Singlet oxygen dominant-activation by hollow structural cobalt-based MOF/peroxymonosulfate system for micropollutant removal.

Despite the keen interest in potentially using the metal-organic framework (MOF) in advanced oxidation processes (AOPs), their application for environmental abatement and the corresponding degradation mechanisms have remained largely elusive. This study explores the use of cobalt-based MOF (CoMOF) for peroxymonosulfate (PMS) activation to remove tetracycline (TC) from water resources. Under optimal conditions, the given catalytic system could achieve a TC removal of 83.3%. Radical quenching tests and EPR analysis revealed that SO4•-, HO•, •O2-, and 1O2 could participate in the catalytic degradation, but the discernible removal mechanism was mainly ascribed to the nonradical pathway induced by 1O2. At only 5 mg/L of CoMOF, the performance of the catalytic system was superior to that of PMS alone for different types of micropollutants. The CoMOF/PMS system could also reliably deal with typical anions in water, such as Cl-, SO42-, HCO3-, and PO43-. The MOF catalyst could last for four cycles with a minor decrease in reactivity of ∼30%. However, the removal performance decreased markedly when aromatic natural organic matter (NOM) were present in the water bodies, and the effectiveness was lower in alkaline or acidic environments. Our work offers insights into the catalytic degradation of CoMOF/PMS applied in contaminated water remediation and serves as a baseline for fabricating an efficient MOF with enhanced catalytic performance and stability.

Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma.

TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC.

Monophosphoryl lipid A and poly I:C combination enhances immune responses of equine influenza virus vaccine.

Equine influenza is a contagious respiratory disease caused by H3N8 type A influenza virus. Vaccination against equine influenza is conducted regularly; however, infection still occurs globally because of the short immunity duration and suboptimal efficacy of current vaccines. Hence the objective of this study was to investigate whether an adjuvant combination can improve immune responses to equine influenza virus (EIV) vaccines. Seventy-two mice were immunized with an EIV vaccine only or with monophosphoryl lipid A (MPL), polyinosinic-polycytidylic acid (Poly I:C), or MPL + Poly I:C. Prime immunization was followed by boost immunization after 2 weeks. Mice were euthanized at 4, 8, and 32 weeks post-prime immunization, respectively. Sera were collected to determine humoral response. Bone marrow, spleen, and lung samples were harvested to determine memory cell responses, antigen-specific T-cell proliferation, and lung viral titers. MPL + Poly I:C resulted in the highest IgG, IgG1, and IgG2a antibodies and hemagglutination inhibition titers among the groups and sustained their levels until 32 weeks post-prime immunization. The combination enhanced memory B cell responses in the bone marrow and spleen. At 8 weeks post-prime immunization, the combination induced higher CD8+ central memory T cell frequencies in the lungs and CD8+ central memory T cells in the spleen. In addition, the combination group exhibited enhanced antigen-specific T cell proliferation, except for CD4+ T cells in the lungs. Our results demonstrated improved immune responses when using MPL + Poly I:C in EIV vaccines by inducing enhanced humoral responses, memory cell responses, and antigen-specific T cell proliferation.

Effects of vancomycin and tobramycin on compressive and tensile strengths of antibiotic bone cement: A biomechanical study.

Purpose: This study aims to compare the compressive and tensile strengths of bone cement mixed with various concentrations of vancomycin, tobramycin, and combinations of the two. Methods: 12 mm × 6 mm antibiotic bone cement samples were created by vacuum mixing 0-4 g of vancomycin, tobramycin, and combinations of the two in 0.5 g increments per one pouch (40 g) of Palacos LV cement. An Instron 3369 Universal Testing System was used to determine the compressive and tensile strengths. Results: Compressive and tensile strengths of the bone cement without antibiotics were 118 ± 4 MPa and 30.3 ± 12 MPa, respectively. 4 g of vancomycin alone decreased the compressive strength to 108 ± 4 MPa (p-value 0.001) and decreased the tensile strength beginning at 2 g which yielded a strength of 28.1 ± 12 MPa (p-value 0.016). Tobramycin alone decreased the tensile strength beginning at 1.5 g yielding a strength of 27.7 ± 7 MPa (p-value 0.003). Although it decreased compressive strength at 1 g to 117 ± 7 MPa (p-value 0.002), it demonstrated variable effects with increasing concentrations. A combination of vancomycin and tobramycin decreased both the compressive (111 ± 5 MPa, p-value 0.014) and tensile (27.9 ± 8 MPa, p-value 0.007) strengths beginning at 1 g each. Conclusions: Various combinations of vancomycin and tobramycin affect the compressive and tensile strengths of bone cement. Clinicians should be diligent when mixing these antibiotics in bone cement to prevent possible failure of the constructs.

Immunostimulatory effects of marine algae extracts on in vitro antigen-presenting cell activation and in vivo immune cell recruitment.

Marine algae are photosynthetic eukaryotic organisms that are widely used as sources of food, cosmetics, and drugs. However, their biological and immunological effects on immune cells have not been fully elucidated. To unravel their immunological activity and broaden their application, we generated antigen-presenting cells (APCs), including dendritic cells (DCs) and macrophages, from mouse bone marrow cells and treated them with six different marine algae extracts (MAEs). We evaluated cell viability, activation marker expression, and pro-inflammatory cytokine production by APCs after 2 days of MAE treatment. All six MAEs significantly induced cytokine production of APCs, among which Pyropia yezoensis (PY), Peyssonnelia caulifera (PC), and Meristotheca papulosa (MP) extracts exhibited the strongest effect. Cladophora wrightiana var. minor (CW) extract moderately upregulated cytokine levels but increased the expression of activation markers on DCs. Moreover, PY, PC, MP, Sargassum pectinifera (SP), and Caulerpa okamurae (CO) pre-treated APCs effectively stimulated T-cell proliferation and cytokine production. Furthermore, the mice injected with MAEs exhibited higher cytokine (TNF-α, IL-6, and IL-1ß) production as well as enhanced innate immune cell recruitment capacities (DCs, monocytes, neutrophils, and natural killer cells) in the peritoneal cavity of the mice compared to those of the non-treated mice. Therefore, all MAEs exhibited immunostimulatory potential, with PY, PC, CW, and MP extracts being the most effective in stimulating immune responses and cell activation. To the best of our knowledge, this is the first study to determine the immunomodulatory activities of six MAEs both in vitro and in vivo.

Adjuvant effects of combination monophosphoryl lipid A and poly I:C on antigen-specific immune responses and protective efficacy of influenza vaccines.

Toll-like receptor (TLR) agonists improve vaccine immunogenicity and efficacy, but they are currently unlicensed as adjuvants in influenza vaccines. This study aimed to investigate whether a combination of monophosphoryl lipid A (MPL, a TLR4 agonist) and polyriboinosinic polyribocytidylic acid (poly I:C, a TLR3 agonist) can enhance the protective efficacy of an inactivated A/Puerto Rico/8/1934 (A/PR8) H1N1 influenza vaccine against homologous influenza infection and minimize illness outcomes. Results showed that combination MPL and poly I:C adjuvanted influenza vaccination increased the production of antigen-specific antibodies, decreased the levels of cytokines and cellular infiltrates at the infection sites, and induced significant memory T and B cell responses in mice. The results of this study suggest that the combination of MPL and poly I:C can be developed into a possible adjuvant for enhancing the efficacy of influenza vaccines.

Concomitant Use of Proton Pump Inhibitors and Palbociclib Among Patients With Breast Cancer.

Importance: Proton pump inhibitors (PPIs) are commonly used drugs to relieve gastrointestinal tract symptoms, but their acid-inhibitory action negatively affects the bioavailability and clinical outcomes of orally administered concomitant drugs. Objective: To identify the clinical outcomes of patients with advanced breast cancer who concomitantly use PPIs and palbociclib. Design, Setting, and Participants: This retrospective cohort study used nationwide claims data between November 1, 2016, and July 31, 2021, in South Korea. Patients with breast cancer receiving palbociclib between November 1, 2017, and July 31, 2020, were identified. Patients whose prescriptions for palbociclib and PPI overlapped by at least 33% were classified into a concomitant PPI group. Patients who never received PPI during the palbociclib treatment period were classified into a nonconcomitant PPI group. Patients were selected through 1:3 propensity score matching for analyses. Exposures: Concomitant use of PPIs with palbociclib. Main Outcomes and Measures: Time to progression and death. These outcomes were presented as progression-free survival (PFS) and overall survival (OS) and were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to estimate the hazard ratio (HR) of concomitant PPI use associated with clinical PFS and/or OS. Results: A total of 344 women were included in the concomitant PPI group and 966 in the nonconcomitant PPI group. Among 1310 patients identified after matching, 1108 (84.6%) were older than 50 years; 1111 (84.8%) were treated with letrozole and anastrozole (endocrine sensitive); and 199 (15.2%) were treated with fulvestrant (endocrine resistant). The median clinical PFS in the concomitant PPI group was shorter than that of the nonconcomitant PPI group (25.3 [95% CI, 19.6-33.0] vs 39.8 [95% CI, 34.9 to not applicable] months; P < .001), and the HR was 1.76 (95% CI, 1.46-2.13). Concomitant use of PPI was also associated with shorter OS (HR, 2.71 [95% CI, 2.07-3.53]). Both clinical PFS and OS in the concomitant PPI group were consistently poor in patients receiving endocrine-sensitive and endocrine-resistant treatment. Conclusions and Relevance: These findings suggest that concomitant use of PPIs with palbociclib may hinder the complete therapeutic benefits of palbociclib in patients with breast cancer.

Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement.

Adipose tissues are central in controlling metabolic homeostasis and failure in their preservation is associated with age-related metabolic disorders. The exact role of mature adipocytes in this phenomenon remains elusive. Here we describe the role of adipose branched-chain amino acid (BCAA) catabolism in this process. We found that adipocyte-specific Crtc2 knockout protected mice from age-associated metabolic decline. Multiomics analysis revealed that BCAA catabolism was impaired in aged visceral adipose tissues, leading to the activation of mechanistic target of rapamycin complex (mTORC1) signaling and the resultant cellular senescence, which was restored by Crtc2 knockout in adipocytes. Using single-cell RNA sequencing analysis, we found that age-associated decline in adipogenic potential of visceral adipose tissues was reinstated by Crtc2 knockout, via the reduction of BCAA-mTORC1 senescence-associated secretory phenotype axis. Collectively, we propose that perturbation of BCAA catabolism by CRTC2 is critical in instigating age-associated remodeling of adipose tissue and the resultant metabolic decline in vivo.

Chronic allergic asthma induces T-cell exhaustion and impairs virus clearance in mice.

BACKGROUND: Allergic asthma, one of the most common types of asthma, is thought to be highly susceptible to respiratory viral infections; however, its pathological mechanism needs to be elucidated. Recent studies have found impaired T-cell function in asthmatic mice. Therefore, we aimed to investigate the way by which asthma induction affects T-cell exhaustion in the lungs and assess the relationship between T-cell exhaustion and influenza viral infection. METHODS: Chronic allergic asthma mice were induced by intranasal injection of ovalbumin for 6 weeks and asthmatic features and T cell populations in lung or airway were assessed. To determine the influenza virus susceptibility, control and asthma mice were challenged with the human influenza virus strain A/Puerto Rico/8/1934 H1N1 and evaluated the survival rate, lung damage, and virus titer. RESULTS: Six weeks of OVA sensitization and challenge successfully induced chronic allergic asthma in a mouse model showing significant increase of sera IgE level and broncho-pathological features. A significant decrease in interferon-γ-producing T-cell populations and an increase in exhausted T-cell populations in the lungs of OVA-induced asthmatic mice were observed. Asthmatic mice were more susceptible to influenza virus infection than control mice showing lower survival rate and higher virus titer in lung, and a positive correlation existed between T-cell exhaustion in the lung and virus titer. CONCLUSIONS: Asthma induction in mice results in the exhaustion of T-cell immunity, which may contribute to the defective capacity of viral protection. This study demonstrates a correlation between asthma conditions and viral susceptibility by investigating the functional characteristics of T-cells in asthma. Our results provide insights into the development of strategies to overcome the dangers of respiratory viral disease in patients with asthma.