18F-FDG PET/CT metrics-based stratification of large B-cell lymphoma receiving CAR-T cell therapy: immunosuppressive tumor microenvironment as a negative prognostic indicator in patients with high tumor burden.

Chimeric antigen receptor T (CAR-T) cell therapy has greatly improved the prognosis of relapsed and refractory patients with large B-cell lymphoma (LBCL). Early identification and intervention of patients who may respond poorly to CAR-T cell therapy will help to improve the efficacy. Ninety patients from a Chinese cohort who received CAR-T cell therapy and underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans at the screening stage (median time to infusion 53.5 days, range 27-176 days), 1 month and 3 months after CAR-T cell infusion were analyzed, with RNA-sequencing conducted on 47 patients at the screening stage. Patients with maximum diameter of the largest lesion (Dmax) < 6 cm (N = 60) at screening stage showed significantly higher 3-month complete response rate (85.0% vs. 33.3%, P < 0.001), progression-free survival (HR 0.17; 95% CI 0.08-0.35, P < 0.001) and overall survival (HR 0.18; 95% CI 0.08-0.40, P < 0.001) than those with Dmax ≥ 6 cm (N = 30). Besides, at the screening stage, Dmax combined with extranodal involvement was more efficient in distinguishing patient outcomes. The best cut-off values for total metabolic tumor volume (tMTV) and total lesion glycolysis (tTLG) at the screening stage were 50cm3 and 500 g, respectively. A prediction model combining maximum standardized uptake value (SUVmax) at 1 month after CAR-T cell therapy (M1) and tTLG clearance rate was established to predict early progression for partial response/stable disease patients evaluated at M1 after CAR-T cell therapy and validated in Lyon cohort. Relevant association of the distance separating the two farthest lesions, standardized by body surface area to the severity of neurotoxicity (AUC = 0.74; P = 0.034; 95% CI, 0.578-0.899) after CAR-T cell therapy was found in patients received axicabtagene ciloleucel. In patients with Dmax ≥ 6 cm, RNA-sequencing analysis conducted at the screening stage showed enrichment of immunosuppressive-related biological processes, as well as increased M2 macrophages, cancer-associated fibroblasts, myeloid-derived suppressor cells, and intermediate exhausted T cells. Collectively, immunosuppressive tumor microenvironment may serve as a negative prognostic indicator in patients with high tumor burden who respond poorly to CAR-T cell therapy.

Postsynaptic lncRNA Sera/Pkm2 pathway orchestrates the transition from social competition to rank by remodeling the neural ensemble in mPFC.

Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.

Phenotypes and functions of "aged" neutrophils in cardiovascular diseases.

Neutrophils are important effector cells of innate immunity and undergo several phenotypic changes after release from the bone marrow. Neutrophils with a late life cycle phenotype are often referred to as "aged" neutrophils. These neutrophils undergo functional changes that accompany stimuli of inflammation, tissue senescence and injury, inducing their maturation and senescence in the circulation and locally in damaged tissues, forming a unique late-life neutrophil phenotype. "Aged" neutrophils, although attenuated in antibacterial capacity, are more active in aging and age-related diseases, exhibit high levels of mitochondrial ROS and mitochondrial DNA leakage, promote senescence of neighboring cells, and exacerbate cardiac and vascular tissue damage, including vascular inflammation, myocardial infarction, atherosclerosis, stroke, abdominal aortic aneurysm, and SARS-CoV-2 myocarditis. In this review, we outline the phenotypic changes of "aged" neutrophils characterized by CXCR4high/CD62Llow, investigate the mechanisms driving neutrophil aging and functional transformation, and analyze the damage caused by "aged" neutrophils to various types of heart and blood vessels. Tissue injury and senescence promote neutrophil infiltration and induce neutrophil aging both in the circulation and locally in damaged tissues, resulting in an "aged" neutrophil phenotype characterized by CXCR4high/CD62Llow. We also discuss the effects of certain agents, such as neutralizing mitochondrial ROS, scavenging IsoLGs, blocking VDAC oligomers and mPTP channel activity, activating Nrf2 activity, and inhibiting neutrophil PAD4 activity, to inhibit neutrophil NET formation and ameliorate age-associated cardiovascular disease, providing a new perspective for anti-aging therapy in cardiovascular disease.

Oral Decoctions Based on Qi-Yin Syndrome Differentiation After Adjuvant Chemotherapy in Resected Stage ΙΙΙA Non-Small Cell Lung Cancer: A Randomized Controlled Trial.

OBJECTIVE: Powerful adjuvant strategies are required to improve the survival of patients with completely resected stage ΙΙΙA non-small cell lung cancer (NSCLC). We aimed to compare the efficacy of traditional Chinese medicine (TCM) treatment versus observation after adjuvant chemotherapy in these patients. METHODS: Eligible patients were randomized 1:1 to receive either oral decoctions based on Qi-Yin syndrome differentiation (TCM group) or observation (observation group). The intervention lasted for 12 months. The primary endpoint was 1-year disease-free survival (DFS). Secondary endpoints were DFS, quality of life, regulatory T cells (Tregs), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on the surface of Tregs in peripheral blood. We used EORTC QLQ-LC43 to evaluate quality of life. RESULTS: Between Apr 29, 2019, and Nov 11, 2021, 75 patients were randomly assigned to oral decoctions based on Qi-Yin syndrome differentiation (n = 38) or observation (n = 37). The full analysis set included 35 patients in the TCM group and 35 in the observation group. After a median follow-up of 24.2 months, oral decoctions based on Qi-Yin syndrome differentiation improved DFS compared with observation (HR 0.378, 95% CI: 0.157-0.912; P = .03). One-year DFS was 82.1% in the TCM group and 61.9% in the observation group (P = .06). Three months after randomization, scores of total health, role function, emotional function, and social function in the TCM group were higher than those in the observation group (P < .01 for all), scores of fatigue, pain, insomnia, appetite loss, constipation, cough, and chest pain were lower than those in the observation group (P < .05 for all); there was no significant difference in the proportion of Tregs between the TCM group and the observation group (P = .58); the proportion of CTLA-4+Tregs in the TCM group was lower than that in the observation group (P = .046). There were no adverse events that occurred in both groups. CONCLUSIONS: Oral decoctions based on Qi-Yin syndrome differentiation after adjuvant chemotherapy prolonged DFS, reduced the risk of disease recurrence and metastasis, improved quality of life, and down-regulated the proportion of CTLA-4+Tregs in completely resected stage ΙΙΙA NSCLC patients. TRIAL REGISTRATION: Chinese Clinical Trial Register, No. ChiCTR1800019396. Date of registration: 9 November 2018.

Cholesterol efflux from C1QB-expressing macrophages is associated with resistance to chimeric antigen receptor T cell therapy in primary refractory diffuse large B cell lymphoma.

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated promising efficacy in early trials for relapsed/refractory diffuse large B cell lymphoma (DLBCL). However, its efficacy in treating primary refractory DLBCL has not been comprehensively investigated, and the underlying resistance mechanisms remain unclear. Here, we report the outcomes of a phase I, open-label, single-arm clinical trial of relmacabtagene autoleucel (relma-cel), a CD19-targeted CAR-T cell product, with safety and efficacy as primary endpoints. Among the 12 enrolled patients, 8 experienced grade 4 hematologic toxicity of treatment-emergent adverse event. No grade ≥3 cytokine release syndrome or neurotoxicity occurred. Single-cell RNA sequencing revealed an increase proportion of C1QB-expressing macrophages in patients with progressive disease before CAR-T cell therapy. Cholesterol efflux from M2 macrophages was found to inhibit CAR-T cells cytotoxicity by inducing an immunosuppressive state in CD8+ T cells, leading to their exhaustion. Possible interactions between macrophages and CD8+ T cells, mediating lipid metabolism (AFR1-FAS), immune checkpoint activation, and T cell exhaustion (LGALS9-HAVCR2, CD86-CTLA4, and NECTIN2-TIGIT) were enhanced during disease progression. These findings suggest that cholesterol efflux from macrophages may trigger CD8+ T cell exhaustion, providing a rationale for metabolic reprogramming to counteract CAR-T treatment failure. Chinadrugtrials.org.cn identifier: CTR20200376.

4'-O-methylbavachalcone alleviates ischemic stroke injury by inhibiting parthanatos and promoting SIRT3.

Cerebral ischemia-reperfusion injury (CIRI) can induce massive death of ischemic penumbra neurons via oxygen burst, exacerbating brain damage. Parthanatos is a form of caspase-independent cell death involving excessive activation of PARP-1, closely associated with intense oxidative stress following CIRI. 4'-O-methylbavachalcone (MeBavaC), an isoprenylated chalcone component in Fructus Psoraleae, has potential neuroprotective effects. This study primarily investigates whether MeBavaC can act on SIRT3 to alleviate parthanatos of ischemic penumbra neurons induced by CIRI. MeBavaC was oral gavaged to the middle cerebral artery occlusion-reperfusion (MCAO/R) rats after occlusion. The effects of MeBavaC on cerebral injury were detected by the neurological deficit score and cerebral infarct volume. In vitro, PC-12 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R), and assessed cell viability and cell injury. Also, the levels of ROS, mitochondrial membrane potential (MMP), and intracellular Ca2+ levels were detected to reflect mitochondrial function. We conducted western blotting analyses of proteins involved in parthanatos and related signaling pathways. Finally, the exact mechanism between the neuroprotection of MeBavaC and parthanatos was explored. Our results indicate that MeBavaC reduces the cerebral infarct volume and neurological deficit scores in MCAO/R rats, and inhibits the decreased viability of PC-12 cells induced by OGD/R. MeBavaC also downregulates the expression of parthanatos-related death proteins PARP-1, PAR, and AIF. However, this inhibitory effect is weakened after the use of a SIRT3 inhibitor. In conclusion, the protective effect of MeBavaC against CIRI may be achieved by inhibiting parthanatos of ischemic penumbra neurons through the SIRT3-PARP-1 axis.

Surfactant Micelle-Driven High-Efficiency and High-Resolution Length Separation of Carbon Nanotubes for Electronic Applications.

High-efficiency extraction of long single-wall carbon nanotubes (SWCNTs) with excellent optoelectronic properties from SWCNT solution is critical for enabling their application in high-performance optoelectronic devices. Here, a straightforward and high-efficiency method is reported for length separation of SWCNTs by modulating the concentrations of binary surfactants. The results demonstrate that long SWCNTs can spontaneously precipitate for binary-surfactant but not for single-surfactant systems. This effect is attributed to the formation of compound micelles by binary surfactants that squeeze the free space of long SWCNTs due to their large excluded volumes. With this technique, it can readily separate near-pure long (≥500 nm in length, 99% in content) and short (≤500 nm in length, 98% in content) SWCNTs with separation efficiencies of 26% and 64%, respectively, exhibiting markedly greater length resolution and separation efficiency than those of previously reported methods. Thin-film transistors fabricated from extracted semiconducting SWCNTs with lengths >500 nm exhibit significantly improved electrical properties, including a 10.5-fold on-state current and 14.7-fold mobility, compared with those with lengths <500 nm. The present length separation technique is perfectly compatible with various surfactant-based methods for structure separations of SWCNTs and is significant for fabrication of high-performance electronic and optoelectronic devices.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Novel beagle model of gastric local fibrotic target lesions for the evaluation and training of endoscopic techniques.

BACKGROUND: Novel endoscopic techniques used in the treatment of gastric lesions with local submucosal fibrosis need preclinical evaluation and training due to safety limitations. Therefore, the purpose of our study was to establish an animal model of gastric local fibrotic target lesions and assess its feasibility in the evaluation and training of endoscopic techniques. METHODS: In six experimental beagles, a 50% glucose solution was injected into three submucosal areas of the fundus, body, and antrum of the stomach to create gastric local fibrotic target lesions (experimental group). On post-injection day (PID) 7, the injection sites were assessed endoscopically to confirm the presence of submucosal fibrosis formation, and the dental floss clip traction assisted endoscopic submucosal dissection (DFC-ESD) procedure was performed on the gastric local fibrotic target lesions to confirm its feasibility after endoscopic observation. The normal gastric mucosa of six control beagles underwent the same procedure (control group). All the resected specimens were evaluated by histological examination. RESULTS: All 12 beagles survived without postoperative adverse events. On PID 7, 16 ulcer changes were observed at the injection sites (16/18) under the endoscope, and endoscopic ultrasonography confirmed the local submucosal fibrosis formation in all ulcer lesions. The subsequent DFC-ESD was successfully performed on the 32 gastric target lesions, and the mean submucosal dissection time in the ulcer lesions was greater than that in the normal gastric mucosa (15.3 ± 5.6 vs. 6.8 ± 0.8 min; P < 0.001). There was no difference in rates of en bloc resection, severe hemorrhage, or perforation between the two groups. Histological analysis of the ulcer lesions showed the absence of epithelial or muscularis mucosae and extensive submucosal fibrous tissue proliferations compared with normal gastric mucosa. Overall, endoscopists had high satisfaction with the realism and feasibility of the animal model. CONCLUSION: We developed a novel animal model of gastric local fibrotic target lesions to simulate difficult clinical situations, which strongly appeared to be suitable for the preclinical evaluation and learning of advanced endoscopic techniques.

Magnetic ring-assisted endoscopic submucosal dissection for gastric lesions with submucosal fibrosis: A preliminary study in beagle model.

BACKGROUND: During endoscopic submucosal dissection (ESD) for gastric lesions with fibrosis, appropriate traction could provide clear submucosal dissection visualization to improve safety and efficiency of procedures. Therefore, the aim of this study was to evaluate the feasibility of magnetic ring-assisted ESD (MRA-ESD) for gastric fibrotic lesions. METHOD: In the eight healthy beagles, 2-3 mL of 50% glucose solution was injected into submucosal layer of the stomach to induce gastric fibrotic lesions. A week after submucosal injection, two endoscopists at different levels performed MRA-ESD or standard ESD (S-ESD) for gastric simulated lesions, respectively. The magnetic traction system consisted of external handheld magnet and internal magnetic ring. The feasibility and procedure outcomes of the magnetic traction system were mainly evaluated. RESULTS: Forty-eight gastric simulated lesions with ulceration were confirmed to have submucosal fibrosis formation by preoperative endoscopic ultrasonography. The magnetic traction system could be easily established, only took 1.57 min, and allowed excellent submucosal visualization. The total procedure time was significantly shorter in the MRA-ESD group than in the S-ESD group for both endoscopists (mean: 46.83 vs. 25.09 min, p < 0.001), and this difference was accentuated in non-skilled endoscopist. There was significant difference between two groups in bleeding and perforation rates. Histological analysis showed the depth of resected specimens was a little deeper around the fibrotic portion in the S-ESD group (p < 0.001). CONCLUSION: The magnetic ring-assisted ESD technique may be an effective and safe treatment for gastric fibrotic lesions and may shorten the endoscopic learning curve for non-skilled endoscopists.

4'­O­methylbavachalcone inhibits succinate induced cardiomyocyte hypertrophy via the NFATc4 pathway.

Pathological cardiac hypertrophy is an independent risk factor for complications such as arrhythmia, myocardial infarction, sudden mortality and heart failure. Succinate, an intermediate product of the Krebs cycle, is released into the bloodstream by cells; its levels increase with exacerbations of hypertension, myocardial and other tissue damage and metabolic disease. Succinate may also be involved in several metabolic pathways and mediates numerous pathological effects through its receptor, succinate receptor 1 (SUCNR1; previously known as GPR91). Succinate-induced activation of SUCNR1 has been reported to be related to cardiac hypertrophy, making SUCNR1 a potential target for treating cardiac hypertrophy. Traditional Chinese medicine (TCM) and its active ingredients have served important roles in improving cardiac functions and treating heart failure. The present study investigated whether 4'-O-methylbavachadone (MeBavaC), an active ingredient of the herbal remedy Fructus Psoraleae, which is often used in TCM and has protective effect on myocardial injury and hypertrophy induced by adriamycin, ischemia-reperfusion and sepsis, could ameliorate succinate-induced cardiomyocyte hypertrophy by inhibiting the NFATc4 pathway. Using immunofluorescence staining, reverse transcription-quantitative PCR, western blotting and molecular docking analysis, it was determined that succinate activated the calcineurin/NFATc4 and ERK1/2 pathways to promote cardiomyocyte hypertrophy. MeBavaC inhibited cardiomyocyte hypertrophy, nuclear translocation of NFATc4 and ERK1/2 signaling activation in succinate-induced cardiomyocytes. Molecular docking analysis revealed that MeBavaC interacts with SUCNR1 to form a relatively stable binding and inhibits the succinate-SUCNR1 interaction. The results demonstrated that MeBavaC suppressed cardiomyocyte hypertrophy by blocking SUCNR1 receptor activity and inhibiting NFATc4 and ERK1/2 signaling, which will contribute to the preclinical development of this compound.

Simultaneous development of pneumonitis and autoimmune diabetes secondary to immune checkpoint inhibitor treatment with durvalumab in an advanced small cell lung cancer patient: A case report.

RATIONALE: Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of various types of cancers worldwide, which is the most significant breakthrough in cancer therapy in recent years. Despite their excellent benefits in anti-tumor efficacy, a subset of patients will experience various autoimmune toxicities, termed as immune-related adverse events (irAEs), which can affect almost any organ systems, but related to the pulmonary and pancreatic islets simultaneously has rarely been reported and discussed. PATIENT CONCERNS: In this report, we describe a rare case of a 65-year-old man patient with advanced small cell lung cancer (SCLC) who suffered general fatigue, dry cough, chest tightness, shortness of breath and polyuria-polydipsia syndrome after the eighth cycle treatment with programmed cell death ligand-1 (PD-L1) inhibitor durvalumab. DIAGNOSES: According to the results of laboratory tests, chest computed tomography and multidisciplinary discussion, the patient was eventually diagnosed with ICI-related pneumonitis and autoimmune diabetes mellitus. INTERVENTIONS: Multiple daily subcutaneous insulin injections, empirical anti-infection and immunosuppression treatment with corticosteroids were performed. OUTCOMES: After the cessation of durvalumab and comprehensive treatment, the patient's respiratory condition was relieved significantly and his blood glucose was well controlled with insulin therapy. LESSONS: With the widespread use of ICIs, there will be more patients developing these rare but severe irAEs in clinical practice, which should attract great attention of both clinicians and patients.

Mechanism of tonifying-kidney Chinese herbal medicine in the treatment of chronic heart failure.

According to traditional Chinese medicine (TCM), chronic heart failure has the basic pathological characteristics of "heart-kidney yang deficiency." Chronic heart failure with heart- and kidney-Yang deficiency has good overlap with New York Heart Association (NYHA) classes III and IV. Traditional Chinese medicine classical prescriptions for the treatment of chronic heart failure often take "warming and tonifying kidney-Yang" as the core, supplemented by herbal compositions with functions of "promoting blood circulation and dispersing blood stasis." Nowadays, there are still many classical and folk prescriptions for chronic heart failure treatment, such as Zhenwu decoction, Bushen Huoxue decoction, Shenfu decoction, Sini decoction, as well as Qili Qiangxin capsule. This review focuses on classical formulations and their active constituents that play a key role in preventing chronic heart failure by suppressing inflammation and modulating immune and neurohumoral factors. In addition, given that mitochondrial metabolic reprogramming has intimate relation with inflammation, cardiac hypertrophy, and fibrosis, the regulatory role of classical prescriptions and their active components in metabolic reprogramming, including glycolysis and lipid ß-oxidation, is also presented. Although the exact mechanism is unknown, the classical TCM prescriptions still have good clinical effects in treating chronic heart failure. This review will provide a modern pharmacological explanation for its mechanism and offer evidence for clinical medication by combining TCM syndrome differentiation with chronic heart failure clinical stages.

Differential microRNA expression analyses across two brain regions in Alzheimer's disease.

Dysregulation of microRNAs (miRNAs) is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Hitherto, sample sizes from differential miRNA expression studies in AD are exceedingly small aggravating any biological inference. To overcome this limitation, we investigated six candidate miRNAs in a large collection of brain samples. Brain tissue was derived from superior temporal gyrus (STG) and entorhinal cortex (EC) from 99 AD patients and 91 controls. MiRNA expression was examined by qPCR (STG) or small RNA sequencing (EC). Brain region-dependent differential miRNA expression was investigated in a transgenic AD mouse model using qPCR and FISH. Total RNA sequencing was used to assess differential expression of miRNA target genes. MiR-129-5p, miR-132-5p, and miR-138-5p were significantly downregulated in AD vs. controls both in STG and EC, while miR-125b-5p and miR-501-3p showed no evidence for differential expression in this dataset. In addition, miR-195-5p was significantly upregulated in EC but not STG in AD patients. The brain region-specific pattern of miR-195-5p expression was corroborated in vivo in transgenic AD mice. Total RNA sequencing identified several novel and functionally interesting target genes of these miRNAs involved in synaptic transmission (GABRB1), the immune-system response (HCFC2) or AD-associated differential methylation (SLC16A3). Using two different methods (qPCR and small RNA-seq) in two separate brain regions in 190 individuals we more than doubled the available sample size for most miRNAs tested. Differential gene expression analyses confirm the likely involvement of miR-129-5p, miR-132-5p, miR-138-5p, and miR-195-5p in AD pathogenesis and highlight several novel potentially relevant target mRNAs.

Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising novel therapeutic approach. However, primary and secondary resistance to CAR-T cell therapy is commonly encountered in various clinical trials. Despite the comprehensive studies to elucidate the mechanisms of resistance, effective resolution in clinical practice is still elusive. Inadequate persistence and subsequent loss of infused CAR-T cells are proposed major resistance mechanism associated with CAR-T cell treatment failure. Thus, we generated CAR-T cells armored with IL-7 to prolong the persistence of infused T-cells, particularly CD4 + T cells, and enhanced anti-tumor response. IL-7 increased CAR-T-cell persistence in vivo and contributed to the distinct T-cell cytotoxicity profile. Using mass cytometry (CyTOF), we further assessed the phenotypic and metabolic profiles of IL-7-secreting CAR-T cells, along with conventional CAR-T cells at the single-cell level. With in-depth analysis, we found that IL-7 maintained CAR-T cells in a less differentiated T-cell state, regulated distinct metabolic activity, and prevented CAR-T-cell exhaustion, which could be essential for CAR-T cells to maintain their metabolic fitness and anti-tumor response. Our findings thus provided clinical rationale to exploit IL-7 signaling for modulation and metabolic reprogramming of T-cell function to enhance CAR-T cell persistence and induce durable remission upon CAR-T cell therapy.

Temperature Change between Neighboring Days Contributes to Years of Life Lost per Death from Respiratory Disease: A Multicounty Analysis in Central China.

BACKGROUND: Many epidemiological studies have recently assessed respiratory mortality attributable to ambient temperatures. However, the associations between temperature change between neighboring days and years of life lost are insufficiently studied. Therefore, we assessed the attributable risk of temperature change between neighboring days on life loss due to respiratory disease. METHODS: We obtained daily mortality and weather data and calculated crude rates of years of life lost for 70 counties in Hunan Province, Central China, from 2013 to 2017. A time-series design with distributed lag nonlinear model and multivariate meta-regression was used to pool the relationships between temperature change between neighboring days and rates of years of life lost. Then, we calculated the temperature change between neighboring days related to average life loss per death from respiratory disease. RESULTS: The total respiratory disease death was 173,252 during the study period. The association between temperature change and years of life lost rates showed a w-shape. The life loss per death attributable to temperature change between neighboring days was 2.29 (95% CI: 0.46-4.11) years, out of which 1.16 (95% CI: 0.31-2.01) years were attributable to moderately high-temperature change between neighboring days, and 0.99 (95% CI: 0.19-1.79) years were attributable to moderately low-temperature change between neighboring days. The temperature change between neighboring days related to life loss per respiratory disease death for females (2.58 years, 95% CI: 0.22-4.93) and the younger group (2.97 years, 95% CI: -1.51-7.44) was higher than that for males (2.21 years, 95% CI: 0.26-4.16) and the elderly group (1.96 years, 95% CI: 0.85-3.08). An average of 1.79 (95% CI: 0.18-3.41) life loss per respiratory disease death was related to non-optimal ambient temperature. CONCLUSIONS: The results indicated that more attention should be given to temperature change, and more public health policies should be implemented to protect public health.

Mechanism underlying the effect of Liujunzi decoction on advanced-stage non-small cell lung cancer in patients after first-line chemotherapy.

OBJECTIVE: To further clarify the anticancer mechanisms of Liujunzi decoction and provide possible targets for the treatment of advanced-stage nonsmall cell lung cancer (NSCLC) by re-analyzing differential gene expression profile of peripheral blood mononuclear cells (PBMCs) from Liujunzi decoctiontreated NSCLC patients receiving first-line chemotherapy. METHODS: The PBMC gene expression microarray data set GSE61926 was retrieved from a high throughput gene expression database. Differentially expressed genes (DEGs) were screened by paired sample t-test and the multiple ratio method. Gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were performed using the DAVID database. The protein-protein interaction (PPI) network was constructed using interaction gene library retrieval tools and Cytoscape software. RESULTS: A total of 162 DEGs were identified, with 67 upregulated genes and 95 downregulated genes. The functional distribution of Gene Oncology (GO) genes showed that DEGs were mostly concentrated in extracellular regions, calcium ion binding, and transcriptase activity. KEGG pathway analysis showed that cytokine-cytokine receptor interactions were significantly enriched. PPI network analysis screened out the top 10 central protein-coding genes with the highest nodal degree: IL2, PIWIL4, DICER1, PIWIL2, SAA1, XCL1, IL22RA1, ARHGAP11A, DCP1A, and GDNF. Among them, the central protein-coding gene with the highest node degree was IL2. In addition, the central protein-coding genes with high node degrees and high molecular complex detection (MCODE) scores were PIWIL4, DICER1, PIWIL2, and DCP1A, all of which are related to tumor development. CONCLUSIONS: One signaling pathway and 10 central protein-coding genes related to anticancer mechanisms were screened by re-analysis of GSE61926 data. IL2, PIWIL4, DICER1, PIWIL2, and DCP1A may have important roles in the mechanism of Liujunzi decoction treatment against NSCLC. Our results suggest that the anticancer mechanism of Liujunzi decoction may be related to gene silencing by RNA and the biological processes of piwi-interacting RNA and other small RNAs.

Role of the renin-angiotensin system in NETosis in the coronavirus disease 2019 (COVID-19).

Myocardial infarction and stroke are the leading causes of death in the world. Numerous evidence has confirmed that hypertension promotes thrombosis and induces myocardial infarction and stroke. Recent findings reveal that neutrophil extracellular traps (NETs) are involved in the induction of myocardial infarction and stroke. Meanwhile, patients with severe COVID-19 suffer from complications such as myocardial infarction and stroke with pathological signs of NETs. Due to the extremely low amount of virus detected in the blood and remote organs (e.g., heart, brain and kidney) in a few cases, it is difficult to explain the mechanism by which the virus triggers NETosis, and there may be a different mechanism than in the lung. A large number of studies have found that the renin-angiotensin system regulates the NETosis at multiple levels in patients with COVID-19, such as endocytosis of SARS-COV-2, abnormal angiotensin II levels, neutrophil activation and procoagulant function at multiple levels, which may contribute to the formation of reticular structure and thrombosis. The treatment of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARBs) and neutrophil recruitment and active antagonists helps to regulate blood pressure and reduce the risk of net and thrombosis. The review will explore the possible role of the angiotensin system in the formation of NETs in severe COVID-19.

Impact of ambient temperature on life loss per death from cardiovascular diseases: a multicenter study in central China.

BACKGROUND: In the context of global climate change, studies have focused on the ambient temperature and mortality of cardiovascular diseases (CVDs). However, little is known about the effect of ambient temperature on year of life lost (YLL), especially the life loss per death caused by ambient temperature. In this study, we aimed to assess the relationship between ambient temperature and life loss and estimate the impact of ambient temperature on life loss per death. METHODS: We collected daily time series of mortality and meteorological data from 70 locations in Hunan province, central China, in periods ranging from Jan. 1, 2013, to Dec. 31, 2017. Crude rates of YLL were calculated per 100,000 people per year (YLL/100,000 population) for each location. A distributed lag nonlinear model and multivariate meta-regression were used to estimate the associations between ambient temperature and YLL rates. Then, the average life loss per death attributable to ambient temperature was calculated. RESULTS: There were 711,484 CVD deaths recorded within the study period. The exposure-response curve between ambient temperature and YLL rates was inverted J or U-shaped. Relative to the minimum YLL rate temperature, the life loss risk of extreme cold temperature lasted for 10 to 12 days, whereas the risk of extreme hot temperature appeared immediately and lasted for 3 days. On average, the life loss per death attributable to non-optimum ambient temperatures was 1.89 (95% CI, 1.21-2.56) years. Life loss was mainly caused by cold temperature (1.13, 95% CI, 0.89­1.37), particularly moderate cold (1.00, 95% CI, 0.78­1.23). For demographic characteristics, the mean life loss per death was relatively higher for males (2.07, 95% CI, 1.44­2.68) and younger populations (3.72, 95% CI, 2.06­5.46) than for females (1.88, 95% CI, 1.21-2.57) and elderly people (1.69, 95% CI, 1.28-2.10), respectively. CONCLUSIONS: We found that both cold and hot temperatures significantly aggravated premature death from CVDs. Our results indicated that the whole range of effects of ambient temperature on CVDs should be given attention.

Expression of Matrix Metalloproteinases and Tissue Inhibitor of Matrix Metalloproteinases during Apical Periodontitis Development.

INTRODUCTION: Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are considered important mediators of the periapical immune response to infection. This study aimed to clarify the putative relationship between MMPs and TIMPs by elucidating the activity of MMP-1, MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 in the temporal development of apical periodontitis (AP) in mice. METHODS: AP was induced in the lower first molars of 30 male Kunming mice. The animals were randomly killed at 0, 7, 14, 28, 60, and 90 days after pulp exposure. The jaws were removed and subjected to quantitative real-time reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis. RESULTS: The MMP-1, MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 messenger RNA and protein expression levels increased with periapical inflammation progression (P < .05). The MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 messenger RNA and protein expression levels increased during the acute and chronic stages of periapical lesions, with less MMP-2 and MMP-9 expression levels at the chronic stage (P < .05). The MMP-8 expression increased at the chronic stage of inflammation (P < .05) but not at the acute stage. Immunostained MMP-2 and TIMP-1 were observed in all experimental periods. CONCLUSIONS: MMP-1, MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were expressed in all periapical samples with varying levels between them. MMP expression could be related to TIMP expression in the temporal development of AP.