Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Gastrointestinal (GI) cancers are a leading cause of cancer morbidity and mortality worldwide. Despite advances in treatment, cancer relapse remains a significant challenge, necessitating novel therapeutic strategies. In this study, we engineered nanobody-based chimeric antigen receptor (CAR) natural killer (NK) cells targeting cadherin 17 (CDH17) for the treatment of GI tumors. In addition, to enhance the efficacy of CAR-NK cells, we also incorporated CV1, a CD47-SIRPα axis inhibitor, to evaluate the anti-tumor effect of this combination. We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner. CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47-signal regulatory protein α (SIRPα) axis inhibitor CV1, likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment. Collectively, our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers. The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy. Further investigations are warranted to speed up the clinical translation of these findings.

The thalamic reticular nucleus (TRN) plays a crucial role in regulating sensory encoding, even at the earliest stages of visual processing, as evidenced by numerous studies. Orientation selectivity, a vital neural response, is essential for detecting objects through edge perception. Here, we demonstrate that somatostatin (SOM)-expressing and parvalbumin (PV)-expressing neurons in the TRN project to the dorsal lateral geniculate nucleus and modulate orientation selectivity and the capacity for visual information processing in the primary visual cortex (V1). These findings show that SOM-positive and PV-positive neurons in the TRN are powerful modulators of visual information encoding in V1, revealing a novel role for this thalamic nucleus in influencing visual processing.
Animals ; Somatostatin/metabolism* ; Parvalbumins/metabolism* ; Neurons/physiology* ; Thalamic Nuclei/physiology* ; Visual Pathways/physiology* ; Mice ; Mice, Inbred C57BL ; Visual Perception/physiology* ; Male ; Mice, Transgenic ; Visual Cortex/physiology* ; Primary Visual Cortex/cytology*

Objective To analyze the clinical efficacy of transcatheter tricuspid valve replacement (TTVR) in cardiac implantable electronic lead-related tricuspid regurgitation (TR). Methods The patients with severe TR who underwent LuX-Valve TTVR in 9 Chinese medical centers from June 2020 to August 2021 were retrospectively enrolled. They were divided into a cardiac implantable electronic device (CIED) group and a non-CIED group based on whether they had pre-existing CIED implantation. Success of the procedure was defined as safe implantation of the LuX-Valve and complete withdrawal of the delivery system. Prognostic improvement was defined as a decrease of TR grade to≤2+ and an improvement of cardiac function by≥2 grades. Surgical success and postoperative prognosis were compared between the two groups. Results A total of 190 patients were collected, including 50 males and 140 females with a mean age of 66.2±7.8 years. There were 29 patients in the CIED group, and 161 patients in the non-CIED group. In the CIED group, 28 patients were implanted with a permanent pacemaker and 1 patient with a cardioverter-defibrillator. Preoperative New York Heart Association (NYHA) cardiac function class, TR degree, left ventricular ejection fraction, tricuspid annular plane systolic excusion, and cardiac risk scores were comparable between the two groups (P>0.05). Postoperative TR was reduced to≤2+ in all patients, and there was no statistical difference in the incidence of perivalvular leakage between the two groups (P=0.270). Postoperative CT of CIED patients showed the valve was in place, and the lead was not extruded, twisted, or deflected. The in-hospital mortality of the two groups were 10.3% and 1.9%, respectively, and the difference was statistically significant (P=0.047). In addition, there was no statistical difference between the two groups in terms of postoperative improvement of cardiac function and mortality in the 1- and 2-year follow-up. Conclusion TTVR is feasible, safe, and effective in patients with CIED implantation, and the pre-existing lead has no significant effect on the clinical efficacy.

In order to understand the prevalence of Akabane disease(AKAD)in Guizhou Province and the molecular characteristics of the isolates,the whole-genome sequence of a strain of Akabane virus(AKAV)from a bovine AKAD-positive sample was determined and analyzed.The genotype and genetic variation of the strain were also explored.Based on the conserved S sequence,a fluores-cence quantitative PCR(qPCR)detection method was established and applied for the investigation of AKAV infection status in four large-scale beef cattle farms of Guizhou.Results showed that the S,M and L fragments of the bovine strain were highly homologous to the Tianjin strain(TJ2016/China/2016)and the Australian strain(JaLAB39/Australia/1959),where they were in the same evolutionary branch and belonged to genotype Ⅱ.Sensitivity assay found that the lowest detection limit was 2.5 X 101 copies/μL.Specificity assay showed the established method detected only AKAV with no amplification on bovine bluetongue virus(BLUV),Pasteurella multocida(PM),bovine infectious rhinotracheitis virus(IBRV)and bovine Mycoplasma bovis.The variation coefficients of inter-and intra batches in the repeatability test were both lower than 2.26％.These findings illus-trated that the established qPCR method had high sensitivity,good specificity and repeatability.A total of 298 serum samples from 4 large-scale beef cattle farms in Qianxi City and Huangping County of Guizhou Province were collected and tested for AKAV by the method.Out of 298 sam-ples,25 positive samples(25/298)were detected as positive with a positive rate of 8.39％.In sum-mary,this work provided the reference data for a deep understanding of the molecular prevalence of AKAV in Guizhou Province and laid foundation for the prevention and control of AKAD.

Itaconate is a pivotal intermediate metabolite in the tricarboxylic acid (TCA) cycle of immune cells. It is produced by decarboxylation of cis-aconitic acid under the catalysis of aconitate decarboxylase 1 (ACOD1), which is encoded by the immune response gene 1 (IRG1). Itaconate has become a focal point of research on immunometabolism. Studies have demonstrated that itaconate plays a crucial role in diseases by regulating inflammation, remodeling cell metabolism, and participating in epigenetic regulation. This paper reviewed the research progress in itaconnate from its chemical structure, regulatory effects on different diseases, and mechanisms, proposes the future research directions, aiming to provide a theoretical basis for the development of itaconate-related drugs.
Humans ; Succinates/metabolism* ; Carboxy-Lyases/genetics* ; Inflammation/metabolism* ; Citric Acid Cycle ; Animals ; Epigenesis, Genetic ; Neoplasms/immunology*

Objective To explore the effect of mucle force on contact force, peak pressure and contact area of foot joint in in vitro biomechanical experiment of foot and ankle, so as to provide references for choosing appropriate loading modes. Methods In neutral position of the ankle joint, fresh calf and foot specimens were simulated with or without mucle force loading. The contact force, peak pressure and contact area of the 1st metatarsophalangeal joint, the 2nd metatarsophalangeal joint, the 1st tarsometatarsal joint, the 2nd tarsometatarsal joint, the medial cuneonavicular joint, the intermediate cuneonavicular joint, the talonavicular joint, the calcicocuboid joint, the subtalar joint ( posterior articular surface) and the tibiotalar joint of normal foot under loading were measured, the results are compared and analyzed. Results Under muscle force loading, the contact force of the 1st metatarsophalangeal joint, the 2nd metatarsophalangeal joint, the 1st tarsometatarsal joint,the 2nd tarsometatarsal joint, the medial cuneonavicular joint, the intermediate cuneonavicular joint, the talonavicular joint and the tibiotalar joint were significantly greater than those without muscle force loading (P<0. 05), and the change percentages were 719. 28% , 311. 37% , 128. 67% , 50. 82% , 54. 89% , 57. 63% ,79. 98% and 50. 34% , respectively. The peak pressures of the 1st metatarsophalangeal joint , the 1st tarsometatarsal joint and the talonavicular joint under muscle force loading were significantly higher than those without muscle force loading ( P < 0. 05), and the change percentages were 176. 14% , 62. 91% and 40. 07% ,respectively. The contact area of the 1st metatarsophalangeal joint, the 1st tarsometatarsal joint, the intermediate cuneonavicular joint and the subtalar joint ( posterior articular surface) under muscle force loading increased significantly (P<0. 05), and the change percentages were 132. 20% , 55. 41% , 30. 97% and 26. 87% , respectively. Conclusions In biomechanical experiment of foot and ankle specimens, muscle force loading has a significant effect on contact force, peak pressure and contact area of each foot joint, especially the forefoot.Therefore, it is necessary to consider the effect of muscle force loading on stress of foot and ankle in the study ofrelated in vitro specimens

Objective:To explore the clinical outcomes of recipients with refractory heart failure requiring an insertion of mechanical circulation support(MCS)device prior to heart transplantation(HT).Methods:From March 2017 to December 2021, retrospective review is performed for clinical data of 7 recipients with refractory heart failure requiring a bridging placement of MCS.There are 2 males and 5 females with an average age of(39.0±16.3)years(7~56 years)and an average weight of(57.6±19.9)kg(7~56 kg).The primary diseases of recipients are dilated cardiomyopathy(4 cases)severe viral myocarditis(2 cases)and ischemic cardiomyopathy(1 case).All of them develope acute decompensation of congestive heart failure.Before implanting MCS, two or more inotropic drugs are offered at maximal doses ages or IABP device, 6 cases required cardio-pulmonary resuscitation treatment and another patient for Heartcon assistance.All the patients bridge to heart transplatation.Results:Adjuvant therapy of MCS was offered for(20.0±11.5)d(7~34 d).Emergency HT is performed.Two post-HT deaths occurr due to multiple organ failure(1 case)and severe infection(1 case).The remainders recover smoothly during a follow-up period of(6~24 months).Conclusions:MCS device is recommended as a bridging too for HT recipients with refractory heart failure.It is imperative to improve clinical outcomes with MCS support before an onset of multiple organ dysfunction.Despite a perioperative mortality, long-term prognosis is generally satisfactory.

The neurotrophin-tyrosine receptor kinase B (TrkB) signaling pathway plays an important role in regulating the balance of excitation and inhibition in the primary visual cortex (V1). Previous studies have revealed its mechanism of regulating the level of cortical excitability by increasing the efficiency of excitatory transmission, but it has not been elucidated how TrkB receptors regulate the balance of excitation and inhibition through the inhibitory system, which in turn affects visual cortex function. Therefore, the objective of this study was to investigate how the TrkB signaling pathway specifically regulates the most important inhibitory neuron-PV neurons affects the visual cortex function of mice. The expression of TrkB receptor on PV neurons in the V1 region was specifically reduced by the virus, the functional changes of inhibitory and excitatory neurons in the primary visual cortex were recorded by multi-channel electrophysiological in vivo. The orientation discrimination ability of mice was tested by behavioral experiments, and altered orientation discrimination ability of mice was tested by behavioral experiments. The results showed that reduced expression of TrkB receptors on PV inhibitory neurons in primary visual cortex significantly increased the response intensity of excitatory neurons, reduced the orientation discrimination ability of inhibitory and excitatory neurons, and increased the signal-to-noise ratio, but the orientation discrimination ability at the individual level in mice showed a decrease. These results suggest that the TrkB signaling pathway does not modulate the function of PV neurons solely by increasing excitatory transmission targeting PV neurons, and its effect on neuronal signal-to-noise ratio is not due to enhancement of the inhibitory system.
Mice ; Animals ; Receptor, trkB/metabolism* ; Neurons/metabolism* ; Signal Transduction

【Objective】 To observe the uric acid-lowering effect of 3,4-dihydroxy-5-nitrobenzaldehyde (DHNB) on hyperuricemia models in mice and quails so as to improve the pharmacodynamic validation on hyperuricemia models. 【Methods】 The mouse hyperuricemia animal model was prepared by intraperitoneal injection of potassium oxonate 300 mg/kg; 30 g/(kg·d) yeast powder mixed feed (yeast powder∶feed, 1∶4) was used to prepare the quail hyperuricemia animal model. DHNB, 100 mg/kg, was intraperitoneally injected into the mice 1 hour prior to modeling; DHNB, 100 mg/kg, was intragastrically administered for two days consecutively into the quail hyperuricemia models. Control groups in mice and quails were set up respectively. Biochemical kits were used to detect serum uric acid, aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), creatinine (Cr), and blood urea nitrogen (BUN) in mouse and quail serum. Heart, lung, liver and kidney tissues of mice and quails were stained with HE. 【Results】 The serum uric acid in the mouse and quail hyperuricemia model groups was higher than that in the control group [(277.37±94.89) μmol/L vs. (176.49±44.83) μmol/L, P<0.05; (313.58±191.87) μmol/L vs. (167.26±66.56) μmol/ L, P<0.05)], indicating that the modeling was successful. DHNB could not reduce serum uric acid in hyperuricemia mouse model [(277.37±94.89) μmol/L vs. (238.72±63.43) μmol/L, P>0.05]. However, it significantly decreased serum uric acid in the quail model of hyperuricemia (313.58±191.87) μmol/L vs. (160.44±49.90)μmol/L, P<0.05]. Administration of DHNB 100 mg/kg one or two times had no effect on the liver and kidney functions of mice and quails, and had no toxicity to the heart, lung, liver or kidney tissues of mice and quails. 【Conclusion】 DHNB has a uric acid-lowering effect on the hyperuricemia quail model, and a single dose that caused the uric acid-lowering effect has no obvious toxicity to mouse or quail viscera. The quail hyperuricemia model is more suitable for the validation of the uric acid-lowering efficacy of DHNB than the mouse hyperuricemia model.