Suction versus non-suction drainage strategy after uniportal thoracoscopic lung surgery: a prospective cohort study.

Background: The postoperative outcomes of suction drainage versus non-suction drainage after uniportal video-assisted thoracoscopic surgery (UniVATS) come with little consensus. This study aimed to prospectively compare the postoperative outcomes of suction drainage versus non-suction drainage in patients who underwent UniVATS. Methods: Between October 2022 and January 2023, patients undergoing UniVATS were prospectively enrolled. The choice of drainage strategy (suction or non-suction) was at the surgeon's discretion. The primary outcome was chest tube duration, with secondary outcomes including postoperative drainage volume, pain scores, postoperative complications, length of hospital stay, and hospitalization cost. Baseline characteristics and postoperative outcomes were compared. Univariable and multivariable analyses were used to identify risk factors for postoperative outcomes. Results: A total of 206 patients were enrolled in this study, with 103 patients in each group. Baseline characteristics were well-balanced. The chest tube duration did not significantly differ between the two groups. However, suction drainage exhibited a significantly lower total drainage volume compared to non-suction drainage (280.00 vs. 400.00 mL, P=0.03). Suction drainage was associated with a significantly shorter postoperative hospital stay (3.00 vs. 4.00 days, P<0.001) and lower pain score on the second postoperative day (POD). Multivariable analyses also confirmed that suction drainage was significantly correlated with a lower total drainage volume and a shorter postoperative hospital stay. Conclusions: These findings suggested that the suction drainage was superior to non-suction drainage in terms of postoperative drainage volume and length of hospital stay in patients undergoing UniVATS.

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer.

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

Cetuximab combined with chemotherapy for simultaneous esophageal squamous cell carcinoma and colon adenocarcinoma: A case report.

BACKGROUND: Multiple primary carcinomas (MPCs) are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual. Synchronous MPCs are rarer than solitary cancers or metachronous MPCs. Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases. CASE SUMMARY: A 64-year-old patient presented with dysphagia, without obvious cause. A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results. After multi-disciplinary consultations, combination chemotherapy (a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14) and esophageal cancer radiotherapy were initiated. Based on the results of genetic testing, we switched to a regimen of leucovorin + fluorouracil + oxaliplatin and cetuximab regimen for 8 cycles. Subsequently, capecitabine and bevacizumab were administered until the most recent follow-up, at which the tumor remained stable. CONCLUSION: Successful cetuximab chemotherapy treatment provides a reference for the non-operative and homogeneous treatment of different pathological types of synchronous MCPs.

Enhancing the acidic oxygen evolution reaction performance of RuO2-TiO2by a reduction-oxidation process.

As a promising alternative to Ir based acidic oxygen evolution reaction (OER) catalysts, Ru suffers from severe fading issues. Supporting it on robust oxides such as TiO2is a simple and effective way to enhance its lifetime. Here, we find that a simple reduction-oxidation process can further improve both activity and stability of RuO2-TiO2composites at high potentials. In this process, the degree of oxidation was carefully controlled to form Ru/RuO2heterostructure to improve OER activity. Moreover, due to the oxophilicity difference of Ru and Ti, the structure of catalysts was changed from supported to embedded, which enhanced the protective effect of TiO2and mitigated the dissolution of Ru element in acidic electrolyte, making as-prepared Ru/RuO2-TiO2with better durability at all tested potentials.

Danshensu reduces neuronal excitability by enhancing potassium currents in bushy cells in the mouse cochlear nucleus.

Danshensu, also known as salvianic acid A, is a primary active compound extracted from a traditional Chinese herb Danshen (Salvia miltiorrhiza). While its antioxidative and neuroprotective effects are well-documented, the underlying mechanisms are poorly understood. In this study, we sought out to investigate if and how Danshensu modulates neuronal excitability and voltage-gated ionic currents in the central nervous system. We prepared brain slices of the mouse brainstem and performed patch-clamp recording in bushy cells in the anteroventral cochlear nucleus, with or without Danshensu incubation for 1 h. QX-314 was used internally to block Na+ current, while tetraethylammonium and 4-aminopyridine were used to isolate different subtypes of K+ current. We found that Danshensu of 100 µm decreased the input resistance of bushy cells by approximately 60% and shifted the voltage threshold of spiking positively by approximately 7 mV, resulting in significantly reduced excitability. Furthermore, we found this reduced excitability by Danshensu was caused by enhanced voltage-gated K+ currents in these neurons, including both low voltage-activated IK,A, by approximately 100%, and high voltage-activated IK,dr, by approximately 30%. Lastly, we found that the effect of Danshensu on K+ currents was dose-dependent in that no enhancement was found for Danshensu of 50 µm and Danshensu of 200 µm failed to cause significantly more enhancement on K+ currents when compared to that of 100 µm. We found that Danshensu reduced neuronal excitability in the central nervous system by enhancing voltage-gated K+ currents, providing mechanistic support for its neuroprotective effect widely seen in vivo.

THAP3 recruits SMYD3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma.

Mitochondria harbor the oxidative phosphorylation (OXPHOS) system to sustain cellular respiration. However, the transcriptional regulation of OXPHOS remains largely unexplored. Through the cancer genome atlas (TCGA) transcriptome analysis, transcription factor THAP domain-containing 3 (THAP3) was found to be strongly associated with OXPHOS gene expression. Mechanistically, THAP3 recruited the histone methyltransferase SET and MYND domain-containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. The levels of THAP3 and SMYD3 were altered by metabolic cues. They collaboratively supported liver cancer cell proliferation and colony formation. In clinical human liver cancer, both of them were overexpressed. THAP3 positively correlated with OXPHOS gene expression. Together, THAP3 cooperates with SMYD3 to epigenetically upregulate cellular respiration and liver cancer cell proliferation.

Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth.

Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related fatalities globally. In this study, we observed a significant increase in the expression level of the YEATS2 gene in HCC patients, and it is negatively correlated with the patients' survival rate. While we have previously identified the association between YEATS2 and the survival of pancreatic cancer cells, the regulatory mechanisms and significance in HCC are still to be fully elucidated. Our study shows that knockdown (KD) of YEATS2 expression leads to DNA damage, which in turn results in an upregulation of γ-H2A.X expression and activation of the canonical senescence-related pathway p53/p21Cip1. Moreover, our transcriptomic analysis reveals that YEATS2 KD cells can enhance the expression of p21Cip1 via the c-Myc/miR-93-5p pathway, consequently fostering the senescence of HCC cells. The initiation of cellular senescence through dual-channel activation suggests that YEATS2 plays a pivotal regulatory role in the process of cell proliferation. Ultimately, our in vivo research utilizing a nude mouse tumor model revealed a notable decrease in both tumor volume and weight after the suppression of YEATS2 expression. This phenomenon is likely attributable to the attenuation of proliferative cell activity, coupled with a concurrent augmentation in the population of natural killer (NK) cells. In summary, our research results have supplemented the understanding of the regulatory mechanisms of HCC cell proliferation and indicated that targeting YEATS2 may potentially inhibit liver tumor growth.

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Nr4a1 enhances Wnt4 transcription to promote mesenchymal stem cell osteogenesis and alleviates inflammation-inhibited bone regeneration.

Intense inflammatory response impairs bone marrow mesenchymal stem cell (BMSC)-mediated bone regeneration, with transforming growth factor (TGF)-ß1 being the most highly expressed cytokine. However, how to find effective and safe means to improve bone formation impaired by excessive TGF-ß1 remains unclear. In this study, we found that the expression of orphan nuclear receptor Nr4a1, an endogenous repressor of TGF-ß1, was suppressed directly by TGF-ß1-induced Smad3 and indirectly by Hdac4, respectively. Importantly, Nr4a1 overexpression promoted BMSC osteogenesis and reversed TGF-ß1-mediated osteogenic inhibition and pro-fibrotic effects. Transcriptomic and histologic analyses confirmed that upregulation of Nr4a1 increased the transcription of Wnt family member 4 (Wnt4) and activated Wnt pathway. Mechanistically, Nr4a1 bound to the promoter of Wnt4 and regulated its expression, thereby enhancing the osteogenic capacity of BMSCs. Moreover, treatment with Nr4a1 gene therapy or Nr4a1 agonist Csn-B could promote ectopic bone formation, defect repair, and fracture healing. Finally, we demonstrated the correlation of NR4A1 with osteogenesis and the activation of the WNT4/ß-catenin pathway in human BMSCs and fracture samples. Taken together, these findings uncover the critical role of Nr4a1 in bone formation and alleviation of inflammation-induced bone regeneration disorders, and suggest that Nr4a1 has the potential to be a therapeutic target for accelerating bone healing.

DNA methylation clocks for estimating biological age in Chinese cohorts.

Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation at specific CpG sites. However, available DNA methylation (DNAm) age predictors are based on datasets with limited ethnic representation. Moreover, a systematic comparison between DNAm data and other omics datasets has not yet been performed. To address these knowledge gaps, we generated and analyzed DNA methylation datasets from two independent Chinese cohorts, revealing age-related DNAm changes. Additionally, a DNA methylation (DNAm) aging clock (iCAS-DNAmAge) and a group of DNAm-based multi-modal clocks for Chinese individuals were developed, with most of them demonstrating strong predictive capabilities for chronological age. The clocks were further employed to predict factors influencing aging rates. The DNAm aging clock, derived from multi-modal aging features (compositeAge-DNAmAge), exhibited a close association with multi-omics changes, lifestyles, and disease status, underscoring its robust potential for precise biological age assessment. Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace, providing basis for evaluating aging intervention strategies.

Immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus.

OBJECTIVES: We evaluated the immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus (adoSLE) receiving either high- or low-dose immunosuppressant (High-IS and Low-IS). METHODS: Patients aged 12-18 years diagnosed with SLE were enrolled. High-IS was defined as >7.5 mg/day prednisolone or with other immunosuppressant, while Low-IS was defined as only ≤7.5 mg/day of prednisolone and no immunosuppressant. Two doses of BNT162b2 vaccination were given 4 weeks apart, followed by a booster (third) dose at 4-6 months later. Anti-spike receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NT) against Wuhan and Omicron variants, and cellular immune response by IFN-γ-ELISpot assay were evaluated following vaccination. Adverse events (AEs) and SLE flare were monitored. RESULTS: A total of 73 participants were enrolled, 40 and 33 in the High-IS and Low-IS group, respectively. At 4 weeks following the 2nd dose, overall anti-RBD IgG seropositivity was 97.3%, with no difference between the groups (p = .498). AdoSLE on High-IS had lower anti-RBD IgG (p < .001), Wuhan NT (p < .001), and IFN-γ-ELISpot (p = .022) than those on Low-IS. A 3rd dose induced significantly higher antibody responses than after the 2nd dose (p < .001) in both groups and established seroconversion against Omicron variants, with persistent lower antibody levels in High-IS group. SELENA-SLEDAI scores within 12 weeks after 2-dose vaccination was higher than before vaccination (3.1 vs 2.5; p < .036); however, the occurrence of disease flare by SELENA-SLEDAI flare index was not different after vaccination compared to before vaccination, consistent across groups. Non-severe AEs occurred similarly in both groups. CONCLUSION: AdoSLE on High-IS induced lower SARS-CoV-2 vaccine immune responses than Low-IS. Vaccination can increase disease activity and requires close monitoring for disease flare.

[Effect of stump-preserving repair on rotator cuff healing and shoulder function for degenerative total rotator cuff tears].

Objective: To analyze the effect of stump-preserving repair on rotator cuff healing and shoulder function for degenerative total rotator cuff tears. Methods: A clinical data of 152 patients with degenerative total rotator cuff tears, who underwent arthroscopic repair between April 2019 and May 2022, was retrospectively analyzed. There were 76 males and 76 females with an average age of 55.4 years (range, 24-78 years). MRI was performed at 6 months postoperatively to evaluate the rotator cuff healing according to the Sugaya classification. Pre- and intra-operative related factors were included for univariate analysis, including age (≥60 years/<60 years), gender (male/female), passive activity disorder (yes/no), disease duration (≤3 months/>3 months), stump-preserving repair (yes/no), use of suture bridge technique (yes/no), shoulder joint abduction angle at knotting (<45°/≥45°), acromioplasty (yes/no), glucocorticoid injection (yes/no), time for patients to start postoperative passive exercise (≤2 weeks/>2 weeks), and time for patients to start postoperative active exercise (≤3 months/>3 months). The influencing factors of tendon healing were screened; further logistic regression was used to conduct multivariate analysis to screen for risk factors. Two sets of data were balanced by propensity score matching. The American Shoulder and Elbow Surgeons (ASES) score and Constant-Murley score of shoulder joint function at 6 and 12 months postoperatively, as well as rotator cuff healing rate at 6 months postoperatively, were compared between groups based on whether or not stump-preserving repair was used. Results: All patients were followed up 12-33 months (mean, 23.8 months). MRI at 25-31 weeks postoperatively showed the 121 cases of rotator cuff healing and 31 cases of non healing. Univariate analysis showed that the disease duration, stump-preserving repair, shoulder joint abduction angle at knotting, and the time for patients to start postoperative active exercise were the influencing factors of rotator cuff healing ( P<0.05). Multivariate analysis showed that non-stump-preserving repair, shoulder abduction angle more than 45° at knotting, and the time to start active exercise within 3 months postoperatively were risk factors affecting rotator cuff healing ( P<0.05). A total of 51 pairs of cases were matched based on the grouping criteria of whether the disease duration exceeded 3 months, whether the shoulder abduction angle at knotting exceeded 45°, and whether the time to start postoperative active exercise exceeded 3 months. The rotator cuff healing rate, ASES score, and Constant-Murley score of the preserving repair group at 6 months postoperatively were superior to those of the non-preserving repair group, and the differences were significant ( P<0.05). There was no significant difference in ASES score and Constant-Murley score between the two groups at 12 months postoperatively ( P>0.05). Conclusion: For degenerative total rotator cuff tears, the stump-preserving repair can shorten the healing time and promote the shoulder function recovery, but has no significant effect on shoulder function at 1 year postoperatively.

Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs.

BACKGROUND & AIMS: Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. METHODS: A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. RESULTS: The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. CONCLUSIONS: Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.

Molecular subtypes of disulfidptosis-regulated genes and prognosis models for predicting prognosis, tumor microenvironment infiltration, and therapeutic response in hepatocellular carcinoma.

Disulfidptosis, a recently identified mode of cellular demise marked by excess SLC7A11-reliant cystine, has been proved to affect the development and resilience of tumor cells through the production of glutathione from cystine. Glutathione synthesis plays a crucial role in chemotherapy resistance and the survival of liver cancer cells. Thus, understanding the relationship between disulfidptosis and hepatocellular carcinoma (HCC) is imperative. A molecular typing approach was employed to classify patients with HCC into two distinct subtypes, namely disulfidptosis and disulfide-homeostasis, based on the expression of genes associated with disulfidptosis. Patients with disulfidptosis exhibited a longer survival time, improved immune status, and heightened sensitivity to conventional chemotherapeutic drugs and immunotherapy. Patients with disulfide-homeostasis demonstrated an immunosuppressive microenvironment, drug resistance, and unfavorable prognosis. A prognostic model was constructed utilizing the significant prognostic variables of the disulfidptosis-regulated genes. A real-world cohort was subjected to multiplex immunofluorescence to validate the clinical outcomes and immune context. Ultimately, our study delved into the prognostic relevance of disulfidptosis in HCC and provides insights into potential avenues for future research.

Effect of a prior thyroid cancer on the survival of lung cancer patients: a retrospective study based on SEER database.

PURPOSE: The effect of a history of thyroid cancer on the prognosis of lung cancer patients has not been fully investigated. Therefore, we aimed to evaluate this effect based on a large cohort. METHODS: Data of 154844 lung cancer patients, of whom 406 had prior thyroid cancer, were collected from SEER database. Primary survival analysis was conducted between patients with and without prior thyroid cancer using Kaplan-Meier method. Secondary survival analysis was conducted to investigate the effects of the stage and histological subtype of the prior thyroid cancer on the survival of lung cancer patients. Propensity adjustment was used to reduce confounding effect. RESULTS: Compared to patients without prior malignancy, patients with prior thyroid cancer were predominantly female (72.4% vs. 48.7%, p < 0.001), had lower stage (proportion of localized tumor: 40.4% vs. 25.6%, p < 0.001), and larger proportion of surgery (52.2% vs. 29.4%, p < 0.001), and had better survival (5-year survival rate: 55.53% vs. 33.16%, p < 0.001). After propensity adjustment, the survival was similar between the groups (5-year survival rate: 55.53% vs. 51.78%, p = 0.24). The survival of patients with different stages (localized tumor vs. regional tumor: p = 0.88) or different histological subtypes (p = 0.46) of prior thyroid cancer were comparable. CONCLUSION: Survival of lung cancer patients with or without prior thyroid cancer was similar after propensity adjustment, and the stage or histological subtype of the prior thyroid cancer had no significant effect on the survival of lung cancer patients.

PET/MRI in Endometrial Cancer: Imaging Biomarkers are Associated with Disease Progression and Overall Survival.

RATIONALE AND OBJECTIVES: To evaluate the association between positron emission tomography (PET)/magnetic resonance imaging (MRI) biomarkers and survival outcomes in patients with endometrial cancer. MATERIALS AND METHODS: Between April 2014 and April 2016, 88 patients with newly diagnosed endometrial cancer participated this prospective study and underwent [18F] fluorodeoxyglucose PET/MRI. Sixty-nine patients with measurable tumors on PET/MRI were included in the image analysis. Imaging biomarkers included the minimum and mean apparent diffusion coefficients (ADCmin and ADCmean), maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumors. The log-rank test and Cox proportional hazards model were used to assess the relationship between imaging biomarkers and survival. RESULTS: After a median follow-up of 80 months, 15 (22%) patients had tumor progression and six (9%) patients died. The results of ADCmin, ADCmean, and SUVmax did not show a significant association with progression-free survival (PFS) and overall survival (OS). Significantly shorter PFS was noted in patients with primary tumors with higher MTV (P < 0.001) and TLG (P < 0.001). Significantly shorter OS was also noted in patients with primary tumors with higher MTV (P = 0.048) and TLG (P = 0.034). In the multivariate analysis, MTV was an independent predictor of PFS (hazard ratio = 10.84, P = 0.033). CONCLUSION: PET/MRI biomarkers, particularly MTV and TLG, are associated with PFS and OS in patients with endometrial cancer. MTV was an independent predictor of PFS.

Sirtuin 6 ameliorates bleomycin-induced pulmonary fibrosis via activation of lipid catabolism.

Pulmonary fibrosis is a chronic and serious interstitial lung disease with little effective therapies currently. Our incomplete understanding of its pathogenesis remains obstacles in therapeutic developments. Sirtuin 6 (SIRT6) has been shown to mitigate multiple organic fibrosis. However, the involvement of SIRT6-mediated metabolic regulation in pulmonary fibrosis remains unclear. Here, we demonstrated that SIRT6 was predominantly expressed in alveolar epithelial cells in human lung tissues by using a single-cell sequencing database. We showed that SIRT6 protected against bleomycin-induced injury of alveolar epithelial cells in vitro and pulmonary fibrosis of mice in vivo. High-throughput sequencing revealed enriched lipid catabolism in Sirt6 overexpressed lung tissues. Mechanismly, SIRT6 ameliorates bleomycin-induced ectopic lipotoxicity by enhancing lipid degradation, thereby increasing the energy supply and reducing the levels of lipid peroxides. Furthermore, we found that peroxisome proliferator-activated receptor α (PPARα) was essential for SIRT6-mediated lipid catabolism, anti-inflammatory responses, and antifibrotic signaling. Our data suggest that targeting SIRT6-PPARα-mediated lipid catabolism could be a potential therapeutic strategy for diseases complicated with pulmonary fibrosis.

Functional characterization of four antenna-biased chemosensory proteins in Dioryctria abietella reveals a broadly tuned olfactory DabiCSP1 and its key residues in ligand-binding.

The orientation of the oligophagous cone-feeding moth Dioryctria abietella (Lepidoptera: Pyralidae) to host plants primarily relies on olfactory-related proteins, particularly those candidates highly expressed in antennae. Here, through a combination of expression profile, ligand-binding assay, molecular docking and site-directed mutagenesis strategies, we characterized the chemosensory protein (CSP) gene family in D. abietella. Quantitative real-time PCR (qPCR) analyses revealed the detectable expression of all 22 DabiCSPs in the antennae, of which seven genes were significantly enriched in this tissue. In addition, the majority of the genes (19/22 relatives) had the expression in at least one reproductive tissue. In the interactions of four antenna-dominant DabiCSPs and different chemical classes, DabiCSP1 was broadly tuned to 27 plant-derived odors, three man-made insecticides and one herbicide with high affinities (Ki < 6.60 µM). By contrast, three other DabiCSPs (DabiCSP4, CSP6 and CSP17) exhibited a narrow odor binding spectrum, in response to six compounds for each protein. Our mutation analyses combined with molecular docking simulations and binding assays further identified four key residues (Tyr25, Thr26, Ile65 and Val69) in the interactions of DabiCSP1 and ligands, of which binding abilities of this protein to 12, 15, 16 and three compounds were significantly decreased compared to the wildtype protein, respectively. Our study reveals different odor binding spectra of four DabiCSPs enriched in antennae and identifies key residues responsible for the binding of DabiCSP1 and potentially active compounds for the control of this pest.

Association of M-Type Phospholipase A2 Receptor Deposition in Kidney Tissue with Treatment Outcomes in Patients with Idiopathic Membranous Nephropathy.

Objective: The purpose of this study was to investigate the correlation between the deposition of M-type phospholipase A2 receptor (PLA2R) in the kidney tissues of patients with idiopathic membranous nephropathy (IMN). Method: We enrolled a total of 61 patients diagnosed with IMN in the past 8 years who were admitted at the Jinjiang Municipal Hospital and the 2nd Affiliated Hospital of Fujian Medical University. PLA2R immunofluorescence was used to stain kidney tissues, and all patients were treated with steroid combined with immunosuppressive agents or conservative regimens. The duration of follow-up was more than 48 weeks. Based on the deposition of PLA2R in kidney tissues, we divided the patients into the PLA2R Positive group and the PLA2R Negative group. Further, patients with PLA2R-positive kidney tissues were divided into "1+", "2+", and "3+" groups based on the extent of their PLA2R deposition, and we compared the therapeutic outcomes of the various groups. Results: At week 12 of follow-up, the partial remission rate of kidney tissues in the PLA2R Negative group was significantly higher than that in the Positive group (P = 0.004). Among the various deposition groups with PLA2R-positive kidney tissues, the complete remission rate of the "2+" group was higher than that of the "3+" group at weeks 24, 36, and 48 of follow-up (P < 0.05). In IMN patients treated with a combination regimen of steroid and tacrolimus, the complete remission rate in kidney tissues of the PLA2R Negative group was higher than that of the Positive group at weeks 24 and 48 of follow-up (P < 0.05). Conclusion: The overall effective rate of treatment in kidney tissues of PLA2R-negative patients was higher than that in the kidney tissues of PLA2R-positive patients. The varied levels of PLA2R deposition in kidney tissues were related to the treatment outcomes of IMN, and those with lower PLA2R deposition levels had better outcomes.

Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs. METHODS: We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers. RESULTS: Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment. CONCLUSIONS: The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes. A Schematic illustration of the role of NR5A2 in cancer stem cells versus differentiated cancer cells, along with the action of the NR5A2 inhibitor Cpd3. B Overall survival of tumor-bearing mice following allocated treatment. A total of 18 PDX models were treated using a 2 x 1 x 1 approach (two animals per model per treatment); n=36 per group (illustration created with biorender.com ).