Feasibility and tolerability of anlotinib plus PD-1 blockades as rechallenge immunotherapy in previously treated advanced ESCC: a retrospective study.

BACKGROUND: Rechallenge with immune checkpoint inhibitor (ICI) seemed favorable in several tumors, but clinical experience on esophageal squamous cell carcinoma (ESCC) was scanty. This real-world study aimed to assess the feasibility and safety of anlotinib plus ICI for patients with previously ICI-treated advanced ESCC. MATERIALS AND METHODS: We retrospectively identified advanced ESCC patients who received anlotinib plus ICI in the rechallenge setting for evaluation of clinical outcomes and safety. Totally 110 ICI-pretreated patients, of which 89 (80.9%) received prior first- or second-line treatment, were included from September 9, 2019, to November 30, 2022. Most patients (63.6%) discontinued initial ICI due to disease progression. RESULTS: After rechallenge, median overall survival (OS) and progression-free survival (PFS) were 11.1 (95% CI, 8.6-13.7) and 5.6 (95% CI, 4.4-6.8) months, respectively; estimated OS and PFS rates at 12 months were 47.6% (95% CI, 36.8%-57.7%) and 21.4% (95% CI, 10.9%-34.2%), respectively. No complete response was reported and 21 (19.1%) patients attained partial response; the objective response rate was 19.1%. Fifty-five (50.0%) had stable disease for a disease control rate of 69.1%. Of the 21 responders, median duration of response was 6.4 months. Tendencies for longer OS were observed in patients with Eastern Cooperative Oncology Group Performance of 0 (P = .056). The incidence of grade 3 or higher treatment-related adverse events was 10.0%. CONCLUSION: Anlotinib plus ICI in the rechallenge setting was promising and resulted in encouraging benefits for patients with previously ICI-treated advanced ESCC. Our findings provided preliminary but unique evidence to help select ESCC patients benefiting from this strategy. TRIAL REGISTRATION: chictr.org.cn; number ChiCTR2300070777.

Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by recurrent edema and a potentially fatal risk. Despite its severity, there is a notable lack of effective methods for predicting and preventing HAE attacks. This study aims to thoroughly investigate the underlying pathological mechanisms of HAE and identify potential biomarkers that could aid in its prediction and prevention. RESULTS: In our investigation, we have discovered a novel pathogenic variant of the SERPING1 gene, specifically c.708T > G, in a Han family affected by HAE. Our observations indicate that this variant leads to an increase in the accumulation of C1-INH within the endoplasmic reticulum (ER), resulting in the upregulation of GRP75 protein expression. This cascade of events resulted in Ca2+ overload, disruption of mitochondrial structure and function, and eventually triggered apoptosis. Using siRNA to knock down GRP75 mitigates cellular calcium overload and mitochondrial damage induced by the SERPING1 mutation. CONCLUSION: Based on our findings, we propose that the detection of intracellular Ca2+ concentration could serve as a valuable biomarker for predicting acute attacks of HAE in patients. This discovery holds significant implications for the development of more targeted and effective strategies in the management of HAE.

Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1.

INTRODUCTION: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. OBJECTIVES: This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. METHODS: Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. RESULTS: Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin-proteasome degradation, restoring SIRT1's role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. CONCLUSION: Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.

The value of intervention with radiotherapy after first-line chemo-immunotherapy in locally advanced or metastatic esophageal squamous cell carcinoma: A multi-center retrospective study.

Background: Chemotherapy plus immunotherapy has become the standard first-line treatment of advanced or metastatic esophageal squamous cell carcinoma (ESCC), but median duration of response is only 7.0-8.3 months and progression-free survival (PFS, ∼6 months) is still far from satisfactory. We aim to evaluate whether early involvement of radiotherapy might improve the treatment outcome if objective response to first-line chemo-immunotherapy was observed in locally advanced or metastatic ESCC. Methods: Patients were retrospectively collected from 3 institutions in China. Patients with histopathologically confirmed diagnoses of locally advanced or metastatic ESCC were identified, who objectively responded to first-line chemo-immunotherapy (complete or partial response, or stable disease) and also received radiotherapy of primary lesions with radiation dose of over 40 Gy, with or without radiotherapy of metastatic lesions before the first disease progression. Results: A total of 72 eligible patients were identified. With median follow-up duration of 14.6 (range, 7.1-34.8) months, median progression-free survival (PFS) and overall survival (OS) were 13.5 (95 % CI,10.4-NA) months and 31.8 (95 % CI, 23.0-NA) months, respectively. Median duration from initiation of chemo-immunotherapy to radiotherapy was 2.9 (range, 0-15.1) months. Besides lower tumor burden as a significant factor of better treatment outcome, radiation dose ≥ 50 Gy was associated with superior PFS, while OS might be mainly related to tumor response to the induction chemo-immunotherapy. A low incidence of Grade 3 or above treatment-related adverse events were observed (19 %), and no treatment-related death occurred. Conclusion: Our multi-center retrospective study showed survival benefit brought by early involvement of radiotherapy after first-line chemo-immunotherapy for patients with locally advanced or metastatic ESCC. However, further investigation is warranted in future prospective, controlled trials to assess the value of radio-immunotherapy in advanced or metastatic ESCC.

Single-cell BCR and transcriptome analysis reveals peripheral immune signatures in patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is the most prevalent orbital disease in adults caused by an autoimmune disorder, which can lead to disfigurement and vision impairment. Developing effective treatments for this condition presents challenges due to our limited understanding of its underlying immune aberrations. In this study, we profiled the immune components in the peripheral blood of patients with TAO as well as healthy individuals, utilizing single-cell RNA sequencing and B-cell receptor repertoires (BCR) analysis. We observed a significant reduction in the proportions of regulatory B cells (Bregs) and type 2 conventional dendritic cells (DCs) in patients with TAO during the active phase. Conversely, there was a significant increase in the proportion of type 1 DCs. Further analysis of cell differentiation trajectory revealed potential impairment in the transition of B cells towards Breg phenotype during the active phase of TAO. Besides, the activation process of TAO appeared to involve inflammation and immune dysfunction, as indicated by the dynamic changes in the activities of key regulators. The abnormalities in the peripheral immune system, such as the reduced capacity of Bregs to suppress inflammation, were primarily driven by the enhanced interaction among Breg, DCs, and monocytes (i.e., CD22-PTPRC and BTLA-TNFRSF14). Collectively, our findings offer a comprehensive insight into the molecular regulation and cellular reconfiguration during the active phase of TAO at the single-cell level, in order to explore the pathogenesis of TAO and provide new ideas for the future treatment of TAO.

The circulating IL-35+ regulatory B cells are associated with thyroid associated opthalmopathy.

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is the most common orbital disease in adults, potentially leading to disfigurement and visual impairment. However, the causes of TAO are not fully understood. IL-35+B cells are a newly identified regulatory B cells (Bregs) in maintaining immune balance in various autoimmune diseases. Yet, the influence of IL-35+Bregs in TAO remains unexplored. METHODS: This study enrolled 36 healthy individuals and 14 TAO patients. We isolated peripheral blood mononuclear cells and stimulated them with IL-35 and CpG for 48 h. Flow cytometry was used to measure the percentages of IL-35+Bregs. RESULTS: The percentage of circulating IL-35+Bregs was higher in TAO patients, and this increase correlated positively with disease activity. IL-35 significantly increased the generation of IL-35+Bregs in healthy individuals. However, B cells from TAO patients exhibited potential impairment in transitioning into IL-35+Breg phenotype under IL-35 stimulation. CONCLUSIONS: Our results suggest a potential role of IL-35+Bregs in the development of TAO, opening new avenues for understanding disease mechanisms and developing therapeutic approaches.

Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer.

BACKGROUND: Programmed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) combined with the PD-1 inhibitor toripalimab in patients with resectable ESCC. METHODS: From July 2020 to July 2022, 21 patients with histopathologically confirmed thoracic ESCC and clinical staged as cT1-4aN1-2M0/cT3-4aN0M0 were enrolled. Eligible patients received radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week) with concurrent chemotherapy of paclitaxel/cisplatin (paclitaxel 45 mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 and two cycles of toripalimab 240 mg every 3 weeks after nCRT for neoadjuvant therapy before surgery, four cycles of toripalimab 240 mg every 3 weeks for adjuvant therapy after surgery. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints were safety and survival outcomes. RESULTS: A total of 21 patients were included, of whom 20 patients underwent surgery, 1 patient refused surgery and another patient was confirmed adenocarcinoma after surgery. The MPR and pathological complete response (pCR) rates were 78.9% (15/19) and 47.4% (9/19) for surgery ESCC patients. 21 patients (100.0%) had any-grade treatment-related adverse events, with the most common being lymphopenia (100.0%), leukopenia (85.7%), neutropenia (52.4%). 14 patients (66.7%) had adverse events of grade 3 with the most common being lymphopenia (66.7%). The maximum standardized uptake value and total lesion glycolysis of positron emission tomography/CT after neoadjuvant therapy well predicted the pathological response. The peripheral CD4+%, CD3+HLA-DR+/CD3+%, CD8+HLA-DR+/CD8+%, and IL-6 were significant differences between pCR and non-pCR groups at different times during neoadjuvant therapy. Three patients had tumor relapse and patients with MPR have longer disease-free survival than non-MPR patients. CONCLUSIONS: nCRT combined with perioperative toripalimab is effective and safe for locally advanced resectable ESCC. Long-term survival outcomes remain to be determined. TRIAL REGISTRATION NUMBER: NCT04437212.

Development of Serum Lactate Level-Based Nomograms for Predicting Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients.

Purpose: To establish nomograms integrating serum lactate levels and traditional risk factors for predicting diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients. Patients and methods: A total of 570 T2DM patients and 100 healthy subjects were enrolled. T2DM patients were categorized into normal and high lactate groups. Univariate and multivariate logistic regression analyses were employed to identify independent predictors for DKD. Then, nomograms for predicting DKD were established, and the model performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration, and decision curve analysis (DCA). Results: T2DM patients exhibited higher lactate levels compared to those in healthy subjects. Glucose, platelet, uric acid, creatinine, and hypertension were independent factors for DKD in T2DM patients with normal lactate levels, while diabetes duration, creatinine, total cholesterol, and hypertension were indicators in high lactate levels group (P<0.05). The AUC values were 0.834 (95% CI, 0.776 to 0.891) and 0.741 (95% CI, 0.688 to 0.795) for nomograms in both normal lactate and high lactate groups, respectively. The calibration curve demonstrated excellent agreement of fit. Furthermore, the DCA revealed that the threshold probability and highest Net Yield were 17-99% and 0.36, and 24-99% and 0.24 for the models in normal lactate and high lactate groups, respectively. Conclusion: The serum lactate level-based nomogram models, combined with traditional risk factors, offer an effective tool for predicting DKD probability in T2DM patients. This approach holds promise for early risk assessment and tailored intervention strategies.

Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes.

Hyperglycaemia-induced endothelial dysfunction is a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy. STING, which is a newly discovered regulator of innate immunity, has also been reported to play an important role in various metabolic diseases. However, the role of STING in diabetes-induced endothelial cell dysfunction is unknown. In this study, we established a diabetic macroangiopathy mouse model by streptozotocin (STZ) injection combined with high-fat diet (HFD) feeding and a glucotoxicity cell model in high glucose (HG)-treated rat aortic endothelial cells (RAECs). We found that STING expression was specifically increased in the endothelial cells of diabetic arteries, as well as in HG-treated RAECs. Moreover, genetic deletion of STING significantly ameliorated diabetes-induced endothelial cell dysfunction and apoptosis in vivo. Likewise, STING inhibition by C-176 reversed HG-induced migration dysfunction and apoptosis in RAECs, whereas STING activation by DMXAA resulted in migration dysfunction and apoptosis. Mechanistically, hyperglycaemia-induced oxidative stress promoted endothelial mitochondrial dysfunction and mtDNA release, which subsequently activated the cGAS-STING system and the cGAS-STING-dependent IRF3/NF-kB pathway, ultimately resulting in inflammation and apoptosis. In conclusion, our study identified a novel role of STING in diabetes-induced aortic endothelial cell injury and suggested that STING inhibition was a potential new therapeutic strategy for the treatment of diabetic macroangiopathy. Video Abstract.

Phase II multicenter trial: first-line immunochemotherapy with or without radiotherapy in metastatic esophageal squamous cell cancer (SCR-ESCC-01).

This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24 months. In arm A, LDRT (2 Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50 Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. Clinical Trial Registration: NCT05978193 (clinicaltrials.gov).

Valuation of EQ-5D-5L health states from cancer patients' perspective: a feasibility study.

OBJECTIVES: To assess the feasibility of estimating an EQ-5D-5L value set using a small study design in cancer patients and to compare the EQ-5D-5L values based on the preferences of cancer patients with those of the general public. METHODS: Patients with clinically diagnosed cancers were recruited from two hospitals in Shanghai, China. In face-to-face interviews using the EQ-PVT survey, health states were valued by cancer patients using both cTTO and DCE methods. cTTO data was modelled alone or jointly with DCE data. Forty-eight models using different model specifications (cross-attribute level effect [CALE] and additive models), random/fixed effects model assumptions, data heteroscedasticity and censoring were estimated. The best performed model was identified in terms of monotonicity of estimated model coefficients and out-of-sample prediction accuracy. RESULTS: Data collected from 221 cancer patients who participated in the study were included. The hybrid CALE model using both TTO and DCE data performed best in terms of prediction accuracy (Lin's concordance coefficient = 0.989; root mean squared error = 0.058) and suggested that pain/discomfort and anxiety/depression were the most undesirable health problems. Compared to values based on general Chinese public's health preferences, the values based on cancer patients' preferences were much higher and lower for health states characterized by extreme mobility problems and severe/extreme pain or discomfort, respectively. CONCLUSION: This study demonstrated the feasibility of using a small design to develop EQ-5D-5L value sets based on cancer patients' health preferences. Since there were signs of differences between preferences of patients and general population, it may be valuable to develop patient-specific value sets and use them in clinical decision making and economic evaluations.

The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction.

Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the mortality of diabetic patients. Endothelial dysfunction, which has been recognized as a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy, is characterized by a reduction in NO bioavailability. Oxidative stress, which is the main pathogenic factor in diabetes, is one of the major triggers of endothelial dysfunction through the reduction in NO. In this review, we summarize the four sources of ROS in the diabetic vasculature and the underlying molecular mechanisms by which the pathogenic factors hyperglycaemia, hyperlipidaemia, adipokines and insulin resistance induce oxidative stress in endothelial cells in the context of diabetes. In addition, we discuss oxidative stress-targeted interventions, including hypoglycaemic drugs, antioxidants and lifestyle interventions, and their effects on diabetes-induced endothelial dysfunction. In summary, our review provides comprehensive insight into the roles of oxidative stress in diabetes-induced endothelial dysfunction.

Sleep disturbances and the risk of lung cancer: a meta-epidemiological study.

BACKGROUND: The relationship between sleep disturbances and lung cancer is complex and bidirectional. This meta-epidemiological study aimed to explore the potential association between sleep disruption and the risk of pulmonary cancer. METHODS: We conducted a comprehensive literature search of the PubMed, Embase, Cochrane Library, and Web of Science databases to retrieve relevant studies. We employed the Newcastle-Ottawa Scale to assess the quality of the observational studies. Stata 17.0 was used to synthesize and conduct a meta-analysis of odds ratios (ORs) and corresponding 95% confidence intervals (CIs). We used funnel plot analysis and Egger's regression test to evaluate potential publication bias. RESULTS: A total of 11 studies were included with 469,691 participants. The methodological quality of the included studies ranged from moderate to high. Compared with 7-8 h of sleep time, short sleep duration was associated with a 13% higher lung cancer risk [OR, 1.13; 95%CI: 1.02-1.25; I2 = 67.6%; P = 0.018] and long sleep duration with a 22% higher risk [OR, 1.22; 95%CI: 1.12-1.33; I2 = 6.9%; P < 0.001]. Insomnia symptoms [OR, 1.11; 95%CI: 1.07-1.16; I2 = 0%; P < 0.001] and evening chronotype [OR, 1.15; 95%CI: 1.05-1.26; P = 0.002] were all related to a higher risk of lung cancer. Egger's test revealed no publication bias for sleep duration (P = 0.13). DISCUSSION: This systematic review is the first one which observes positive correction between sleep disturbances and the incidence of lung cancer. While the plausible mechanism is not clear, it is hypothesized that the association of short sleep duration and lung cancer mainly mediated by melatonin secretion and the immune-inflammatory balance. Further studies are needed to examine whether other risk factors, such as age, occupation, cumulative effect of sleep disturbances might mediate the relationship between sleep disturbances and lung cancer risk. CONCLUSION: The present study revealed that insufficient and excessive sleep duration, insomnia symptoms, and evening chronotype were significantly predictive of an increased risk of lung cancer. This finding underscores the need to account for sleep disturbances as an independent risk factor for evaluating susceptibility to lung cancer. TRIAL REGISTRATION: CRD42023405351.

Effectiveness and safety of Shenqi Fuzheng injection combined with platinum-based chemotherapy for treatment of advanced non-small cell lung cancer: a systematic review and meta-analysis.

Objective: To evaluate the efficacy and safety of Shenqi Fuzheng Injection (SFI) combined with platinum-based chemotherapy (PBC) for the treatment of advanced non-small cell lung cancer (NSCLC). Methods: Seven electronic databases, including CNKI and Wanfang, were comprehensively searched to screen randomized controlled trials (RCTs) until May 1, 2022. The quality of each trial was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions, and systematic reviews were conducted according to the PRISMA guidelines. Statistical analysis was performed using Review Manager 5.3, and the results were expressed as relative risk (RR) and 95% confidence interval (95% CI). The primary outcome measures were objective response rate (ORR) and disease control rate (DCR). The secondary outcome measures were quality of life and toxicity. Subgroup analysis was performed according to the number of days of SFI single-cycle treatment and combined PBC regimen. Results: A total of 44 RCTs involving 3475 patients were included in the study. The meta-analysis results showed that, compared with PBC alone, SFI combined with PBC significantly improved the ORR (RR = 1.27, 95% CI = 1.18-1.37, P < 0.00001), DCR (RR = 1.12, 95% CI = 1.08-1.15, P < 0.00001), and quality of life (RR = 1.41, 95% CI = 1.31-1.52, P < 0.00001). It also reduced chemotherapy-induced hemoglobin reduction (RR = 0.57, 95% CI = 0.48-0.67, P < 0.00001), leukopenia (RR = 0.61, 95% CI = 0.53-0.71, P < 0.00001), thrombocytopenia (RR = 0.62, 95% CI = 0.55-0.70, P < 0.00001), and simple bone marrow suppression (RR = 0.55, 95% CI = 0.41-0.73, P < 0.0001). Nausea and vomiting (RR = 0.63, 95% CI = 0.52-0.77, P < 0.00001), diarrhea (RR = 0.48, 95% CI = 0.37-0.64, P < 0.00001), and simple digestive tract reactions (RR = 0.63, 95% CI = 0.49-0.80, P = 0.0002) also decreased with the treatment of SFI. Conclusion: SFI combined with PBC for the treatment of advanced NSCLC improved the ORR, DCR, and quality of life, and reduced the incidence of myelosuppression and gastrointestinal adverse reactions. However, considering the limitations of existing evidence, further verification using high-quality RCTs is required. Systematic review registration: https://inplasy.com/inplasy-2022-7-0026, identifier INPLASY202270026.

Laggera alata Attenuates Inflammatory Response by Regulating Macrophage Polarization in Rheumatoid Arthritis Mice.

Rheumatoid arthritis (RA) is a type of joint injury, which can induce the activation of inflammatory factors and polarization of tissue macrophages. Total phenolics from Laggera alata (TPLA) has been reported to exhibit anti-inflammatory effect in various diseases. However, its specific function in RA is still unknown. Here, the protective properties of TPLA were studied in collagen-induced arthritis (CIA)-induced RA mice. RA mouse model was established through the CIA induction. Arthritis score, hind paw thickness, and the body weight of the RA mice were evaluated in each group. H&E staining was conducted in hind paw and joint tissues for histopathological staining. The distal femur was analyzed by microCT, and bone loss-related indicators were assessed. The expression of macrophage polarization markers was detected by immunofluorescence staining in RA mice. The serum levels of inflammatory markers were determined by enzyme-linked immunosorbent assay (ELISA). TPLA reduced the CIA-induced arthritis score and hind paw thickness in mice. The body weight of the CIA mouse was significantly increased by TPLA treatment. TPLA improved the CIA-induced histopathological changes in the hind paw and joint tissues from the mice. TPLA inhibited the bone loss and alleviated bone destruction in CIA mouse model. TPLA altered the macrophage phenotype from M1 macrophages into M2 in CIA mice. TPLA suppressed the levels of inflammatory markers both in the serum and joint tissues of the CIA mice. TPLA mitigated RA development by suppressing inflammatory reaction through the inhibition of M1 microphage polarization.

Single-Nucleus Transcriptome Profiling of Locally Advanced Cervical Squamous Cell Cancer Identifies Neural-Like Progenitor Program Associated with the Efficacy of Radiotherapy.

Radiotherapy is the first-line treatment for locally advanced cervical squamous cell cancer (CSCC). However, ≈50% of patients fail to respond to therapy and, in some cases, tumors progress after radical radiotherapy. Here, single-nucleus RNA-seq is performed to construct high-resolution molecular landscapes of various cell types in CSCC before and during radiotherapy, to better understand radiotherapy related molecular responses within tumor microenvironment. The results show that expression levels of a neural-like progenitor (NRP) program in tumor cells are significantly higher after radiotherapy and these are enriched in the tumors of nonresponding patients. The enrichment of the NRP program in malignant cells from the tumors of nonresponders in an independent cohort analyzed by bulk RNA-seq is validated. In addition, an analysis of The Cancer Genome Atlas dataset shows that NRP expression is associated with poor prognosis in CSCC patients. In vitro experiments on the CSCC cell line demonstrate that downregulation of neuregulin 1 (NRG1), a key gene from NRP program, is associated with decreased cell growth and increased sensitivity to radiation. Immunohistochemistry staining in cohort 3 validated key genes, NRG1 and immediate early response 3 from immunomodulatory program, as radiosensitivity regulators. The findings reveal that the expression of NRP in CSCC can be used to predict the efficacy of radiotherapy.

Exploring rumor behavior during the COVID-19 pandemic through an information processing perspective: The moderating role of critical thinking.

In the midst of the pervasive disruption caused by the proliferation of rumors, it is unclear how individuals react to such information. Guided by the SOR theory (Stimuli-Organism-Response), our study investigates the association between different information sources (stimuli), emotions experienced by individuals (organism), and resulting rumor behaviors such as sharing and refuting (response). Furthermore, we examine the moderating role of individual critical thinking in this process. Using the COVID-19 pandemic as a study scenario, we collected questionnaire data from 4588 respondents. Our results reveal a large positive association between pandemic-related information and feelings of fear. Additionally, a medium negative correlation between fear and rumor sharing was observed while a moderate positive correlation between fear and rumor refuting was identified. Moreover, we found that individual critical thinking abilities can effectively moderate the relationship between fear and online COVID-19-related information and strengthen the link between fear and rumor sharing while weakening the link between fear and rumor refuting. Additionally, our study indicates that an individual's fear plays a mediating role in the relationship between information sources and rumor behavior. Our findings shed light on the information processing mechanisms underlying rumor behaviors and yield practical and policy implications for managing them.

High glucose-induced STING activation inhibits diabetic wound healing through promoting M1 polarization of macrophages.

Diabetic wound (DW) is characterized by elevated pro-inflammatory cytokines and cellular dysfunction consistent with elevated reactive oxygen species (ROS) levels. Recent advances in immunology have dissected molecular pathways involved in the innate immune system where cytoplasmic DNA can trigger STING-dependent inflammatory responses and play an important role in metabolic-related diseases. We investigated whether STING regulates inflammation and cellular dysfunction in DW healing. We found that STING and M1 macrophages were increased in wound tissues from DW in patients and mice and delayed the wound closure. We also noticed that the massively released ROS in the High glucose (HG) environment activated STING signaling by inducing the escape of mtDNA to the cytoplasm, inducing macrophage polarization into a pro-inflammatory phenotype, releasing pro-inflammatory cytokines, and exacerbating endothelial cell dysfunction. In Conclusion, mtDNA-cGAS-STING pathway activation under diabetic metabolic stress is an important mechanism of DW refractory healing. While using STING gene-edited macrophages for wound treatment by cell therapy can induce the polarization of wound macrophages from pro-inflammatory M1 to anti-inflammatory M2, promote angiogenesis, and collagen deposition to accelerate DW healing. STING may be a promising therapeutic target for DW.

Polyphenols in twenty cultivars of blue honeysuckle (Lonicera caerulea L.): Profiling, antioxidant capacity, and α-amylase inhibitory activity.

The polyphenols extracted from 20 blue honeysuckle cultivars were comprehensively characterized and quantified by HPLC-DAD and HPLC-ESI-QTOF-MS2 analyses and evaluated for antioxidant capacity (ABTS, DPPH, FRAP) and α-amylase inhibitory activity. The 17 anthocyanins and 59 non-anthocyanin phenolics were characterized. Among them, cyanidin-3-glucoside, quercetin-3-galactoside, myricetin-3-galactoside, and 3-caffeoylquinic acid were the major polyphenols. These polyphenols not only contributed to the antioxidant capacity, but were also good α-amylase inhibitors. 'Lanjingling' showed the strongest antioxidant capacity evaluated by FRAP, while 'CBS-2' and '14-13-1' showed the strongest antioxidant capacity evaluated by ABTS and DPPH. All the twenty cultivars showed α-amylase inhibitory activity, and the IC50 values ranged from 0.12 ± 0.01 to 0.69 ± 0.02 mg/mL. 'Lanjingling' showed the most potent α-amylase inhibitory activity. Additionally, principal component analysis indicated that Lonicera. caerulea subsp. emkuyedao bred in Japan differed markedly in phenolics and bioactivity compared to the other four subspecies bred in China and Russia.