: To compare the effects of maternal subclinical hypothyroidism (SCH) diagnosed by the 2011 or 2017 “Guidelines of the American Thyroid Association (ATA) for the diagnosis and management of thyroid disease during pregnancy and the postpartum” during the first trimester on adverse pregnancy outcomes in thyroid peroxidase antibody (TPOAb)–negative pregnant women. Methods: There were 1,556 Chinese singleton pregnant women with negative TPOAb diagnosed with either SCH or euthyroidism who were investigated, and the prevalence and risk of obstetric outcomes were compared between the two groups using 2011 and 2017 ATA standards, respectively. The effects of a mildly elevated thyroid-stimulating hormone (TSH) concentration on adverse pregnancy outcomes were evaluated by binary logistic regression. Results: Maternal SCH identified by the 2011 ATA guidelines correlated with higher rates and risks of pregnancy-induced hypertension (PIH), preeclampsia, and low-birth-weight infants, while maternal SCH diagnosed by the 2017 ATA guidelines was more likely to develop PIH, preeclampsia, cesarean delivery, preterm delivery, placenta previa, and total adverse maternal and neonatal outcomes. Moreover, a mildly elevated TSH level was significantly associated with PIH after adjustment for confounding factors. Conclusions: Compared with the 2011 ATA guidelines, the 2017 ATA guidelines could be more applicable to Chinese pregnant women to screen the effects of SCH on the majority of adverse pregnancy outcomes.

Our aims were to uncover the role of FAM172A (Family with sequence similarity 172 member A) in the pathogenesis of follicular thyroid carcinoma (FTC) and to evaluate its value in the differential diagnosis between malignant and benign thyroid follicular lesions. FAM172A expression was evaluated by q-PCR, immunoblotting and immunohistochemistry (IHC). The ability of proliferation, migration and invasion of cells were assessed by Cell Counting Kit-8 assay (CCK8), clone-formation and Transwell assays. Nude mouse tumorigenicity assays were used to investigate the role of FAM172A in the pathogenesis of FTC in vivo. The value of FAM172A in the differential diagnosis for FTC was assessed using 120 formalin-fixed paraffin-embedded (FFPE) tissues after the operation and 81 fine-needle aspiration biopsy (FNAB) samples before the operation. FAM172A was highly expressed in FTC tissues and FTC cell lines. Downregulation of FAM172A inhibited the proliferation, invasion and migration of FTC cells through Erk1/2 and JNK pathways. Subcutaneous tumorigenesis in nude mice showed that knockdown of FAM172A inhibited tumor growth and progression in vivo. The FAM172A IHC scores of 3.5 had 92% sensitivity and 63% specificity to separate FTC from benign/borderline thyroid follicular lesions, and 92% sensitivity and 80% specificity to discriminate FTC from benign thyroid follicular lesions in postoperative FFPE samples. The corresponding values were 75 and 78%, and 75 and 89% in preoperative FNA samples, respectively. FAM172A plays an important role in the pathogenesis of FTC through Erk1/2 and JNK pathways. FAM172A may be a potential marker for the preoperative diagnosis of FTC based on the IHC results of thyroid FNAB samples.

Amphiphilic copolymers, poly(styrene)-block-Tb complex (PS-b-Tb complex), were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The honeycomb structured porous films were fabricated via dropping the PS-b-Tb complex copolymer solutions on glass substrates by the breath figures method (BFM). The structure and composition of the amphiphilic copolymer PS-b-Tb complex were confirmed by gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FT-IR) and 1H nuclear magnetic resonance spectroscopy (1H NMR). The surface morphology and elemental mapping of the highly ordered porous films were investigated by field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDX) and laser scanning confocal microscopy (LSCM). The results indicated that the solvent type and copolymer concentration can affect the surface morphology of the porous films. The average diameter of the pores in the porous films decreased with the polymer concentration and the molecular weight of the copolymers increased. The FESEM-EDX analysis further verified that the hydrophilic groups (Tb complex groups) were mainly distributed at the pore wall, instead of at the outer surface layer of the films, which was consistent with the LSCM results.

Despite remarkable advancements in our understanding of breast cancer, it remains the leading cause of cancer deaths in women. Distant recurrence and metastasis is the main reason for death due to breast cancer. It is well recognized that the GATA binding protein 3 (GATA3), a transcription factor, is a tumor suppressor in breast cancer. To date, the mechanistic molecular details of GATA3 remain elusive, because, as a transcription factor, it is not a direct executor in physiological and pathological processes. Here, we demonstrate that GATA3 reduces the ATP level in the breast cancer microenvironment and inhibits breast cancer metastasis by up-regulating ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3). The extracellular ATP concentration is significantly higher in tumor tissues than in normal tissues and promotes the migration of cancer cells from the primary site. ENTPD3 hydrolyzes ATP in tumor microenvironment and suppresses breast cancer metastasis. Furthermore, ENTPD3 inhibits epithelial-to-mesenchymal transition, a key program responsible for the development of metastatic disease. These findings provide novel insights into the tumor suppressor activity of GATA3.

Recent studies suggest that histone modification is one of the mechanisms regulating inflammatory cytokine gene expression in hyperglycemic conditions. However, it remains unknown how histone methylation is initiated and involved in changes of inflammatory cytokine gene expression under high glucose (HG) conditions. Our aim was to investigate whether H3K9 methylation was involved in HG-induced expression of inflammatory cytokines in macrophages. Expression profile of cytokine genes under hyperglycemia in THP-1-derived macrophages was determined by human cytokine antibody array. Based on the results from the human cytokine antibody array analyses, the H3K9me3 levels of 4 inflammatory cytokine genes, including interleukin-6 (IL-6), IL-12p40, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β under HG were determined by ChIP assays. Furthermore, the expression of these 4 inflammatory cytokine genes under either HG or chaetocin (an inhibitor of SUV39H1 methyltransferase) exposure or overexpression of SUV39H1 (a H3K9me3-specific methyltransferase) was analyzed by quantitative polymerase chain reaction. Macrophages cultured in HG conditions showed increased gene expression and decreased H3K9me3 levels of inflammatory cytokine genes compared with macrophages incubated in normal glucose (NG) culture. Inhibition of SUV39H1 with chaetocin in NG-treated macrophages also increased the expression of IL-6, IL-12p40, MIP-1α, and MIP-1β. Furthermore, inhibition of SUV39H1 with chaetocin in HG-treated macrophages further increased the expression of these inflammatory cytokines. Contrarily, NG-treated macrophages transfected with SUV39H1 plasmids show decreased expression of inflammatory cytokines. Furthermore, overexpression of SUV39H1 in HG-treated macrophages alleviated the expression of inflammatory cytokines under HG conditions. Finally, HG also increases the expression of inflammation cytokines in mouse bone marrow-derived macrophages. Our data demonstrated that HG increases the expression of inflammatory cytokines in macrophages through decreased H3K9me3 levels, which was partly mediated by SUV39H1. Dysregulation of epigenetic histone modification may be one of the underlying mechanisms for HG-induced inflammatory cytokine expression in macrophages.

Amphiphilic copolymers, poly(styrene)

Objective: Serum uric acid (SUA) is associated with many cardiovascular risk factors such as hypertension (HTN) and metabolic syndrome (MetS). However, the association of SUA with atherosclerosis remains controversial. Our aim was to investigate the relationships of SUA with HTN, MetS and atherosclerosis in Chinese inpatients with type 2 diabetes. Methods: This cross-sectional study was performed with a sample of 2388 hospitalized Chinese patients with type 2 diabetes. Both carotid and lower limb atherosclerotic lesions were assessed for intima–media thickness, plaque and stenosis by Doppler ultrasound. Atherosclerotic plaque and stenosis were defined as the presence of either carotid or lower limb plaques and stenoses, respectively. Results: There were significant increases in the prevalence of both HTN and MetS across the SUA quartiles (HTN: 43.4, 49.6, 56.1 and 66.3% for the first, second, third and fourth quartiles, respectively, P

Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4+CXCR5+ follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4+CXCR5+ T cells were enriched with the interferon (IFN)-γ-secreting Th1-subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4-secreting Th2 subtype. We further demonstrated that a host of microbial motifs, including Pam3CSK4, poly(I:C), LPS, imiquimod, and CpG, could significantly stimulate IFN-γ, IL-17, and/or IL-21 from circulating CD4+CXCR5+ T cells in PBC patients, especially in the presence of monocytes and B cells. Whole bacterial cells of Escherichia coli, Novosphingobium aromaticivorans, and Mycobacterium gordonae, could also potently stimulate IFN-γ, IL-17, and/or IL-21 production from circulating CD4+CXCR5+ T cells. But interestingly, while the whole cell could potently stimulate circulating CD4+CXCR5+ T cells from both healthy controls and PBC patients, the cell protein lysate could only potently stimulate circulating CD4+CXCR5+ T cells from PBC patients, but not those from healthy controls, suggesting that circulating CD4+CXCR5+ T cells in PBC patients had distinctive antigen-specificity from those in healthy individuals. Together, these data demonstrated that bacterial antigen stimulation is a potential source of aberrant Tfh cell activation in PBC patients.

Aims/Introduction Microalbuminuria is positively related to metabolic syndrome (MetS). Our aim was to investigate whether urinary albumin-to-creatinine ratio (UACR) within the normal range is independently associated with MetS in Chinese community-based patients with type 2 diabetes. Materials and Methods A total of 514 participants (206 males and 308 females; mean age 66 years) with UACR less than 3.5 mg/mmol were enrolled from two downtown areas of Shanghai. The participants were stratified into quartiles according to UACR levels. The prevalence of MetS was assessed and compared among the four groups by binary logistic regression. Results Compared with participants with UACRs in the first quartile, the other quartiles had a higher prevalence of MetS (65.9%, 74.4% and 81.3%, respectively, P = 0.001) after adjustment for sex and age. After adjusting for potential confounders, participants in the second to the fourth quartile group had a 1.36-, 1.84- and 2.73-fold risk of MetS, respectively, relative to those in the lowest quartile. Furthermore, UACR, whether as quartile groups or as a continuous variable, is an independent predictor of MetS after fully adjusting for other variables. Conclusions These results suggest that UACR even within the normal range is independently associated with MetS in Chinese community-based patients with type 2 diabetes mellitus.

Aims/Introduction To compare carotid and lower limb atherosclerotic lesions, and examine if carotid atherosclerotic lesions are in line with lower limb atherosclerotic lesions, and can reflect generalized atherosclerosis in inpatients with type 2 diabetes. Materials and Methods This was an observational study carried out in 867 Chinese inpatients with type 2 diabetes, including 573 previously known and 294 newly diagnosed patients. Ultrasonographic assessments of intima-media thickness (IMT), plaques, and stenosis in the carotid and lower limb arteries were evaluated. Atherosclerotic lesions between the carotid and lower limb arteries were compared in both previously known and newly diagnosed diabetes, respectively. Results In both the known (77.3% vs 49.4%, P

Background Both carotid and lower limb atherosclerosis are associated with increased cardiovascular and cerebrovascular risks. However, it is still unclear whether the concomitant presence of carotid and lower extremity atherosclerosis further increases the cardiovascular and cerebrovascular risks. Therefore, our aim is to investigate whether the coexistence of carotid and lower extremity atherosclerosis was associated with higher cardiovascular and cerebrovascular risks in patients with type 2 diabetes. Methods This cross-sectional study was performed in 2830 hospitalized patients with type 2 diabetes. Based on carotid and lower limb Doppler ultrasound results, the patients were divided into three groups including 711 subjects without atherosclerosis, 999 subjects with either carotid or lower limb atherosclerosis, and 1120 subjects with both carotid and lower limb atherosclerosis. And we compared the clinical characteristics and prevalence of both cardio-cerebrovascular events (CCBVEs) and self-reported cardio- cerebrovascular diseases (CCBVDs) among the three groups. Results After adjusting for age, sex, and duration of diabetes, there were significant increases in the prevalence of both CCBVEs (3.8 vs. 11.8 vs. 26.4 %, p

The central-loop TEM technology has been widely used in geological exploration. For efficient working, a square (or rectangular) loop is generally used instead of the circular one. One may define a range of one ninth of central part (can be approximately regarded as uniform) as the central survey location, which can be referred as a modified central-loop configuration. However, the obtained field parameters at such non central positions usually calculated by the central-loop formula result in decreased accuracy in the explanation. The large-fixed loop has advantage to calculate the induction potential at any point inside or outside the loop. We in this study introduced the formula for the larger fixed loop into the above modified central-loop system and solve the problem, in which electromagnetic response of any field point has been obtained by using an electric dipole integration method. Both theoretical modeling and real application indicate that such combination not only improves the accuracy for the TEM survey, but also enlarges the exploration depth due to a large loop is used in the deployment.

Aroused by the differential stiffness of pile and soil, the upper load on subgrade is apt to be transferred to pile rather than soil among piles in pile supported embankment(soil arching effect), which optimizes the load-transfer path and effectively limits total settlement of the subgrade. In this paper the properties of soil arch under dynamic load have been investigated by performing numerical studies using the Finite Element Method. The influence of stiffness difference between soil and pile on the soil arch is also proposed in this paper. According to the calculation results, the softer the soil between piles is, the larger proportion of load imposes on pile. Dynamic load has negative effects on the static soil arch, but it does not ruin the shape of the arch. Simultaneously, the larger N (the ratio of dynamic modulus of pile to that of soil)is, the weaker the negative effects of dynamic load on static soil arch are. The static soil arch (soil arch formed when the model only bears static load) has optimized the load transformation path, leading more load undertaken by the pile. Besides, When the stiffness difference between pile and soil among piles is relatively small, the height of soil arch increases sharply with the decrease of N; while when the stiffness difference reaches some certain value, the further increasing of N has little influence on soil arch’s height.

The central-loop TEM technology has been widely used in mineral exploration, engineering and environmental investigations and assorted geologic studies. For easy and efficient working conditions, a square (or rectangular) loop is generally employed instead of a circular one. Any position within the inner one ninth of the central part of the loop is often designated as the central survey location (within which the field is assumed to be uniform), and referred to as a modified central-loop configuration. However, the deduced field parameters at such non-central positions when calculated by a central-loop formula result in decreased accuracy and possibly erroneous interpretation. A large-fixed loop offers the advantage of being able to determine the induced potential at any point inside or outside the loop. In this study we provide the formula for the large-fixed loop and receiver positions within the modified central-loop system and solve the problem. Specifically, we compute the electromagnetic response of any field point by using an electric dipole integration method. The full time-domain apparent resistivity values are then extracted by using an iterative method. Both theoretical modeling and real data examples indicate that such a configuration not only improves the accuracy for the TEM survey, but also enlarges the exploration depth, due to a large loop used in the deployment. The method is used for locating the water enriched areas in coal mines in Yangquan region of Shanxi province and in Bin County of Shaanxi province, China. The interpreted results are tested by later drilling, which confirmed our combined method to be a reliable and efficient method for deep sounding.

The slab track is a new sort of track structure, which has been widely used in high-speed rail and special line for passenger. However, the ballastless track structure design theory is still not perfect and can not meet the requirements of current high-speed rail and passenger line ballastless track. In this paper, composite beam method is used to calculate the deflection of the track plate and in this way the vertical supporting stress distribution of the track plate can be gotten which set a basis for the follow-up study of the dynamic stress distribution in the subgrade. Slab track plate’s bearing stress under moving load is analyzed through Matlab program. By calculation and analysis, it is found that the deflection of track plate and the rail in the double-point-supported finite beam model refers to the rate of spring coefficient of the fastener and the mortar.The supporting stress of the rail plate is inversely proportional to the supporting stress of the rail. The two boundary conditions of that model ,namely, setting the end of the model in the seams of the track plate or not , have little effect on the results. We can use the supporting stress of the track plates on state 1to get the distribution of the supporting stress in the track plate when bogies pass. Also, when the dynamic load magnification factor is 1.2, the track plate supporting stress of CRST I & CRST II-plate non-ballasted structure is around 40kPa.

The role of miR-26a in carcinogenesis appears to be a complicated one, in the sense that both oncogenic and tumor suppressive effects were reported in cancers such as glioblastoma and hepatocellular carcinoma, respectively. Here, we report for the first time that miR-26a is downregulated in breast cancer specimens and cell lines and its transient transfection initiates apoptosis of breast cancer cell line MCF7 cells. Furthermore, retrovirus-delivered miR-26a impairs the in vitro colony forming and in vivo tumor-loading ability of MCF7 cells. Subsequently, MTDH and EZH2 are identified as two direct targets of miR-26a and they are significantly upregulated in breast cancer. MCF7 xenografts with exogenous miR-26a show that a decrease in expression of both MTDH and EZH2 is accompanied by an increase in apoptosis. Moreover, knockdown of MTDH causes apoptosis while reexpression of MTDH partially reverses the proapoptotic effect of miR-26a in MCF7 cells. Our findings suggest that miR-26a functionally antagonizes human breast carcinogenesis by targeting MTDH and EZH2.

Family with sequence similarity 172, member A (FAM172A), was cloned from human aortic tissues and confirmed in our previous study in 2009, however, its functions remain to be fully elucidated. In our previous studies, the protein expression of FAM172A in human aortic smooth muscle cells was found to be upregulated by high glucose in a concentration‑ and time‑dependent manner. Several reports have shown that insulin resistance is associated with papillary thyroid carcinoma (PTC). Thus, in the present study, the protein expression levels of FAM172A in human papillary thyroid carcinoma were investigated, and the effect of the FAM172A protein on the proliferation of IHH‑4 human papillary thyroid carcinoma cells, and its potential molecular underlying mechanisms were examined. Immunohistochemistry and western blotting demonstrated that the protein expression of FAM172A in papillary thyroid carcinoma tissues was not only significantly higher than that in noncancerous tissues adjacent to the carcinoma tissues, but it was also markedly higher than that in normal thyroid and thyroid adenoma tissues. Overexpression of the FAM172A protein activated the p38 MAPK pathway, but not the PI3K and AMPK pathways, in the IHH‑4 cells. In addition, overexpression of the FAM172A protein accelerated IHH‑4 cell proliferation, compared with the control group, and the pro‑proliferative effect of FAM172A protein on IHH4 cells was markedly attenuated by SB202190, an inhibitor of p38 MAPK. Taken together, these results suggest that the FAM172A protein is expressed at high levels in human PTC, which may promote cell proliferation via activation of the p38 MAPK signaling pathway, and be involved in the pathogenesis of PTC.

Background The clinical features of atherosclerotic lesions in ketosis-onset diabetes are largely absent. We aimed to compare the characteristics of lower limb atherosclerotic lesions among type 1, ketosis-onset and non-ketotic type 2 diabetes. Methods A cross-sectional study was performed in newly diagnosed Chinese patients with diabetes, including 53 type 1 diabetics with positive islet-associated autoantibodies, 208 ketosis-onset diabetics without islet-associated autoantibodies, and 215 non-ketotic type 2 diabetics. Sixty-two subjects without diabetes were used as control. Femoral intima-media thickness (FIMT), lower limb atherosclerotic plaque and stenosis were evaluated and compared among the four groups based on ultrasonography. The risk factors associated with lower limb atherosclerotic plaque were evaluated via binary logistic regression in patients with diabetes. Results After adjusting for age and sex, the prevalence of lower limb plaque in the patients with ketosis-onset diabetes (47.6%) was significantly higher than in the control subjects (25.8%, p = 0.013), and showed a higher trend compared with the patients with type 1 diabetes (39.6%, p = 0.072), but no difference was observed in comparison to the patients with non-ketotic type 2 diabetes (62.3%, p = 0.859). The mean FIMT in the ketosis-onset diabetics (0.73 ± 0.17 mm) was markedly greater than that in the control subjects (0.69 ± 0.13 mm, p = 0.045) after controlling for age and sex, but no significant differences were found between the ketosis-onset diabetics and the type 1 diabetics (0.71 ± 0.16 mm, p = 0.373), and the non-ketotic type 2 diabetics (0.80 ± 0.22 mm, p = 0.280), respectively. Age and FIMT were independent risk factors for the presence of lower limb plaque in both the ketosis-onset and non-ketotic type 2 diabetic patients, while sex and age in the type 1 diabetic patients. Conclusions The prevalence and risk of lower limb atherosclerotic plaque in the ketosis-onset diabetes were remarkably higher than in the control subjects without diabetes. The features and risk factors of lower limb atherosclerotic lesions in the ketosis-onset diabetes resembled those in the non-ketotic type 2 diabetes, but different from those in the type 1 diabetes. Our findings provide further evidences to support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes rather than idiopathic type 1 diabetes.