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CircDLGAP4 overexpression relieves oxygen-glucose deprivation-induced neuronal injuries by boosting NEGR1 by means of splashing miR-503-3p.
Indoleamine 2,3-dioxygenase 1 (IDO1) is closely associated with immune escape in many tumor tissues, and is considered to be a valuable therapeutic target in cancer immunotherapy. In this study, the modification of amino sidechain was performed with the hydroxyamidine core kept intact to optimize lead compound Epacadostat. 19 new compounds with hydrazide, thietane or sulfonamide moiety as polar capping group in sidechain were prepared and their IDO1 inhibitory activities were evaluated. Sulfonamide 3a showed potent IDO1 inhibition in both enzymatic and cellular assays with the IC50 value of 71 nM and EC50 value of 11 nM, respectively. Furthermore, in vivo Lewis lung cancer (LLC) allograft studies of 3a indicated that it handicapped the tumor growth with similar efficacy to Epacadostat. Molecular docking demonstrated that the change of polar capping group affords influence on the orientation of amino ethylene side chain and forms new hydrogen bonding. BACKGROUND The Bismuth-Corlette (BC) classification is used to categorize hilar cholangiocarcinoma by proximal extension along the biliary tree. As the right hepatic artery crosses just behind the left bile duct, we hypothesized that BC IIIb tumors would have a higher likelihood of local unresectability due to involvement of the contralateral artery. METHODS A retrospective review of a prospectively maintained database identified patients with hilar cholangiocarcinoma taken to the operating room for intended curative resection between April 2008 and September 2016. Cases were assigned BC stages based on preoperative imaging. RESULTS Sixty-eight patients were included in the study. All underwent staging laparoscopy after which 16 cases were aborted for metastatic disease. selleck kinase inhibitor Of the remaining 52 cases, 14 cases were explored and aborted for locally advanced disease. Thirty-eight underwent attempt at curative resection. After excluding cases aborted for metastatic disease, the chance of proceeding with resection was 55.6% for BC IIIb staged lesions compared to 80.0% of BC IIIa lesions and to 82.4% for BC I-IIIa staged lesions (P less then 0.05). About 44.4% of BC IIIb lesions were aborted for locally advanced disease versus 17.6% of remaining BC stages. CONCLUSIONS When hilar cholangiocarcinoma is preoperatively staged as BC IIIb, surgeons should anticipate higher rates of locally unresectable disease, likely involving the right hepatic artery. Sphingomyelin synthase 2 (SMS2) has attracted attention as a drug target for the treatment of various cardiovascular and metabolic diseases. The modification of a high throughput screening hit, 2-quinolone 10, enhanced SMS2 inhibition at nanomolar concentrations with good selectivity against SMS1. To improve the pharmaceutical properties such as passive membrane permeability and aqueous solubility, adjustment of lipophilicity was attempted and 1,8-naphthyridin-2-one 37 was identified as a potent and selective SMS2 inhibitor. A significant reduction in hepatic sphingomyelin levels following repeated treatment in mice suggested that compound 37 could be an effective in vivo tool for clarifying the role of SMS2 enzyme and developing the treatment for SMS2-related diseases. Histone-lysine N-methyltransferase SET7 emerged as a potential target for multiple cancers. In a virtual screening program used to explore new and potent inhibitors of SET7, compound 16 was discovered as a top hit with an IC50 value of 6.02 μM. A further similarity search afforded a new compound 23, which exhibited better activity against SET7 with an IC50 value of 1.96 μM. Importantly, compound 23 selectively inhibited the proliferation of MV4-11 cells. Comprehensively, compound 23 can serve as a lead for further identification and development of more potent SET7 inhibitors. OBJECTIVE To validate a Spanish-language questionnaire on adolescent eating behavior based on Social Cognitive Theory. DESIGN The validity (reliability and construct validity) of a self-administered questionnaire containing 28 questions with Likert scale-type response options was evaluated. SETTING School located in Tonala, Jalisco, Mexico (a peri-urban area) with approximately 1,400 students enrolled. PARTICIPANTS One hundred fifty-two adolescents enrolled in the second year of a middle school in Tonalá, Jalisco, Mexico (mean age, 13.7 years; SD, 0.5 years; 64% female). The retest was completed by 70 adolescents chosen at random. OUTCOME MEASURES AND ANALYSIS The questionnaire's reliability was measured through internal consistency (Cronbach α) and reproducibility (intraclass correlation coefficient [ICC]). Construct validity was assessed using exploratory factor analysis. RESULTS Five questions were eliminated from the questionnaire because of a lack of temporal stability (ICC ≤0.4). The exploratory factor analysis was satisfactory for 3 factors (41.89% of variance) environmental facilitators and social support, self-efficacy and self-regulation, and outcome expectations and outcome expectations value. The questionnaire had good internal consistency (α = 0.824) and excellent temporal stability (ICC = 0.849). CONCLUSIONS AND IMPLICATIONS The results substantiate the reliability and construct validity of this questionnaire. The questionnaire has the potential to use the assessment of Social Cognitive Theory constructs in clinical practice or in nutrition interventions aimed at modifying the eating habits of Spanish-speaking adolescents. OBJECTIVE To evaluate the association of early involvement in cooking activities with cooking skills in adulthood, the importance of different sources for the acquisition, and the link between cooking skills and healthy eating. DESIGN Cross-sectional survey. PARTICIPANTS A random sample of 3,659 Swiss adults (47% men; average age = 58.8 years). MAIN OUTCOME MEASURE Self-reported cooking skills. ANALYSIS ANOVA, Pearson correlations, t tests, and multiple regressions. RESULTS More frequent involvement in cooking activities during childhood predicted better cooking skills in adulthood in males (β = .13, P less then .001) and females (β = .12, P less then .001). Females were more involved than males in most age groups (P less then .001). Women learned most about cooking from their mothers, cooking courses, and self-study using different media. Men identified their partners/spouses and mothers as the 2 most important sources. The study found associations between cooking skills and diet quality in men (r = .11; P less then .001; r2 = .01) and women (r = .12; P less then .001; r2 = .01). CONCLUSIONS AND IMPLICATIONS In children and adolescents, frequent involvement in cooking at home may promote better cooking skills in later life. Additional prospective research into the impact of cooking classes and interventions on developing cooking skills in children and adolescents is warranted. This article describes the processes employed to revise the widely used curriculum, Eating Smart • Being Active. Because of its popularity among nutrition education programs serving the low-income population, the curriculum developers felt it was important to share the revision process after the release of the 2015-2020 Dietary Guidelines for Americans. Extensive feedback during formative evaluation, updated content from the Dietary Guidelines for Americans, and a modern look resulted in a fully revised curriculum released in 2017. Program leaders should have confidence that their educators will be able to implement this evidence-based curriculum with fidelity. An outcome evaluation of the revised Eating Smart • Being Active curriculum is recommended. Acid Sphingomyelinase Deficiency (ASMD), or Niemann-Pick type A/B disease, is a rare lipid storage disorder leading to accumulation of sphingomyelin and its precursors primarily in macrophages. The disease has a broad phenotypic spectrum ranging from a fatal infantile form with severe neurological involvement (the infantile neurovisceral type) to a primarily visceral form with different degrees of pulmonary, liver, spleen and skeletal involvement (the chronic visceral type). link2 With the upcoming possibility of treatment with enzyme replacement therapy, the need for biomarkers that predict or reflect disease progression has increased. Biomarkers should be validated for their use as surrogate markers of clinically relevant endpoints. In this review, clinically important endpoints as well as biochemical and imaging markers of ASMD are discussed and potential new biomarkers are identified. We suggest as the most promising biomarkers that may function as surrogate endpoints in the future diffusion capacity measured by spirometry, spleen volume, platelet count, low-density lipoprotein cholesterol, liver fibrosis measured with a fibroscan, lysosphingomyelin and walked distance in six minutes. Currently, no biomarkers have been validated. link3 Several plasma markers of lipid-laden cells, fibrosis or inflammation are of high potential as biomarkers and deserve further study. Based upon current guidelines for biomarkers, recommendations for the validation process are provided. This article reassesses historical studies of Inuit metabolism in light of recent developments in evolutionary genetics. It discusses the possible selective advantage of a variant of CPT1a, which encodes the rate limiting enzyme in hepatic fatty acid oxidation. The L479 variant of CPT1a underwent one of the strongest known selective sweeps in human history and is specific to Inuit and Yu'pik populations. Recent hypotheses predict that this variant may have been selected in response to possible detrimental effects of chronic ketosis in communities with very low carbohydrate consumption. Assessing these hypotheses alongside several alternative explanations of the selective sweep, this article challenges the notion that the selection of L479 is linked to predicted detrimental effects of ketosis. Bringing together for the first time data from biochemical, metabolic, and physiological studies inside and outside the Inuit sphere, it aims to provide a broader interpretative framework and a more comprehensive way to understand the selective sweep. It suggests that L479 may have provided a selective advantage in glucose conservation as part of a metabolic adaptation to very low carbohydrate and high protein consumption, but not necessarily a ketogenic state, in an extremely cold environment. A high intake of n-3 fatty acids may be linked to selection through the mitigation of a detrimental effect of the mutation that arises in the fasted state. The implications of these conclusions for our broader understanding of very low carbohydrate metabolism, and for dietary recommendations for Inuit and non-Inuit populations, are discussed. BACKGROUND People who are blind (PWB) are often perceived as being incompetent with common tasks and functions. When patients detect that their healthcare providers (HCPs) have negative perceptions of them, they often report less satisfaction with their healthcare and disengage in their own healthcare. OBJECTIVE A scale assessing the experiences of PWB interacting with HCPs was developed and validated across two studies. METHODS In Study 1, 144 participants completed the scale and provided feedback. In Study 2, 214 participants completed the scale and 4 additional scales to assess construct validity. RESULTS An exploratory factor analysis in Study 1 revealed a two-factor model consisting of General Quality of Health Care (30.5% variance explained) and Stereotype Content-related items (9.4% variance explained). Study 2 confirmed and validated this two-factor structure (RMSEA (90% CI) = 0.068 (0.057, 0.079), CFI = 0.898, SRMR = 0.066, AIC = 14568.902). CONCLUSIONS This scale is one of the first tools developed from the perspectives of PWB.
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