A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

Exposure to polystyrene nanoplastics induces hepatotoxicity involving NRF2-NLRP3 signaling pathway in mice.

Nanoplastic contamination has been of intense concern by virtue of the potential threat to human and ecosystem health. Animal experiments have indicated that exposure to nanoplastics (NPs) can deposit in the liver and contribute to hepatic injury. To explore the mechanisms of hepatotoxicity induced by polystyrene-NPs (PS-NPs), mice and AML-12 hepatocytes were exposed to different dosages of 20 nm PS-NPs in this study. The results illustrated that in vitro and in vivo exposure to PS-NPs triggered excessive production of reactive oxygen species and repressed nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway and its downstream antioxidase expression, thus leading to hepatic oxidative stress. Moreover, PS-NPs elevated the levels of NLRP3, IL-1ß and caspase-1 expression, along with an activation of NF-κB, suggesting that PS-NPs induced hepatocellular inflammatory injury. Nevertheless, the activaton of NRF2 signaling by tert-butylhydroquinone mitigated PS-NPs-caused oxidative stress and inflammation, and inbihited NLRP3 and caspase-1 expression. Conversely, the rescuing effect of NRF2 signal activation was dramatically supressed by treatment with NRF2 inhibitor brusatol. In summary, our results demonstrated that NRF2-NLRP3 pathway is involved in PS-NPs-aroused hepatotoxicity, and the activation of NRF2 signaling can protect against PS-NPs-evoked liver injury. These results provide novel insights into the hepatotoxicity elicited by NPs exposure.

A novel entity of HIPK2::YAP1 pulmonary fibromatosis.

BACKGROUND: Pulmonary fibromatosis (PF) is a specific variant of fibromatosis, which is rarely reported occurring in the lung. PF with HIPK2-YAP1 fusion was a novel entity. CASE PRESENTATION: In this report, a 66-year-old male with PF had been smoking over 40 years. Multiple cords and small nodules in both lungs had been detected in a health examination two years earlier at our hospital. But approximately twofold enlarged in the lingual segment of the upper lobe in the left lung were disclosed in this year. Immunohistochemical analysis demonstrated that the vimentin and ß-Catenin were positive in the largest nodule. After underwent a DNA/RNA panel next-generation sequencing (NGS), missense mutations and HIPK2-YAP1 fusion were found in this sample. Ultimately, the case diagnosis as PF with HIPK2-YAP1 fusion after multidisciplinary treatment. Currently, the patient is doing well and recurrence-free at 14 months post-surgery. CONCLUSIONS: It's difficult for patients with complex morphology to make accurate diagnosis solely based on morphology and immunohistochemistry. But molecular detection is an effective method for further determining pathological subtypes.

Prevalence of metabolic syndrome among patients with hepatocellular carcinoma of different etiologies: a retrospective study.

AIMS: This study compared the prevalences of metabolic syndrome and of cardiac or kidney comorbidities among patients with hepatocellular carcinoma (HCC) associated with metabolic dysfunction-related fatty liver disease (MAFLD), chronic infection with hepatitis B or C virus (HBV or HCV), or the combination of MAFLD and chronic HBV infection. METHODS: Medical records were retrospectively analyzed for patients with HCC who underwent hepatectomy between March 2013 and March 2023. Patients with HCC of different etiologies were compared in terms of their clinicodemographic characteristics and laboratory data before surgery. RESULTS: Of the 2422 patients, 1,822 (75.2%) were chronically infected with HBV without MAFLD and HCV, 415 (17.2%) had concurrent MAFLD and chronic HBV infection but no HCV infection, 121 (5.0%) had MAFLD without hepatitis virus infection, and 64 (2.6%) were chronically infected with HCV in the presence or absence of MAFLD and HBV infection. Compared to patients chronically infected with HBV without MAFLD and HCV, those with MAFLD but no hepatitis virus infection showed significantly lower prevalence of cirrhosis, ascites, portal hypertension, alpha-fetoprotein concentration ≥ 400 ng/mL, tumor size > 5 cm, multinodular tumors and microvascular invasion. Conversely, they showed significantly higher prevalence of metabolic syndrome, hypertension, type 2 diabetes, abdominal obesity, history of cardiovascular disease, T-wave alterations, hypertriglyceridemia and hyperuricemia, as well as higher risk of arteriosclerotic cardiovascular disease. Compared to patients with MAFLD but no hepatitis virus infection, those with concurrent MAFLD and chronic infection with HBV showed significantly higher prevalence of cirrhosis, ascites and portal hypertension, but significantly lower prevalence of hypertension and history of cardiovascular disease. Compared to patients with other etiologies, those chronically infected with HCV in the presence or absence of MAFLD and HBV infection, showed significantly higher prevalence of cirrhosis, portal hypertension, ascites, and esophagogastric varices. CONCLUSION: Patients with HCC associated with MAFLD tend to have a background of less severe liver disease than those with HCC of other etiologies, but they may be more likely to suffer metabolic syndrome or comorbidities affecting the heart or kidneys.

Nitric Oxide Ameliorates the Effects of Hypoxia in Mice by Regulating Oxygen Transport by Hemoglobin.

Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. High Alt Med Biol. 00:00-00, 2024.-Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system in vivo remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O2 affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO2%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO2% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In ex vivo experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (-0.72 ± 0.062 vs.-0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94ß-His146ß in nitrosyl -Hb(NO-Hb), NO-HbßCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues.

Impact of tumour stroma-immune interactions on survival prognosis and response to neoadjuvant chemotherapy in bladder cancer.

BACKGROUND: The tumour stroma is associated with unfavourable prognosis in diverse solid tumours, but its prognostic and predictive value in bladder cancer (BCa) is unclear. METHODS: In this multicentre, retrospective study, we included 830 patients with BCa from six independent cohorts. Differences in overall survival (OS) and cancer-specific survival (CSS) were investigated between high-tumour stroma ratio (TSR) and low-TSR groups. Multi-omics analyses, including RNA sequencing, immunohistochemistry, and single-cell RNA sequencing, were performed to study stroma-immune interactions. TSR prediction models were developed based on pelvic CT scans, and the best performing model was selected based on receiver operator characteristic analysis. FINDINGS: Compared to low-TSR tumours, high-TSR tumours were significantly associated with worse OS (HR = 1.193, 95% CI: 1.046-1.361, P = 0.008) and CSS (HR = 1.337, 95% CI: 1.139-1.569, P < 0.001), and lower rate of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). High-TSR tumours exhibited higher infiltration of immunosuppressive cells, including Tregs and tumour-associated neutrophils, while low-TSR tumours exhibited higher infiltration of immune-activating cells such as CD8+ Teff and XCR1+ dendritic cells. The TSR prediction model was developed by combining the intra-tumour and tumour base radiomics features, and showed good performance to predict high-TSR, as indicted by area under the curve of 0.871 (95% CI: 0.821-0.921), 0.821 (95% CI: 0.731-0.911), and 0.801 (95% CI: 0.737-0.865) in the training, internal validation, and external validation cohorts, respectively. In patients with low predicted TSR, 92.3% (12/13) achieved pCR, while only 35.3% (6/17) of patients with high predicted TSR achieved pCR. INTERPRETATION: The tumour stroma was found to be significantly associated with clinical outcomes in patients with BCa as a result of tumour stroma-immune interactions. The radiomics prediction model provided non-invasive evaluation of TSR and was able to predict pCR in patients receiving NAC for BCa. FUNDING: This work was supported by National Natural Science Foundation of China (Grant No. 82373254 and 81961128027), Guangdong Provincial Natural Science Foundation (Grant No. 2023A1515010258), Science and Technology Planning Project of Guangdong Province (Grant No. 2023B1212060013). Science and Technology Program of Guangzhou (SL2022A04J01754), Sun Yat-Sen Memorial Hospital Clinical Research 5010 Program (Grant No. SYS-5010Z-202401).

Does Focal Kyphotic Deformity at Non-responsible Levels Affect the Outcomes of Anterior Cervical Decompression and Fusion?

OBJECTIVE: Focal cervical kyphotic deformity (FCK) without neurologic compression is not uncommon in patients with cervical spondylotic myelopathy (CSM) who underwent anterior cervical decompression and fusion (ACDF) surgery. It remains unclear whether FCK at non-responsible levels needs to be treated simultaneously. This study aims to investigate whether FCK at non-responsible levels is the prognostic factor for CSM and elucidate the surgical indication for FCK. METHODS: Patients with CSM who underwent ACDF between January 2016 and April 2021 were included. Patients were divided into two groups according to the presence of FCK and two classifications according to global cervical sagittal alignment. Clinical outcomes were compared using Japanese Orthopaedic Association (JOA) scores and recovery rate (RR) of neurologic function. Univariate and multivariate analysis based on RR assessed the relationship between various possible prognostic factors and clinical outcomes. The receiver operating characteristic curve (ROC) was used to determine the optimal cutoff value of the focal Cobb angle to predict poor clinical outcomes. RESULTS: A total of 94 patients were included, 41 with FCK and 53 without. Overall, the RR of neurologic function was significantly lower in the FCK than in the non-FCK group. Further analysis showed that the RR difference between the two groups was only observed in hypo-lordosis classification (kyphotic and sigmoid alignment), but not in the lordosis classification. Multivariate analysis showed that the preoperative focal Cobb angle in the FCK level (OR = 0.42; 95% CI = 0.18-0.97) was independently associated with clinical outcomes in the hypo-lordosis classification. The optimal cutoff point of the preoperative focal kyphotic Cobb angle was calculated at 4.05°. CONCLUSION: For CSM with hypo-lordosis, FCK was a risk factor for poor postoperative outcomes. Surgeons may consider treating the FCK simultaneously if the focal kyphotic Cobb angle of FCK is greater than 4.05° and is accompanied by cervical global kyphotic or sigmoid deformity.

Expression and Significance of LINC02418 in Breast Cancer.

Purpose: The complicated pathogenesis and poor prognosis of breast cancer have become a major difficulty in medical research. This study aims to explore new lncRNA as prognostic markers for breast cancer and explore their roles and molecular mechanisms to lay a foundation for the treatment of cancer patients. Patients and Methods: The expression of LINC02418 and miR-766-5p in breast cancer tissues and cells was first identified using polymerase chain reaction, and Pearson was used to examine the correlation between the two. The cancer cells activities under different transfection conditions were detected using the Transwell assay and CCK8 assay. The correlation between LINC02418 and patient prognosis was analyzed using multifactor Cox regression and Kaplan-Meier. Results: It was shown that LINC02418 expression was upregulated in breast cancer tissues and cells. There are significant differences in lymph node metastasis and TNM stage between high and low LINC02418 expression groups. The higher the expression of LINC02418, the higher the mortality rate of breast cancer patients. miR-766-5p expression was downregulated and negatively correlated with LINC02418. There are binding sites between LINC02418 and miR-766-5p; Transfection with miR-766-5p inhibitor boosted LINC02418 luciferase activity, but transfection with miR-766-5p mimic decreased it. Knockdown of LINC02418 promoted miR-766-5p expression and inhibited cancer progression, which was alleviated to some extent by transfection with miR-766-5p inhibitors. Conclusion: LINC02418 has the potential to serve as a poor prognostic marker for breast cancer and plays a pro-oncogenic role by targeting miR-766-5p.

Suitability of the MP1000 Platform for Robot-assisted Prostatectomy: A Prospective Randomised Controlled Trial.

Background and objective: Robot-assisted radical prostatectomy (RARP) is widely used because of the many advantages of a robotic approach. The da Vinci Si robot is one of the most commonly used surgical robot systems, but it may be associated with higher costs owing to the use of consumable surgical supplies. Our aim was to conduct a preliminary investigation of the capability of the MP1000 system for RARP. Methods: In this prospective, multicentre, single-blinded study, we randomly assigned 42 patients scheduled to undergo RARP between April and September 2021 to a da Vinci Si group (control) or an MP1000 group (intervention). Patients underwent RARP performed using the assigned robotic system and were followed up at 3-mo intervals. The primary outcome was the rate of conversion to open/laparoscopic surgery. Secondary outcomes were installation and operation times, intraoperative blood loss, postoperative surgical margin status, hospital stay, incontinence, complications, safety indicators, and surgeon ergonomics. Key findings and limitations: All procedures were successfully completed without conversion to open/laparascopic surgery or major complications. Secondary outcomes, including oncological and ergonomic indicators, did not differ significantly between the groups over the study period. One patient in the control group experienced dysuria (Clavien-Dindo grade 3). No patients had incontinence at 3 mo. A limitation of the study is the small sample size. Conclusions and clinical implications: RARP with the MP1000 system is feasible, safe, and effective in the management of localised prostate cancer. Patient summary: We assessed the effectiveness and safety of the new MP1000 robot system for robot-assisted removal of the prostate in comparison to the da Vinci Si robot. We found no difference in effectiveness or safety among 42 patients with prostate cancer who were assigned randomly to one of the two systems. We conclude that the MP1000 is a suitable robot for this surgery.

Mitofilin in cardiovascular diseases: Insights into the pathogenesis and potential pharmacological interventions.

The impact of mitochondrial dysfunction on the pathogenesis of cardiovascular disease is increasing. However, the precise underlying mechanism remains unclear. Mitochondria produce cellular energy through oxidative phosphorylation while regulating calcium homeostasis, cellular respiration, and the production of biosynthetic chemicals. Nevertheless, problems related to cardiac energy metabolism, defective mitochondrial proteins, mitophagy, and structural changes in mitochondrial membranes can cause cardiovascular diseases via mitochondrial dysfunction. Mitofilin is a critical inner mitochondrial membrane protein that maintains cristae structure and facilitates protein transport while linking the inner mitochondrial membrane, outer mitochondrial membrane, and mitochondrial DNA transcription. Researchers believe that mitofilin may be a therapeutic target for treating cardiovascular diseases, particularly cardiac mitochondrial dysfunctions. In this review, we highlight current findings regarding the role of mitofilin in the pathogenesis of cardiovascular diseases and potential therapeutic compounds targeting mitofilin.

Chitinase 3-like 1 expression associated with lymphatic metastasis and prognosis in urothelial carcinoma of the bladder.

Objectives: Lymphatic metastasis, an early stage of the metastasis process, is associated with adverse clinical outcomes in urothelial carcinoma of the bladder (UCB). However, the role of inflammation in triggering lymphatic metastasis remains unclear. Methods: We employed an RNA-sequencing cohort (n = 50) from Sun Yat-Sen Memorial Hospital (SYMH) to identify the most highly upregulated inflammatory gene associated with lymphatic metastasis. Using immunohistochemistry and immunofluorescence analyses, we validated the association of the identified molecule with clinical features and prognosis in an independent UCB cohort (n = 244) from SYMH. We also analysed TCGA-BLCA cohort (n = 408) to identify its potential biological pathways and immune landscape. Results: In our study, chitinase 3-like 1 (CHI3L1) emerged as a significantly overexpressed proinflammatory mediator in UCB tissues with lymphatic metastasis compared to those without lymphatic metastasis (81.1% vs. 47.8%, P < 0.001). Within UCB tissues, CHI3L1 was expressed in both stromal cells (52.8%) and tumor cells (7.3%). Moreover, CHI3L1+ stromal cells, but not tumor cells, exhibited independent prognostic significance for both overall survival (P < 0.001) and recurrence-free survival (P = 0.006). CHI3L1+ stromal cells were positively associated with D2-40+ lymphatic vessel density (P < 0.001) and the immunosuppressive PD-L1/PD-1/CD8 axis in UCB tissues (all P < 0.05). A bioinformatics analysis also identified a positive association between CHI3L1 expression and lymphangiogenesis or immunosuppression pathways. Conclusion: Our study established a clear association between stromal CHI3L1 expression and lymphatic metastasis, suggesting that stromal CHI3L1 expression is a potential prognostic marker for bladder cancer patients.

Type III interferon inhibits bladder cancer progression by reprogramming macrophage-mediated phagocytosis and orchestrating effective immune responses.

BACKGROUND: Interferons (IFNs) are essential for activating an effective immune response and play a central role in immunotherapy-mediated immune cell reactivation for tumor regression. Type III IFN (λ), related to type I IFN (α), plays a crucial role in infections, autoimmunity, and cancer. However, the direct effects of IFN-λ on the tumor immune microenvironment have not been thoroughly investigated. METHODS: We used mouse MB49 bladder tumor models, constructed a retroviral vector expressing mouse IFN-λ3, and transduced tumor cells to evaluate the antitumor action of IFN-λ3 in immune-proficient tumors and T cell-deficient tumors. Furthermore, human bladder cancer samples (cohort 1, n=15) were used for immunohistochemistry and multiplex immunoflurescence analysis to assess the expression pattern of IFN-λ3 in human bladder cancer and correlate it with immune cells' infiltration. Immunohistochemistry analysis was performed in neoadjuvant immunotherapy cohort (cohort 2, n=20) to assess the correlation between IFN-λ3 expression and the pathological complete response rate. RESULTS: In immune-proficient tumors, ectopic Ifnl3 expression in tumor cells significantly increased the infiltration of cytotoxic CD8+ T cells, Th1 cells, natural killer cells, proinflammatory macrophages, and dendritic cells, but reduced neutrophil infiltration. Transcriptomic analyses revealed significant upregulation of many genes associated with effective immune response, including lymphocyte recruitment, activation, and phagocytosis, consistent with increased antitumor immune infiltrates and tumor inhibition. Furthermore, IFN-λ3 activity sensitized immune-proficient tumors to anti-PD-1/PD-L1 blockade. In T cell-deficient tumors, increased Ly6G-Ly6C+I-A/I-E+ macrophages still enhanced tumor cell phagocytosis in Ifnl3 overexpressing tumors. IFN-λ3 is expressed by tumor and stromal cells in human bladder cancer, and high IFN-λ3 expression was positively associated with effector immune infiltrates and the efficacy of immune checkpoint blockade therapy. CONCLUSIONS: Our study indicated that IFN-λ3 enables macrophage-mediated phagocytosis and antitumor immune responses and suggests a rationale for using Type III IFN as a predictive biomarker and potential immunotherapeutic candidate for bladder cancer.

Elucidation of the Anti-Lung Cancer Mechanism of Xiao'ai Jiedu Prescription Based on Network Pharmacology and Molecular Docking.

Objective: Network pharmacology is an emerging discipline that applies computational methods to understand drug actions and interactions with multiple molecular targets. Xiao'ai Jiedu is a valued traditional Chinese medicine preparation for which the mechanism of action is not yet established. This study aims to explore the mechanism of Xiao'ai Jiedu in treating lung cancer through network pharmacology. Methods: First, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) data platform was used to analyze the target treatment results of different medicinal materials in Mr. Zhou's cancer prescriptions. Then, functional enrichment analysis was performed to conduct a secondary analysis of the dissemination of cancer biological and pharmacological information in the human body. The Cancer Genome Atlas (TCGA) was used to obtain several cancer-aggressive target groups, and their transcription RNA was extracted for collection. The CIBERSORT evaluation method was used to conduct a Spearman correlation analysis on the data processing results. Then the matching degree between the experimental cells and the principle of drug treatment was analyzed to improve the statistical analysis. Results: Pharmacology research results showed that the network can accurately eliminate cancer detoxification targeted target correlation set, and through the data interpretation found that four different gene transcription have significant influence on lung cancer. The findings also confirmed that the degree of immune cell infiltration has a key role in lung cancer The study summarizes the active ingredients and their targets and mechanisms of action of the elimination of Xiao'ai Jiedu formula for the treatment of lung cancer. Conclusion: Network pharmacology can carry on the processing of the data, find the key to conform to the goal of research data, and the corresponding results are obtained, and the development of network pharmacology is not limited to, the study of lung cancer.

Development of a novel humanized anti-TSLP monoclonal antibody HZ-1127 with anti-allergic diseases and cancer potential.

Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family and has been widely recognized as a master regulator of type 2 inflammatory responses at barrier surfaces. Recent studies found dysregulation of the TSLP-TSLP receptor (TSLPR) pathway is associated with the pathogenesis of not only allergic diseases but also a wide variety of cancers including both solid tumors and hematological tumors. Thus, the blockade of TSLP represents an attractive therapeutic strategy for allergic diseases and cancer. In this study, we report the development of a novel humanized anti-TSLP monoclonal antibody (mAb) HZ-1127. Binding affinity, specificity, and ability of HZ-1127 in inhibiting TSLP were tested. HZ-1127 selectively binds to the TSLP cytokine with high affinity and specificity. Furthermore, HZ-1127 dramatically inhibits TSLP-dependent STAT5 activation and is more potent than Tezepelumab, which is an FDA-approved humanized mAb against TSLP for severe asthma treatment in inhibiting TSLP-induced CCL17 and CCL22 chemokines secretion in human peripheral blood mononuclear cells. Our pre-clinical study demonstrates that HZ-1127 may serve as a potential therapeutic agent for allergic diseases and cancer.

Development and validation of an artificial intelligence-based model for detecting urothelial carcinoma using urine cytology images: a multicentre, diagnostic study with prospective validation.

Background: Urine cytology is an important non-invasive examination for urothelial carcinoma (UC) diagnosis and follow-up. We aimed to explore whether artificial intelligence (AI) can enhance the sensitivity of urine cytology and help avoid unnecessary endoscopy. Methods: In this multicentre diagnostic study, consecutive patients who underwent liquid-based urine cytology examinations at four hospitals in China were included for model development and validation. Patients who declined surgery and lacked associated histopathology results, those diagnosed with rare subtype tumours of the urinary tract, or had low-quality images were excluded from the study. All liquid-based cytology slides were scanned into whole-slide images (WSIs) at 40 × magnification and the WSI-labels were derived from the corresponding histopathology results. The Precision Urine Cytology AI Solution (PUCAS) was composed of three distinct stages (patch extraction, features extraction, and classification diagnosis) and was trained to identify important WSI features associated with UC diagnosis. The diagnostic sensitivity was mainly used to validate the performance of PUCAS in retrospective and prospective validation cohorts. This study is registered with the ChiCTR, ChiCTR2300073192. Findings: Between January 1, 2018 and October 31, 2022, 2641 patients were retrospectively recruited in the training cohort, and 2335 in retrospective validation cohorts; 400 eligible patients were enrolled in the prospective validation cohort between July 7, 2023 and September 15, 2023. The sensitivity of PUCAS ranged from 0.922 (95% CI: 0.811-0.978) to 1.000 (0.782-1.000) in retrospective validation cohorts, and was 0.896 (0.837-0.939) in prospective validation cohort. The PUCAS model also exhibited a good performance in detecting malignancy within atypical urothelial cells cases, with a sensitivity of over 0.84. In the recurrence detection scenario, PUCAS could reduce 57.5% of endoscopy use with a negative predictive value of 96.4%. Interpretation: PUCAS may help to improve the sensitivity of urine cytology, reduce misdiagnoses of UC, avoid unnecessary endoscopy, and reduce the clinical burden in resource-limited areas. The further validation in other countries is needed. Funding: National Natural Science Foundation of China; Key Program of the National Natural Science Foundation of China; the National Science Foundation for Distinguished Young Scholars; the Science and Technology Planning Project of Guangdong Province; the National Key Research and Development Programme of China; Guangdong Provincial Clinical Research Centre for Urological Diseases.

Tea Polyphenol Epigallocatechin Gallate Protects Against Nonalcoholic Fatty Liver Disease and Associated Endotoxemia in Rats via Modulating Gut Microbiota Dysbiosis and Alleviating Intestinal Barrier Dysfunction and Related Inflammation.

Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation and inflammation. Epigallocatechin gallate (EGCG) has been proven to be effective against NAFLD, but its hepatoprotective mechanisms based on the "gut microbiota-barrier-liver axis" are still not fully understood. Herein, the results demonstrated that EGCG effectively ameliorated NAFLD phenotypes and metabolic disorders in rats fed a high-fat diet (HFD), and inhibited intestinal barrier dysfunction and inflammation, which is also supported in the experiment of Caco-2 cells. Moreover, EGCG could restore gut microbiota diversity and composition, particularly promoting beneficial microbes, including short-chain fatty acids (SCFAs) producers, such as Lactobacillus, and suppressing Gram-negative bacteria, such as Desulfovibrio. The microbial modulation raised SCFA levels, decreased lipopolysaccharide levels, inhibited the TLR4/NF-κB pathway, and strengthened intestinal barrier function via Nrf2 pathway activation, thereby alleviating liver steatosis and inflammation. Spearman's correlation analysis showed that 24 key OTUs, negatively or positively associated with NAFLD and metabolic disorders, were also reshaped by EGCG. Our results suggested that a combinative improvement of EGCG on gut microbiota dysbiosis, intestinal barrier dysfunction, and inflammation might be a potential therapeutic target for NAFLD.

Transcatheter or Surgical Aortic Valve Replacement in Women With Small Annuli at Low or Intermediate Surgical Risk.

There are limited data from randomized controlled trials assessing the impact of transcatheter aortic valve replacement (TAVR) or surgery in women with aortic stenosis and small aortic annuli. We evaluated 2-year clinical and hemodynamic outcomes after aortic valve replacement to understand acute valve performance and early and midterm clinical outcomes. This post hoc analysis pooled women enrolled in the randomized, prospective, multicenter Evolut Low Risk and SURTAVI intermediate risk trials. Women with severe aortic stenosis at low or intermediate surgical risk who had a computed tomography-measured annular perimeter of ≤72.3 mm were included and underwent self-expanding, supra-annular TAVR or surgery. The primary end point was 2-year all-cause mortality or disabling stroke rate. The study included 620 women (323 TAVR, 297 surgery) with a mean age of 78 years. At 2 years, the all-cause mortality or disabling stroke was 6.5% for TAVR and 8.0% for surgery, p = 0.47. Pacemaker rates were 20.0% for TAVR and 8.3% for surgery, p <0.001. The mean effective orifice area at 2 years was 1.9 ± 0.5 cm2 for TAVR and 1.6 ± 0.5 cm2 for surgery and the mean gradient was 8.0 ± 4.1 versus 12.7 ± 6.0 mm Hg, respectively (both p <0.001). Moderate or severe patient-prothesis mismatch at discharge occurred in 10.9% of patients who underwent TAVR and 33.2% of patients who underwent surgery, p <0.001. In conclusion, in women with small annuli, the clinical outcomes to 2 years were similar between self-expanding, supra-annular TAVR and surgery, with better hemodynamics in the TAVR group and fewer pacemakers in the surgical group.