Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.

Cytomegalovirus Triplex vaccine in pediatric hematopoietic stem cell transplant patients at high risk for cytomegalovirus complications: evaluation of vaccine safety, immunogenicity and impact on viremia requiring antivirals.

Not available.

Experimental Study on the Chemical Reaction Characteristics in the Calcination Process of an 811 Ternary Cathode Material.

The research on 811 ternary cathode materials is mainly based on synthesis and modification. However, the preparation process of these materials is accompanied by complex chemical reactions, and the reaction process and corresponding kinetic analysis have not been widely explored. Under different oxygen concentrations, this study analyzed the chemical reaction mechanism of the raw material's (namely, Ni0.8Co0. 1Mn0. 1(OH)2 and LiOH·H2O mixture, which is referred to as the raw material hereinafter) calcination process by non-isothermal thermogravimetry, differential scanning calorimetry, and in situ X-ray diffraction. Based on the obtained data, multiple heating rate methods were used to calculate the reaction mechanism functions and kinetic parameters at each stage as well as the corresponding activation energy and pre-exponential factor. Results showed that four chemical reactions occurred successively during the calcination process of the raw materials with each corresponding to a different kinetic function, pre-exponential factor, and activation energy. Comparing the calcination characteristics under different oxygen concentrations showed that the activation energy was the smallest when the oxygen concentration was 60%.

[Screening and obataining of aptamers for the blood group antigen-binding adhesin (BabA) to block Helicobacter pylori (H.pylori) colonization in the stomach of mice].

Objective To explore the aptamer specific binding blood group antigen-binding adhesin (BabA) of Helicobacter pylori (H.pylori) for blocking of H.pylori adhering host cell. Methods H.pylori strain was cultured and its genome was extracted as templates to amplify the BabA gene by PCR with designed primers. The BabA gene obtained was cloned and constructed into prokaryotic expression plasmid, which was induced by isopropyl beta-D-galactoside (IPTG) and purified as target. The single stranded DNA (ssDNA) aptamers that specifically bind to BabA were screened by SELEX. Enzyme-linked oligonucleotide assay (ELONA) was used to detect and evaluate the characteristics of candidate aptamers. The blocking effect of ssDNA aptamers on H.pylori adhesion was subsequently verified by flow cytometry and colony counting at the cell level in vitro and in mouse model of infection, respectively. Meanwhile, the levels of cytokines, interleukin 6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), IL-10 and IL-4 in the homogenate of mouse gastric mucosa cells were detected by ELISA. Results The genome of H.pylori ATCC 43504 strains was extracted and the recombinant plasmid pET32a-BabA was constructed. After induction and purification, the relative molecular mass (Mr) of the recombinant BabA protein was about 39 000. The amino acid sequence of recombinent protein was consistent with BabA protein by peptide mass fingerprint (PMF). Five candidate aptamers were selected to bind to the above recombinent BabA protein by SELEX. The aptamers A10, A30 and A42 identified the same site, while A3, A16 and the above three aptamers identified different sites respectively. The aptamer significantly blocked the adhesion of H.pylori in vitro. Animal model experiments showed that the aptamers can block the colonization of H.pylori in gastric mucosa by intragastric injection and reduce the inflammatory response. The levels of IL-4, IL-6, IL-8 and TNF-α in gastric mucosal homogenates in the model group with aptamer treatment were lower than that of model group without treatment. Conclusion Aptamers can reduce the colonization of H.pylori in gastric mucosa via binding BabA to block the adhesion between H.pylori and gastric mucosal epithelial cells.

Integrated single-cell and bulk sequencing analyses with experimental validation identify the prognostic and immunological implications of CD226 in pan-cancer.

PURPOSE: CD226 (DNAM-1) is an activating receptor mainly expressed in CD8 + and NK cells. CD226 deficiency and blockade have been shown to impair tumor suppression, while enhanced CD226 expression positively correlated with the increased efficacy of immune checkpoint blockade (ICB) therapies. However, the detailed function and role of CD226 in pan-cancer are largely unknown and require further in-depth investigation. Therefore, this study aims to investigate the biological functions of CD226, its role in tumor immunity, and its potential to predict prognosis and immunotherapy response in pan-cancer. METHODS: By taking advantage of single-cell and bulk sequencing analyses, we analyzed the expression profile of CD226, its correlation with patient prognosis, immune infiltration level, immune-related genes, tumor heterogeneity, and stemness in pan-cancer. We also investigated the biological functions of CD226 using gene set enrichment analysis (GSEA) and evaluated its predictive value in response to immunotherapy and small-molecule targeted drugs. In addition, we validated the expression of CD226 in tumor-infiltrating CD8 + and NK cells and studied its association with their functions using a murine B16F10 melanoma model. RESULTS: CD226 exhibited differential expression across most tumor types, and its elevated expression was associated with improved clinical outcomes in multiple cancer types. CD226 is closely correlated with numerous tumor-infiltrating immune cells, tumor stemness, and heterogeneity in most cancers. Furthermore, based on single-cell sequencing analysis, CD226 expression was found to be higher on effector CD4 + T cells than naïve CD4 + T cells, and its expression level was decreased in exhausted CD8 + T cells relative to effector CD8 + T cells in multiple cancer types. Additionally, flow cytometric analysis demonstrated that CD226 was highly correlated with the function of tumor-infiltrating NK and CD8 + T cells in murine B16F10 melanoma. Moreover, GSEA analysis revealed that CD226 was closely associated with T cell activation, natural killer cell mediated immunity, natural killer cell-mediated cytotoxicity, and T cell receptor signaling pathway. Finally, CD226 showed promising predictive potential for responsiveness to both ICB therapies and various small-molecule targeted drugs. CONCLUSION: CD226 has shown great potential as an innovative biomarker for predicting patient prognosis, immune infiltration levels, and the function of tumor-infiltrating CD8 + T cells, as well as immunotherapy response. Additionally, our findings suggest that the optimal modification of CD226 expression and function, combined with current ICBs, could be a promising strategy for tumor immunotherapy.

Effects of Different Yeast Selenium Levels on Rumen Fermentation Parameters, Digestive Enzyme Activity and Gastrointestinal Microflora of Sika Deer during Antler Growth.

The aim of this experiment was to study the effects of different selenium supplemental levels on rumen fermentation microflora of sika deer at the velvet antler growth stage. A total of 20 5-year-old, healthy sika deer at the velvet antler growth stage with an average body weight of (98.08 ± 4.93) kg were randomly divided into 4 groups, and each group was fed in a single house. The SY1 group was the control group, and the SY2 group, SY3 group and SY4 group were fed a basal diet supplemented with 0.3, 1.2 and 4.8 mg/kg selenium, respectively. The pretest lasted for 7 days, and the formal trial period lasted for 110 days. The results show that: At the velvet antler growth stage, the digestibility of neutral detergent fiber and acid detergent fiber of sika deer in the SY2 group was significantly higher than that in the control group (p < 0.01). The digestibility of cellulose and crude fiber of sika deer in the SY2 group was significantly higher than those in the SY3 and SY4 groups (p < 0.01) and significantly higher than that in the control group (p < 0.05). The contents of acetic acid and propionic acid in the rumen fluid of sika deer in the SY2 group were significantly higher than those in the SY1 group (p < 0.05). Digestive enzyme analysis of rumen fluid at the velvet antler growth stage showed that the activity of protease in rumen fluid in the SY2 group was significantly lower than those in the SY1 group and SY4 group (p < 0.05). The relative abundance of Fibrobacter succinogenes in the SY2 group was significantly higher than that in the SY1 group (p < 0.05) and extremely significantly higher than those in the SY3 and SY4 groups (p < 0.01). Correlation analysis between yeast selenium level and bacterial abundance showed that the yeast selenium content in rumen fluid was significantly positively correlated with Butyrivibrio and Succiniclasticum (p < 0.01). Further verification of bacterial flora functioning showed that the SY2 group was more inclined to the degradation and utilization of fiber. In conclusion, 0.3 mg/kg selenium supplementation can increase the abundance of Prevotella ruminicola and Fibrobacter succinogenes in the rumen of sika deer and improve the degradation of fibrous substances by mediating the catabolite repression process.

Global, regional, and national burden of kidney dysfunction from 1990 to 2019: a systematic analysis from the global burden of disease study 2019.

OBJECTIVE: We aim to explore the prevalence and temporal trends of the burden of kidney dysfunction (KD) in global, regional and national level, since a lack of related studies. DESIGN: Cross-sectional study. MATERIALS: The data of this research was obtained from Global Burden of Diseases Study 2019. The estimation of the prevalence, which was measured by the summary exposure value (SEV), and attributable burden of KD was performed by DisMod-MR 2.1, a Bayesian meta-regression tool. The Spearman rank order correlation method was adopted to perform correlation analysis. The temporal trends were represented by the estimated annual percentage change (EAPC). RESULTS: In 2019, there were total 3.16 million deaths and 76.5 million disability-adjusted life years (DALYs) attributable to KD, increased by 101.1% and 81.7% compared with that in 1990, respectively. From 1990 to 2019, the prevalence of KD has increased in worldwide, but decreased in High-income Asia Pacific. Nearly 48.5% of countries globally, such as South Africa, Egypt and Mexico had increased mortality rates of KD from 1990 to 2019 while 44.6% for disability rate. Countries with lower socio-demographic index (SDI) are facing a higher prevalence as well as mortality and disability rate compared with those with higher SDI. Compared with females, the prevalence of KD was lower in males, however the attributable mortality and disability rate were higher in all years from 1990 to 2019. CONCLUSION: With the progress of senescent, we will face more severe challenges of reducing the prevalence and attributable burden of KD, especially in regions with lower SDI. Effective measures are urgently required to alleviate the prevalence and burden of KD.

Different Diet Energy Levels Alter Body Condition, Glucolipid Metabolism, Fecal Microbiota and Metabolites in Adult Beagle Dogs.

Diet energy is a key component of pet food, but it is usually ignored during pet food development and pet owners also have limited knowledge of its importance. This study aimed to explore the effect of diet energy on the body condition, glucolipid metabolism, fecal microbiota and metabolites of adult beagles and analyze the relation between diet and host and gut microbiota. Eighteen healthy adult neutered male beagles were selected and randomly divided into three groups. Diets were formulated with three metabolizable energy (ME) levels: the low-energy (Le) group consumed a diet of 13.88 MJ/kg ME; the medium-energy (Me) group consumed a diet of 15.04 MJ/kg ME; and the high-energy (He) group consumed a diet of 17.05 MJ/kg ME. Moreover, the protein content of all these three diets was 29%. The experiment lasted 10 weeks, with a two-week acclimation period and an eight-week test phase. Body weight, body condition score (BCS), muscle condition score (MCS) and body fat index (BFI) decreased in the Le group, and the changes in these factors in the Le group were significantly higher than in the other groups (p < 0.05). The serum glucose and lipid levels of the Le and He groups changed over time (p < 0.05), but those of the Me group were stable (p > 0.05). The fecal pH of the Le and He groups decreased at the end of the trial (p < 0.05) and we found that the profiles of short-chain fatty acids (SCFAs) and bile acids (BAs) changed greatly, especially secondary BAs (p < 0.05). As SCFAs and secondary BAs are metabolites of the gut microbiota, the fecal microbiota was also measured. Fecal 16S rRNA gene sequencing found that the Me group had higher α-diversity indices (p < 0.05). The Me group had notably higher levels of gut probiotics, such as Faecalibacterium prausnitzii, Bacteroides plebeius and Blautia producta (p < 0.05). The diet-host-fecal microbiota interactions were determined by network analysis, and fecal metabolites may help to determine the best physical condition of dogs, assisting pet food development. Overall, feeding dogs low- or high-energy diets was harmful for glucostasis and promoted the relative abundance of pathogenic bacteria in the gut, while a medium-energy diet maintained an ideal body condition. We concluded that dogs that are fed a low-energy diet for an extended period may become lean and lose muscle mass, but diets with low energy levels and 29% protein may not supply enough protein for dogs losing weight.

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma.

BACKGROUND: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC-1 study. Cytokine release syndrome (CRS), a known manifestation of T-cell redirection, was observed in 119 of 165 patients (72.1%). METHODS: Patients received once-weekly teclistamab 1.5 mg/kg subcutaneously after two step-up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. RESULTS: Most cases of CRS occurred during the step-up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. CONCLUSIONS: Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T-cell-engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. PLAIN LANGUAGE SUMMARY: Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC-1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation. Most CRS occurred during the step-up schedule, requiring vigilance during treatment initiation. Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step-up schedule or administering the next teclistamab dose, to avoid exacerbating CRS. Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity.

Experimental Study of the Pore Structure and Gas Desorption Characteristics of a Low-Rank Coal: Impact of Moisture.

Coal-water interactions have a prominent impact on the prediction of coal mine gas disasters and coalbed methane extraction. The change of characteristics in the microscopic pores of coal caused by the existence of water is an important factor affecting the diffusion and migration of gas in coal. The low-pressure nitrogen adsorption experiments and gas desorption experiments of a low-rank coal with different equilibrium moisture contents were conducted. The results show that both the specific surface area and pore volume decrease significantly as the moisture content increases, and the micropores (pore diameter <10 nm) are most affected by the water adsorbed by coal. In particular, for a water-equilibrated coal sample at 98% relative humidity, micropores with pore sizes smaller than 4 nm as determined by the density functional theory model almost disappear, probably due to the blocking effects of water clusters and capillary water. In this case, micropores with a diameter less than 10 nm still contribute most of the specific surface area for gas adsorption in coal. Furthermore, the fractal dimensions at relative pressures of 0-0.5 (D 1) and 0.5-1 (D 2) calculated by the Frenkel-Halsey-Hill model indicate that when the moisture content is less than 4.74%, D 1 decreases rapidly, whereas D 2 shows a slight reduction as the moisture content increased. In contrast, when the moisture content exceeds 4.74%, further increases in the moisture content cause D 2 to decrease significantly, while there is nearly no change for D 1. The correlation analyses show that the ultimate desorption volume and initial desorption rate are closely related to the fractal dimension D 1, while the desorption constant (K t) mainly depends on the fractal dimension D 2. Therefore, the gas desorption performances of coal have a close association with the pore properties of coal under water-containing conditions, which indicate that the fluctuation in moisture content should be carefully considered in the evaluation of gas diffusion and migration performances of in situ coal seams.

CRISPR/Cas9 Screens Reveal that Hexokinase 2 Enhances Cancer Stemness and Tumorigenicity by Activating the ACSL4-Fatty Acid ß-Oxidation Pathway.

Metabolic reprogramming is often observed in carcinogenesis, but little is known about the aberrant metabolic genes involved in the tumorigenicity and maintenance of stemness in cancer cells. Sixty-seven oncogenic metabolism-related genes in liver cancer by in vivo CRISPR/Cas9 screening are identified. Among them, acetyl-CoA carboxylase 1 (ACC1), aldolase fructose-bisphosphate A (ALDOA), fatty acid binding protein 5 (FABP5), and hexokinase 2 (HK2) are strongly associated with stem cell properties. HK2 further facilitates the maintenance and self-renewal of liver cancer stem cells. Moreover, HK2 enhances the accumulation of acetyl-CoA and epigenetically activates the transcription of acyl-CoA synthetase long-chain family member 4 (ACSL4), leading to an increase in fatty acid ß-oxidation activity. Blocking HK2 or ACSL4 effectively inhibits liver cancer growth, and GalNac-siHK2 administration specifically targets the growth of orthotopic tumor xenografts. These results suggest a promising therapeutic strategy for the treatment of liver cancer.

Pathogenesis of Concanavalin A induced autoimmune hepatitis in mice.

Autoimmune hepatitis (AIH) is an autoimmune disease characterized by liver parenchymal destruction and chronic fibrosis. Its exact etiology and pathogenesis are not yet fully understood.(Please connect with the following, do not leave a line) Concanavalin A (Con A)-induced mice hepatitis model is a liver injury mediated by T cell and macrophage activation, and its pathogenesis and pathological changes are similar to human AIH. The establishment of this model has greatly promoted the research progress of AIH pathogenesis. However, the exact mechanism of Con A induced liver injury in mice, and its possible defects or deficiencies, has not yet been described in a clear and detailed manner. Therefore, the model has some limitations when applied to the study of the pathogenesis and treatment mechanism of AIH. This article reveals the pathogenesis of Con A induced liver injury in mice from the aspects of immune disorder and coagulation mechanism, expounds the significance of non-coding RNA in this model, summarizes the signal transduction pathways involved in this model, and summarizes the advantages and disadvantages of the model, which provides a theoretical basis and research target for the application of Con A induced liver injury model in AIH in the future.

Ubiquitin Ligases CBL and CBL-B Maintain the Homeostasis and Immune Quiescence of Dendritic Cells.

Dendritic cells (DCs) are composed of multiple lineages of hematopoietic cells and orchestrate immune responses upon detecting the danger and inflammatory signals associated with pathogen and damaged tissues. Under steady-state, DCs are maintained at limited numbers and the functionally quiescent status. While it is known that a fine balance in the DC homeostasis and activation status is also important to prevent autoimmune diseases and hyperinflammation, mechanisms that control DC development and activation under stead-state remain not fully understood. Here we show that DC-specific ablation of CBL and CBL-B (CBL-/-CBL-B-/-) leads to spontaneous liver inflammation and fibrosis and early death of the mice. The mutant mice have a marked expansion of classic CD8α+/CD103+ DCs (cDC1s) in peripheral lymphoid organs and the liver. These DCs exhibit atypical activation phenotypes characterized by an increased production of inflammatory cytokines and chemokines but not the cell surface MHC-II and costimulatory ligands. While the mutant mice also have massive T cell activation, lymphocytes are not required for the disease development. The CBL-/-CBL-B-/- mutation enhances FLT3-mTOR signaling, due to defective FLT3 ubiquitination and degradation. Blockade of FLT3-mTOR signaling normalizes the homeostasis of cDC1s and attenuates liver inflammation. Our result thus reveals a critical role of CBLs in the maintenance of DC homeostasis and immune quiescence. This regulation could be relevant to liver inflammatory diseases and fibrosis in humans.

Current Management and New Developments in the Treatment of ALL.

With the recent advent of newer targeted therapies, including blinatumomab, inotuzumab ozogamicin, tyrosine kinase inhibitors (TKIs), and CAR T cells, treatment approaches to newly diagnosed as well as relapsed/refractory acute lymphoblastic leukemia (ALL) have changed. This chapter summarizes the newest treatment approaches in newly diagnosed T-cell and B-cell ALL, as well as the use of novel therapies for relapsed and refractory ALL.

Mechanism confirmation of organofunctional silanes modified sodium silicate/polyurethane composites for remarkably enhanced mechanical properties.

Hybrid reinforced sodium silicate/polyurethane (SS/PU) composites mainly derived from low-cost SS and polyisocyanate are produced by a one-step method based on the addition of 3-chloropropyltrimethoxysilane (CTS). The wettability of SS on PU substrate surface is much improved as CTS content increases from 0.0 to 3.5 wt%. Furthermore, with 2.5 wt% of CTS optimal addition, the fracture surface morphology and elemental composition of the resulting SS/PU composites are characterized, as well as mechanical properties, chemical structure and thermal properties. The results indicate that the CTS forms multiple physical and chemical interactions with the SS/PU composites to induce an optimized organic-inorganic hybrid network structure thus achieving simultaneous improvement of compressive strength, flexural strength, flexural modulus and fracture toughness of the SS/PU composites, with the improvement of 12.9%, 6.6%, 17.5% and 9.7%, respectively. Moreover, a reasonable mechanism explanation for CTS modified SS/PU composites is confirmed. Additionally, the high interface areas of the organic-inorganic phase and the active crosslinking effect of the CTS are the main factors to determine the curing process of the SS/PU composites.

Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: the IDEAL trial.

Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL's end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation. These trials were registered at www.clinicaltrials.gov as #NCT02708108 (IDEAL trial) and #NCT01317940 (historical control).

Axial Ligand Coordination Tuning of the Electrocatalytic Activity of Iron Porphyrin Electrografted onto Carbon Nanotubes for the Oxygen Reduction Reaction.

The oxygen reduction reaction (ORR) is essential in many life processes and energy conversion systems. It is desirable to design transition metal molecular catalysts inspired by enzymatic oxygen activation/reduction processes as an alternative to noble-metal-Pt-based ORR electrocatalysts, especially in view point of fuel cell commercialization. We have fabricated bio-inspired molecular catalysts electrografted onto multiwalled carbon nanotubes (MWCNTs) in which 5,10,15,20-tetra(pentafluorophenyl) iron porphyrin (iron porphyrin FeF20 TPP) is coordinated with covalently electrografted axial ligands varying from thiophene to imidazole on the MWCNTs' surface. The catalysts' electrocatalytic activity varied with the axial coordination environment (i. e., S-thiophene, N-imidazole, and O-carboxylate); the imidazole-coordinated catalyst MWCNTs-Im-FeF20 TPP exhibited the highest ORR activity among the prepared catalysts. When MWCNT-Im-FeF20 TPP was loaded onto the cathode of a zinc-air battery, an open-cell voltage (OCV) of 1.35 V and a maximum power density (Pmax ) of 110 mW cm-2 were achieved; this was higher than those of MWCNTs-Thi-FeF20 TPP (OCV=1.30 V, Pmax =100 mW cm-2 ) and MWCNTs-Ox-FeF20 TPP (OCV=1.28 V, Pmax =86 mW cm-2 ) and comparable with a commercial Pt/C catalyst (OCV=1.45 V, Pmax =120 mW cm-2 ) under similar experimental conditions. This study provides a time-saving method to prepare covalently immobilized molecular electrocatalysts on carbon-based materials with structure-performance correlation that is also applicable to the design of other electrografted catalysts for energy conversion.

Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study.

PURPOSE: The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover. METHODS: Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed. RESULTS: With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached v 52.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P < .0001) and by 48% after adjustment for crossover (hazard ratio, 0.52; 95% CI, 0.42 to 0.64; P < .0001). Apalutamide plus ADT delayed second progression-free survival and castration resistance (P < .0001 for both). Health-related quality of life, per total Functional Assessment of Cancer Therapy-Prostate, in both groups was maintained through the study. Safety was consistent with previous reports. CONCLUSION: The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC.

lncRNA­MALAT1 promotes high glucose­induced H9C2 cardiomyocyte pyroptosis by downregulating miR­141­3p expression.

Diabetic cardiomyopathy (DCM) is caused by diabetes and can result in heart failure. Long non­coding RNAs (lncRNAs) have been demonstrated to be closely associated with DCM development. The present study aimed to investigate whether lncRNA­metastasis­associated lung adenocarcinoma transcript­1 (MALAT1) altered high glucose (HG)­induced H9C2 cardiomyocyte pyroptosis by targeting microRNA (miR)­141­3p. H9C2 cells were treated with normal glucose (NG) or HG. lncRNA­MALAT1 and miR­141­3p expression levels were determined via reverse transcription­quantitative PCR (RT­qPCR). MALAT1 and miR­141­3p knockdown and overexpression were established and confirmed via RT­qPCR. The association between MALAT1 expression and miR­141­3p expression, as well as the induction of pyroptosis and gasdermin D (GSDMD)­N expression were evaluated by performing dual luciferase reporter, TUNEL staining and immunofluorescence staining assays, respectively. Western blotting was conducted to measure the expression levels of pyroptosis­associated proteins, including apoptosis­associated speck­like protein, GSDMD­N, caspase­1, nucleotide oligomerization domain­like receptor protein 3 and GSDMD. MALAT1 mRNA expression levels were significantly increased, whereas miR­141­3p expression levels were significantly decreased in HG­treated H9C2 cells compared with the NG group. Compared with the HG group, MALAT1 overexpression significantly reduced miR­141­3p expression levels, increased the rate of TUNEL positive cells and upregulated the expression levels of pyroptosis­associated proteins. MALAT1 knockdown displayed the opposite effect on the rate of TUNEL positive cells and the expression levels of pyroptosis­associated proteins. Furthermore, the rate of TUNEL positive cells, and GSDMD­N and pyroptosis­associated protein expression levels were significantly reduced by miR­141­3p overexpression in MALAT1­overexpression H9C2 cells. The results indicated that compared with NG treatment, HG treatment increased MALAT1 expression levels and decreased miR­141­3p expression levels in H9C2 cells. Therefore, the present study suggested that lncRNA­MALAT1 targeted miR­141­3p to promote HG­induced H9C2 cardiomyocyte pyroptosis.