Microbiota-induced plastic T cells enhance immune control of antigen-sharing tumors.

Therapies that harness the immune system to target and eliminate tumor cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumor immune response by inhibiting negative regulators of T cell activation 1-3 , is remarkably successful in a subset of cancer patients, yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB 4-9 . The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with multiple studies demonstrating association of microbiota composition with clinical response 10-16 . However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we utilized a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific Th17 cell effector program 17 , to investigate how colonization with it affects the efficacy of ICB in restraining distal growth of tumors sharing antigen with SFB. We find that anti-PD-1 treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor clonal lineage tracing, fate mapping, and peptide-MHC tetramer staining, we identify tumor-associated SFB-specific Th1-like cells derived from the homeostatic Th17 cells induced by SFB colonization in the small intestine lamina propria. These gut-educated ex-Th17 cells produce high levels of the pro-inflammatory cytokines IFN-γ and TNF-α, and promote expansion and effector functions of CD8 + tumor-infiltrating cytotoxic lymphocytes, thereby controlling tumor growth. A better understanding of how distinct intestinal commensal microbes can promote T cell plasticity-dependent responses against antigen-sharing tumors may allow for the design of novel cancer immunotherapeutic strategies.

Laparoscopic simultaneous anterograde inguinal and pelvic lymphadenectomy for penile cancer: two planses, three holes, and six steps.

Objective: To assess the feasibility, safety, and efficiency of simultaneous anterograde video laparoscopic inguinal and pelvic lymphadenectomy for penile cancer. Materials and methods: We reviewed retrospectively the records of 22 patients (44 lateral) who underwent inguinal lymph nodes dissection for penile cancer. The procedure was standardized as two planes, three holes, and six steps. Two Separate-planes: superior plane of eternal oblique aponeurosis/ / fascia lata; inferior plane of superficial camper fascia. Three holes: two artificial lateral boundary holes, the internal and external boundary holes, and the hole of oval fossa. Six steps: separate the first separate-plane; separate the second layer; separate two artificial lateral boundary holes; free great saphenous vein; separate the third hole and clean up the deep inguinal lymph nodes; pelvic lymphadenectomy. Results: A total of 22 cases were included and 9 patients underwent simultaneous pelvic lymphadenectomy. The average operation time on both sides was 7.52 ± 3.29 h, which was 0.5-1 h/side after skilled. The average amount of bleeding was 93.18 ± 50.84 ml. A total of 8 patients had postoperative complications, accounting for 36.36%, and no complications great than Clavien-Dindo class III occurred. Conclusion: This study demonstrated that the video laparoscopic simultaneous anterograde inguinal and pelvic lymphadenectomy is a feasible and safe technique. Indocyanine Green was helpful for lymph node identify.

ALKBH5-mediated m6A modification of circFOXP1 promotes gastric cancer progression by regulating SOX4 expression and sponging miR-338-3p.

Circular RNAs (circRNAs) have recently been suggested as potential functional modulators of cellular physiology processes in gastric cancer (GC). In this study, we demonstrated that circFOXP1 was more highly expressed in GC tissues. High circFOXP1 expression was positively associated with tumor size, lymph node metastasis, TNM stage, and poor prognosis in patients with GC. Cox multivariate analysis revealed that higher circFOXP1 expression was an independent risk factor for disease-free survival (DFS) and overall survival (OS) in GC patients. Functional studies showed that increased circFOXP1 expression promoted cell proliferation, cell invasion, and cell cycle progression in GC in vitro. In vivo, the knockdown of circFOXP1 inhibited tumor growth. Mechanistically, we observed ALKBH5-mediated m6A modification of circFOXP1 and circFOXP1 promoted GC progression by regulating SOX4 expression and sponging miR-338-3p in GC cells. Thus, our findings highlight that circFOXP1 could serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for GC.

A Bis-Cyclopentadienyl Ligand-Supported Di-Iron Trihydride Motif as a Synthon for Access to Heterobimetallic Trinuclear Complexes.

Herein, we report the synthesis of a flexible bis-cyclopentadienyl ligand L (the doubly deprotonated form of H2L (1,3-bis(2,4-di-tert-butylcyclopentadienyldimethylsilyl)benzene)), demonstrating its ability to stabilize a series of di-iron hydrido complexes. Notably, this ligand facilitates the isolation of an unprecedented anionic cyclopentadienyl ligand-supported di-iron trihydride complex, LFe2(µ-H)3Li(THF) (2), functioning as a synthon for the [Fe2(µ-H)3]- core and providing access to heterobimetallic complexes 4-6 with coinage metals.

Turtle peptide and its derivative peptide ameliorated DSS-induced ulcerative colitis by inhibiting inflammation and modulating the composition of the gut microbiota.

Ulcerative colitis (UC) is a recurrent intestinal disease with an increasing incidence worldwide that seriously affects the life of patients. Turtle peptide (TP) is a bioactive peptide extracted from turtles that has anti-inflammatory, antioxidant and anti-aging properties. However, studies investigating the effect of TP on the progression of UC are lacking. The aim of this study was to investigate effects and underlying mechanisms of TP and its derivative peptide GPAGPIGPV (GP-9) in alleviating UC in mice. The results showed that 500 mg/kg TP treatment significantly ameliorated colitis symptoms and oxidative stress in UC mice. TP alleviated intestinal barrier damage in UC mice by promoting mucosal repair and increasing the expression of tight junction proteins (ZO1, occludin and claudin-1). TP also modulated the composition of the gut microbiota by increasing the abundance of the beneficial bacteria Anaerotignum, Prevotellaceae_UCG-001, Alistipes, and Lachno-spiraceae_NK4A136_group and decreasing the abundance of the harmful bacteria Prevotella_9 and Parasutterella. Furthermore, we characterized the peptide composition of TP and found that GP-9 ameliorated the symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, TP and its derivative peptides ameliorated DSS-induced ulcerative colitis by inhibiting the expression of inflammatory factors and modulating the composition of the intestinal microbiota; this study provides a theoretical basis for the application of TP and its derivative peptides for their anti-inflammatory activity.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

Tongxinluo Activates PI3K/AKT Signaling Pathway to Inhibit Endothelial Mesenchymal Transition and Attenuate Myocardial Fibrosis after Ischemia-Reperfusion in Mice.

OBJECTIVE: To investigate the potential role of Tongxinluo (TXL) in attenuating myocardial fibrosis after myocardial ischemia-reperfusion injury (MIRI) in mice. METHODS: A MIRI mouse model was established by left anterior descending coronary artery ligation for 45 min. According to a random number table, 66 mice were randomly divided into 6 groups (n=11 per group): the sham group, the model group, the LY-294002 group, the TXL group, the TXL+LY-294002 group and the benazepril (BNPL) group. The day after modeling, TXL and BNPL were administered by gavage. Intraperitoneal injection of LY-294002 was performed twice a week for 4 consecutive weeks. Echocardiography was used to measure cardiac function in mice. Masson staining was used to evaluate the degree of myocardial fibrosis in mice. Qualitative and quantitative analysis of endothelial mesenchymal transition (EndMT) after MIRI was performed by immunohistochemistry, immunofluorescence staining and flow cytometry, respectively. The protein expressions of platelet endothelial cell adhesion molecule-1 (CD31), α-smoth muscle actin (α-SMA), phosphatidylinositol-3-kinase (PI3K) and phospho protein kinase B (p-AKT) were assessed using Western blot. RESULTS: TXL improved cardiac function in MIRI mice, reduced the degree of myocardial fibrosis, increased the expression of CD31 and inhibited the expression of α-SMA, thus inhibited the occurrence of EndMT (P<0.05 or P<0.01). TXL significantly increased the protein expressions of PI3K and p-AKT (P<0.05 or P<0.01). There was no significant difference between TXL and BNPL group (P>0.05). In addition, the use of the PI3K/AKT pathway-specific inhibitor LY-294002 to block this pathway and combination with TXL intervention, eliminated the protective effect of TXL, further supporting the protective effect of TXL. CONCLUSION: TXL activated the PI3K/AKT signaling pathway to inhibit EndMT and attenuated myocardial fibrosis after MIRI in mice.

Chronic Low Back Pain and Sleep Disturbance in Adults in the US: The NHANES 2009-2010 Study.

BACKGROUND: Chronic low back pain (CLBP) is a significant health challenge with a high prevalence rate. Sleep disorders, which are prevalent among adults, have been linked with CLBP. However, the intricate relationship between sleep and pain adds complexity to our understanding of CLBP. OBJECTIVES: To investigate the association between CLBP and sleep disorders, with a focus on the potential role of sleep disorders as a risk factor for CLBP. STUDY DESIGN: Cross-sectional study based on publicly available data from the National Health and Nutrition Examination Survey (NHANES) for one cycle (2009-2010). SETTING: The NHANES employs a complex, multistage probability sampling design to select a nationally representative sample. METHODS: In this study, we included patients aged 20 to 69 years from the NHANES 2009-2010 cycle. After eliminating cases with missing data, a total of 863 patients remained. Baseline characteristics were analyzed by stratifying patients based on their CLBP status to assess initial inter-group disparities. Due to age imbalances between groups, we employed a 1:1 propensity score matching (PSM) method, reducing the sample to 508 patients. The association between CLBP and trouble sleeping was investigated following this calibration using a multivariate logistic regression analysis. RESULTS: Upon categorizing the baseline characteristics of 863 patients based on CLBP, we identified that those within the CLBP group tended to be older and had a greater prevalence of health conditions, including cancer, hypertension, and cardiovascular disease (CVD). Notably, the prevalence of sleep disorders was higher in the CLBP group than in the non-CLBP group (P < 0.001). After implementing an age-based PSM for the 2 groups, 508 patients were selected from the initial 863 patients. After adjusting for various confounders using multivariate logistic regression, our analysis revealed a strong association between sleep disorders and an increased risk of CLBP. LIMITATIONS: This is a cross-sectional study, and therefore causality cannot be established. CONCLUSIONS: This study underscores the significant association between sleep disorders and an elevated risk of CLBP, highlighting the need for comprehensive management strategies that consider the role of sleep disorders in CLBP.

A high resolution and wide range valve for micronewton cold gas thrusters.

Numerous scientific satellites require micronewton thrusters for compensating environmental disturbances. The mass flow control proportional valve plays a crucial role in precisely regulating the thrust. To meet the high resolution and wide range requirements of the thrusters, this paper introduces a novel proportional valve with two sets of independently controllable piezoelectric stack. One set of the piezo-stack is used to compensate the stroke loss of the valve core, mainly caused by the deformation of the valve seat. The valve sealing mechanism is carefully analyzed to reduce the stroke loss. Another set of the stack works as the primary actuator, enabling the high mass flow control resolution. Two sets of independently controlled piezoelectric stacks not only expand the range and improve the range ratio but also provide redundancy and enhance reliability. This means that the actuator can still operate at lower ranges even if one piezo-stack is damaged. The piezo-actuators are assembled using U-shaped connectors, creating a compact and space-efficient overall design. Experimental tests have been conducted to verify the performance of the valve, which demonstrated a mass flow range of 0-675 µg/s with a resolution better than 0.1 µg/s and a flow noise below 0.1 µg/s/Hz1/2 at 0.1 mHz-1 Hz.

Perforated gastric ulcer causing mediastinal emphysema: A case report.

BACKGROUND: Mediastinal emphysema is a condition in which air enters the mediastinum between the connective tissue spaces within the pleura for a variety of reasons. It can be spontaneous or secondary to chest trauma, esophageal perforation, medically induced factors, etc. Its common symptoms are chest pain, tightness in the chest, and respiratory distress. Most mediastinal emphysema patients have mild symptoms, but severe mediastinal emphysema can cause respiratory and circulatory failure, resulting in serious consequences. CASE SUMMARY: A 75-year-old man, living alone, presented with sudden onset of severe epigastric pain with chest tightness after drinking alcohol. Due to the remoteness of his residence and lack of neighbors, the patient was found by his nephew and brought to the hospital the next morning after the disease onset. Computed tomography (CT) showed free gas in the abdominal cavity, mediastinal emphysema, and subcutaneous pneumothorax. Upper gastrointestinal angiography showed that the esophageal mucosa was intact and the gastric antrum was perforated. Therefore, we chose to perform open gastric perforation repair on the patient under thoracic epidural anesthesia combined with intravenous anesthesia. An operative incision of the muscle layer of the patient's abdominal wall was made, and a large amount of subperitoneal gas was revealed. And a continued incision of the peritoneum revealed the presence of a perforation of approximately 0.5 cm in the gastric antrum, which we repaired after pathological examination. Postoperatively, the patient received high-flow oxygen and cough exercises. Chest CT was performed on the first and sixth postoperative days, and the mediastinal and subcutaneous gas was gradually reduced. CONCLUSION: After gastric perforation, a large amount of free gas in the abdominal cavity can reach the mediastinum through the loose connective tissue at the esophageal hiatus of the diaphragm, and upper gastrointestinal angiography can clarify the site of perforation. In patients with mediastinal emphysema, open surgery avoids the elevation of the diaphragm caused by pneumoperitoneum compared to laparoscopic surgery and avoids increasing the mediastinal pressure. In addition, thoracic epidural anesthesia combined with intravenous anesthesia also avoids pressure on the mediastinum from mechanical ventilation.

Early generation of a precursor CD8 T cell that can adapt to acute or chronic viral infection.

Virus specific PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells are essential for maintaining T cell responses during chronic infection and are also critical for PD-1 directed immunotherapy. In this study we have used the mouse model of chronic LCMV infection to examine when these virus specific stem-like CD8+ T cells are generated during the course of chronic infection and what is the role of antigen in maintaining the stem-like program. We found that these stem-like CD8+ T cells are generated early (day 5) during chronic infection and that antigen is essential for maintaining their stem-like program. This early generation of stem-like CD8+ T cells suggested that the fate commitment to this cell population was agnostic to the eventual outcome of infection and the immune system prepares a priori for a potential chronic infection. Indeed, we found that an identical virus specific stem-cell like CD8+ T cell population was also generated during acute LCMV infection but these cells were lost once the virus was cleared. To determine the fate of these early PD-1+TCF-1+TOX+ stem-like CD8+ T cells that are generated during both acute and chronic LCMV infection we set up two reciprocal adoptive transfer experiments. In the first experiment we transferred day 5 stem-like CD8+ T cells from chronically infected into acutely infected mice and examined their differentiation after viral clearance. We found that these early stem-like CD8+ T cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. In the second experiment, we transferred day 5 stem-like cells from acutely infected mice into chronically infected mice and found that these CD8+ T cells could function like resource cells after transfer into a chronic environment by generating effector CD8+ T cells in both lymphoid and non-lymphoid tissues while also maintaining the number of stem-like CD8+ T cells. These findings provide insight into the generation and maintenance of virus specific stem-like CD8+ T cells that play a critical role in chronic viral infection. In particular, our study highlights the early generation of stem-like CD8+ T cells and their ability to adapt to either an acute or chronic infection. These findings are of broad significance since these novel stem-like CD8+ T cells play an important role in not only viral infections but also in cancer and autoimmunity.

[Platelet Count Doubling after One Course of Demethylated Drug Therapeutic Predicts the Treatment Response and Efficacy of Patients with Myelodysplastic Syndrome].

OBJECTIVE: To investigate the predictive value of platelet doubling (platelet count doubling) after one course of hypomethylating agents (HMA) on the treatment response and efficacy of myelodysplastic syndrome (MDS). METHODS: Clinical and pathological data of 75 patients who received HMA in our hospital from January 2017 to March 2022 were collected and analyzed. All patients were divided into two groups according to whether their platelet count doubled after one course of treatment, including platelet doubling group and non-doubling group, and statistical analysis was performed to compare the treatment response and efficacy between the two groups. In addition, platelet count changes were compared between azacitidine and decitabine therapy. RESULTS: Compared with the non-doubling platelet count group, the ORR of the doubling platelet group was significantly better after 3 courses of treatment (P =0.002), and there was a statistically significant difference in the number of HI between the two groups (P =0.005). In addition, the median survival time (MST) was 26 months in the platelet doubling group and 11 months in the non-doubling group (P =0.001). The overall survival (OS) and 1- and 2-year survival rates of the platelet doubling group were also significantly better than those of the non-doubing group. Multivariate COX analysis showed that platelet count doubling was an independent predictor of OS in MDS patients after 1 course of treatment (P =0.013). There was no significant difference in the response rate of platelet count doubling between MDS patients treated with azacitidine and decitabine (33.3% vs 23.8%, P >0.05). CONCLUSION: Platelet count doubling after one course of treatment can be used as a predictor of response rate and survival of demethylated drug therapy in MDS patients. In addition, there was no significant difference in the response rate of platelets in MDS patients treated with azacitidine or dicetabine.

A mucus production programme promotes classical pancreatic ductal adenocarcinoma.

OBJECTIVE: The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators. DESIGN: We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models. RESULTS: Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA - the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2/IRE1ß that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation. CONCLUSIONS: Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.

Intrathecal injections of angiotensin IV and oxytocin conjugates induce antihyperalgesia and antiallodynia in both sexes of rats.

Our previous studies have established that intrathecal oxytocin (OT) and angiotensin IV (Ang IV) injections induce antihyperalgesia and antiallodynia in rodents. Ang IV, a renin-angiotensin system hexapeptide, acts as an endogenous inhibitor that inhibits the oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP). The pain inhibitory effects by Ang IV were found to be through its inhibition on IRAP to potentiate the effect of OT. However, these effects were found to be with a significant sex difference, which could be partially due to the higher expression of IRAP at the spinal cords of female. Therefore, we synthesized Ang IV and OT conjugates connected with a peptide bond and tested for their effects on hyperalgesia and allodynia. Carrageenan-induced hyperalgesia and partial sciatic nerve ligation (PSNL) were performed using rat models. Conjugates Ang IV-OT (Ang IV at the N-terminal) and OT-Ang IV (OT at the N-terminal) were synthesized and intrathecally injected into male and female rats. Our results showed that Ang IV-OT exhibited prominent antihyperalgesia in male rats, particularly during hyperalgesia recovery, whereas OT-Ang IV was more effective during development stage. Ang IV-OT showed clear antihyperalgesia in female rats, but OT-Ang IV had no significant effect. Notably, both conjugates alleviated neuropathic allodynia in male rats; however, OT-Ang IV had no effect in female rats, whereas Ang IV-OT induced significant antiallodynia. In conclusion, Ang IV-OT has greater therapeutic potential for treating hyperalgesia and allodynia than OT-Ang IV. Its effects were not affected by sex, unlike those of OT and OT-Ang IV, extending its possible clinical applications.

2024 TSOC/TSPS Joint Consensus: Strategies for Advanced Vascular Wound Management in Arterial and Venous Diseases.

The Taiwan Society of Cardiology (TSOC) and Taiwan Society of Plastic Surgery (TSPS) have collaborated to develop a joint consensus for the management of patients with advanced vascular wounds. The taskforce comprises experts including preventive cardiologists, interventionists, and cardiovascular and plastic surgeons. The consensus focuses on addressing the challenges in diagnosing, treating, and managing complex wounds; incorporates the perfusion evaluation and the advanced vascular wound care team; and highlights the importance of cross-disciplinary teamwork. The aim of this joint consensus is to manage patients with advanced vascular wounds and encourage the adoption of these guidelines by healthcare professionals to improve patient care and outcomes. The guidelines encompass a range of topics, including the definition of advanced vascular wounds, increased awareness, team structure, epidemiology, clinical presentation, medical treatment, endovascular intervention, vascular surgery, infection control, advanced wound management, and evaluation of treatment results. It also outlines a detailed protocol for assessing patients with lower leg wounds, provides guidance on consultation and referral processes, and offers recommendations for various wound care devices, dressings, and products. The 2024 TSOC/TSPS consensus for the management of patients with advanced vascular wounds serves as a catalyst for international collaboration, promoting knowledge exchange and facilitating advancements in the field of advanced vascular wound management. By providing a comprehensive and evidence-based approach, this consensus aims to contribute to improved patient care and outcomes globally.

Melitoxin Inhibits Proliferation, Metastasis, and Invasion of Glioma U251 Cells by Down-regulating F2RL1.

As the principal active component of bee venom, melittin has an anti-cancer effect in different cancers. This study was aimed to investigate the effect of melittin in glioma and explore whether F2RL1 is closely involved in glioblastoma cells proliferation. TCGA and GES databases were used to evaluate the role of F2RL1 in gliomas. The U251 cells were divided into a control lentivirus + PBS group (NC-PBS), F2RL1 intervention lentivirus + PBS group (KD-PBS), control lentivirus + melittin group (NC-melittin), and F2RL1 intervention lentivirus + melittin group (KD-melittin). Cell proliferation was detected by MTT and EDU staining assays. The apoptosis rate was assessed by flow cytometry. Expressions of genes related to apoptosis, cycle arrest, migration, and invasion were detected by qRT-PCR. Cellular LDH concentrations were detected by ELISA. The subcutaneous tumor volume of nude mice was analyzed by xenograft method. F2RL1 was significantly overexpressed in glioma tissues and were reduced in the melittin-treated group compared to the blank group. F2RL1 knockdown and melittin alone or in combination increased the proportion of cells in the G1-phase, and the combination was more pronounced. The KD-melittin group showed a decrease in the number of viable cells at 24, 48, 72, and 96 h compared to the NC-PBS group. The number of cell migration and invasion was decreased in the KD-melittin group compared to the other groups. Moreover, the genes related to cell cycle arrest and apoptosis were significantly changed in the KD-melittin group. At weeks 4, 5, and 6, the tumor volume in the KD-melittin group was smaller than that in the KD-PBS group and NC-melittin group. Interference with the target gene F2RL1 inhibited the proliferation of glioma U251 cells, and melittin treatment inhibited the proliferation of glioma U251 cells. Melittin inhibited the proliferation of glioma U251 cells by suppressing the expression of target gene F2RL1.

An Autologous Macrophage-Based Phenotypic Transformation-Collagen Degradation System Treating Advanced Liver Fibrosis.

In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines. However, there is still no effective strategy to regulate macrophages because of the difficulty and complexity of macrophage inflammatory phenotypic modulation and the insufficient therapeutic efficacy caused by the extracellular matrix (ECM) barrier. Here, AC73 and siUSP1 dual drug-loaded lipid nanoparticle is designed to carry milk fat globule epidermal growth factor 8 (MFG-E8) (named MUA/Y) to effectively inhibit macrophage proinflammatory signals and degrade the ECM barrier. MFG-E8 is released in response to the high reactive oxygen species (ROS) environment in LF, transforming macrophages from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype and inducing macrophages to phagocytose collagen. Collagen ablation increases AC73 and siUSP1 accumulation in hepatic stellate cells (HSCs) and inhibits HSCs overactivation. Interestingly, complete resolution of liver inflammation, significant collagen degradation, and HSCs deactivation are observed in methionine choline deficiency (MCD) and CCl4 models after tail vein injection of MUA/Y. Overall, this work reveals a macrophage-focused regulatory treatment strategy to eliminate LF progression at the source, providing a new perspective for the clinical treatment of advanced LF.

Antigen perception in T cells by long-term Erk and NFAT signaling dynamics.

Immune system threat detection hinges on T cells' ability to perceive varying peptide-major histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs but diverge only over longer (9+ h) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception and establish a framework for understanding T cell responses under diverse contexts.

Prediction model for hepatocellular carcinoma recurrence after hepatectomy: Machine learning-based development and interpretation study.

Background: Identifying patients with hepatocellular carcinoma (HCC) at high risk of recurrence after hepatectomy can help to implement timely interventional treatment. This study aimed to develop a machine learning (ML) model to predict the recurrence risk of HCC patients after hepatectomy. Methods: We retrospectively collected 315 HCC patients who underwent radical hepatectomy at the Third Affiliated Hospital of Sun Yat-sen University from April 2013 to October 2017, and randomly divided them into the training and validation sets at a ratio of 7:3. According to the postoperative recurrence of HCC patients, the patients were divided into recurrence group and non-recurrence group, and univariate and multivariate logistic regression were performed for the two groups. We applied six machine learning algorithms to construct the prediction models and performed internal validation by 10-fold cross-validation. Shapley additive explanations (SHAP) method was applied to interpret the machine learning model. We also built a web calculator based on the best machine learning model to personalize the assessment of the recurrence risk of HCC patients after hepatectomy. Results: A total of 13 variables were included in the machine learning models. The multilayer perceptron (MLP) machine learning model was proved to achieve optimal predictive value in test set (AUC = 0.680). The SHAP method displayed that γ-glutamyl transpeptidase (GGT), fibrinogen, neutrophil, aspartate aminotransferase (AST) and total bilirubin (TB) were the top 5 important factors for recurrence risk of HCC patients after hepatectomy. In addition, we further demonstrated the reliability of the model by analyzing two patients. Finally, we successfully constructed an online web prediction calculator based on the MLP machine learning model. Conclusion: MLP was an optimal machine learning model for predicting the recurrence risk of HCC patients after hepatectomy. This predictive model can help identify HCC patients at high recurrence risk after hepatectomy to provide early and personalized treatment.