Lymphatic vessels are necessary for cardiac function and inflammation resolution in sepsis-induced cardiomyopathy.

BACKGROUND: Sepsis-induced cardiomyopathy (SICM), is defined as a global but reversible dysfunction of both the left and right sides of the heart, which plays a significant role in the pathogenesis of sepsis. Lymphatic vessels are crucial for maintaining tissue fluid balance and regulating inflammatory responses. However, the role of lymphatics in SICM is still unknown. METHODS: The SICM model was established by intraperitoneal injection of lipopolysaccharide (LPS) for 12 h. To evaluate the effects of VEGF-C on LPS-induced SICM, the mice were treated with VEGFC-156S (0.1 mg/kg) via tail vein injection 6 h after LPS challenged and sacrificed 6 h after being treated with VEGFC. To evaluate the effects of the VEGF-C-VEGFR-3 signaling pathway in SICM. MAZ51, a specific inhibitor of VEGFR-3, was given intraperitoneally once daily for a total of 30 days before challenge with LPS. RESULTS: We found that cardiac function was impaired in SICM, along with a significant reduction in the area of lymphatic vessels. Then, we revealed that stimulation of cardiac lymphangiogenesis with vascular endothelial growth factor C (VEGFC) effectively improved cardiac function and promoted neutrophil clearance. Meanwhile, lymphatic inhibition by MAZ51, a specific inhibitor of VEGFR3, could further exacerbate cardiac dysfunction during SICM. Furthermore, the protective effect of VEGFC on SICM could be blocked by MAZ51. Finally, combined with transcriptomics sequencing, we found that VEGFC effectively inhibited the mitogen-activated protein kinase (MAPK) signaling pathway to protect the septic heart. CONCLUSIONS: Our data show that effective lymphatic vessels are necessary for cardiac function and inflammation resolution in SICM. Our findings offer a novel therapeutic approach to SICM by promoting lymphatic function.

CPK28-mediated phosphorylation enhances nitrate transport activity of NRT2.1 during nitrogen deprivation.

Nitrate (NO3 -) serves as the primary inorganic nitrogen source assimilated by most terrestrial plants. The acquisition of nitrate from the soil is facilitated by NITRATE TRANSPORTERS (NRTs), with NRT2.1 being the key high-affinity nitrate transporter. The activity of NRT2.1, which has multiple potential phosphorylation sites, is intricately regulated under various physiological conditions. Here, we discovered that CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28) positively regulates nitrate uptake under nitrogen deprivation conditions. We found CPK28 as the kinase targeted by immunoprecipitation followed by mass spectrometry and examined the in-planta phosphorylation status of NRT2.1 in cpk28 mutant plants by employing quantitative MS-based phosphoproteomics. Through a combination of in vitro phosphorylation experiment and immunoblotting using phospho-specific antibody, we successfully demonstrated that CPK28 specifically phosphorylates NRT2.1 at Ser21. Functional analysis conducted in Xenopus oocytes revealed that co-expression of CPK28 significantly enhanced high-affinity nitrate uptake of NRT2.1. Further investigation using transgenic plants showed that the phosphomimic variant NRT2.1S21E, but not the nonphosphorylatable variant NRT2.1S21A, fully restored high-affinity 15NO3 - uptake ability in both nrt2.1 and cpk28 mutant backgrounds. This study clarifies that the kinase activity of CPK28 is promoted during nitrogen deprivation conditions. These significant findings provide valuable insights into the intricate regulatory mechanisms that govern nitrate-demand adaptation.

Symbiotic probiotic communities with multiple targets successfully combat obesity in high-fat-diet-fed mice.

Probiotics hold great potential for treating metabolic diseases such as obesity. Given the complex and multifactorial nature of these diseases, research on probiotic combination with multiple targets has become popular. Here, we choose four obesity-related targets to perform high-throughput screening, including pancreatic lipase activity, bile salt hydrolase activity, glucagon-like peptide-1 secretion and adipocyte differentiation. Then, we obtained 649 multi-strain combinations with the requirement that each must cover all these targets in principle. After in vitro co-culture and in vivo co-colonization experiments, only four (<0.7%) combinations were selected as symbiotic probiotic communities (SPCs). Next, genome-scale metabolic model analysis revealed that these SPCs showed lower metabolic resource overlap and higher metabolic interaction potential involving amino acid metabolism (Ammonium, L-Lysine, etc.) and energy metabolism (Phosphate, etc.). Further animal experiments demonstrated that all SPCs exhibited a good safety profile and excellent effects in improving obesity and associated glucose metabolism disruptions and depression-like behaviors in high-fat-diet-fed mice. This anti-obesity improvement was achieved through reduced cholesterol level, fat accumulation and inhibited adipocyte differentiation. Taken together, our study provides a new perspective for designing multi-strain combinations, which may facilitate greater therapeutic effect on obesity and other complex diseases in the future.

Monolayer M2X2O as potential 2D altermagnets and half-metals: a first principles study.

Realizing novel two-dimensional (2D) magnetic states would accelerate the development of advanced spintronic devices and the understandings of 2D magnetic physics. In this paper, we have examined the magnetic and electronic properties of 20 dynamically stable and exfoliable M2X2O (M = Ti ~ Ni; X = S ~ Te; excluding Co2Te2O). It has been unveiled that [X4O2]-D2hand [M4]-D4hcrystal fields govern the M-3dorbital splittings in M2X2O. The splittings further lead to the antiferromagnetic orderings in Ti2S2O/Fe2S2O/Fe2Se2O/M2X2O (M = V, Cr, Mn and Ni; X = S ~ Se) as well as the ferromagnetic orderings in Ti2Se2O/Ti2Te2O/Fe2Te2O/Co2S2O/Co2Se2O through kinetic and superexchange mechanisms. Notably, all the antiferromagnetic M2X2O are 2D altermagnets, and Ti2Se2O/Ti2Te2O/Co2S2O/Co2Se2O are 2D half-metals. In particular, the anisotropicd-d/phoppings lead to the tunable altermagnetic splitting in Ti2S2O/Cr2Te2O, while the parity of V-3dyzorbital contributes to the symmetry-protected altermagnetic splitting within V2X2O. These altermagnetic and half-metallic monolayer M2X2O provide promising candidates applied in low-dimensional spintronic devices. In addition, the potential 2D altermagnetic Weyl semimetal of Fe2S2O/Fe2Se2O, nodal-loop half-metal of Ti2Se2O and half-semi metal of Ti2Te2O facilitate to uncover novel low-dimensional topological physics. These theoretical results would expand the platform in particular for 2D altermagnets and nontrivial systems. .

Effects of bile acids on the growth, composition and metabolism of gut bacteria.

Bile acids (BAs) exert a profound influence on the body's pathophysiology by intricately shaping the composition of gut bacteria. However, the complex interplay between BAs and gut microbiota has impeded a systematic exploration of their impact on intestinal bacteria. Initially, we investigated the effects of 21 BAs on the growth of 65 gut bacterial strains in vitro. Subsequently, we examined the impact of BAs on the overall composition of intestinal bacteria, both in vivo and in vitro. The results unveiled distinct effects of various BAs on different intestinal strains and their diverse impacts on the composition of gut bacteria. Mechanistically, the inhibition of intestinal strains by BAs occurs through the accumulation of these acids within the strains. The intracellular accumulation of deoxycholic acid (DCA) significantly influenced the growth of intestinal bacteria by impacting ribosome transcription and amino-acid metabolism. The metabolomic analysis underscores the pronounced impact of DCA on amino-acid profiles in both in vivo and in vitro settings. This study not only elucidates the effects of BAs on a diverse range of bacterial strains and their role in shaping the gut microbiota but also reveals underlying mechanisms essential for understanding and maintaining a healthy gut microbiota.

Flexible and Stretchable Photoelectrochemical Sensing toward True-to-Life Monitoring of Hydrogen Peroxide Regulation in Endothelial Mechanotransduction.

Hydrogen peroxide (H2O2) levels play a vital role in redox regulation and maintaining the physiological balance of living cells, especially in cell mechanotransduction. Despite the achievements on strain-induced cellular H2O2 monitoring, the applied voltage for H2O2 electrooxidation possibly gave rise to an abnormal expression and inadequate accuracy, which was still an inescapable concern. Hence, we decorated an interlaced CuO@TiO2 nanowires (NWs) semiconductor meshwork onto a polydimethylsiloxane film-supported gold nanotubes substrate (Au NTs/PDMS) to construct a flexible photoelectrochemical (PEC) sensing platform. Under white light irradiation, CuO@TiO2 NWs synergistically exhibited great stretchability and the PEC platform enabled stable photocurrent responses from the reduction of H2O2 even during mechanical deformation. Moreover, the admirable biocompatibility and an almost negligible open circuit voltage of +0.18 V for the CuO@TiO2 NWs/Au NTs/PDMS sensor guaranteed human umbilical vein endothelial cells (HUVECs) adhesion tightly thereon even under continuous illumination for 30 min. Finally, the as-proposed stretchable PEC sensor achieved sensitive and true-to-life monitoring of transient H2O2 release during HUVECs deformation, in which H2O2 release was positively correlated to mechanical strains. This investigation opens a new shade path on in situ cellular sensing and meanwhile greatly expands the application mode of the PEC approach.

Triple-combination therapy did not improve prognosis in anti-MDA5 positive dermatomyositis: a multicentre longitudinal cohort study.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is frequently linked with interstitial lung disease (ILD), especially the rapidly progressive ILD (RP-ILD). We conduct this research to evaluate the efficacy and safety of triple-combination (triple-combo) therapy consisting of high-dose corticosteroids, tacrolimus and intravenous cyclophosphamide in treating MDA5+ DM patients with ILD. METHODS: A multicentre longitudinal cohort study involving 115 MDA5+ DM patients from the Nanjing Medical University Myositis Associated ILD (NMMI) cohort was conducted between January 2019 and November 2022. Patients were categorised into triple-combo and non-triple therapy groups, and their outcomes were assessed. RESULTS: Contrary to expectations, triple-combo therapy did not improve the prognosis for MDA5+ DM patients but was linked to increased mortality rates, especially among those at high risk for RP-ILD. CONCLUSIONS: Our study suggests that triple-combo therapy might not be effective in improving prognosis in MDA5+ DM patients. Further research is needed to establish safer and more effective treatment modalities for this patient population.

Retrospective analysis of patients with hepatocellular carcinoma complicated with human immunodeficiency virus infection after hepatectomy.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with a 5-year relative survival rate of approximately 18%. The similarity between incidence and mortality (830000 deaths per year) underscores the bleak prognosis associated with the disease. HCC is the fourth most common malignancy and the second leading cause of cancer death in China. Most patients with HCC have a history of chronic liver disease such as chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholism or alcoholic steatohepatitis, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis. Early diagnosis and effective treatment are the keys to improving the prognosis of patients with HCC. Although the total number of human immunodeficiency virus (HIV)-infected patients is declining globally the incidence of HCC is increasing in HIV-infected patients, especially those who are coinfected with HBV or HCV. As a result, people infected with HIV still face unique challenges in terms of their risk of developing HCC. AIM: To investigate the survival prognosis and clinical efficacy of surgical resection in patients with HCC complicated with HIV infection. METHODS: The clinical data of 56 patients with HCC complicated with HIV admitted to the Third Affiliated Hospital of Nantong University from January 2013 to December 2023 were retrospectively analyzed. Among these, 27 patients underwent hepatectomy (operation group) and 29 patients received conservative treatment (nonoperation group). All patients signed informed consents in line with the provisions of medical ethics. The general data, clinicopathological features and prognoses for the patients in the two groups were analyzed and the risk factors related to the prognoses of the patients in the operation group were identified. RESULTS: The median disease-free survival (DFS) and overall survival (OS) of HIV-HCC patients in the surgical group were 13 months and 17 months, respectively, and the median OS of patients in the nonsurgical group was 12 months. The OS of the surgical group was significantly longer than that of the control group (17 months vs 12 months, respectively; P < 0.05). The risk factors associated with DFS and OS in the surgical group were initial HIV diagnosis, postoperative microvascular invasion (MVI), a CD4+ T-cell count < 200/µL, Barcelona stage C-D, and men who have sex with men (MSM; P < 0.05). CONCLUSION: Hepatectomy can effectively prolong the survival of patients with HIV-HCC but MVI identified during postoperative pathological examination, late tumor detection, late BCLC stage, CD4+ T < 200/µL and MSM are risk factors affecting the survival and prognosis of patients undergoing hepatectomy. In addition, there were significant differences between the surgical group and the nonsurgical group in terms of the initial diagnosis of HIV, Child-Pugh score, alpha-fetoprotein measurement value, and HART-efficient antiretroviral therapy after the diagnosis of HIV (P < 0.05). Therefore, these factors may also affect the survival and prognosis of patients.

[Sensory neural innervation of adipose tissue in metabolic disorders].

The regulation of adipose tissue homeostasis is essential for maintaining energy and metabolism balance in the body. The peripheral nervous system plays a crucial role in this process. Previous related research primarily focused on the sympathetic nervous system and its release of norepinephrine, while recent attention has shifted to the field of adipose sensory nerves. Studies demonstrate that external stimuli can activate adipose sensory nerves through pathways involving transient receptor potential vanilloid-1 (TRPV1), adipokines, and fatty acids, thereby transmitting signals to the brain. Emerging techniques, such as adipose nerve imaging and denervation of tissues, have revealed the critical role of sensory nerves in the glucose and lipid metabolism, thermogenic function, and vascular regulation of adipose tissue. This article comprehensively reviews the latest research on the regulation and function of sensory nerves in adipose tissue, with a focus on the impact of metabolic diseases on adipose sensory nerves. This review discusses current issues and prospects on the mechanisms behind neural regulation in adipose tissue, hoping to contribute to a comprehensive understanding and providing directions for future research.

Cotinine exposure enhances the association of blood manganese and non-alcoholic fatty liver disease in American children: a cross-sectional study.

This cross-sectional survey aims to determine whether cotinine exposure would enhance the relationship between blood manganese (Mn) and non-alcoholic fatty liver disease (NAFLD) in children using the NHANES database. Restricted cubic spline (RCS) and logistic regression analyses were adopted to determine the potential relationship. Besides, we tested the robustness of the results by performing trend tests and subgroup analyses. The study finally enrolled 866 children aged 18 years and below. Blood Mn was linearly linked to NAFLD and the risk of NAFLD was increased with the blood Mn elevation (P < 0.05). There was a notable relationship between blood Mn and NAFLD in crude model 1, which was still significant upon adjustment of all the identified covariates (all P < 0.05). Under Mn exposure, the cotinine-exposed group had a higher risk of NAFLD than the cotinine-unexposed group. In conclusion, blood Mn level is an independent risk factor for pediatric NAFLD, and cotinine exposure can enhance this relationship to some degree. Therefore, reducing cotinine exposure may alleviate detrimental consequences related to exposure to heavy metals in children.

Efficient and easy-to-use capturing three-dimensional metagenome interactions with GutHi-C.

Hi-C can obtain three-dimensional chromatin structure information and is widely used for genome assembly. We constructed the GutHi-C technology. As shown in the graphical abstract, it is a highly efficient and quick-to-operate method and can be widely used for human, livestock, and poultry gut microorganisms. It provides a reference for the Hi-C methodology of the microbial metagenome. DPBS, Dulbecco's phosphate-buffered saline; Hi-C, high-through chromatin conformation capture; LB, Luria-Bertani; NGS, next-generation sequencing; PCR, polymerase chain reaction; QC, quality control.

DFT Investigation on Palladium-Catalyzed [2 + 2 + 1] Spiroannulation between Aryl Halides and Alkynes: Mechanism, Base Additive Role, and Solvent and Ligand Effects.

Transition metal-catalyzed spiroannulations are practical strategies for constructing spirocyclic skeletons of pharmaceutical and biological significance, yet the microscopic mechanism still lacks in-depth explorations. Here, the palladium-catalyzed [2 + 2 + 1] spiroannulation between aryl halides and alkynes was studied by employing the density functional theory (DFT) method. Based on comprehensive explorations on a couple of possible reaction pathways, it is found that the reaction probably experiences C-I oxidative addition, alkyne migration insertion, Cs2CO3-assisted aryl C-H activation, C-Br bond oxidative addition, C-C coupling, arene dearomatization and reductive elimination in sequence and leads to the formation of the spiro[4,5]decane pentacyclic product (P) ultimately. Among these, the C-Br bond oxidative addition step acts as the rate-determining step (RDS) of the whole reaction, featuring a practical free energy barrier of 32.4 kcal·mol-1 at 130 °C. Computationally predicted kinetics such as half-life transferred from the RDS step's barrier on the optimal reaction pathway (1.2 × 101 h) coincides well with corresponding experimental results (91% yield of the spiro[4,5]decane pentacyclic product P after reacting 10 h at 130 °C). In addition, theoretical predictions regarding the solvent/ligand effects and base additive role in the reaction, rationalized by distortion-interaction/natural population/noncovalent interaction analyses, are also in good agreement with experimental data and trend. This good agreement between experiment and theory makes sense for new designations and further experimental improvements of such Pd-catalyzed transformations.

Analysis of the correlation between Hashimoto's thyroiditis and food intolerance.

Objective: This study aims to explore the correlation between patients with Hashimoto's thyroiditis and food intolerance. Methods: A total of 172 subjects who visited Guangdong Provincial Hospital of Traditional Chinese Medicine between January 2020 and March 2023 were selected and tested for 90 food-specific IgG antibodies. The study group composed 85 individuals diagnosed with Hashimoto's thyroiditis, while the control group consisted of 87 healthy individuals. Data were analyzed to determine the correlation between Hashimoto's thyroiditis and food intolerance. Results: Among the 85 patients with Hashimoto's thyroiditis, 97.65% exhibited food intolerance, with an average of 15.76 ± 10.61 types of food intolerances. The most common intolerances were to eggs (75.29%), bok choy (71.76%), and milk (65.88%), each exceeding a 60% intolerance rate. In the control group of 87 healthy individuals, the intolerance rate was 95.40%, with an average of 9.57 ± 8.90 types of food intolerances. The most prevalent intolerances in the control group were to bok choy (54.02%) and eggs (52.87%), each exceeding a 50% intolerance rate. Conclusion: The findings suggest that patients with Hashimoto's thyroiditis are more likely to develop food intolerance compared to the healthy population, which may indicate a correlation between Hashimoto's thyroiditis and food intolerance. Different dietary patterns may affect the activity of the thyroid axis and may even be the cause of autoimmune thyroid disease. The technique of detecting food intolerance IgG antibodies has the potential to be an important reference for dietary interventions in patients with Hashimoto's thyroiditis.

Histidine phosphatase-ferroptosis crosstalk modulation for efficient hepatocellular carcinoma treatment.

Altering the mechanisms of tumor cell death and overcoming the limitations of traditional chemotherapy is pivotal to contemporary tumor treatment. Inducing ferroptosis, while circumventing safety concerns associated with ferrous vectors, through nonferrous ferroptosis is a promising but underexplored frontier in cancer therapy. Histidine phosphatase (LHPP) has emerged as a novel therapeutic target in treating hepatocellular carcinoma (HCC), but the precise mechanism of LHPP against HCC remains unclear. Herein, we explore the effects of upregulating LHPP expression on ferroptosis and tumor immunogenicity induction by simply delivering a miRNA-363-5p inhibitor (miR-363-5pi) via a previously optimized gemcitabine-oleic acid (GOA) prodrug. Efficient miRNA encapsulation was achieved through hydrogen bonding at an optimized GOA/miRNA molar feed ratio of 250:1, affording spherical nanoparticles with a uniform hydrodynamic size of 147.1 nm and a negative potential of -21.5 mV. The mechanism of this LHPP-ferroptosis crosstalk is disclosed to be an inhibited phosphorylation of the PI3K/Akt pathway, leading to a remarkable tumor inhibition rate of 88.2% in nude mice bearing Bel-7402 tumor xenografts via a combination of LHPP-triggered nonferrous ferroptosis and GOA-induced chemotherapy. The biocompatibility of GOA/miR-363-5pi is strongly supported by their non-hematologic toxicity and insignificant organ damage. In addition, the tumor immunogenic activation potential of GOA/miR-363-5pi was finally explored. Overall, this study is the first work that elucidates the precise mechanism of LHPP for treating HCC via ferroptosis induction and achieves the transformation of chemotherapy and gene therapy into ferroptosis activation with tumor cell immunogenicity, which lays a new therapeutic foundation for the clinical treatment of HCC.

LncRNA lncLLM Facilitates Lipid Deposition by Promoting the Ubiquitination of MYH9 in Chicken LMH Cells.

The liver plays an important role in regulating lipid metabolism in animals. This study investigated the function and mechanism of lncLLM in liver lipid metabolism in hens at the peak of egg production. The effect of lncLLM on intracellular lipid content in LMH cells was evaluated by qPCR, Oil Red O staining, and detection of triglyceride (TG) and cholesterol (TC) content. The interaction between lncLLM and MYH9 was confirmed by RNA purification chromatin fractionation (CHIRP) and RNA immunoprecipitation (RIP) analysis. The results showed that lncLLM increased the intracellular content of TG and TC and promoted the expression of genes related to lipid synthesis. It was further found that lncLLM had a negative regulatory effect on the expression level of MYH9 protein in LMH cells. The intracellular TG and TC content of MYH9 knockdown cells increased, and the expression of genes related to lipid decomposition was significantly reduced. In addition, this study confirmed that the role of lncLLM is at least partly through mediating the ubiquitination of MYH9 protein to accelerate the degradation of MYH9 protein. This discovery provides a new molecular target for improving egg-laying performance in hens and treating fatty liver disease in humans.

Panorama of artery endothelial cell dysfunction in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a fatal lung disease characterized by progressive pulmonary vascular remodeling. The initial cause of pulmonary vascular remodeling is the dysfunction of pulmonary arterial endothelial cells (PAECs), manifested by changes in the categorization of cell subtypes, endothelial programmed cell death, such as apoptosis, necroptosis, pyroptosis, ferroptosis, et al., overproliferation, senescence, metabolic reprogramming, endothelial-to-mesenchymal transition, mechanosensitivity, and regulation ability of peripheral cells. Therefore, it is essential to explore the mechanism of endothelial dysfunction in the context of PAH. This review aims to provide a comprehensive understanding of the molecular mechanisms underlying endothelial dysfunction in PAH. We highlight the developmental process of PAECs and changes in PAH and summarise the latest classification of endothelial dysfunction. Our review could offer valuable insights into potential novel EC-specific targets for preventing and treating PAH.

Immortalized mesenchymal stromal cells overexpressing alpha-1 antitrypsin protect acinar cells from apoptotic and ferroptotic cell death.

Chronic pancreatitis (CP) is a progressive inflammatory disorder that impairs endocrine and exocrine function. Our previous work showed that mesenchymal stem/stromal cells (MSCs) and MSCs overexpressing alpha-1 antitrypsin (AAT-MSCs) could be therapeutic tools for CP. However, primary MSCs are predisposed to undergo senescence during culture expansion, which limits their therapeutic applications. We generated and characterized immortalized human MSCs (iMSCs) and AAT-MSCs (iAAT-MSCs) and tested their protective effect on 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced acinar cell death in an in vitro cell culture system. Primary MSCs were immortalized by transduction with simian virus 40 large T antigen (SV40LT), and the resulting iMSC and iAAT-MSC lines were analysed for proliferation, senescence, phenotype and multi-differentiation potential. Subsequently, apoptosis and ferroptosis pathways were investigated by assessing changes before and after TNBS treatment. Coculture of iMSCs and iAAT-MSCs with acinar cell lines inhibited early cell death induced by TNBS, reduced ER stress and reversed TNBS-induced protein reduction at tight junctions. Additionally, iMSCs and iAAT-MSCs exerted such protection by regulating mitochondrial respiration, ATP content and ROS production in TNBS-induced acinar cells. Furthermore, iMSCs and iAAT-MSCs ameliorated TNBS-induced ferroptosis by modulating iron generation and ROS production and regulating the ferritin heavy chain 1 (FTH1)/protein disulfide isomerase (PDI)/glutathione peroxide 4 (GPX4) signalling pathways in acinar cells. These findings identify ferroptosis as an unrecognized mechanism that leads to TNBS-induced cell death and offer mechanistic insights relevant to using stem cell therapy to treat acinar cell death associated with CP.

Comprehensive Analysis of Prognostic Alternative Splicing Signatures in Tumor Immune Infiltration in Bladder Cancer.

BACKGROUND: Bladder cancer exhibits substantial heterogeneity encompassing genetic expressions and histological features. This heterogeneity is predominantly attributed to alternative splicing (AS) and AS-regulated splicing factors (SFs), which, in turn, influence bladder cancer development, progression, and response to treatment. OBJECTIVE: This study aimed to explore the immune landscape of aberrant AS in bladder cancer and establish the prognostic signatures for survival prediction. METHODS: Bladder cancer-related RNA-Seq, transcriptome, and corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). Gene set enrichment analysis (GSEA) was used to identify significantly enriched pathways of cancer-related AS events. The underlying interactions among differentially expressed genes (DEGs) and cancer-related AS events were assessed by a protein-protein interaction network. Univariate and multivariate Cox regression analyses were performed to identify crucial prognostic DEGs that co-occurred with cancer-related AS events (DEGAS) for overall survival. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to assess the efficiency of the prognostic signatures. The CIBERSORT algorithm was used to explore the abundance of immune infiltrating cells. RESULTS: A total of 3755 cancer-related AS events and 3110 DEGs in bladder cancer were identified. Among them, 379 DEGs co-occurred with cancer-related AS events (DEGAS), of which 102 DEGAS were associated with 14 dysregulated SFs. GSEA and KEGG analysis showed that cancer-related AS events were predominantly enriched in pathways related to immunity, tumorigenesis, and treatment difficulties of bladder cancer. Multivariate Cox regression analysis identified 8 DEGAS (CABP1, KCNN2, TNFRSF13B, PCDH7, SNRPA1, APOLD1, CX3CL1, and DENND5A) significantly associated with OS, and they were further integrated into the prediction model with good AUCs at 3-year, 5-year and 7-year ROC curves (all>0.7). Immune infiltration analysis revealed the significant enrichment of three immune cell types (B cells naïve, dendritic cells resting, and dendritic cell activated) in high-risk bladder cancer patients. CONCLUSION: This study not only unveiled comprehensive prognostic signatures of AS events in bladder cancer but also established a robust prognostic model based on survival-related DEGAS. These aberrant AS events, dysregulated SFs, and the identified 8 DEGAS may have significant clinical potential as therapeutic targets for bladder cancer.

Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients.

Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.

A Novel ANG-BSA/BCNU/ICG MNPs Integrated for Targeting Therapy of Glioblastoma.

PURPOSE: Develop an albumin nanoparticle-based nanoprobe for targeted glioblastoma (GBM) diagnosis and treatment, utilizing Angopep-2 for low-density lipoprotein receptor-related protein (LRP) targeting. METHODS: Combined albumin-coated superparamagnetic iron oxide (SPIO), Carmustine (BCNU), and indocyanine green (ICG). Assessed morphology, size, Zeta potential, fluorescence, and drug encapsulation. Conducted in vitro fluorescence/MRI imaging and cell viability assays, and in vivo nanoprobe accumulation evaluation in brain tumors. RESULTS: ANG-BSA/BCNU/ICG MNPs exhibited superior targeting and cytotoxicity against GBM cells in vitro. In vivo, enhanced brain tumor accumulation during imaging was observed. CONCLUSION: This targeted imaging and drug delivery system holds promise for efficient GBM therapy and intraoperative localization, addressing Blood-brain barrier (BBB) limitations with precise drug delivery and imaging capabilities.