PCAO2: an ontology for integration of prostate cancer associated genotypic, phenotypic and lifestyle data.

Disease ontologies facilitate the semantic organization and representation of domain-specific knowledge. In the case of prostate cancer (PCa), large volumes of research results and clinical data have been accumulated and needed to be standardized for sharing and translational researches. A formal representation of PCa-associated knowledge will be essential to the diverse data standardization, data sharing and the future knowledge graph extraction, deep phenotyping and explainable artificial intelligence developing. In this study, we constructed an updated PCa ontology (PCAO2) based on the ontology development life cycle. An online information retrieval system was designed to ensure the usability of the ontology. The PCAO2 with a subclass-based taxonomic hierarchy covers the major biomedical concepts for PCa-associated genotypic, phenotypic and lifestyle data. The current version of the PCAO2 contains 633 concepts organized under three biomedical viewpoints, namely, epidemiology, diagnosis and treatment. These concepts are enriched by the addition of definition, synonym, relationship and reference. For the precision diagnosis and treatment, the PCa-associated genes and lifestyles are integrated in the viewpoint of epidemiological aspects of PCa. PCAO2 provides a standardized and systematized semantic framework for studying large amounts of heterogeneous PCa data and knowledge, which can be further, edited and enriched by the scientific community. The PCAO2 is freely available at https://bioportal.bioontology.org/ontologies/PCAO, http://pcaontology.net/ and http://pcaontology.net/mobile/.

Capturing the start point of the virus-cell interaction with high-speed 3D single-virus tracking.

The early stages of the virus-cell interaction have long evaded observation by existing microscopy methods due to the rapid diffusion of virions in the extracellular space and the large three-dimensional cellular structures involved. Here we present an active-feedback single-particle tracking method with simultaneous volumetric imaging of the live cell environment called 3D-TrIm to address this knowledge gap. 3D-TrIm captures the extracellular phase of the infectious cycle in what we believe is unprecedented detail. We report what are, to our knowledge, previously unobserved phenomena in the early stages of the virus-cell interaction, including skimming contact events at the millisecond timescale, orders of magnitude change in diffusion coefficient upon binding and cylindrical and linear diffusion modes along cellular protrusions. Finally, we demonstrate how this method can move single-particle tracking from simple monolayer culture toward more tissue-like conditions by tracking single virions in tightly packed epithelial cells. This multiresolution method presents opportunities for capturing fast, three-dimensional processes in biological systems.

CCDC50 promotes tumor growth through regulation of lysosome homeostasis.

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAFV600E inhibition. Thus, we demonstrate critical roles of CCDC50-mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma.

Tumor-associated macrophages in colorectal cancer metastasis: molecular insights and translational perspectives.

Metastasis is the leading cause of high mortality in colorectal cancer (CRC), which is not only driven by changes occurring within the tumor cells, but is also influenced by the dynamic interaction between cancer cells and components in the tumor microenvironment (TME). Currently, the exploration of TME remodeling and its impact on CRC metastasis has attracted increasing attention owing to its potential to uncover novel therapeutic avenues. Noteworthy, emerging studies suggested that tumor-associated macrophages (TAMs) within the TME played important roles in CRC metastasis by secreting a variety of cytokines, chemokines, growth factors and proteases. Moreover, TAMs are often associated with poor prognosis and drug resistance, making them promising targets for CRC therapy. Given the prognostic and clinical value of TAMs, this review provides an updated overview on the origin, polarization and function of TAMs, and discusses the mechanisms by which TAMs promote the metastatic cascade of CRC. Potential TAM-targeting techniques for personalized theranostics of metastatic CRC are emphasized. Finally, future perspectives and challenges for translational applications of TAMs in CRC development and metastasis are proposed to help develop novel TAM-based strategies for CRC precision medicine and holistic healthcare.

Integrated mRNA- and miRNA-sequencing analyses unveil the underlying mechanism of tobacco pollutant-induced developmental toxicity in zebrafish embryos.

Tobacco pollutants are prevalent in the environment, leading to inadvertent exposure of pregnant females. Studies of these pollutants' toxic effects on embryonic development have not fully elucidated the potential underlying mechanisms. Therefore, in this study, we aimed to investigate the developmental toxicity induced by cigarette smoke extract (CSE) at concentrations of 0.25, 1, and 2.5% using a zebrafish embryo toxicity test and integrated transcriptomic analysis of microRNA (miRNA) and messenger RNA (mRNA). The findings revealed that CSE caused developmental toxicity, including increased mortality and decreased incubation rate, in a dose-dependent manner. Moreover, CSE induced malformations and apoptosis, specifically in the head and heart of zebrafish larvae. We used mRNA and miRNA sequencing analyses to compare changes in the expression of genes and miRNAs in zebrafish larvae. The bioinformatics analysis indicates that the mechanism underlying CSE-induced developmental toxicity was associated with compromised genetic material damage repair, deregulated apoptosis, and disturbed lipid metabolism. The enrichment analysis and RT-qPCR show that the ctsba gene plays a crucial function in embryo developmental apoptosis, and the fads2 gene mainly regulates lipid metabolic toxicity. The results of this study improve the understanding of CSE-induced developmental toxicity in zebrafish embryos and contribute insights into the formulation of novel preventive strategies against tobacco pollutants during early embryonic development.

U-shaped association between triglyceride-glucose index and all-cause mortality among critically ill pediatrics: a population-based retrospective cohort study.

BACKGROUND: Previous studies have shown that an elevated triglyceride-glucose (TyG) index was associated with all-cause mortality in both general adult individuals and critically ill adult patients. However, the relationship between the TyG index and clinical prognosis in pediatric patients admitted to the intensive care unit (ICU) remains unknown. We aimed to investigate the association of the TyG index with in-hospital all-cause mortality in critically ill pediatric patients. METHODS: A total of 5706 patients in the Pediatric Intensive Care database were enrolled in this study. The primary outcome was 30-day in-hospital all-cause mortality, and secondary outcome was 30-day in-ICU all-cause mortality. The restricted cubic spline (RCS) curves and two-piecewise multivariate Cox hazard regression models were performed to explore the relationship between the TyG index and outcomes. RESULTS: The median age of the study population was 20.5 [interquartile range (IQR): 4.8, 63.0] months, and 3269 (57.3%) of the patients were male. The mean TyG index level was 8.6 ± 0.7. A total of 244 (4.3%) patients died within 30 days of hospitalization during a median follow-up of 11 [7, 18] days, and 236 (4.1%) patients died in ICU within 30 days of hospitalization during a median follow-up of 6 [3, 11] days. The RCS curves indicated a U-shape association between the TyG index and 30-day in-hospital and in-ICU all-cause mortality (both P values for non-linear < 0.001). The risk of 30-day in-hospital all-cause mortality was negatively correlated with the TyG index until it bottoms out at 8.6 (adjusted hazard ratio [HR], 0.72, 95% confidence interval [CI] 0.55-0.93). However, when the TyG index was higher than 8.6, the risk of primary outcome increased significantly (adjusted HR, 1.51, 95% CI 1.16-1.96]). For 30-day in-ICU all-cause mortality, we also found a similar relationship (TyG < 8.6: adjusted HR, 0.75, 95% CI 0.57-0.98; TyG ≥ 8.6: adjusted HR, 1.42, 95% CI 1.08-1.85). Those results were consistent in subgroups and various sensitivity analysis. CONCLUSIONS: Our study showed that the association between the TyG index and 30-day in-hospital and in-ICU all-cause mortality was nonlinear U-shaped, with a cutoff point at the TyG index of 8.6 in critically ill pediatric patients. Our findings suggest that the TyG index may be a novel and important factor for the short-term clinical prognosis in pediatric patients.

An ABHD17-like hydrolase screening system to identify de-S-acylation enzymes of protein substrates in plant cells.

Protein S-acylation is an important post-translational modification in eukaryotes, regulating the subcellular localization, trafficking, stability, and activity of substrate proteins. The dynamic regulation of this reversible modification is mediated inversely by protein S-acyltransferases and de-S-acylation enzymes, but the de-S-acylation mechanism remains unclear in plant cells. Here, we characterized a group of putative protein de-S-acylation enzymes in Arabidopsis thaliana, including 11 members of Alpha/Beta Hydrolase Domain-containing Protein 17-like acyl protein thioesterases (ABAPTs). A robust system was then established for the screening of de-S-acylation enzymes of protein substrates in plant cells, based on the effects of substrate localization and confirmed via the protein S-acylation levels. Using this system, the ABAPTs, which specifically reduced the S-acylation levels and disrupted the plasma membrane localization of five immunity-related proteins, were identified respectively in Arabidopsis. Further results indicated that the de-S-acylation of RPM1-Interacting Protein 4, which was mediated by ABAPT8, resulted in an increase of cell death in Arabidopsis and Nicotiana benthamiana, supporting the physiological role of the ABAPTs in plants. Collectively, our current work provides a powerful and reliable system to identify the pairs of plant protein substrates and de-S-acylation enzymes for further studies on the dynamic regulation of plant protein S-acylation.

CD276 enhances sunitinib resistance in clear cell renal cell carcinoma by promoting DNA damage repair and activation of FAK-MAPK signaling pathway.

OBJECTIVE: This study aimed to explore the effect of CD276 expression on the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cell and animal models and the potential mechanisms involved. METHODS: CD276 expression levels of ccRCC and normal samples were analyzed via online databases and real-time quantitative PCR (RT-qPCR). CD276 was knocked down in ccRCC cell models (sunitinib-resistant 786-O/R cells and sunitinib-sensitive 786-O cells) using shRNA transfection, and the cells were exposed to a sunitinib (2 µM) environment. Cells proliferation was then analyzed using MTT assay and colony formation experiment. Alkaline comet assay, immunofluorescent staining, and western blot experiments were conducted to assess the DNA damage repair ability of the cells. Western blot was also used to observe the activation of FAK-MAPK pathway within the cells. Finally, a nude mouse xenograft model was established and the nude mice were orally administered sunitinib (40 mg/kg/d) to evaluate the in vivo effects of CD276 knockdown on the therapeutic efficacy of sunitinib against ccRCC. RESULTS: CD276 was significantly upregulated in both ccRCC clinical tissue samples and cell models. In vitro experiments showed that knocking down CD276 reduced the survival rate, IC50 value, and colony-forming ability of ccRCC cells. Knocking down CD276 increased the comet tail moment (TM) values and γH2AX foci number, and reduced BRCA1 and RAD51 protein levels. Knocking down CD276 also decreased the levels of p-FAK, p-MEK, and p-ERK proteins. CONCLUSION: Knocking down CD276 effectively improved the sensitivity of ccRCC cell and animal models to sunitinib treatment.

Efficacy of Rituximab for Minimal Change Disease and Focal Segmental Glomerulosclerosis with Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome in Adults: A Chinese Multicenter Retrospective Study.

INTRODUCTION: Rituximab has been proven effective and safe in pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). We aimed to analyze the efficacy and safety of rituximab in adult FR/SDNS patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). METHODS: A retrospective cohort study at three nephrology centers in China included adult FR/SDNS patients with biopsy-proven MCD or FSGS. Primary outcomes were relapse frequency and first relapse-free survival time. Adverse events were well recorded, and logistic regression analyses were used to investigate the risk factors of relapse. RESULTS: Eighty-one patients (age, 25.0 years; interquartile range, 20.0-40.5; 67% males; 82.7% MCD) received an average rituximab dose of 1,393.8 ± 618.7 mg/2 years during the 2-year follow-up period. The relapse frequency, calculated as the ratio of relapse times to follow-up years, significantly decreased after rituximab treatment (0.04 [0.00, 0.08] vs. 1.71 [1.00, 2.45], p < 0.001). The first relapse-free survival time was 16.7 ± 8.0 months. Fifty-seven patients (70.4%) achieved cessation of corticosteroids and immunosuppressants within 3 months after the first rituximab infusion. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. Low serum albumin level before rituximab and high CD56+CD16+ natural killer cell count after rituximab were independent risk factors of relapse within 2 years after rituximab treatment. CONCLUSION: Rituximab was proven an effective and safe treatment option for adult FR/SDNS patients with MCD or FSGS in maintaining disease remission and minimizing corticosteroid exposure.

Bioinformatic Analysis and Clinical Case Studies Identify CD276 as a Promising Diagnostic Biomarker for Clear Cell Renal Cell Carcinoma.

OBJECTIVE: This study aimed to explore the relationship between CD276 and clear cell renal carcinoma (ccRCC) and assess the diagnostic value of CD276 in ccRCC. METHODS: Expression levels of CD276 in ccRCC and para-cancer tissues were compared and analyzed retrospectively using data obtained from TCGA and GEO databases. The clinical data was analyzed prospectively. Immunohistochemistry and RT-PCR analyses were used to analyze the expression of CD276 at the mRNA and protein levels. These analyses compared the expression between ccRCC tissues and para-cancer tissues obtained from 70 patients with ccRCC. Next, ELISA was used to analyze peripheral blood samples from 70 patients with ccRCC and 72 healthy individuals, facilitating the differentiation of ccRCC patients from normal controls. Finally, we utilized the Kaplan-Meier method to generate ROC curves for assessing the diagnostic value of CD276 for ccRCC. RESULTS: Analysis of TCGA and GEO data revealed that the mRNA expression of CD276 was higher in ccRCC tissues than in para-cancer tissues (P < .05). Clinical validation using IHC and RT-PCR confirmed that the expression of CD276 was higher in ccRCC tissues than in para-cancer tissues, both at the mRNA and protein levels (P < .05). ELISA demonstrated that the expression of CD276 was higher in ccRCC patients than in normal individuals, and patients with a higher pathological grade showed higher expression of CD276 in the peripheral blood than those with a lower pathological grade (P < .05). ROC curves drawn from the above three datasets demonstrated that CD276 had a high diagnostic value for ccRCC (AUC = .894, .795, .938, respectively). CONCLUSION: The expression of CD276 was higher in ccRCC tissues and positively associated with the pathological grade. Therefore, CD276 may serve as a molecular biomarker for ccRCC prediction.

CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3.

The NLRP3-directed inflammasome complex is crucial for the host to resist microbial infection and monitor cellular damage. However, the hyperactivation of NLRP3 inflammasome is implicated in pathogenesis of inflammatory diseases, including inflammatory bowel disease (IBD). Autophagy and autophagy-related genes are closely linked to NLRP3-mediated inflammation in these inflammatory disorders. Here, we report that CCDC50, a novel autophagy cargo receptor, negatively regulates NLRP3 inflammasome assembly and suppresses the cleavage of pro-caspase-1 and interleukin 1ß (IL-1ß) release by delivering NLRP3 for autophagic degradation. Transcriptome analysis showed that knockdown of CCDC50 results in upregulation of signaling pathways associated with autoinflammatory diseases. CCDC50 deficiency leads to enhanced proinflammatory cytokine response triggered by a wide range of endogenous and exogenous NLRP3 stimuli. Ccdc50-deficient mice are more susceptible to dextran sulfate (DSS)-induced colitis and exhibit more severe gut inflammation with elevated NLRP3 inflammasome activity. These results illustrate the physiological significance of CCDC50 in the pathogenicity of inflammatory diseases, suggesting protective roles of CCDC50 in keeping gut inflammation under control.

Clinical characteristics of pyogenic liver abscess with and without biliary surgery history: a retrospective single-center experience.

BACKGROUND & AIMS: Pyogenic liver abscess (PLA) is a common hepatobiliary infection that has been shown to have an increasing incidence, with biliary surgery being identified as a trigger. Our aim was to investigate the clinical characteristics and treatments of PLA patients with and without a history of biliary surgery (BS). METHODS: The study included a total of 353 patients with PLA who received treatment at our hospital between January 2014 and February 2023. These patients were categorized into two groups: the BS group (n = 91) and the non-BS group (n = 262). In the BS group, according to the anastomosis method, they were further divided into bilioenteric anastomoses group (BEA, n = 22) and non-bilioenteric anastomoses group (non-BEA, n = 69). Clinical characteristics were recorded and analyzed. RESULTS: The percentage of PLA patients with BS history was 25.78%. The BS group exhibited elevated levels of TBIL and activated APTT abnormalities (P = 0.009 and P = 0.041, respectively). Within the BS group, the BEA subgroup had a higher prevalence of diabetes mellitus (P < 0.001) and solitary abscesses (P = 0.008) compared to the non-BEA subgroup. Escherichia coli was more frequently detected in the BS group, as evidenced by positive pus cultures (P = 0.021). The BS group exhibited reduced treatment efficacy compared to those non-BS history (P = 0.020). Intriguingly, the BS group received a higher proportion of conservative treatment (45.05% vs. 21.76%), along with reduced utilization of surgical drainage (6.59% vs. 16.41%). CONCLUSIONS: Patients with BS history, especially those who have undergone BEA, have an increased susceptibility to PLA formation without affecting prognosis.

An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis.

Nuclear factor κB (NF-κB)-mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In this study, we demonstrated that ankyrin repeat and suppressor of cytokine signaling box containing 1 (ASB1) is involved in the positive regulation of inflammatory responses by enhancing the stability of TAB2 and its downstream signaling pathways, including NF-κB and mitogen-activated protein kinase pathways. Mechanistically, unlike other members of the ASB family that induce ubiquitination-mediated degradation of their target proteins, ASB1 associates with TAB2 to inhibit K48-linked polyubiquitination and thereby promote the stability of TAB2 upon stimulation of cytokines and lipopolysaccharide (LPS), which indicates that ASB1 plays a noncanonical role to further stabilize the target protein rather than induce its degradation. The deficiency of Asb1 protects mice from Salmonella typhimurium- or LPS-induced septic shock and increases the survival of mice. Moreover, Asb1-deficient mice exhibited less severe colitis and intestinal inflammation induced by dextran sodium sulfate. Given the crucial role of ASB proteins in inflammatory signaling pathways, our study offers insights into the immune regulation in pathogen infection and inflammatory disorders with therapeutic implications.

Postoperative Intermaxillary Elastic Traction Contributes to the Stability of Absorbable Plates Fixation for Bilateral Mandibular Fracture.

The use of absorbable plates can be challenging for mandibular fractures involving bilateral dentition. Chewing and mouth opening movements may cause loosening or breakage of absorbable materials, leading to displacement of bone segments and resulting in malocclusion. The use of absorbable materials for bilateral mandibular fracture surgery itself raises concerns for surgeons. Timely intermaxillary elastic traction is essential for these patients after surgery to maintain correct occlusion. The surgical approaches were performed with intraoral mandibular sulcus incisions. During the surgery, intermaxillary fixation screws were implanted and steel wires were used for intermaxillary ligation and fixation to restore the occlusal. After the fractured segments were sequentially reduced, they were fixed with inion 2.0 absorbable plates. The patient underwent intermaxillary elastic traction for 1 week. Elastic mask was used to assist in stabilizing the position of the jawbone and maintaining occlusion. After discharge, the patient continued traction at home for 3 weeks before removing the intermaxillary fixation screws. The patient recovered well after surgery without any complications. The postoperative occlusal relationship is good. Postoperative CT showed good reduction of the fractured segments. For the case reported in this article, elastic traction was promptly implemented after surgery. We emphasize that restoring occlusion is always the treatment goal for jawbone fractures. We believe that keeping the intermaxillary fixation screws for a month is a wise choice to be prepared for unexpected needs.

Management of Atypical M-Shaped Zygomatic Arch Fractures.

BACKGROUND: M-shaped zygomatic arch fractures can usually be treated effectively through closed reduction. It consists of 2 fracture segments: the anterior zygomatic segment and the posterior temporal bone segment. In clinical practice, atypical M-shaped fractures are often encountered, in which the anterior and posterior fracture segments are discontinuous and separated. Closed reduction usually cannot achieve the desired anatomic reduction effect for this type of fracture. METHODS: The preoperative design showed that the anatomic reduction of the posterior zygomatic arch fracture segment was hindered due to bone spurs in the most concave area of the anterior zygomatic bone fracture segment. Open reduction and fixation were performed to achieve anatomic reduction and restore facial symmetry. The fracture sites were exposed through a hemicoronal incision. After the bone spurs are removed, the posterior bone segment can be anatomically reduced. Absorbable plates were used for fixation. RESULTS AND DISCUSSION: The patient's facial appearance was restored after the surgery. The postoperative computed tomography scan showed a good alignment of the fracture. The authors believe that for patients with high requirements for facial symmetry, the presence of atypical M-shaped fractures can indicate open reduction and fixation.

Management of Mandibular Condylar Sagittal Fracture Accompanied by Lateral Condylar Crest Defect.

BACKGROUND: The sagittal fracture of the mandibular condyle can be fixed with absorbable long screws. Absorbable long screws are generally inserted from the lateral crest of the condyle and are as close as possible to the medial pole of the condyle to obtain sufficient retention force. However, in clinical practice, patients with locally comminuted condylar fractures and partial defects in the lateral crest are often encountered. We validated the use of absorbable plates and long screws to fix mandibular condylar fractures with lateral crest defects, and postoperative follow-up showed good results. METHODS: The preoperative design indicated that if conventional long screws were used, more soft tissue need to be pulled downward to achieve the appropriate drilling angle. If an absorbable plate was used, the degree of downward pulling of soft tissue was smaller, which can better protect the parotid gland tissue and facial nerve. The surgery was performed according to the preoperative design, using an absorbable plate scheme. RESULTS AND DISCUSSION: Postoperative CT confirmed a stable anatomical reduction of condyle. Four-month follow-up showed that the patient's facial shape, occlusion, and mouth opening were all good. Follow-up CT showed good fracture healing. It is feasible to use absorbable plates and long absorbable screws to fix mandibular condylar sagittal fracture accompanied by lateral condylar crest defect.

Overcoming the Low-Stability Bottleneck in the Clinical Translation of Liposomal Pressurized Metered-Dose Inhalers: A Shell Stabilization Strategy Inspired by Biomineralization.

Currently, several types of inhalable liposomes have been developed. Among them, liposomal pressurized metered-dose inhalers (pMDIs) have gained much attention due to their cost-effectiveness, patient compliance, and accurate dosages. However, the clinical application of liposomal pMDIs has been hindered by the low stability, i.e., the tendency of the aggregation of the liposome lipid bilayer in hydrophobic propellant medium and brittleness under high mechanical forces. Biomineralization is an evolutionary mechanism that organisms use to resist harsh external environments in nature, providing mechanical support and protection effects. Inspired by such a concept, this paper proposes a shell stabilization strategy (SSS) to solve the problem of the low stability of liposomal pMDIs. Depending on the shell material used, the SSS can be classified into biomineralization (biomineralized using calcium, silicon, manganese, titanium, gadolinium, etc.) biomineralization-like (composite with protein), and layer-by-layer (LbL) assembly (multiple shells structured with diverse materials). This work evaluated the potential of this strategy by reviewing studies on the formation of shells deposited on liposomes or similar structures. It also covered useful synthesis strategies and active molecules/functional groups for modification. We aimed to put forward new insights to promote the stability of liposomal pMDIs and shed some light on the clinical translation of relevant products.

[Application of the cigarette purchase tasks in achieving China' s tobacco control goals].

OBJECTIVE: To assess cigarette demand among Chinese smokers through a cigarette purchase task (CPT) and to evaluate cigarette prices under different hypothetical scenarios in order to meet the goals of smoking prevalence reduction in China. METHODS: In the study, 447 participants completed a hypothetical CPT at baseline assessments of a trial, thus, cigarette demand curves were individually fitted for each participant using an exponentiated version of the exponential demand model. Typically, five demand indices were derived, intensity (consumption when free), breakpoint (first price at which consumption is suppressed to 0), maximum output (Omax), maximum price (Pmax, price at which Omax occurred), and elasticity (the ratio of the change in quantity demanded to the change in price). A one-way analysis of variance was used to explore the correlations between the cigarette purchase task indices and socio-demographic and smoking characteristics. The one-way decay model was employed to simulate the smoking cessation rates and determine optimal cigarette prices in a series of scenarios for achieving 20% smoking prevalence. RESULTS: The price elasticity drawn from CPT was 0.54, indicating that a 10% price increase could reduce smoking by 5.4% in the participated smokers. Smokers with higher income were less sensitive to cigarette prices (elasticity=-2.31, P=0.028). Cigarette purchase task indices varied significantly among the smokers with different prices of commonly used cigarettes, tobacco dependence, and smoking volume. The smokers who consumed cigarettes of higher prices reported higher breakpoint, Omax and Pmax, but lower intensity (P=0.001). The smokers who were moderately or highly nicotine dependent reported higher intensity, breakpoint, Omax and Pmax, and they had lower intensity (P=0.001). The smokers who had a higher volume of cigarettes reported higher intensity and Omax, and lower intensity (P < 0.001). To achieve the goal of reducing smoking prevalence to 20% in mainland China, we estimated the desired increase on smoking cessation rate and prices accordingly in a series of scenarios, considering the gender variance and reduced smoking initiation. In scenario (a), to achieve a smoking prevalence goal of 20%, it would be necessary for 24.81% of the current smokers to quit smoking when there were no new smokers. Our fitting model yielded a corresponding value of 59.64 yuan (95%CI 53.13-67.24). Given the assumption in scenario (b) that only males quitted smoking, the desired cessation rates would be 25.82%, with a higher corresponding price of 62.15 yuan (95%CI 55.40-70.06) to induce desired cessation rates. In the proposed scenario (c) where 40 percent of the reduction in smoking prevalence came from reduced smoking initiation, and females and males equally quitted smoking due to increased cigarette prices, the price of a pack of cigarettes would be at least 37.36 yuan (95%CI 32.32-42.69) (equals to $ 5.20) per pack to achieve the cessation rate of 14.89 percent. In scenario (d) where only males quitted smoking due to increased cigarette prices considering the reduced smoking initiation, the respective smoking cessation rates should be 15.49% with the desired prices of 38.60 yuan (95%CI 33.53-44.02). After adjusting for education levels and income levels in scenario (c), the price of cigarettes would be at least 37.37 yuan/pack (equals to $ 5.20) (95%CI 30.73-44.94) and 37.84 yuan/pack (equals to $ 5.26) (95%CI 31.94-44.53), respectively. CONCLUSION: Cigarette purchase task indices are significantly associated with income levels and prices of commonly used cigarettes, levels of tobacco dependence, and smoking volume, which is inspiring in studying price factors that influence smoking behavior. It is suggested that higher cigarette prices, surpassing the current actual market level, is imperative in mainland China. Stronger policy stra-tegies should be taken to increase tobacco taxes and retail cigarette prices to achieve the Healthy China 2030 goal of reducing smoking prevalence to 20%.

CBX3 promotes clear cell renal carcinoma through PI3K/AKT activation and aberrant immunity.

BACKGROUND: A chromobox homologue 3 (CBX3) is elevated in various cancers and significantly contributes to the promotion of malignant behavior; despite this, its exact involvement in clear cell renal cell carcinoma (ccRCC) is yet unknown. METHODS: The Cancer Genome Atlas database served to evaluate CBX3 production and its connection to survival in patients with ccRCC. Our team evaluated the effects of knockdown of CBX3 levels in ccRCC cell populations using in vitro together with in vivo models. CBX3, proteins related to death, and epithelial-to-mesenchymal transition (EMT)-related proteins were measured in ccRCC cells using western blotting and immunohistochemical assays. Through the analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneOntology (GO) and Gene Set Enrichment Analysis (GSEA), the biological processes and signal pathways related to CBX3 expression were identified. Immune-related activity reduced by CBX3 was assessed using various online tools. RESULTS: Both genomic and protein expression showed that CBX3 was upregulated in ccRCC. Further functional analyses revealed that CBX3 played a crucial role in enhancing cell growth, migration, and EMT in vitro along with in vivo. Moreover, the study results provided distinct mechanistic evidence that CBX3 exerts its pathological functions in ccRCC by activating the PI3K/AKT pathway. Finally, immunoassays revealed that CBX3, a possible biomarker of ccRCC, was significantly associated with immunity. CONCLUSIONS: Our results suggest that the overexpression of CBX3 promotes ccRCC advancement through PI3K/AKT activation and even immunological dysregulation, making it a potentially viable and beneficial therapeutic target.

The efficacy of rituximab plus belimumab or telitacicept in refractory lupus nephritis.

OBJECTIVE: Lupus nephritis is a severe and common complication of systemic lupus erythematosus (SLE). The pathogenesis of lupus nephritis is characterized by B-cell activation and autoantibody formation. Rituximab and belimumab, as well as telitacicept, target B cells through different mechanisms, potentially exerting a synergistic effect in the treatment of lupus nephritis. This study aims to investigate the efficacy and safety of treatment with rituximab followed by belimumab or telitacicept in the management of refractory lupus nephritis. METHODS: We conducted a single-center, open-label, retrospective study, including 25 patients with refractory lupus nephritis. All patients received combination therapy with rituximab in individualized dosages to achieve peripheral B-cell depletion, and then followed by belimumab or telitacicept. The follow-up period was at least 12 months, and the primary end point was renal remission rate at the last follow-up. RESULTS: During a median follow-up of 19 (13, 29) months, 20 of 25 (80%) patients achieved objective remission (OR), including 19 (76%) patients achieved complete renal response (CRR). After rituximab (712 ± 416mg in average), 18 patients received belimumab and seven patients received telitacicept. In the rituximab plus telitacicept group, all patients achieved CRR; while in the rituximab plus belimumab group, 12 (66.7%) patients achieved CRR and 13 (72.2%) patients achieved OR. The mean SLEDAI-2K score decreased from 15 ± 6 to 6 ± 6, representing an average reduction of 60%. At the last follow-up, 18/25 (72%) had prednisone ≤ 5 mg/d or even discontinued prednisone use. Adverse effects were mainly immunoglobulin deficiency, respiratory tract infection, urinary tract infections, and rash. No death occurred. CONCLUSIONS: Rituximab followed by belimumab or telitacicept may be effective in inducing remission in refractory lupus nephritis, with tolerable adverse effects.