Pneumocystis pneumonia in stage IIIA lung adenocarcinoma with immune-related acute kidney injury and thoracic radiotherapy: A case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are therapeutic agents for advanced and metastatic non-small cell lung cancer (NSCLC) with high clinical antitumor efficacy. However, immune-related adverse events occur in 20% of these patients and often requiring treatment with immunosuppressive agents, such as corticosteroids. Consequently, this may increase the risk of patients to opportunistic infections. Pneumocystis jirovecii pneumonia (PJP), a rare but serious opportunistic infection typically observed in patients with human immunodeficiency virus, can also occur in cancer patients undergoing long-term glucocorticoid treatment. CASE SUMMARY: We report a case of a 56-year-old male with squamous NSCLC treated with triplimab combined with paclitaxel, carboplatin, and radical thoracic radiation therapy. Following this regimen, he developed acute kidney injury (AKI) with elevated creatinine levels. After concurrent radical chemoradiotherapy ended, he developed a grade 3 immune-related AKI. High-dose corticosteroids were administered to treat AKI, and renal function gradually recovered. Corticosteroids were reduced to a dose of 10 mg prednisone equivalent daily eight weeks later; however, he developed severe pneumonia with spontaneous pneumothorax. Next-generation sequencing of the bronchoscopic lavage revealed PJP co-infection with herpes simplex virus 1 and cytomegalovirus. The inflammation was more severe in areas exposed to radiation. Piperacillin-tazobactam, acyclovir, sulfamethoxazole, and trimethoprim were used to control the infection. The patient recovered, and immunotherapy was terminated. CONCLUSION: PJP is rare but can occur in patients with ICI adverse events and should be differentiated from tumor progression or immune-related adverse events. Thoracic radiation may increase risk, necessitating careful monitoring and prevention.

RNA editing in response to COVID-19 vaccines: unveiling dynamic epigenetic regulation of host immunity.

Background: COVID-19 vaccines are crucial for reducing the threat and burden of the pandemic on global public health, yet the epigenetic, especially RNA editing in response to the vaccines remains unelucidated. Results: Our current study performed an epitranscriptomic analysis of RNA-Seq data of 260 blood samples from 102 healthy and SARS-CoV-2 naïve individuals receiving different doses of the COVID-19 vaccine and revealed dynamic, transcriptome-wide adenosine to inosine (A-to-I) RNA editing changes in response to COVID-19 vaccines (RNA editing in response to COVID-19 vaccines). 5592 differential RNA editing (DRE) sites in 1820 genes were identified, with most of them showing up-regulated RNA editing and correlated with increased expression of edited genes. These deferentially edited genes were primarily involved in immune- and virus-related gene functions and pathways. Differential ADAR expression probably contributed to RNA editing in response to COVID-19 vaccines. One of the most significant DRE in RNA editing in response to COVID-19 vaccines was in apolipoprotein L6 (APOL6) 3' UTR, which positively correlated with its up-regulated expression. In addition, recoded key antiviral and immune-related proteins such as IFI30 and GBP1 recoded by missense editing was observed as an essential component of RNA editing in response to COVID-19 vaccines. Furthermore, both RNA editing in response to COVID-19 vaccines and its functions dynamically depended on the number of vaccine doses. Conclusion: Our results thus underscored the potential impact of blood RNA editing in response to COVID-19 vaccines on the host's molecular immune system.

Bioaccessibility and bioavailability assessment of cadmium in rice: In vitro simulators with/without gut microbiota and validation through in vivo mouse and human data.

Assessing the bioaccessibility and bioavailability of cadmium (Cd) is crucial for effective evaluation of the exposure risk associated with intake of Cd-contaminated rice. However, limited studies have investigated the influence of gut microbiota on these two significant factors. In this study, we utilized in vitro gastrointestinal simulators, specifically the RIVM-M (with human gut microbial communities) and the RIVM model (without gut microbial communities), to determine the bioaccessibility of Cd in rice. Additionally, we employed the Caco-2 cell model to assess bioavailability. Our findings provide compelling evidence that gut microbiota significantly reduces Cd bioaccessibility and bioavailability (p<0.05). Notably, strong in vivo-in vitro correlations (IVIVC) were observed between the in vitro bioaccessibilities and bioavailabilities, as compared to the results obtained from an in vivo mouse bioassay (R2 = 0.63-0.65 and 0.45-0.70, respectively). Minerals such as copper (Cu) and iron (Fe) in the food matrix were found to be negatively correlated with Cd bioaccessibility in rice. Furthermore, the results obtained from the toxicokinetic (TK) model revealed that the predicted urinary Cd levels in the Chinese population, based on dietary Cd intake adjusted by in vitro bioaccessibility from the RIVM-M model, were consistent with the actual measured levels (p > 0.05). These results indicated that the RIVM-M model represents a potent approach for measuring Cd bioaccessibility and underscore the crucial role of gut microbiota in the digestion and absorption process of Cd. The implementation of these in vitro methods holds promise for reducing uncertainties in dietary exposure assessment.

Photomodulation of Charge Transfer through Excited-State Processes: Directing Donor-Acceptor Binding Dynamics.

Modulating charge transfer (CT) interactions between donor and acceptor molecules may give rise to unique dynamic changes in physicochemical properties, exhibiting great importance in supramolecular chemistry and materials science. In this work, we demonstrate the first instance of reversible photomodulation of donor-acceptor (D-A) CT interaction in the solid state.Pyridinium-based chromophore featuring π-conjugated D-A structures can not only function as a good electron acceptor to undergo photoinduced electron transfer (ET) or engage in intermolecular CT interaction, but also exhibit unique dual emission depending on the excitation wavelengths. The rotatable C-C single bonds within D-A pairs enhance the tunability of molecular structure. Through the synergy of a photoinduced ET and an excited-state conformational change, the intermolecular CT interaction can be switched on and off by alternate light irradiation to enables reversibly modulation of the affinity between donor and acceptor molecules, accompanied by visual color switching and fluorescence on-off as feedback signals.

Photodynamic Therapy Using RGD-Functionalized Quantum Dots Elicit a Potent Immune Response in a Syngeneic Mouse Model of Pancreatic Cancer.

Purpose: Photodynamic therapy (PDT) induces anti-tumor immune responses by triggering immunogenic cell death in tumor cells. Previously, we demonstrated that novel QDs-RGD nanoparticles exhibited high efficiency as photosensitizers in the treatment of pancreatic cancer. However, the underlying mechanism of the anti-tumor immune effects induced by the photosensitizer remains unknown. This study assessed the anticancer immune effect of QDs-RGD, as well as the conventional photosensitizer chlorine derivative, YLG-1, for comparison, against pancreatic cancer in support of superior therapeutic efficacy. Methods: The pancreatic cancer cell line, Panc02, was used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies to assess the anti-tumor effects of QDs-RGD-PDT and YLG-1-PDT. The immunostimulatory ability of both photosensitizers was examined by measuring the expression of damage-associated molecular patterns (DAMP), such as calreticulin (CRT), assessing dendritic cell (DC) maturation, and analyzing cytokine expression. The specific immunity of QDs-RGD and YLG-1-PDT on distant tumor were determined by combining PDT with anti-CTLA-4 antibody. Results: QDs-RGD-PDT and YLG-1-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. While both photosensitizers significantly promoted CRT release, DC maturation, and interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) expression, QDs-RGD exerted a stronger immunostimulatory effect than YLG-1. Combination treatment with QDs-RGD and CTLA-4 blockade was able to significantly inhibit the growth of distant tumors. Conclusion: QDs-RGD is a novel and effective PDT strategy for treating pancreatic tumors by inducing anti-tumor immune responses.

The actin cytoskeleton is important for pseudorabies virus infection.

Viruses are dependent on the host factors for their replication and survival. Therefore, identification of host factors that druggable for antiviral development is crucial. The actin cytoskeleton plays an important role in the virus infection. The dynamics change of actin and its function are regulated by multiple actin-associated proteins (AAPs). However, the role and mechanism of various AAPs in the life cycle of virus are still enigmatic. In this study, we analyzed the roles of actin and AAPs in the replication of pseudorabies virus (PRV). Using a library of compounds targeting AAPs, our data found that multiple AAPs, such as Rho-GTPases, Rock, Myosin and Formin were involved in PRV infection. Besides, our result demonstrated that the actin-binding protein Drebrin was also participated in PRV infection. Further studies are necessary to elucidate the molecular mechanism of AAPs in the virus life cycle, in the hope of mining host factors for antiviral developments.

Weight, CYP3A5 Genotype, and Voriconazole Co-administration Influence Tacrolimus Initial Dosage in Pediatric Lung Transplantation Recipients with Low Hematocrit based on a Simulation Model.

OBJECTIVE: The method of administering the initial doses of tacrolimus in recipients of pediatric lung transplantation, especially in patients with low hematocrit, is not clear. The present study aims to explore whether weight, CYP3A5 genotype, and voriconazole co-administration influence tacrolimus initial dosage in recipients of pediatric lung transplantation with low hematocrit based on safety and efficacy using a simulation model. METHODS: The present study utilized the tacrolimus population pharmacokinetic model, which was employed in lung transplantation recipients with low hematocrit. RESULTS: For pediatric lung transplantation recipients not carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-13, 13-19, 19-22, 22-35, 35-38, and 38-40 kg are 0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-18, 18-30, and 30-40 kg are 0.06, 0.08, 0.11 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients not carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20 and 20-40 kg are 0.02 and 0.03 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20, 20-33, and 33-40 kg are 0.03, 0.04, and 0.05 mg/kg/day, which are split into two doses, respectively. CONCLUSION: The present study is the first to recommend the initial dosages of tacrolimus in recipients of pediatric lung transplantation with low hematocrit using a simulation model.

Camrelizumab, apatinib and hepatic artery infusion chemotherapy combined with microwave ablation for advanced hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion chemotherapy and camrelizumab plus apatinib (TRIPLET protocol) is promising for advanced hepatocellular carcinoma (Ad-HCC). However, the usefulness of microwave ablation (MWA) after TRIPLET is still controversial. AIM: To compare the efficacy and safety of TRIPLET alone (T-A) vs TRIPLET-MWA (T-M) for Ad-HCC. METHODS: From January 2018 to March 2022, 217 Ad-HCC patients were retrospectively enrolled. Among them, 122 were included in the T-A group, and 95 were included in the T-M group. A propensity score matching (PSM) was applied to balance bias. Overall survival (OS) was compared using the Kaplan-Meier curve with the log-rank test. The overall objective response rate (ORR) and major complications were also assessed. RESULTS: After PSM, 82 patients were included both the T-A group and the T-M group. The ORR (85.4%) in the T-M group was significantly higher than that (65.9%) in the T-A group (P < 0.001). The cumulative 1-, 2-, and 3-year OS rates were 98.7%, 93.4%, and 82.0% in the T-M group and 85.1%, 63.1%, and 55.0% in the T-A group (hazard ratio = 0.22; 95% confidence interval: 0.10-0.49; P < 0.001). The incidence of major complications was 4.9% (6/122) in the T-A group and 5.3% (5/95) in the T-M group, which were not significantly different (P = 1.000). CONCLUSION: T-M can provide better survival outcomes and comparable safety for Ad-HCC than T-A.

Small Conjugated Organic Ligand-Modified Polyoxometalate-Based Hybrid Materials for Boosting Photocatalytic CO2 Reduction.

Photocatalytic carbon dioxide (CO2) reduction to value-added chemicals is a multielectron transfer process, and the crucial step is the synthesis of photocatalysts. The introduction of small conjugated organic ligands can make the catalytic active site of the compound easier to be exposed in the reaction system and fully contact with the substrate, accelerating the photocatalytic reaction process. In this paper, we synthesized two isomorphic compounds, namely, {[Co(mtrz)3·(H2O)2]2·[SiW12O40]}·6H2O (1) and {[Ni(mtrz)3·(H2O)2]2·[SiW12O40]}·6H2O (2) (mtrz = 1-methyl-1,2,4-triazole). We found that compound 1 has a great photocatalytic performance through a series of experiments, with a CO reduction yield of 7364.92 µmol g-1 h-1 and a CO selectivity of 82.5%. Furthermore, the high catalytic activity can be maintained over four cycle experiments. The catalytic mechanism of its photocatalytic system is also elucidated, which provides an idea for realizing efficient catalytic reduction of CO2 to CO.

Gene expression signature for predicting homologous recombination deficiency in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers and may also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a gene expression-based machine learning classifier for homologous recombination deficiency (HRD) in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.93 in MyBrCa validation datasets and 0.84 in TCGA TNBCs. Additionally, the classifier strongly segregated HRD-associated genomic features in TNBCs from TCGA, METABRIC, and ICGC. Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy.

An organic/inorganic hybrid soft material for supramolecular adhesion.

Thioctic acid (TA) has been widely used to construct soft materials via supramolecular copolymerization with organic chemicals. In this study, TA and the inorganic compound MoS2 are used to fabricate poly[TA-MoS2] via dynamic covalent and supramolecular interactions. Poly[TA-MoS2] exhibits good and long-lasting adhesion performance on various artificial surfaces, with an adhesion strength up to 3.72 MPa (15 days). Further, it exhibits tough adhesion effects in an aqueous environment. Moreover, poly[TA-MoS2] displays good thermal processing behavior, thus enabling its molding through 3D printing.

AcornHRD: an HRD algorithm highly associated with anthracycline-based neoadjuvant chemotherapy in breast cancer in China.

PURPOSE: Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. METHODS AND MATERIALS: Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. RESULTS: A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]). CONCLUSION: Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.

Enantioselective synthesis of chiral amides by carbene insertion into amide N-H bond.

Chiral amides are important structure in many natural products and pharmaceuticals, yet their efficient synthesis from simple amide feedstock remains challenge due to its weak Lewis basicity. Herein, we describe our study of the enantioselective synthesis of chiral amides by N-alkylation of primary amides taking advantage of an achiral rhodium and chiral squaramide co-catalyzed carbene N-H insertion reaction. This method features mild condition, rapid reaction rate (in all cases 1 min) and a wide substrate scope with high yield and excellent enantioselectivity. Further product transformations show the synthetic potential of this reaction. Mechanistic studies reveal that the non-covalent interactions between the catalyst and reaction intermediate play a critical role in enantiocontrol.

Association of ESR1 Germline Variants with TP53 Somatic Variants in Breast Tumors in a Genome-wide Study.

In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency. SIGNIFICANCE: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma.

BACKGROUND: Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited. AIM: To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer. METHODS: RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package "DESeq2" in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model. RESULTS: In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma. CONCLUSION: We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.

Ferrous sulfate combined with ultrasound emulsified cinnamaldehyde nanoemulsion to cause ferroptosis in Escherichia coli O157:H7.

The purpose of this study was to investigate ferroptosis in Escherichia coli O157:H7 caused by ferrous sulfate (FeSO4) and to examine the synergistic effectiveness of FeSO4 combined with ultrasound-emulsified cinnamaldehyde nanoemulsion (CALNO) on inactivation of E. coli O157:H7 in vitro and in vivo. The results showed that FeSO4 could cause ferroptosis in E. coli O157:H7 via generating reactive oxygen species (ROS) and exacerbating lipid peroxidation. In addition, the results indicated that FeSO4 combined with CALNO had synergistic bactericidal effect against E. coli O157:H7 and the combined treatment could lead considerable nucleic acids and protein to release by damaging the cell membrane of E. coli O157:H7. Besides, FeSO4 combined with CALNO had a strong antibiofilm ability to inhibit E. coli O157:H7 biofilm formation by reducing the expression of genes related on biofilm formation. Finally, FeSO4 combined with CALNO exhibited the significant antibacterial activity against E. coli O157:H7 in hami melon and cherry tomato.

Clustering of HR + /HER2- breast cancer in an Asian cohort is driven by immune phenotypes.

Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR + /HER2- breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR + /HER2- breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR + /HER2- samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.

LncRNA RGMB-AS1 inhibits HMOX1 ubiquitination and NAA10 activation to induce ferroptosis in non-small cell lung cancer.

Ferroptosis, an iron-dependent regulated cell death caused by excessive lipid peroxide accumulation, has emerged as a promising therapeutic target in various cancers, including non-small cell lung cancer (NSCLC). In this study, we identified the long non-coding RNA RGMB-AS1 as a key regulator of ferroptosis in NSCLC. Mechanistically, RGMB-AS1 interacted with heme oxygenase 1 (HMOX1) and prevented its ubiquitination by the E3 ligase TRC8, leading to increased HMOX1 stability and enhanced ferroptosis. Additionally, RGMB-AS1 bound to the 82-87 amino acid region of N-alpha-acetyltransferase 10 (NAA10), stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, further contributing to ferroptosis. The RGMB-AS1-HMOX1 and RGMB-AS1-NAA10 axes synergistically inhibited NSCLC growth both in vitro and in vivo. Clinically, low RGMB-AS1 expression was associated with advanced tumor stage and poor overall survival in NSCLC patients. Furthermore, adeno-associated virus-mediated RGMB-AS1 overexpression significantly suppressed tumor growth in mouse xenograft models. Our findings uncover a novel lncRNA-mediated regulatory mechanism of ferroptosis and highlight the potential of RGMB-AS1 as a prognostic biomarker and therapeutic target in NSCLC.

Effects of tacrolimus on proteinuria in Chinese and Indian patients with idiopathic membranous nephropathy: the results of machine learning study.

PURPOSE: The present study aims to explore the effects of tacrolimus on proteinuria in patients with idiopathic membranous nephropathy (IMN) and recommend an appropriate dosage schedule via machine learning method. METHODS: The Emax model was constructed to analyze the effects of tacrolimus on proteinuria in patients with IMN. Data were mined from published literature and machine learning was built up with Emax model, among which the efficacy indicator was proteinuria change rates from baseline. 463 IMN patients were included for modeling, and tacrolimus therapeutic window concentrations were 4-10 ng/ml. RESULTS: In machine learning model, the Emax from tacrolimus effecting proteinuria in IMN patients was -72.7%, the ET50 was 0.43 months, and the time to achieving 25% Emax, 50% Emax, 75% Emax, and 80% (plateau) Emax of tacrolimus on proteinuria in patients with IMN were 0.15, 0.43, 1.29, and 1.72 months, respectively. CONCLUSION: For achieving better therapeutic effects from tacrolimus on proteinuria in patients with IMN, tacrolimus concentration range need to be maintained at 4-10 ng/ml for at least 1.72 months.

Association Between Triglyceride-Glucose Index and Hearing Threshold Shifts of Adults in the United States: National Health and Nutrition Examination Survey, 2015-2016.

Objective: Sensorineural Hearing Loss (SNHL) is a representative human sensory impairment, few studies have paid attention to the correlation between the Triglyceride-Glucose (TyG) index and SNHL to date. We conducted this analysis to elucidate the correlation between the TyG index and pure tone hearing thresholds among US adults. Methods: Our analysis included 1226 adults (age range: 20 to 69 years old) from the 2015-2016 National Health and Nutrition Examination Survey (NHANES) data. TyG index was scored into three quartiles. Weighted univariate analysis, weighted multivariate linear regression analyses as well as smooth curve fittings evaluated the associations between TyG index and pure tone hearing thresholds. Results: In the multiple regression analysis, the second tertile of TyG index was negatively associated with high-frequency hearing thresholds shifts. Furthermore, the non-linear relationships between TyG index and speech-frequency and high-frequency hearing thresholds were identified by smooth curve fittings. After adjusting for potential confounders, the fitted smooth curves were approximately U-shaped, and the two-segment linear regression models were constructed to calculate their inflection points. Conclusion: Our findings suggested that the TyG index was nearly U-shaped association with speech-frequency and high-frequency hearing thresholds. These results may imply the importance of maintaining a balanced TyG index in health management.