Variable Selection with False Discovery Control

Technological advances that allow routine identification of high-dimensional risk factors have led to high demand for statistical techniques that enable full utilization of these rich sources of information for genome-wide association studies (GWAS). Variable selection for censored outcome data as well as control of false discoveries (i.e. inclusion of irrelevant variables) in the presence of high-dimensional predictors present serious challenges. In the context of survival analysis with high-dimensional covariates, this paper develops a computationally feasible method for building general risk prediction models, while controlling false discoveries. We have proposed a high-dimensional variable selection method by incorporating stability selection to control false discovery. Comparisons between the proposed method and the commonly used univariate and Lasso approaches for variable selection reveal that the proposed method yields fewer false discoveries. The proposed method is applied to study the associations of 2,339 common single-nucleotide polymorphisms (SNPs) with overall survival among cutaneous melanoma (CM) patients. The results have confirmed that BRCA2 pathway SNPs are likely to be associated with overall survival, as reported by previous literature. Moreover, we have identified several new Fanconi anemia (FA) pathway SNPs that are likely to modulate survival of CM patients

Broadening anticancer spectrum by preprocessing and treatment of T- lymphocytes expressed FcγRI and monoclonal antibodies for refractory cancers

BackgroundChimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of solid tumors, particularly heterogeneity, metabolic aggressiveness, and fewer immune cells in tumor microenvironment (TME), the practical utility of CAR-T cells for solid tumors remains as a challenging issue. Meanwhile, although anti-PD-1 monoclonal antibody (mAb) has shown clinical efficacy, most mAbs also show limited clinical benefits for solid tumors due mainly to the issues associated with the lack of immune cells in TME. Thus, the infiltration of targeted immunological active cells into TME could generate synergistic efficacy for mAbs.MethodsWe present a combinational strategy for solid tumor treatment, which combines armored-T cells to express Fc-gamma receptor I (FcγRI) fragment on the surfaces for targeting various tumors with therapeutically useful mAbs. Choosing CD20 and HER-2 as the targets, we characterized the in vitro and in vivo efficacy and latent mechanism of the combination drug by using flow cytometry, ELISA and other methods.ResultsThe combination and preprocessing of armored T-cells with corresponding antibody of Rituximab and Pertuzumab exerted profound anti-tumor effects, which is demonstrated to be mediated by synergistically produced antibody-dependent cellular cytotoxicity (ADCC) effects. Meanwhile, mAb was able to carry armored-T cell by preprocessing for the infiltration to TME in cell derived xenograft (CDX) model.ConclusionsThis combination strategy showed a significant increase of safety profiles from the reduction of antibody doses. More importantly, the present strategy could be a versatile tool for a broad spectrum of cancer treatment, with a simple pairing of engineered T cells and a conventional antibody

Direct field evidence of autocatalytic iodine release from atmospheric aerosol

Reactive iodine plays a key role in determining the oxidation capacity, or cleansing capacity, of the atmosphere in addition to being implicated in the formation of new particles in the marine boundary layer. The postulation that heterogeneous cycling of reactive iodine on aerosols may significantly influence the lifetime of ozone in the troposphere not only remains poorly understood but also heretofore has never been observed or quantified in the field. Here, we report direct ambient observations of hypoiodous acid (HOI) and heterogeneous recycling of interhalogen product species (i.e., iodine monochloride [ICI] and iodine monobromide [IBr]) in a midlatitude coastal environment. Significant levels of ICI and IBr with mean daily maxima of 4.3 and 3.0 parts per trillion by volume (1-min average), respectively, have been observed throughout the campaign. We show that the heterogeneous reaction of HOI on marine aerosol and subsequent production of iodine interhalogens are much faster than previously thought. These results indicate that the fast formation of iodine interhalogens, together with their rapid photolysis, results in more efficient recycling of atomic iodine than currently considered in models. Photolysis of the observed ICI and IBr leads to a 32% increase in the daytime average of atomic iodine production rate, thereby enhancing the average daytime iodine-catalyzed ozone loss rate by 10 to 20%. Our findings provide direct field evidence that the autocatalytic mechanism of iodine release from marine aerosol is important in the atmosphere and can have significant impacts on atmospheric oxidation capacity.Peer reviewe

Effect of Tempering Time on the Microstructure and Properties of Martensitic Stainless Steel

Martensitic stainless steels (MSSs) have been widely used in the manufacture of turbine blades, surgical instruments, and cutting tools because of their hardness and corrosion resistance. The MSSs are usually tempered at a temperature no higher than 250 °C after quenching to avoid the decline in the hardness, strength, and corrosion resistance of the steels. However, some short-time thermal shocks are inevitable in processes like welding, water grinding, laser marking, etc., in the manufacturing of kitchen knives, all of which may have negative effects on the mechanical properties and corrosion resistance. The effects of these short-time thermal shocks have rarely been studied. In this paper, the martensitic stainless steel 5Cr15MoV (X50CrMoV15 is European Standards) was selected to be tempered at the sensitization temperatures (480 to 600 °C) for a series of times (0.5 to 128 min) after quenching, and the microstructures, hardness, and corrosion resistance of the steel after tempering were investigated. It was shown that the variation in hardness and corrosion resistance of the 5Cr15MoV steel could be divided into four stages over time during tempering at the sensitization temperatures. The hardness of steel was found to increase at first and then decrease with time; accordingly, good corrosion resistance was retained in the initial few minutes of tempering, which then deteriorated fast. The variation in hardness and corrosion resistance of the 5Cr15MoV steel is related to the diffusion of C and Cr atoms at different tempering temperatures. The mechanism of the mechanical properties and corrosion resistance variation caused by the diffusion of C and Cr atoms during tempering at the sensitization temperatures was also discussed

ZnO@ZIF-8 Core-Shell Structure Gas Sensors with Excellent Selectivity to H2

As the energy crisis becomes worse, hydrogen as a clean energy source is more and more widely used in industrial production and people’s daily life. However, there are hidden dangers in hydrogen storage and transportation, because of its flammable and explosive features. Gas detection is the key to solving this problem. High quality sensors with more practical and commercial value must be able to accurately detect target gases in the environment. Emerging porous metal-organic framework (MOF) materials can effectively improve the selectivity of sensors as a result of high surface area and coordinated pore structure. The application of MOFs for surface modification to improve the selectivity and sensitivity of metal oxides sensors to hydrogen has been widely investigated. However, the influence of MOF modified film thickness on the selectivity of hydrogen sensors is seldom studied. Moreover, the mechanism of the selectivity improvement of the sensors with MOF modified film is still unclear. In this paper, we prepared nano-sized ZnO particles by a homogeneous precipitation method. ZnO nanoparticle (NP) gas sensors were prepared by screen printing technology. Then a dense ZIF-8 film was grown on the surface of the gas sensor by hydrothermal synthesis. The morphology, the composition of the elements and the characters of the product were analyzed by X-ray diffraction analysis (XRD), transmission electron microscope (TEM), scanning electron microscope (SEM), energy dispersive spectrometer (EDS), Brunauer-Emmett-Teller (BET) and differential scanning calorimetry (DSC). It is found that the ZIF-8 film grown for 4 h cannot form a dense core-shell structure. The thickness of ZIF-8 reaches 130 nm at 20 h. Through the detection and analysis of hydrogen (1000 ppm), ethanol (100 ppm) and acetone (50 ppm) from 150 °C to 290 °C, it is found that the response of the ZnO@ZIF-8 sensors to hydrogen has been significantly improved, while the response to ethanol and acetone was decreased. By comparing the change of the response coefficient, when the thickness of ZIF-8 is 130 nm, the gas sensor has a significantly improved selectivity to hydrogen at 230 °C. The continuous increase of the thickness tends to inhibit selectivity. The mechanism of selectivity improvement of the sensors with different thickness of the ZIF-8 films is discussed

Effects of dietary β-1,3-glucan addition on the growth performance, mRNA expression in jejunal barrier, and cecal microflora of broilers challenged with Clostridium perfringens

ABSTRACT: This experiment aimed to explore the interaction of β-1,3-glucan and Clostridium perfringens on the growth performance, intestinal health and cecal microflora of broilers. A total of 384 one-day-old Arbor Acre broilers were sorted into 4 treatments with 6 replications. There were 2 factors in this trial: dietary β-1,3-glucan addition including 0 and 250 mg/kg, intestinal enteritis challenged with Clostridium perfringens attack or not. Results showed that Clostridium perfringens infection disrupted the integrity of the intestinal mucosa by reducing the jejunal Occludin and Claudin-1 mRNA expression of broiler chickens at 21 d of age (P < 0.05). Meanwhile, when considering Clostridium perfringens as the main effect, it also decreased the mRNA expression of the glucose transporter recombinant sodium/glucose cotransporter 1 (SGLT1) at d 21 and the fatty acid transporter liver fatty acid-binding protein (L-FABP) at d 42 (P < 0.05) as well as affect cecum microbial diversity, especially in relative abundance of Firmicutes and Bacteroidetes. In addition, Clostridium perfringens infection reduced body weight, daily weight gain, and feed-gain ratio (FCR) in broilers at d 42 (P < 0.05). The dietary β-1,3-glucan could alleviate intestinal mucosal damage caused by the Clostridium perfringens to some extent. When considering β-1,3-glucan as the main effect, it increased the SGLT1 at 42 d of age (P < 0.05), and stabilized gut microbiota disorder caused by Clostridium perfringens. More over dietary β-1,3-glucan addition increased body weight at 42-day-old (P < 0.05), and improved daily weight gain and FCR during 1 to 42 d (P < 0.05). In conclusion, dietary β-1,3-glucan could improve growth performance and intestinal health in broilers infected with Clostridium perfringens

Sorafenib Inhibits Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Inhibition of Macrophage Infiltration

Aims: Sorafenib, which has been used extensively for the treatment of renal cell cancer and advanced hepatocellular carcinoma (HCC), has also been shown to have antifibrotic effects in liver fibrosis. However, the effects of sorafenib on renal fibrosis are unknown. Therefore, we investigated whether sorafenib inhibited renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and further explored the potential mechanism. Methods: Mice underwent UUO followed by vehicle or sorafenib treatment. The expression of CD68, a macrophage marker, and the pro-inflammatory cytokines, MCP1 and CXCR3, were immunohistochemically analyzed. The involvement of macrophages in the formation of renal fibrosis was studied using confocal microscopy. Results: Renal histopathology improved in the UUO-sorafenib mice. Sorafenib notably suppressed TGF-β1-mediated renal fibrogenic effects. The mRNA and protein expressions of CD68, MCP1, and CXCR3 in the obstructed kidney were significantly decreased by sorafenib. Immunohistochemistry showed that CD68 and CXCR3 had a similar distribution, whereas MCP1 was observed predominantly in the tubular epithelial cells. Double immunofluorescence demonstrated that CD68-positive macrophages could co-localize with CXCR3. It also revealed that CXCR3 interacted with CXCL11 in the UUO mouse kidneys. Widespread adhesion of macrophages to myofibroblasts was markedly inhibited in UUO-sorafenib mouse kidneys. Conclusions: Taken together, the results indicated that sorafenib had protective effects against renal fibrosis; its mechanism of action was associated with inhibition of macrophage infiltration via the CXCR3/CXCL11 pathway. These data suggest the clinical potential of sorafenib for treatment of renal fibrosis and illustrate the immunological mechanisms underlying the protective effects of sorafenib

Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway