Lipotoxicity-polarised macrophage-derived exosomes regulate mitochondrial fitness through Miro1-mediated mitophagy inhibition and contribute to type 2 diabetes development in mice.

AIMS/HYPOTHESIS: Insulin resistance is a major pathophysiological defect in type 2 diabetes and obesity. Numerous experimental and clinical studies have provided evidence that sustained lipotoxicity-induced mitophagy deficiency can exacerbate insulin resistance, leading to a vicious cycle between mitophagy dysfunction and insulin resistance, and thereby the onset of type 2 diabetes. Emerging evidence suggests that exosomes (Exos) from M2 macrophages play an essential role in modulating metabolic homeostasis. However, how macrophages are affected by lipotoxicity and the role of lipotoxicity in promoting macrophage activation to the M1 state have not been determined. The objective of this study was to determine whether M1 macrophage-derived Exos polarised by lipopolysaccharide (LPS) + palmitic acid (PA)-induced lipotoxicity contribute to metabolic homeostasis and impact the development of insulin resistance in type 2 diabetes. METHODS: Lipotoxicity-polarised macrophage-derived M1 Exos were isolated from bone marrow (C57BL/6J mouse)-derived macrophages treated with LPS+PA. Exos were characterised by transmission electron microscopy, nanoparticle tracking analysis and western blotting. Flow cytometry, H&E staining, quantitative real-time PCR, immunofluorescence, glucose uptake and output assays, confocal microscopy imaging, western blotting, GTTs and ITTs were conducted to investigate tissue inflammation, mitochondrial function and insulin resistance in vitro and in vivo. The roles of miR-27-3p and its target gene Miro1 (also known as Rhot1, encoding mitochondrial rho GTPase 1) and relevant pathways were predicted and assessed in vitro and in vivo using specific miRNA mimic, miRNA inhibitor, miRNA antagomir and siRNA. RESULTS: miR-27-3p was highly expressed in M1 Exos and functioned as a Miro1-inactivating miRNA through the miR-27-3p-Miro1 axis, leading to mitochondria fission rather than fusion as well as mitophagy impairment, resulting in NOD-like receptor 3 inflammatory activation and development of insulin resistance both in vivo and in vitro. Inactivation of miR-27-3p induced by M1 Exos prevented type 2 diabetes development in high-fat-diet-fed mice. CONCLUSIONS/INTERPRETATION: These findings suggest that the miR-27-3p-Miro1 axis, as a novel regulatory mechanism for mitophagy, could be considered as a new therapeutic target for lipotoxicity-related type 2 diabetes disease development.

PET/CT morphology and cardiac conduction disorders help discriminate primary cardiac lymphoma from primary cardiac sarcoma.

BACKGROUND: Primary cardiac lymphoma (PCL) and primary cardiac sarcoma (PCS) are similar in clinical presentation but differ in management and outcomes. We aim to explore the role of PET morphology and clinical characteristics in distinguishing PCL from PCS. METHODS: Pretreatment 18F-FDG PET/CT and contrast-enhanced CT were performed in PCL (n = 14) and PCS (n = 15) patients. Patient demographics, overall survival, and progression-free survival were reviewed. PET/CT morphological and metabolic features were extracted. Specifically, R_Kurtosis, a PET-morphology parameter reflecting the tumor expansion within the heart, was calculated. RESULTS: Compared with PCS, PCL occurred at an older age, resulted in more cardiac dysfunctions and arrhythmias, and showed higher glucometabolism (SUVmax, SUVpeak, SUVmean, MTV, and TLG). Curative treatments improved survival for PCL but not for PCS. Multivariable logistic regression identified R_Kurtosis (OR = 27.025, P = .007) and cardiac conduction disorders (OR = 37.732, P = .016) independently predictive of PCL, and classification and regression tree analysis stratified patients into three subgroups: R_Kurtosis ≥ 0.044 (probability of PCL 88.9%), R_Kurtosis < 0.044 with conduction disorders (80.0%), and R_Kurtosis < 0.044 without conduction disorders (13.3%). CONCLUSION: PET-derived tumor expansion pattern (R_Kurtosis) and cardiac conduction disorders were helpful in distinguishing PCL from PCS, which might assist the clinical management.

Yoga training modulates adipokines in adults with high-normal blood pressure and metabolic syndrome.

Metabolic syndrome (MetS) is associated with diabetes mellitus and cardiovascular diseases. Our previous study indicated that people with MetS showed a decrease in waist circumference and a decreasing trend in blood pressure after 1-year yoga. This study investigated the effect of yoga on MetS people with high-normal blood pressure by exploring modulations in proinflammatory adipokines (leptin, chemerin, visfatin, and plasminogen activator inhibitor-1 or PAI-1) and an anti-inflammatory adipokine (adiponectin). A total of 97 Hong Kong Chinese individuals aged 57.6 ± 9.1 years with MetS and high-normal blood pressure were randomly assigned to control (n = 45) and yoga groups (n = 52). Participants in the control group were not given any intervention but were contacted monthly to monitor their health status. Participants in the yoga group underwent a yoga training program with three 1-hour yoga sessions weekly for 1 year. The participants' sera were harvested and assessed for adipokines. Generalized estimating equation (GEE) was used to examine the interaction effect between 1-year time (pre vs post), and intervention (control vs yoga). GEE analyses revealed significant interaction effects between 1-year time and yoga intervention for the decreases in leptin and chemerin and the increase in adiponectin concentration in the sera examined. These results demonstrated that 1-year yoga training decreased proinflammatory adipokines and increased anti-inflammatory adipokine in adults with MetS and high-normal blood pressure. These findings support the beneficial role of yoga in managing MetS by favorably modulating adipokines.

Pathway analysis of complex diseases for GWAS, extending to consider rare variants, multi-omics and interactions.

BACKGROUND: Genome-wide association studies (GWAS) is a major method for studying the genetics of complex diseases. Finding all sequence variants to explain fully the aetiology of a disease is difficult because of their small effect sizes. To better explain disease mechanisms, pathway analysis is used to consolidate the effects of multiple variants, and hence increase the power of the study. While pathway analysis has previously been performed within GWAS only, it can now be extended to examining rare variants, other "-omics" and interaction data. SCOPE OF REVIEW: 1. Factors to consider in the choice of software for GWAS pathway analysis. 2. Examples of how pathway analysis is used to analyse rare variants, other "-omics" and interaction data. MAJOR CONCLUSIONS: To choose appropriate software tools, factors for consideration include covariate compatibility, null hypothesis, one- or two-step analysis required, curation method of gene sets, size of pathways, and size of flanking regions to define gene boundaries. For rare variants, analysis performance depends on consistency between assumed and actual effect distribution of variants. Integration of other "-omics" data and interaction can better explain gene functions. GENERAL SIGNIFICANCE: Pathway analysis methods will be more readily used for integration of multiple sources of data, and enable more accurate prediction of phenotypes.

Implications of MicroRNAs in the Treatment of Gefitinib-Resistant Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) represents about 85% of the reported cases of lung cancer. Acquired resistance to targeted therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is not uncommon. It is thus vital to explore novel strategies to restore sensitivity to gefitinib. Provided that microRNAs (miRNAs) negatively regulate their gene targets at the transcriptional level, it is speculated that miRNA mimetics may reduce the expression, activity and signal transduction of EGFR so that sensitization of tumour sites to gefitinib-induced cytotoxicity can be achieved. Indeed, a growing body of evidence has shown that the manipulation of endogenous levels of miRNA not only attenuates the EGFR/PI3K/Akt phosphorylation cascade, but also restores apoptotic cell death in in vitro models of experimentally-induced gefitinib resistance and provoked tumour regression/shrinkage in xenograft models. These data are in concordant with the clinical data showing that the differential expression profiles of miRNA in tumour tissues and blood associate strongly with drug response and overall survival. Furthermore, another line of studies indicate that the chemopreventive effects of a variety of natural compounds may involve miRNAs. The present review aims to discuss the therapeutic capacity of miRNAs in relation to recent discoveries on EGFR-TKI resistance, including chronic drug exposure and mutations.

DECODE: an integrated differential co-expression and differential expression analysis of gene expression data.

BACKGROUND: Both differential expression (DE) and differential co-expression (DC) analyses are appreciated as useful tools in understanding gene regulation related to complex diseases. The performance of integrating DE and DC, however, remains unexplored. RESULTS: In this study, we proposed a novel analytical approach called DECODE (Differential Co-expression and Differential Expression) to integrate DC and DE analyses of gene expression data. DECODE allows one to study the combined features of DC and DE of each transcript between two conditions. By incorporating information of the dependency between DC and DE variables, two optimal thresholds for defining substantial change in expression and co-expression are systematically defined for each gene based on chi-square maximization. By using these thresholds, genes can be categorized into four groups with either high or low DC and DE characteristics. In this study, DECODE was applied to a large breast cancer microarray data set consisted of two thousand tumor samples. By identifying genes with high DE and high DC, we demonstrated that DECODE could improve the detection of some functional gene sets such as those related to immune system, metastasis, lipid and glucose metabolism. Further investigation on the identified genes and the associated functional pathways would provide an additional level of understanding of complex disease mechanism. CONCLUSIONS: By complementing the recent DC and the traditional DE analyses, DECODE is a valuable methodology for investigating biological functions of genes exhibiting disease-associated DE and DC combined characteristics, which may not be easily revealed through DC or DE approach alone. DECODE is available at the Comprehensive R Archive Network (CRAN): http://cran.r-project.org/web/packages/decode/index.html .

Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis.

KEY POINTS: Doxorubicin induced functional deteriorations and elevations of USP7-related apoptotic/catabolic signalling in the senescent heart Resveratrol protects against doxorubicin-induced alterations through the restoration of SIRT1 deacetylase activity ABSTRACT: A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy. The present study tested the hypothesis that acute intervention with resveratrol, a natural anti-oxidant found in grapes and red wine, reduces the cardiotoxicity of doxorubicin through restoration of sirtuin 1 (SIRT1) deacetylase activity, and attenuation of the catabolic/apoptotic pathways orchestrated by USP7, a p53 deubiquitinating protein, using young (aged 2 months) and old (aged 10 months) senescence-accelerated mice prone 8 (SAMP8). Animals were randomised to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either of the SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8. These doxorubicin-induced alterations were prevented by resveratrol, whereas the protective action of resveratrol was antagonised by sirtinol and EX527. In young SAMP8 hearts, resveratrol attenuated the doxorubicin-induced increases in acetylation of Foxo1 and transactivation of MuRF-1, whereas these mitigations were not found after treatment with SIRT1 inhibitors. However, the protein contents of acetylated Foxo1 and MuRF-1 were not affected by any of the drugs studied in aged SAMP8 hearts. Resveratrol also ameliorated the augmentation of pro-apoptotic markers including p53, Bax, caspase 3 activity and apoptotic DNA fragmentation induced by doxorubicin in hearts from aged animals, whereas these reductions were diminished by combined treatment with SIRT1 inhibitors. These data demonstrate that resveratrol ameliorates doxorubicin-induced cardiotoxicity in aged hearts through the restoration of SIRT1 activity to attenuate USP7-related catabolic/pro-apoptotic signalling.

Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice.

Impairment of insulin signaling in skeletal muscle detrimentally affects insulin-stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level.

Exploring microRNA-mediated alteration of EGFR signaling pathway in non-small cell lung cancer using an mRNA:miRNA regression model supported by target prediction databases.

EGFR signaling pathway and microRNAs (miRNAs) are two important factors for development and treatment in non-small cell lung cancer (NSCLC). Microarray analysis enables the genome-wide expression profiling. However, the information from microarray data may not be fully deciphered through the existing approaches. In this study we present an mRNA:miRNA stepwise regression model supported by miRNA target prediction databases. This model is applied to explore the roles of miRNAs in the EGFR signaling pathway. The results show that miR-145 is positively associated with epidermal growth factor (EGF) in the pre-surgery NSCLC group and miR-199a-5p is positively associated with EGF in the post-surgery NSCLC group. Surprisingly, miR-495 is positively associated with protein tyrosine kinase 2 (PTK2) in both groups. The coefficient of determination (R(2)) and leave-one-out cross-validation (LOOCV) demonstrate good performance of our regression model, indicating that it can identify the miRNA roles as oncomirs and tumor suppressor mirs in NSCLC.

Modulating effect of SIRT1 activation induced by resveratrol on Foxo1-associated apoptotic signalling in senescent heart.

Elevations of cardiomyocyte apoptosis and fibrotic deposition are major characteristics of the ageing heart. Resveratrol, a polyphenol in grapes and red wine, is known to improve insulin resistance and increase mitochondrial biogenesis through the SIRT1-PGC-1α signalling axis. Recent studies attempted to relate SIRT1 activation by resveratrol to the regulation of apoptosis in various disease models of cardiac muscle. In the present study, we tested the hypothesis that long-term (8-month) treatment of resveratrol would activate SIRT1 and improve the cardiac function of senescent mice through suppression of Foxo1-associated pro-apoptotic signalling. Our echocardiographic measurements indicated that the cardiac systolic function measured as fractional shortening and ejection fraction was significantly reduced in aged mice when compared with the young mice. These reductions, however, were not observed in resveratrol-treated hearts. Ageing significantly reduced the deacetylase activity, but not the protein abundance of SIRT1 in the heart. This reduction was accompanied by increased acetylation of the Foxo1 transcription factor and transactivation of its target, pro-apoptotic Bim. Subsequent analyses indicated that pro-apoptotic signalling measured as p53, Bax and apoptotic DNA fragmentation was up-regulated in the heart of aged mice. In contrast, resveratrol restored SIRT1 activity and suppressed elevations of Foxo1 acetylation, Bim and pro-apoptotic signalling in the aged heart. In parallel, resveratrol also attenuated the ageing-induced elevations of fibrotic collagen deposition and markers of oxidative damage including 4HNE and nitrotyrosine. In conclusion, these novel data demonstrate that resveratrol mitigates pro-apoptotic signalling in senescent heart through a deacetylation mechanism of SIRT1 that represses the Foxo1-Bim-associated pro-apoptotic signalling axis.

A high fat diet in glutamate 3-/Y mice causes changes in behavior that resemble human intellectual disability.

Cognitive impairment in individuals with intellectual disability (ID) is characterized by developmental delay and deficits in language and memory. Ionotropic AMPA mediate the majority of excitatory synaptic transmission in the central nervous system and are essential for the induction and maintenances of long-term potentiation (LTP) and long-term depression (LTD), two cellular models of learning and memory underlie many the symptoms of ID. Clinical research has found obese male patients with GluA3 interrupted underlie the symptom of ID. We tested GluA3-/Y mice under high fat diet (HFD) stress on a series of behavioral paradigms associated with symptoms of ID: wild type mice showed significant levels of sociability, while GluA3-/Y mice did not. Wild type mice showed significant preference for social novelty, while GluA3-/Y mice did not. Normal scores on relevant control measures confirmed general health and physical abilities in both GluA3-/Y and wild type mice (WT), ruling out artifactual explanations for social deficits. GluA3-/Y mice also showed working spatial memory behavior impairment in Y-maze test and abnormal anxiety in open-field test, compared to wild-type littermate controls. GluA3-/Y mice had a significantly reduced spontaneous activities tested by elevated plus maze, display both low social approach and resistance to change in routine on the T-maze, consistent with an ID-like phenotype. These findings demonstrate that selective gene deletion of GluA3 receptor in male mice under oxidative stress induced phenotypic abnormalities related to ID-like symptoms.

Microbiota-microglia connections in age-related cognition decline.

Aging is an inevitable process that all individuals experience, of which the extent differs among individuals. It has been recognized as the risk factor of neurodegenerative diseases by affecting gut microbiota compositions, microglia, and cognition abilities. Aging-induced changes in gut microbiota compositions have a critical role in orchestrating the morphology and functions of microglia through the gut-brain axis. Gut microbiota communicates with microglia by its secreted metabolites and neurotransmitters. This is highly associated with age-related cognitive declines. Here, we review the main composition of microbiota in the aged individuals, outline the changes of the brain in age-related cognitive decline from a neuroinflammation perspective, especially the changes of morphology and functions of microglia, discuss the crosstalk between microbiota and microglia in the aged brain and further highlight the role of microbiota-microglia connections in neurodegenerative diseases (Alzheimer's disease and Parkinson's disease).

KEAP1/NFE2L2 Mutations of Liquid Biopsy as Prognostic Biomarkers in Patients With Advanced Non-Small Cell Lung Cancer: Results From Two Multicenter, Randomized Clinical Trials.

PURPOSE: The KEAP1-NFE2L2 (Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)) mutations are associated with resistance to chemotherapy or immunotherapy in non-small cell lung cancer (NSCLC). Conversely, it has been reported that NFE2L2 mutations potentiate improved clinical outcome with immunotherapy. However, therapeutic benefits for patients with KEAP1/NFE2L2 mutations remain unclear. The purpose of this study was to investigate the association between KEAP1/NFE2L2 and NSCLC prognosis, and to explore whether immunotherapy can improve prognosis in populations with KEAP1/NFE2L2 mutations. EXPERIMENTAL DESIGN: The impact of KEAP1/NFE2L2 mutations on survival outcomes in NSCLC patients received immunotherapy and chemotherapy was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, POPLAR (n = 211) and OAK (n = 642)). The Cancer Genome Atlas (TCGA) NSCLC cohort (n=998) and an in-house Chinese NSCLC cohort (n=733) was used For the analysis of immune-related markers. RESULTS: Compared with KEAP1/NFE2L2 wild-type, patients with KEAP1/NFE2L2 mutations were significantly associated with poorer overall survival (OS, HR = 1.97, 95% CI 1.48-2.63, P < 0.001) on atezolizumab and docetaxel (HR = 1.66, 95% CI 1.28-2.16, P < 0.001). In KEAP1/NFE2L2 mutant group, there was no significant difference in median OS between atezolizumab and docetaxel (HR 0.74, 95% CI 0.53-1.03, P = 0.07). NFE2L2/KEAP1 mutations were significantly associated with higher TMB values and PD-L1 expression in the OAK/POPLAR and in-house Chinese NSCLC cohorts. GSEA revealed that KEAP1/NFE2L2mutant subgroup was associated with deficient infiltration of CD4+ T cells, NK T cells and natural Treg cells, and lower expression of DNA damage response genes in TCGA NSCLC cohort. CONCLUSIONS: Our study revealed that patients with KEAP1/NFE2L2 mutations have a worse prognosis than wild-type patients, both on immunotherapy and chemotherapy. In addition, in patients with KEAP1/NFE2L2 mutations, immunotherapy did not significantly improve prognosis compared to chemotherapy.

Combination therapy of gefitinib and miR-30a-5p may overcome acquired drug resistance through regulating the PI3K/AKT pathway in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation often initially respond to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment but may acquire drug resistance due to multiple factors. MicroRNAs are a class of small noncoding and endogenous RNA molecules that may play a role in overcoming the resistance. MATERIALS AND METHODS: In this study, we explored and validated, through in vitro experiments and in vivo models, the ability of a combination treatment of EGFR-TKI, namely gefitinib, and a microRNA mimic, miR-30a-5p, to overcome drug resistance through regulation of the insulin-like growth factor receptor-1 (IGF1R) and hepatocyte growth factor receptor signaling pathways, which all converge on phosphatidylinositol 3 kinase (PI3K), in NSCLC. First, we examined the hypothesized mechanisms of drug resistance in H1650, H1650-acquired gefitinib-resistance (H1650GR), H1975, and H460 cell lines. Next, we investigated a potential combination treatment approach to overcome acquired drug resistance in the H1650GR cell line and an H1650GR cell implanted mouse model. RESULTS: Dual inhibitors of EGFR and IGF1R significantly lowered the expression levels of phosphorylated protein kinase B (p-AKT) and phosphorylated mitogen-activated protein kinase (p-ERK) compared with the control group in all cell lines. With the ability to repress PI3K expression, miR-30a-5p mimics induced cell apoptosis, and inhibited cell invasion and migration in the treated H1650GR cell line. CONCLUSION: Gefitinib, combined with miR-30a-5p mimics, effectively suppressed the growth of H1650GR-induced tumor in xenografts. Hence, a combination therapy of gefitinib and miR-30a-5p may play a critical role in overcoming acquired resistance to EGFR-TKIs. The reviews of this paper are available via the supplemental material section.

ADAM9 Mediates Triple-Negative Breast Cancer Progression via AKT/NF-κB Pathway.

Upregulation of a disintegrin and metalloprotease 9 (ADAM9) is correlated with progression of cancers, such as prostate, bladder, and pancreatic cancers. However, its role in triple-negative breast cancer (TNBC) is still unclear. Our study aimed to investigate whether ADAM9 is upregulated and promoted the aggressiveness in TNBC. Breast cancer cell lines and patient specimens were used to evaluate the ADAM9 expression by western blotting and immunohistochemistry staining, respectively. Compared with the non-TNBC, ADAM9 expression was significantly increased in TNBC cells and TNBC patient specimens. Based on the data acquired from public databases, the correlation between ADAM9 expression and breast cancer patient survival was analyzed by Kaplan-Meier method. It was shown that ADAM9 overexpression was significantly correlated with poorer survival in patients with TNBC. Furthermore, ADAM9 in TNBC cells was knocked down by small interference RNA and then studied by the MTT/colony formation assay, wound healing assay and transwell invasion assay on the cell proliferation, migration, and invasion, respectively. We found that inhibiting ADAM9 expression suppressed TNBC cell proliferation, migration, and invasion by lowering the activation of AKT/NF-κB pathway. Our results demonstrated that ADAM9 is an important molecule in mediating TNBC aggressiveness and may be a potential useful therapeutic target in TNBC treatment.

Obesity-Induced Regulator of Calcineurin 1 Overexpression Leads to ß-Cell Failure Through Mitophagy Pathway Inhibition.

Aims: Type 2 diabetes (T2D) is associated with pancreatic ß-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). The regulator of calcineurin 1 (RCAN1) in islets is an endogenous inhibitor of calcium-activated protein phosphatase. Previous studies have indicated that global RCAN1 overexpression under high nutrient stress is involved in insulin resistance in T2D. However, the specific role and mechanism of this gene's overexpression in pancreatic ß-cells have not been thoroughly elucidated to date. Results: In this study, we showed that mice overexpressing islet-specific RCAN1 exhibited a prediabetic phenotype with markedly reduced GSIS under nutrient stress. Overexpression of RCAN1 increased the autophagy-associated DNA methylation level of Beclin-1 suppressing the induction of autophagy, affected the protein kinase B, and downregulated the activation of mammalian target of rapamycin, leading to Miro1-mediated mitophagy deficiency. Furthermore, the exacerbated impairment of autophagy induction and mitophagy flux failures induced ß-cell apoptosis, resulting in GSIS impairment, lipid imbalance, and NOD-like receptor 3 proinflammation under high nutrient stress in mice. Innovation: Our present data identify a detrimental effect of RCAN1 overexpression on Miro1-mediated mitophagy deficiency and ß-cell dysfunction in high-fat diet-fed RCAN1 overexpressing mice. Conclusion: Our results revealed that strategies targeting RCAN1 in vivo may provide a therapeutic target to enhance ß-cell mitophagy quality and may determine the crucial factor in T2D development.

Informatics in radiology: DICOM-RT-based electronic patient record information system for radiation therapy.

Comprehensive clinical imaging data and additional relevant information are crucial for the planning and delivery of radiation therapy in patients with cancer. Multiple stand-alone systems that make use of technologic advances in imaging, treatment planning, and treatment delivery acquire or generate key data during the course of radiation therapy. However, the data are scattered in various systems throughout the radiation therapy department, thereby compromising efficient clinical work flow. In 1997 and 1999, the Digital Imaging and Communications in Medicine (DICOM) standard was extended from radiology to radiation therapy with the ratification of seven DICOM-RT objects. These objects helped set the standard for (a) data integration and interoperability between radiation therapy equipment and information systems from different manufacturers, and (b) the use of DICOM diagnostic images in radiation therapy. More recently, key radiation therapy imaging and informatics data have been integrated to form an open-architecture comprehensive radiation therapy electronic patient record (ePR) system. The benefits of such a DICOM-RT-based ePR system are threefold: it can be used as a foundation for performing effective and efficient clinical services, as a common platform for radiation therapy data exchange and expert consultation, and for medical imaging informatics research in developing innovative decision support tools and a knowledge base for improved treatment with radiation therapy.

Computer-generated index for evaluation of idiopathic scoliosis in digital chest images: a comparison with digital measurement.

An intelligence system was used to generate index for scoliosis. Tests were designed to evaluate the consistency of the automatic computer-generated index and to quantify the correlation between Cobb angle and computer generated scoliosis classification index (SCI). A fully automatic computer-generated index can be used to assess the extent of spinal curvature rather than manual measurement on radiographs. This study aims to evaluate the relation of an automatic computer-generated index in assessing the spinal curvature of scoliosis quantitatively on digital chest images. Sixty chest radiographs were obtained in this study. Cobb angle measurement and the index generated were compared by parametric statistical tests. The SCI method was demonstrated to be reproducible. There was also statically significant positive correlation between Cobb angle and SCI (Pearson's correlation: r = 0.9229). The Computer-generated index method is valid and reliable in quantifying measurement of spinal curvature of scoliosis as the correlation between Cobb's angle and SCI in nearly perfect positive for Cobb angle more than 10 degree. It is noted that with widely use of this computer method, this quantitative method proposed is a promising method in improving the reliability of scoliosis assessment and reducing the workload of clinical staff.

Multi-scale representation of proteomic data exhibits distinct microRNA regulatory modules in non-smoking female patients with lung adenocarcinoma.

Adenocarcinoma in female non-smokers is an under-explored subgroup of non-small cell lung cancer (NSCLC), in which the molecular mechanism and genetic risk factors remain unclear. We analyzed the protein profiles of plasma samples of 45 patients in this subgroup and 60 non-cancer subjects using surface-enhanced laser desorption/ionization time-of- flight mass spectrometry. Among 85 peaks of mass spectra, the differential expression analysis identified 15 markers based on False Discovery Rate control and the Discrete Wavelet Transforms further selected a cluster of 6 markers that were consistently observed at multiple scales of mass-charge ratios. This marker cluster, corresponding to 7 unique proteins, was able to distinguish the female non-smokers with adenocarcinoma from non-cancer subjects with a value of accuracy of 87.6%. We also predicted the role of competing endogenous RNAs (ceRNAs) in 3 out of these 7 proteins. Other studies reported that these ceRNAs and their targeting microRNAs, miR-206 and miR-613, were significantly associated with NSCLC. This study paves a crucial path for further investigating the genetic markers and molecular mechanism of this special NSCLC subgroup.

Adipokine Profiling in Adult Women With Central Obesity and Hypertension.

Central obesity and hypertension are common risk factors for the metabolic syndrome, cardiovascular and renal diseases. Studies have shown that it is more difficult to control blood pressure and prevent end-organ damage in obese individuals with hypertension compared to their non-obese counterparts, especially among women. Obese females have a 6 times higher risk of developing hypertension than non-obese females while obese males are at a 1.5 times higher risk of developing hypertension, compared to their non-obese counterparts. Indeed, the inter-relationship between obesity and hypertension is unclear. Adipokines have been proposed to play a mediating role in the relationship between obesity and hypertension and are involved in the pathogenesis of metabolic diseases. Therefore, this study sought to determine the role of adipokines (adiponectin, plasminogen activator inhibitor-1, leptin, and tumor necrosis factor-α) in hypertensive Hong Kong Chinese women with central obesity. A total of 387 women aged 58 ± 11 years who were examined with a 2 × 2 factorial design for central obesity (waist circumference ≥ 80 cm) and hypertension (blood pressure ≥ 140/90 mmHg), were recruited from a pool of 1,492 Hong Kong Chinese adults who were previously screened for metabolic syndrome. Subjects with hyperglycemia, hypertriglyceridemia, and dyslipidemia were excluded to eliminate confounding effects. Our findings revealed that hypertensive women with central obesity had a lower anti-inflammatory status (adiponectin) and a higher pro-inflammatory status (TNF-α) than obese alone or hypertensive alone women. Also, women with central obesity had higher circulatory PAI-1 and leptin concentrations than their non-obese counterparts. We conclude that obesity may shift toward a more pro-inflammatory state and may become more severe in the presence of hypertension or vice versa.