Associations between exposure to various air pollutants and risk of metabolic syndrome: a systematic review and meta-analysis.

BACKGROUND: Metabolic Syndrome (MetS) is a widely observed metabolic disorder that is increasingly prevalent worldwide, leading to substantial societal consequences. Previous studies have conducted two separate meta-analyses to investigate the relationship between MetS and air pollutants. However, these studies yielded conflicting results, necessitating a thorough systematic review and meta-analysis to reassess the link between different air pollutants and the risk of developing MetS. METHODS: We conducted a comprehensive search of relevant literature in databases including PubMed, Embase, Cochrane Library, and Web of Science up to October 9, 2023. The search was specifically restricted to publications in the English language. Following the screening of studies investigating the correlation between air pollution and MetS, we utilized random-effects models to calculate pooled effect sizes along with their respective 95% confidence intervals (CIs). We would like to highlight that this study has been registered with PROSPERO, and it can be identified by the registration number CRD42023484421. RESULTS: The study included twenty-four eligible studies. The results revealed that an increase of 10 µg/m3 in annual concentrations of PM1, PM2.5, PM10, NO2, SO2, and O3 was associated with a 29% increase in metabolic syndrome (MetS) risk for PM1 (OR = 1.29 [CI 1.07-1.54]), an 8% increase for PM2.5 (OR = 1.08 [CI 1.06-1.10]), a 17% increase for PM10 (OR = 1.17 [CI 1.08-1.27]), a 24% increase for NO2 (OR = 1.24 [CI 1.01-1.51]), a 19% increase for SO2 (OR = 1.19 [CI 1.04-1.36]), and a 10% increase for O3 (OR = 1.10 [CI 1.07-1.13]). CONCLUSION: The findings of this study demonstrate a significant association between exposure to fine particulate matter (PM1, PM2.5, PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and the incidence of metabolic syndrome (MetS). Moreover, the results suggest that air pollution exposure could potentially contribute to the development of MetS in humans.

Regulating oxygen vacancies by Zn atom doping to anchor and disperse promoter Ba on MgO support to improve Ru-based catalysts activity for ammonia synthesis.

In heterogeneous catalysis, surface defects are widely regarded as an effective means to enhance the catalytic performance of catalysts. In this study, the oxygen vacancy-rich Mg(1-X)ZnXO solid solution support was successfully prepared by doping a small amount of Zn into MgO nanocrystals. Based on this support, Ru/Ba-Mg(1-X)ZnXO catalyst for ammonia synthesis was prepared. Characterization using TEM, EPR, XPS, and DFT calculations confirmed the successful substitution of Zn atoms for Mg atoms leading to the formation of more oxygen vacancies (OVs). N2-TPD, SEM and TEM analyses revealed that a small amount of Zn had minimal influence on the surface morphology and the size of Ru nanoparticles. The abundance of OVs in the support was identified as the primary factor enhancing the catalytic activity. XPS, H2-TPD and kinetics experiment studies further elucidated the mechanism by which OVs promote the reaction, with OVs serving as an anchor point for the promoter Ba on the MgO support and promoted the dispersion of Ba. This anchoring effect not only enhanced the electron density on Ru, favoring the dissociation of the N[triple bond, length as m-dash]N bond, but also mitigated hydrogen poisoning. As a result,the ammonia synthesis rate reached 1.73 mmol g-1 h-1. Furthermore, the CO2-TPD and H2-TPR analyses indicated that Zn doping effectively promotes the metal-support interaction (MSI) and surface alkalinity. The findings of this study offers valuable insights for the design of defective modified catalyst supports.

MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription.

MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.

Predicting COVID-19 Re-Positive Cases in Malnourished Older Adults: A Clinical Model Development and Validation.

Purpose: Building and validating a clinical prediction model for novel coronavirus (COVID-19) re-positive cases in malnourished older adults. Patients and Methods: Malnourished older adults from January to May 2023 were retrospectively collected from the Department of Geriatrics of the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine. They were divided into a "non-re-positive" group and a "re-positive" group based on the number of COVID-19 infections, and into a training set and a validation set at a 7:3 ratio. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to identify predictive factors for COVID-19 re-positivity in malnourished older adults, and a nomogram was constructed. Independent influencing factors were screened by multivariate logistic regression. The model's goodness-of-fit, discrimination, calibration, and clinical impact were assessed by Hosmer-Lemeshow test, area under the curve (AUC), calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CIC), respectively. Results: We included 347 cases, 243 in the training set, and 104 in the validation set. We screened 10 variables as factors influencing the outcome. By multivariate logistic regression analysis, preliminary identified protective factors, risk factors, and independent influencing factors that affect the re-positive outcome. We constructed a clinical prediction model for COVID-19 re-positivity in malnourished older adults. The Hosmer-Lemeshow test yielded χ2 =5.916, P =0.657; the AUC was 0.881; when the threshold probability was >8%, using this model to predict whether malnourished older adults were re-positive for COVID-19 was more beneficial than implementing intervention programs for all patients; when the threshold was >80%, the positive estimated value was closer to the actual number of cases. Conclusion: This model can help identify the risk of COVID-19 re-positivity in malnourished older adults early, facilitate early clinical decision-making and intervention, and have important implications for improving patient outcomes. We also expect more large-scale, multicenter studies to further validate, refine, and update this model.

Relationship between bedtime, nighttime sleep duration, and anxiety symptoms in preschoolers in China.

Background: Sleep problems in preschoolers are becoming increasingly prominent, and the association between sleep status and anxiety symptoms has attracted growing attention. However, studies investigating the relationship between bedtime and nighttime sleep duration in preschoolers and their anxiety symptoms remain scant. We used the large sample data from the Longhua Cohort Study of Children in Shenzhen, China (LCCS) to analyze the association between bedtime and sleep in preschoolers and their anxiety symptoms. Methods: A cross-sectional study of 69,138 preschoolers in Longhua District, Shenzhen, China was conducted in 2022. Data on sociodemographic characteristics of families, bedtime, nighttime sleep duration of preschoolers, and their anxiety symptoms (measured by the Spence Preschool Children Anxiety Scale) were collected through a structured questionnaire completed by the parents. Using binary logistic regression models, the relationship between bedtime, nighttime sleep duration, and childhood anxiety symptoms was examined. Results: The bedtimes of preschoolers were concentrated between 21:01-22:00 (52.41%). Among the preschoolers, 38.70% had bedtimes later than 22:00, and 75.49% had insufficient nighttime sleep duration. The positive screening rate for anxiety symptoms among preschoolers was 3.50%. After adjusting for confounding factors using binary logistic regression models, compared with preschoolers with bedtime ≤21:00, The OR (95%CI) values of anxiety in preschoolers with bedtime ≥23:01, 22:01-23:00 and 21:01-22:00 were 2.86 (2.21-3.69), 1.51 (1.27-1.79) and 1.48 (1.26-1.76), respectively. Compared with those with sufficient nighttime sleep duration, the OR (95%CI) of children with nighttime sleep duration less than 9 h was 1.36 (1.23-1.51). Conclusion: An association exists between bedtime and nighttime sleep duration in preschoolers and their anxiety symptoms. Preschoolers with 21:00 for bedtime and a nighttime sleep duration of 10 h may have lower anxiety symptoms. These findings support the importance of adequate sleep for preventing anxiety symptoms in children.

Non-operative treatment strategy for appendiceal abscess in children under 3 years old: a retrospective observational study.

Background: There are few studies on appendiceal abscess with appendicolith in children under 3 years old. This study aims to explore the success rate of non-surgical treatment of appendiceal abscess and assess the potential influence of an appendicolith on non-surgical treatment outcomes in children under 3 years old. Methods: The clinical data of children under 3 years old who were diagnosed with appendiceal abscess at the Wuhan Children's Hospital, China, from February 2013 to May 2020 were collected. According to the findings of ultrasonography and CT imaging, they were divided into two groups, namely, the appendicolith group and the non-appendicolith group. Results: A total of 94 children with appendiceal abscess were identified, meeting the specified study criteria, and categorized into two groups, namely, the appendicolith group (n = 51, 54.3%) and the non-appendicolith group (n = 43, 45.7%). Non-surgical treatment was unsuccessful in six out of the 94 children, yielding an overall success rate of 93.6% for non-surgical management of appendiceal abscess in children under 3 years old. The success rate for non-surgical treatment in the appendicolith subgroup was 90.2%, whereas that for the non-appendicolith subgroup was 97.7%. No statistically significant distinction was observed between the two groups (P = 0.292). Likewise, there were no significant differences in gender, age, duration of symptoms, fever, vomiting, diarrhea, rebound pain, white blood cell count, C-reactive protein level, and abscess cross-sectional area between the appendicolith group and the non-appendicolith group. However, there is a statistical difference in tenderness in the right lower abdomen. Conclusion: Non-surgical treatment of appendiceal abscess has a high success rate and can be considered an effective treatment strategy. In pediatric patients under 3 years old without evidence of complete intestinal obstruction or diffuse peritonitis, non-surgical treatment may be considered for appendiceal abscess.

MYCN driven oncogenesis involves cooperation with WDR5 to activate canonical MYC targets and G9a to repress differentiation genes.

MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN-binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 is needed to facilitate MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.

Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models.

PURPOSE: Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo. EXPERIMENTAL DESIGN: Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo. RESULTS: Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule. CONCLUSIONS: RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.

Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma.

PURPOSE: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701). PATIENTS AND METHODS: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT). RESULTS: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response. CONCLUSIONS: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.

HAND2 Assists MYCN Enhancer Invasion to Regulate a Noradrenergic Neuroblastoma Phenotype.

Noradrenergic neuroblastoma is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TF) such as PHOX2B, HAND2, and GATA3, which form a network with MYCN. At normal physiologic levels, MYCN mainly binds to promoters but when aberrantly upregulated as in neuroblastoma, MYCN also binds to enhancers. Here, we investigated how MYCN invades enhancers and whether CRC TFs play a role in this process. HAND2 was found to regulate chromatin accessibility and to assist MYCN binding to enhancers. Moreover, HAND2 cooperated with MYCN to compete with nucleosomes to regulate global gene transcription. The cooperative interaction between MYCN and HAND2 could be targeted with an Aurora A kinase inhibitor plus a histone deacetylase inhibitor, resulting in potent downregulation of both MYCN and the CRC TFs and suppression of MYCN-amplified neuroblastoma tumor growth. This study identifies cooperation between MYCN and HAND2 in neuroblastoma and demonstrates that simultaneously targeting MYCN and CRC TFs is an effective way to treat this aggressive pediatric tumor. SIGNIFICANCE: HAND2 and MYCN compete with nucleosomes to regulate global gene transcription and to drive a malignant neuroblastoma phenotype.

Ghrelin regulates the proliferation and apoptosis of high glucose-induced islet cells through the PI3K-Akt signaling pathway.

Ghrelin may have therapeutic value in mitigating insulin resistance and type 2 diabetes, based on which we further explore the action mechanism of ghrelin on islet cells in this research. In the course of experiments, MIN6 cells were induced by glucose and then treated with acylated or unacylated ghrelin. The effects of ghrelin on the viability, proliferation, apoptosis, and insulin release of high glucose-induced islet cells were detected by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, and enzyme-linked immunosorbent assays, respectively. Meanwhile, cells were treated with LY294002 to explore whether and how the inhibited phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signaling pathway participated in the internal mechanism of ghrelin-regulating islet cells. Western blotting was performed to quantify the expression levels of Bcl-2, Bax, Cleaved caspase-3, PI3K, and AKT. As a result, ghrelin alleviated high glucose-induced suppression of viability and proliferation and promotion on apoptosis of MIN6 cells. Ghrelin also attenuated the inhibitory effects of high glucose on expression levels of PI3K-Akt signaling axis-related proteins and insulin release in MIN6 cells. Besides, ghrelin weakened the impacts of high glucose on boosting MIN6 cell apoptosis and hindering proliferation through the PI3K-Akt signaling axis. Collectively, ghrelin regulates the proliferation and apoptosis of high glucose-induced islet cells through the PI3K-Akt signaling pathway.

A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma.

PURPOSE: Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. PATIENTS AND METHODS: Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. RESULTS: Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. CONCLUSIONS: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.

The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

PURPOSE: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS. EXPERIMENTAL DESIGN: Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models. RESULTS: Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis. CONCLUSIONS: We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.

The association between time in the glucose target range and abnormal ankle-brachial index: a cross-sectional analysis.

BACKGROUND: Time in range (TIR), a novel proxy measure of glucose control, is found closely related to diabetic microangiopathy and some other chronic complications, but the correlation between TIR and lower limb angiopathy has not been studied yet. Our purpose is to explore the relationship between TIR and abnormal ankle-brachial index(ABI) in type 2 diabetes. METHODS: We retrospectively collected patients' information from the database and performed cross-sectional analysis. A total of 405 type 2 diabetes patients were enrolled in this study. ABI was measured and patients were stratified into low, normal, and high groups according to ≤ 0.9, > 0.9 and < 1.3, ≥ 1.3 ABI values. All patients underwent continuous glucose monitoring(CGM), and TIR was defined as the percentage of time in which glucose was in the range of 3.9-10 mmol/L during a 24-h period. Correlations between TIR and abnormal ABI were analyzed using Spearman analysis. And logistic regression was used to explore whether TIR is an independent risk factor for abnormal ABI. RESULTS: The overall prevalence of abnormal ABI was 20.2% (low 4.9% and high 15.3%). TIR was lower in patients with abnormal ABI values (P = 0.009). The prevalence of abnormal ABI decreased with increasing quartiles of TIR (P = 0.026). Abnormal ABI was negatively correlated with TIR and positively correlated with hypertension, age, diabetes duration, UREA, Scr, ACR, TAR, MBG, and M values (P < 0.05). The logistic regression revealed a significant association between TIR and abnormal ABI, while HbA1C and blood glucose variability measures had no explicit correlation with abnormal ABI. Additionally, there was a significant difference in LDL between the low and high ABI groups (P = 0.009), and in Scr between normal and low groups (P = 0.007). And there were significant differences in TIR (P = 0.003), age (P = 0.023), UREA (P = 0.006), ACR (P = 0.004), TAR (P = 0.015), and MBG (P = 0.014) between normal and high ABI groups, and in diabetes duration between both normal and low (P = 0.023) and normal and high (P = 0.006) groups. CONCLUSIONS: In type 2 diabetes patients, abnormal ABI is associated with lower TIR, and the correlation is stronger than that with HbA1C. Therefore, the role of TIR should be emphasized in the evaluation of lower limb vascular diseases.

Time in range, assessed with continuous glucose monitoring, is associated with brachial-ankle pulse wave velocity in type 2 diabetes: A retrospective single-center analysis.

Aims: The aim of this retrospective single-center is to research the relationship between time in range(TIR), an important novel metric of glycemic control, assessed with continuous glucose monitoring(CGM) and brachial-ankle pulse wave velocity(BaPWV), a unique index of systemic arterial stiffness in type 2 diabetes. Methods: Study participants included 469 hospitalized patients with type 2 diabetes and no history of serious cardiovascular disease who underwent CGM and BaPWV measurements. TIR of 3.9-10.0 mmol/L was evaluated with CGM. BaPWV was measured by non-invasive arteriosclerosis detector and high baPWV was defined as a mean baPWV≧1800m/s. The spearman correlation and the partial correlation analysis were applied to analyze the correlation between TIR and baPWV. The binary logistic regression was used to examine the independent association of TIR and high BaPWV. Results: The presence of high baPWV was 32.2%. Compared with patients of low baPWV, those with high baPWV had significantly reduced TIR(P<0.001). With the increase of TIR tertiles, the prevalence of high BaPWV progressively decreased. Correlation analysis showed that TIR is inversely correlated with BaPWV. In a fully adjusted model controlling for traditional risk factor of CVD, TIR is associated with the presence of high BaPWV independent of HbA1c. Conclusion: TIR is correlated with BaPWV independent of HbA1c in patients with type 2 diabetes, confirming a link between TIR and arterial stiffness.

Loss of CASZ1 tumor suppressor linked to oncogenic subversion of neuroblastoma core regulatory circuitry.

The neural crest lineage regulatory transcription factors (TFs) form a core regulatory circuitry (CRC) in neuroblastoma (NB) to specify a noradrenergic tumor phenotype. Oncogenic subversion of CRC TFs is well documented, but the role of loss of tumor suppressors plays remains unclear. Zinc-finger TF CASZ1 is a chromosome 1p36 (chr1p36) tumor suppressor. Single-cell RNA sequencing data analyses indicate that CASZ1 is highly expressed in developing chromaffin cells coincident with an expression of NB CRC TFs. In NB tumor cells, the CASZ1 tumor suppressor is silenced while CRC components are highly expressed. We find the NB CRC component HAND2 directly represses CASZ1 expression. ChIP-seq and transcriptomic analyses reveal that restoration of CASZ1 upregulates noradrenergic neuronal genes and represses expression of CRC components by remodeling enhancer activity. Our study identifies that the restored CASZ1 forms a negative feedback regulatory circuit with the established NB CRC to induce noradrenergic neuronal differentiation of NB.

Association between osteocalcin, a pivotal marker of bone metabolism, and secretory function of islet beta cells and alpha cells in Chinese patients with type 2 diabetes mellitus: an observational study.

BACKGROUND: Several recent studies have found that Osteocalcin (OCN), a multifunctional protein secreted exclusively by osteoblasts, is beneficial to glucose metabolism and type 2 diabetes mellitus (T2DM). However, the effects of OCN on islets function especially islet ɑ cells function in patients with type 2 diabetes mellitus characterized by a bi-hormonal disease are still unclear. The purpose of this cross-sectional study was to investigate the relationship between serum OCN and the secretion of islet ß cells and ɑ cells in Chinese patients with type 2 diabetes mellitus. METHODS: 204 patients with T2DM were enrolled. Blood glucose (FBG, PBG0.5h, PBG1h, PBG2h, PBG3h), insulin (FINS, INS0.5h, INS1h, INS2h, INS3h), C-peptide (FCP, CP0.5h, CP1h, CP2h, CP3h), and glucagon (GLA0, GLA0.5 h, GLA1h, GLA2h, GLA3h) levels were measured on 0 h, 0.5 h, 1 h, 2 h, and 3 h after a 100 g standard bread meal load. Early postprandial secretion function of islet ß cells was calculated as Δcp0.5h = CP0.5-FCP. The patients were divided into low, medium and high groups (T1, T2 and T3) according to tertiles of OCN. Comparison of parameters among three groups was studied. Correlation analysis confirmed the relationship between OCN and pancreatic secretion. Multiple regression analysis showed independent contributors to pancreatic secretion. MAIN RESULTS: FBG, and PBG2h were the lowest while Δcp0.5h was the highest in the highest tertile group (respectively, p < 0.05). INS3h, area under the curve of insulin (AUCins3h) in T3 Group were significantly lower than T1 Group (respectively, p < 0.05). GLA1h in T3 group was lower than T1 group (p < 0.05), and GLA0.5 h in T3 group was lower than T2 and T1 groups (p < 0.05). Correlation analysis showed OCN was inversely correlated with Homeostatic model of insulin resistance (HOMA-IR), INS3h, AUCins3h (p < 0.05), and was still inversely correlated with FCP, GLA0.5 h, GLA1h, area under the curve of glucagon (AUCgla3h) (respectively, p < 0.05) after adjustment for body mass index (BMI) and alanine aminotransferase (ALT). The multiple regression analysis showed that OCN was independent contributor to Δcp0.5h, GLA0.5h and GLA1h (respectively, p < 0.05). CONCLUSIONS: Higher serum OCN level is closely related to better blood glucose control, higher insulin sensitivity, increased early-phase insulin secretion of islet ß cells and appropriate inhibition of postprandial glucagon secretion of islet ɑ cells in adult patients with type 2 diabetes mellitus.

Relationship Between Acyl and Desacyl Ghrelin Levels with Insulin Resistance and Body Fat Mass in Type 2 Diabetes Mellitus.

Purpose: Although strong evidence suggests that ghrelin plays an important role in regulating energy balance, the effects of acylated ghrelin (AG) and deacylated ghrelin (DAG) on fat mass are largely undefined. This study aimed to investigate the differential associations of both forms of ghrelin with insulin resistance and body fat mass in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 162 patients with type 2 diabetes were recruited and classified based on BMI and visceral fat area (VFA) as VFA normal group (n = 78), normal-BMI VFA obesity group (n = 20) and high-BMI VFA obesity group (n = 64). VFA and subcutaneous fat area (SFA) were detected by bioelectrical impedance analysis. Blood samples were collected to measure fasting glucose, insulin, lipids, AG and DAG levels after clinical examination. Results: Compared with VFA normal group, DAG levels were significantly lower (421.7 ± 106.0 and 388.7 ± 96.5 pg/mL vs 524.4 ± 141.5 pg/mL, P < 0.01) in the two VFA obesity groups. No significant difference was found in AG levels within three groups. Among all subjects, BMI, VFA, SFA, fasting insulin and HOMA-IR were negatively correlated with DAG but positively with AG/DAG ratio (P < 0.01). In contrast, AG was positively correlated with HOMA-IR and fasting glucose (P < 0.01). Multiple stepwise regression analysis showed that fasting glucose was the independent factor of AG, VFA and HOMA-IR were the independent factors related to DAG. Conclusion: DAG levels have a strong negative association with excess body fat mass and insulin resistance, whereas AG levels are closely related to elevated blood glucose levels in T2DM patients.

Single-cell sequencing reveals activation of core transcription factors in PRC2-deficient malignant peripheral nerve sheath tumor.

Loss-of-function mutations in the polycomb repressive complex 2 (PRC2) occur frequently in malignant peripheral nerve sheath tumor, an aggressive sarcoma that arises from NF1-deficient Schwann cells. To define the oncogenic mechanisms underlying PRC2 loss, we use engineered cells that dynamically reassemble a competent PRC2 coupled with single-cell sequencing from clinical samples. We discover a two-pronged oncogenic process: first, PRC2 loss leads to remodeling of the bivalent chromatin and enhancer landscape, causing the upregulation of developmentally regulated transcription factors that enforce a transcriptional circuit serving as the cell's core vulnerability. Second, PRC2 loss reduces type I interferon signaling and antigen presentation as downstream consequences of hyperactivated Ras and its cross talk with STAT/IRF transcription factors. Mapping of the transcriptional program of these PRC2-deficient tumor cells onto a constructed developmental trajectory of normal Schwann cells reveals that changes induced by PRC2 loss enforce a cellular profile characteristic of a primitive mesenchymal neural crest stem cell.

Circulating osteocalcin is associated with time in range and other metrics assessed by continuous glucose monitoring in type 2 diabetes.

BACKGROUND: Osteocalcin, a protein secreted mainly by mature osteoblasts, has been shown to be involved in glucose metabolism through various pathways. However, few studies has explored the association between osteocalcin and Time in range (TIR). Continuous glucose monitoring (CGM) -derived metrics, such as TIR and other indexes have been gradually and widely used in clinical practice to assess glucose fluctuations. The main purpose of this study was to investigate the correlation between osteocalcin and indexes from CGM in patients with type 2 diabetes mellitus (T2DM). METHOD: The total number of 376 patients with T2D were enrolled, all of them performed three consecutive days of monitoring. They were divided into four groups on account of the quartile of osteocalcin. Time in range, Time below range (TBR), Time above range(TAR) and measures of glycemic variability (GV) were assessed for analysing. After a 100 g standard steamed bread meal, blood glucose (Glu0h Glu0.5 h, Glu1h, Glu2h, GLu3h), C-peptide (Cp0h, Cp0.5 h, Cp1h, Cp2h, Cp3h), serum insulin (INS0h, INS0.5 h, INS1h, INS2h, INS3h) concentrations at different time points were obtained. HOMA-IS, HOMA-ßwas calculated to evaluate insulin sensitivity and insulin secreting of the participants. RESULTS: Patients with higher osteocalcin level had higher TIR (P < 0.05). Spearman correlation analysis showed that osteocalcin was positively correlated with TBR (although the P value for TBR was greater than 0.05) (r = 0.227, P < 0.001 r = 0.068, P = 0.189) and negatively correlated with TAR (- 0.229, P < 0.001). Similarly, there was a negative correlation between osteocalcin and glycemic variability (GV) indicators, including SD, MBG, MODD, ADDR, and MAGE (P value of MAGE > 0.05). Multiple stepwise regression showed that osteocalcin was an independent contributor to TIR, TAR and HOMA-IS. CONCLUSION: Circulating osteocalcin is positively correlated with TIR and negatively correlated with MODD, ADDR, and MAGE. Osteocalcin may have a beneficial impact on glucose homeostasis in T2DM patients.