IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma

Palmitoleate Induces Hepatic Steatosis but Suppresses Liver Inflammatory Response in Mice

The interaction between fat deposition and inflammation during obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD). The present study examined the effects of palmitoleate, a monounsaturated fatty acid (16∶1n7), on liver metabolic and inflammatory responses, and investigated the mechanisms by which palmitoleate increases hepatocyte fatty acid synthase (FAS) expression. Male wild-type C57BL/6J mice were supplemented with palmitoleate and subjected to the assays to analyze hepatic steatosis and liver inflammatory response. Additionally, mouse primary hepatocytes were treated with palmitoleate and used to analyze fat deposition, the inflammatory response, and sterol regulatory element-binding protein 1c (SREBP1c) activation. Compared with controls, palmitoleate supplementation increased the circulating levels of palmitoleate and improved systemic insulin sensitivity. Locally, hepatic fat deposition and SREBP1c and FAS expression were significantly increased in palmitoleate-supplemented mice. These pro-lipogenic events were accompanied by improvement of liver insulin signaling. In addition, palmitoleate supplementation reduced the numbers of macrophages/Kupffer cells in livers of the treated mice. Consistently, supplementation of palmitoleate decreased the phosphorylation of nuclear factor kappa B (NF-κB, p65) and the expression of proinflammatory cytokines. These results were recapitulated in primary mouse hepatocytes. In terms of regulating FAS expression, treatment of palmitoleate increased the transcription activity of SREBP1c and enhanced the binding of SREBP1c to FAS promoter. Palmitoleate also decreased the phosphorylation of NF-κB p65 and the expression of proinflammatory cytokines in cultured macrophages. Together, these results suggest that palmitoleate acts through dissociating liver inflammatory response from hepatic steatosis to play a unique role in NAFLD

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Stability Analysis of Roof and Rib and Source Control Countermeasures of Ultrahigh Roadway in Deep Coal Mine

Driven by the high original rock stress and engineering disturbance, the ultrahigh roadways of about 7∼8 m appear in the deep coal mine. Based on the field measured data, the stability in different zones of roof and rib is divided. From shallow to deep, the roof forms potential leakage and falling zone, metastable zone, and stable zone, and the coal rib forms potential spalling zone, crack developed zone, and transition zone. Based on the theory of transverse isotropy, the mechanical analysis model of layered roof is established, the real stress state at any point of layered roof is deduced, the roof failure criterion is constructed, and the theoretical solution of the failure depth of layered roof is obtained. The mechanical model of pillar bar of the splitting coal body in the potential spalling zone is established, and the deflection deformation expression of the pillar bar is derived. In view of the deformation and failure characteristics of the roof and rib, this paper puts forward the cooperative integrated support technology based on high-strength prestressed cables and deep-shallow hole grouting, which effectively reduce the hidden danger of roof falling and eliminate the formation of ultrahigh roadway from the source

The Role of Housing Tenure Opportunities in the Social Integration of the Aging Pre-1970 Migrants in Beijing

This study focuses on the social integration of the pre-1970 first-generation migrants in reformist China, who were born before the year 1970 while getting old in the destination cities. The pre-1970 first-generation migrants are not a homogeneous group but are composed of: (a) those over 45 years old and still working but facing age discrimination; and (b) the elderly granny as nanny assuming the domestic and child-care work for their sons or daughters in the destination cities. We conceptualized and re-defined the aging migrants’ social integration into three dimensions (i.e., participation practices, communication contacts, and subjective perceptions), and used the 2017 Migrant Dynamics Monitoring Survey (MDMS) data from Beijing to measure and explain the varied integration levels among a total of 1267 aging migrant samples in the Beijing metropolis. It is proven that housing tenure matters and housing tenure entitlement would be conductive to beefing up aging migrants’ integration. However, informal housing should not be “stigmatized” as a segregated world, since those dwelling in the informal housing have reported a higher probability of perceiving a fully integrated status (namely subjective well-being, SWB) than those living in the dormitory-like housing. Additionally, an employment-income paradox is found, which shows that higher economic achievement is NOT equivalent to a higher social integration status for the aging migrants

Lagging effects and prediction of pollutants and their interaction modifiers on influenza in northeastern China

Abstract Background Previous studies have typically explored the daily lagged relations between influenza and meteorology, but few have explored seasonally the monthly lagged relationship, interaction and multiple prediction between influenza and pollution. Our specific objectives are to evaluate the lagged and interaction effects of pollution factors and construct models for estimating influenza incidence in a hierarchical manner. Methods Our researchers collect influenza case data from 2005 to 2018 with meteorological and contaminative factors in Northeast China. We develop a generalized additive model with up to 6 months of maximum lag to analyze the impact of pollution factors on influenza cases and their interaction effects. We employ LASSO regression to identify the most significant environmental factors and conduct multiple complex regression analysis. In addition, quantile regression is taken to model the relation between influenza morbidity and specific percentiles (or quantiles) of meteorological factors. Results The influenza epidemic in Northeast China has shown an upward trend year by year. The excessive incidence of influenza in Northeast China may be attributed to the suspected primary air pollutant, NO2, which has been observed to have overall low levels during January, March, and June. The Age 15–24 group shows an increase in the relative risk of influenza with an increase in PM2.5 concentration, with a lag of 0–6 months (ERR 1.08, 95% CI 0.10–2.07). In the quantitative analysis of the interaction model, PM10 at the level of 100–120 μg/m3, PM2.5 at the level of 60–80 μg/m3, and NO2 at the level of 60 μg/m3 or more have the greatest effect on the onset of influenza. The GPR model behaves better among prediction models. Conclusions Exposure to the air pollutant NO2 is associated with an increased risk of influenza with a cumulative lag effect. Prioritizing winter and spring pollution monitoring and influenza prediction modeling should be our focus

Development and validation of a prognostic nomogram for patients with ganglioneuroblastoma: A SEER-based study

Background: The objective of this study was to construct a prognostic nomogram for ganglioneuroblastoma (GNB), as the prognosis of GNB is difficult to accurately predict before therapy. Methods: The data were collected from the Surveillance, Epidemiology, and End Results (SEER) database. The patients included in this study were randomly divided into a development group and a validation group at a ratio of 7:3. Univariate and multivariate Cox regression analyses were used to filter the variables. Receiver operating characteristic (ROC) curves and calibration curves were used to assess the nomogram. All patients were redivided into two groups based on their nomogram total points, and overall survival was compared. Results: A total of 1194 GNB patients were retrospectively included, with 835 and 359 patients in the development and validation groups, respectively. Five independent prognostic factors, including age, primary tumor site, SEER stage, surgery and chemotherapy, were screened out and included in the nomogram. The consistency index (C-index) of the Cox regression model was 0.862 and 0.827 in the development group and the validation group, respectively. The areas under the receiver operating characteristic (ROC) curve (AUC) showed that the nomogram had good accuracy in predicting 3-, 5- and 10-year overall survival for GNB patients. The calibration curves of the nomogram showed good agreement between the predicted outcomes and the actual observations. The Kaplan-Meier (KM) survival curves revealed that patients with nomogram scores below the median had a better prognosis. Conclusions: Age, primary tumor site, SEER stage, surgery and chemotherapy may be independent prognostic factors for GNB. We constructed a nomogram based on the SEER database to predict the prognosis of GNB, but further optimization by adding more risk factors is needed for clinical application