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Abstract 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.

Blue honeysuckle (Lonicera caerulea L.) serves as a significant reservoir of polyphenol compounds. This impact of ultrasonication processing on the bioaccessibility of blue honeysuckle fruit puree during in vitro digestion was evaluated. The polyphenol compounds, antioxidant capacity and antiproliferative activity were measured, with a particular focus on determining the total proanthocyanidin content of the puree during digestion. The results revealed that the U300 W treatment significantly increased antioxidant content and enhanced the stability of antioxidant capacity, leading to stronger antiproliferative activity. A total of 33 compounds, including 14 phenolic acids, 5 flavanols, 1 flavanol-3-ol, 1 flavanone alcohol, 3 flavanones, 1 flavanone, and 8 non– polyphenols were found in both untreated and ultrasonicated puree during in vitro digestion. The untreated puree contained 22 compounds, while the ultrasonicated puree contained 33. Compared to untreated samples, ultrasonicated samples contained significantly higher levels of loganic acid, dihydrokaempferol, kaempferol derivatives, and plantagoside. Except for vanillic acid, citric acid, protocatechuic acid, and luteolin-4′-O-glucoside, the polyphenols showed a decreasing trend during oral-gastric-small intestinal-colon digestion. The U500 W ultrasonicated fruit puree exhibited the strongest antiproliferative activity. Overall, the results demonstrated that ultrasonication has the potential to enhance the bioaccessibility of antioxidant compounds and the antiproliferative activity of blue honeysuckle fruit puree.

Abstract 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.

Abstract 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

Abstract The eddy covariance (EC) flux stations have great limitations in the evaluation of the global net ecosystem carbon exchange (NEE) and in the uncertainty reduction due to their sparse and uneven distribution and spatial representation. If the EC stations are linked with widely distributed meteorological stations using machine learning (ML) and remote sensing, it will play a big role in effectively improving the accuracy of the global NEE assessment and reducing uncertainty. In this study, we developed a framework for estimating NEE at meteorological stations. We first optimized the hyperparameters and input variables of the ML model based on the optimization method called an adaptive genetic algorithm. Then, we developed 566 random forest (RF)‐based NEE estimation models by the strategy of spatial leave‐out‐one cross‐validation. We innovatively established the Euclidean distance‐based accuracy projection algorithm of the R square (R2), which could test the accuracy of each model to estimate the NEE of the specific flux at the weather station. Only the model with the highest R2 was selected from the models with a prediction accuracy of R2 > 0.5 for the specific meteorological stations to estimate its NEE. 4674 out of 10,289 weather stations around the world might match at least one of the 566 NEE estimation models with a projected accuracy of R2 > 0.5. The NEE estimation models we screened for the meteorological stations showed a reliable performance and a higher accuracy than the former studies. The NEE values of the most (96.9%) screened meteorological stations around the world are negative (carbon sink) and most (65.3%) of those showed an increasing trend in the mean annual NEE (carbon sink). The NEE dataset produced at the meteorological stations could be used as a supplement to the EC observations and quasi‐observation data to assess the NEE products of the global grid. The NEE dataset is publicly available via the figshare with https://doi.org/10.6084/m9.figshare.20485563.v1.

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.

Abstract 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.

The dynamics of Gross Primary Productivity (GPP) is key to understand the global carbon cycle. Multiple GPP products are currently available based on remote sensing, Light Use Efficiency model (LUE) or diagnostic biophysical model. However, little knowledge is available on the spatial patterns of the uncertainty of different GPP products and their potential drivers over the Central Asia (CA), a fragile environment for accurate GPP estimation. This study investigates the sensitivity of the 8-day, monthly and yearly GPP uncertainties based on the three-cornered hat (TCH) method and Shapley additive explanation (SHAP) model in terms of vegetation, energy, water, climate and terrain factors in the dryland ecosystem during the 2003–2015 period. Ten GPP products were examined, including one product (FLUXCOM) from machine learning (ML), six products (EC-LUE, FluxSat, LUEopt, MODIS, MuSyQ and VPM) based on the (LUE), two products (GOSIF and NIRv) from satellite-based direct proxies (Proxies) and one product (PML) from the diagnostic biophysical model. The results indicate that the spatial distribution of the ten GPP products in CA showed similar patterns at different time scales, but with values varied at different products and time scales. According to the eddy covariance (EC) observations and the TCH-based uncertainties, the FLUXCOM product showed smaller relative uncertainties than other products. The attribution analysis denotes that the sources of uncertainty of the GPP varied for each product, and thus the improvement strategies for different products should be implemented separately The FLUXCOM should adapt the vegetation- related module to the dryland environment of CA. The LUE model should optimize the LUE parameters for the dryland ecosystem and incorporate the water related variables in the model. The Proxies model should incorporate the water and energy variables (such as soil moisture and radiation) as input data to improve their performance in CA. The diagnostic model should consider the elevation variable as input data, which may improve the performance of the PML in CA. Our results do not only provide an important basis for the selection of GPP products in the study of the carbon cycle in CA, but also offer a new insight into the GPP model development and improvement for the dryland ecosystem.

Despite various known topological polar structures, the dynamic property of isolated ones is still poorly understood. Here, the authors show the controlled nucleation and ability to move of isolated three-fold vertices under an applied electric field.

Abstract 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.

ObjectiveTo 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).MethodsSeven 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.ResultsA 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.ConclusionSFI 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 registrationhttps://inplasy.com/inplasy-2022-7-0026, identifier INPLASY202270026.

IntroductionOnline health information seeking has been verified to play a crucial role in improving public health and has received close scholarly attention. However, the seeking behavior of older adults, especially the underlying mechanism through which they are motivated to seek health information online, remains unclear. This study addresses the issue by proposing a theoretical model leveraging social cognitive theory.MethodsIT self-efficacy and IT innovativeness were identified as personal factors and professional support and social support were identified as environmental factors. We conducted a survey that included 347 older people in China and examined the research hypotheses with a structural equation model.ResultsIT self-efficacy and IT innovativeness facilitate older adults to seek health information online by increasing their perceived benefit of using the internet. Additionally, professional support and social support enhanced older adults' online seeking behavior by promoting their health awareness. We also found that perceived benefit displayed a stronger impact than health awareness on older adults' behavior related to searching for health information online.ConclusionThis study reveals that IT self-efficacy, IT innovativeness, professional support, and social support will promote older adults to seek health information online by enhancing their health awareness and perceived benefit. The findings of this study provide significant theoretical and practical implications.

Online health communities (OHCs) are popular channels increasingly used by patients for acquiring professional medical knowledge to manage their own health. In OHCs, physicians provide not only consultation services but also educational medical knowledge to improve patient education. So far, it remains unknown regarding how the educational medical knowledge sharing influence engagement of patients in OHCs. Drawing on the signaling theory, we examined the effects of paid vs. free knowledge-sharing of physicians on patients' engagement behaviors (i.e., patient visit and patient consultation). Data collected from one of the largest OHCs in China show that both paid and free knowledge-sharing are favorable for patients' engagement. Particularly, these two types of knowledge-sharing vary in their impacts. Moreover, physicians' registration duration in OHCs has a positive moderating effect on the relationship between physician's knowledge-sharing and patient engagement. Managers seeking to engage patients at OHCs are advised to share educational medical knowledge to entice them and the patient engagement is more salient for the knowledge shared by physicians active at the platforms for longer time history.

Background: Single nucleotide polymorphisms (SNPs) of essential enzymes for alcohol metabolism ADH1B, ADH1C, and ALDH2 are commonly regarded as genetic biomarkers for esophageal squamous cell carcinoma (ESCC) susceptibility. However, there have not been any reports on relations between SNPs of these genes and the prognosis of postoperative radiotherapy in ESCC. The current study aimed to understand the associations between gene variants of alcohol metabolism and adjuvant radiotherapy’s prognosis in ESCC.Methods: This study retrospectively analyzed 110 ESCC patients from our institution who received adjuvant radiotherapy after surgery. The SNPs of ADH1B rs1229984, ADH1C rs1789924, and ALDH2 rs671 were detected by Sanger sequencing using formalin-fixed paraffin-embedded tumor samples. A nomogram was drawn based on prognostic factors associated with overall survival (OS).Results: ADH1C rs1789924 (C>T) was associated with poor DFS and OS in ESCC patients undergoing adjuvant radiotherapy. Multivariate analysis showed that ADH1C rs1789924 (C>T) was one of the independent prognosis factors of DFS and OS. However, the genotypes of ADH1B SNP rs1229984 and ALDH2 rs671 were not associated with differences in the PFS and OS of these patients. Compared with the AJCC staging system, the nomogram containing the ADH1C genotype can more effectively and accurately predict the survival time of ESCC after surgery and adjuvant radiotherapy.Conclusion: ADH1C rs1789924 might be a prognostic genetic biomarker for ESCC patients undergoing surgery and postoperative radiotherapy.

BackgroundRadiotherapy plays an important effect on the standard therapy of esophageal squamous cell carcinoma (ESCC). However, the efficacy of the therapy is limited and a few patients do not achieve satisfactory treatment results due to the existence of radiation resistance. Therefore, it is necessary to identify the potential predictive biomarkers and treatment targets for ESCC.MethodsWe performed the whole-exome sequencing to determine the germline and somatic mutations in ESCC. Functional enrichment and pathway-based protein-protein interaction analyses were used to ascertain potential regulatory networks. Cell survival and cell death after treatment with radiotherapy were determined by CCK-8 and LDH release assays in ESCC cells. The correlations of NOTCH1 and tumor immune infiltration were also analyzed in ESCC.ResultsOur results showed that 344 somatic and 65 germline differentially mutated genes were detected to be radiosensitivity-related loci. The tumor mutational burdens (TMB) or microsatellite instability (MSI) were not significantly correlated with the response to radiotherapy in ESCC patients. Pathway-based protein-protein interaction analyses implied several hub genes with most nodes (such as PIK3CA, NOTCH1, STAT3 and KDR). The in vitro studies showed that the knockdown of NOTCH1 inhibited cell survival and rendered more cell death after the treatment with radiotherapy in ESCC cells, while NOTCH1 overexpression had the opposite effects. Moreover, NOTCH1, frequently up-regulated in ESCC, was negatively correlated with activated B cell and immature dendritic cell in ESCC. High expression of NOTCH1 was accompanied with the low levels of some immunotherapy-related cells, including CD8(+) T cells and NK cells.ConclusionsThese results indicate the differences of the germline mutations and somatic mutations between the radiosensitive and radioresistence groups in ESCC and imply that NOTCH1 plays important roles in regulating the radiosensitivity of ESCC. The findings might provide the biomarkers and potential treatment targets for improving the sensitivity to radiotherapy in ESCC.

BackgroundA novel nomogram based on the Surveillance, Epidemiology, and End Results (SEER) database has been developed to predict the survival of patients with esophageal carcinoma who received neoadjuvant therapy followed by surgery. We aimed to evaluate the accuracy and value of the nomogram with an external validation cohort.MethodsA total of 2,224 patients in SEER database were divided into the training cohort (n = 1556) and the internal validation cohort (n = 668), while 77 patients in our institute were enrolled in the external validation cohort. A Cox proportional hazards regression model was used to develop a nomogram based on the training cohort, while the C-indexes, the calibration curves, receiver operating characteristics curve (ROC), and Kaplan-Meier survival curve were applied in the internal and external validation cohort.ResultsFive independent risk factors were identified and integrated into the nomogram (C-index = 0.645, 95%CI 0.627–0.663). The nomogram exhibited good prognostic value in the internal validation cohort (C-index = 0.648 95%CI 0.622–0.674). However, the C-index, calibration plot, receiver operating characteristics curve (ROC) analysis, Kaplan-Meier survival curve of the nomogram in the external validation cohort were not as good as the training and internal validation cohort (C-index = 0.584 95%CI 0.445–0.723). Further analysis demonstrated that the resection margin involvement (R0, R1, or R2 resection) was an independent risk factor for the patients, which was not included in the SEER cohort.Conclusionsthe nomogram based on the SEER database fails to accurately predict the prognosis of the patients in the external validation cohort, which can be caused by the absence of essential information from the SEER database.

Controlling topological polar vortices promises to open up new applications for ferroelectric materials. Here, the authors proposed a method to mechanically manipulate polar vortices and monitored the transition between vortex and ferroelectric phase by in-situ scanning transmission electron microscopy.

ObjectiveStage I and II cervical cancer with pelvic and/or para-aortic lymph node (LN) metastases are upstaged to stage IIIC under the new FIGO 2018 staging system, and radical chemoradiotherapy was recommended. But heterogeneity in outcome existed in this group of patients. We conducted this retrospective analysis to evaluate the heterogeneity of these patients and tried to provide a more detailed classification to reflect the prognosis and guide the treatment. We also evaluated the efficacy and toxicity of surgery followed by sequential chemoradiotherapy in this cohort.MethodsEarly-stage cervical cancer with LN involvement that had radical hysterectomy followed by sequential chemoradiotherapy were retrospectively analyzed. Survival analyses were conducted to identify the prognostic factors.ResultsA total of 242 patients were included in the study; 64 (26.4%) patients had treatment failure, and 51 (21.1%) died. Pathology, T stage, the number of pathologic LN (pLN), and neoadjuvant chemotherapy or not were independent prognostic factors for disease-free survival and overall survival (OS). Patients with T1N < 3 pLN had significantly better survival than T2N < 3 pLN/T1-2 N≥ 3 pLN, with failure rates of 11.6% and 35.8% in each group; and 5 year OS was 92% and 62%, respectively (P = 0.000). About 1.5% of the patients discontinued radiotherapy, and 14.1% had G3-4 hematological toxic effects during radiotherapy; 1.7% developed G2-3 lower limb edema, and 2.9% developed severe urinary toxicity.ConclusionNodal involvement alone is inadequate as the sole pathologic factor to predict survival in early-stage cervical cancer. The combination of tumor and node subcategory provides better prognostic discrimination.

BackgroundPancreatic cancer (PC) is one of the most lethal human cancers, and radiation therapy (RT) is an important treating option. Many patients diagnosed with PC do not achieve objective responses because of the existence of intrinsic and acquired radioresistance. Therefore, biomarkers, which predict radiotherapy benefit in PC, are eagerly needed to be identified.MethodsWhole-exome sequencing of six pancreatic ductal adenocarcinoma patients (PDAC) (three with a good response and three with a poor response) who had received radical surgery and then radiotherapy has been performed as standard of care treatment. Somatic and germline variants and the mutational signatures were analyzed with bioinformatics tools and public databases. Functional enrichment and pathway-based protein-protein interaction analyses were utilized to address the possibly mechanism in radioresistance. MTT, LDH, and colony formation assay were applied to evaluate cell growth and colony formation ability.ResultsIn the present study, somatic mutations located in 441 genes were detected to be radiosensitivity-related loci. Seventeen genes, including the Smad protein family members (SMAD3 and SMAD4), were identified to influence the radiosensitivity in PDAC. The SMAD3 and SMAD4 genes mutate differently between radiosensitive and radioresistant PDAC patients. Mutation of SMAD3 potentiates the effects of ionizing radiation (IR) on cell growth and colony formation in PDAC cells, whereas mutation of SMAD4 had the opposite effects. SMAD3 and SMAD4 regulate the radiosensitivity of PDAC, at least in part, by P21 and FOXO3a, respectively.ConclusionsThese results indicate that mutations of SMAD3 and SMAD4 likely cause the difference of response to radiotherapy in PDAC, which might be considered as the biomarkers and potential targets for the radiotherapy of pancreatic cancer.

A growing body of evidence suggests that the interaction between immune and metabolic responses is essential for maintaining tissue and organ homeostasis. These interacting disorders contribute to the development of chronic diseases associated with immune-aging such as diabetes, obesity, atherosclerosis, and nonalcoholic fatty liver disease. In Diabetic wound (DW), innate immune cells respond to the Pathogen-associated molecular patterns (PAMAs) and/or Damage-associated molecular patterns (DAMPs), changes from resting to an active phenotype, and play an important role in the triggering and maintenance of inflammation. Furthermore, the abnormal activation of innate immune pathways secondary to immune-aging also plays a key role in DW healing. Here, we review studies of innate immune cellular molecular events that identify metabolic disorders in the local microenvironment of DW and provide a historical perspective. At the same time, we describe some of the recent progress, such as TLR receptor-mediated intracellular signaling pathways that lead to the activation of NF-κB and the production of various pro-inflammatory mediators, NLRP3 inflammatory via pyroptosis, induction of IL-1β and IL-18, cGAS-STING responds to mitochondrial injury and endoplasmic reticulum stress, links sensing of metabolic stress to activation of pro-inflammatory cascades. Besides, JAK-STAT is also involved in DW healing by mediating the action of various innate immune effectors. Finally, we discuss the great potential of targeting these innate immune pathways and reprogramming innate immune cell phenotypes in DW therapy.

The Luo-hua-zi-zhu (LHZZ) granule has been widely used for the treatment of colorectal adenoma (CRA), which is a precursor of colorectal cancer (CRC). However, the active components of LUZZ and its mechanism of action against CRA have not yet been elucidated. This study was designed to investigate the effect of LHZZ on CRA and explore its pharmacological mechanisms. First, a total of 24 chemical constituents were identified in the 50% aqueous methanol extract of LHZZ granule based on the mass fragment patterns and mass spectral library using the high resolution UPLC-Q-TOF MS/MS system. Subsequently, based on a network pharmacology study, 16 bioactive compounds and 28 targets of the LHZZ associated with CRA were obtained, forming a compound-target network. Molecular docking tests showed tight docking of these compounds with predicted targeted proteins. The protein–protein interaction (PPI) network identified AKT1, CASP3, TP53 and EGFR as hub targets. The Kyoto Encyclopedia of Genes and Genomes pathway network and pathway-target-compound network revealed that the apoptosis pathway was enriched by multiple signaling pathways and multiple targets, including the hub targets. Finally, the reliability of the core targets was evaluated using molecular docking technology and in vitro studies. Our study indicated that the LHZZ particle has preventive and treatment effect on colorectal adenoma through multi-component, multi-target and multi-pathway.

Neutrophil is known to critically impact the development of renal diseases (e.g., the clear cell renal cell carcinoma (ccRCC)), whereas the heterogeneity of neutrophils in ccRCC remains unclear. In the present study, kidney biopsies from healthy donors and ccRCC tissues were collected for single-cell RNA sequencing (scRNA-seq). In addition, the subpopulations of neutrophils in a healthy kidney and in the tumor microenvironment (TME) of ccRCC were expressed and then analyzed. The genes reported previously were mapped to all subpopulations identified here. On that basis, biological theme comparison and Gene Set Enrichment Analysis (GSEA) were employed to reveal and compare relevant biological functions. In a healthy kidney, neutrophils exhibit two subpopulations: one is more associated with renal autoimmunity, probably acting as therapeutic target; the other is suggested to resist infectious microorganisms. It is noteworthy that six subpopulations were identified in ccRCC biopsy, and two were more relevant to autoimmunity, while the other four are more relevant to the tumor pathology. Besides, ccRCC neutrophil could resist anticancer immune therapies of ipilimumab and pembrolizumab for their low/no expressions of CTLA-4, PD-1, and PD-L1. Thus, this study can help understand the heterogeneity and pathological significance of neutrophils in renal diseases.

Abstract Metastatic spread is the mechanism in more than 90 percent of cancer deaths and current therapeutic options, such as systemic chemotherapy, are often ineffective. Here we provide a proof of principle for a novel two-pronged modality referred to as Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) having the potential to safely eradicate both primary tumors and distant metastatic foci. Using a combination of immune-checkpoint inhibition and plasmonic gold nanostar (GNS)–mediated photothermal therapy, we were able to achieve complete eradication of primary treated tumors and distant untreated tumors in some mice implanted with the MB49 bladder cancer cells. Delayed rechallenge with MB49 cancer cells injection in mice that appeared cured by SYMPHONY did not lead to new tumor formation after 60 days observation, indicating that SYMPHONY treatment induced effective long-lasting immunity against MB49 cancer cells.

Understanding ferroelectricity at reduced dimensions will be important for future sub-nanoscale devices based on ferroelectrics. Using high resolution electron microscopy; Gaoet al., observe the existence of a measurable polarization at a thickness of just 1.5-unit cells

[Objectives] To establish a TLC and content determination method of Pileostegia tomentellal, with umbelliferone as the indicator component. [Methods] TLC identification was performed by silica gel G thin layer plate with n-hexane-ethyl acetate (4:3) as the developing agent, and the plate was examined by UV lamp (365 nm). The umbelliferone content was determined by HPLC; Inertsil ODS-3 C18 column (4.60 mm x 250 mm, 5 µm); mobile phase acetonitrile-0.2% phosphoric acid gradient elution; detection wavelength 320 nm, flow rate 1.0 mL/min, column temperature 30 °C, injection volume 10 µL. [Results] The chromatogram of P. tomentellal showed the same color spot in the same position as that of reference medicinal material, and the spot was clear with good specificity. Umbelliferone showed a good linear relationship when the injection volume was 2.63 - 131.27 µg/mL (R² = 0.999 7). The average recovery of umbelliferone in the low, middle and high adding groups of P. tomentellal was 99.57% and the RSD was 2.15%. [Conclusions] The method can effectively identify Yao medicine P. tomentellal and accurately determine the content of umbelliferone in medicinal materials, which will provide a scientific basis for the development and utilization of medicinal resources of Yao medicine P. tomentellal. [ABSTRACT FROM AUTHOR]

[Objectives] To establish a method for quality analysis of Medicine Pileostegia tomentella Hand. -Mazz. [Methods] According to the testing method of Chinese Pharmacopoeia (2020 Edition), the water content, total ash and alcohol-soluble extract of P. tomentella Hand. -Mazz. were determined. [Results] 10 batches of P. tomentella Hand. -Mazz. from different habitats and in different collection time in Guan- gxi all had the same plant morphology and medicinal properties. The experimental results showed that the water content was 7.92%-10.35%, the total ash content was 5.53% -6.62%, the acid-insoluble ash content was 0.59%-0.76%, and the extract content was 11.63%-16.12%. [Conclusions] The identification method in this study can be used for the quality analysis of P. tomentella Hand. -Mazz., and the experimen- tal results can provide a scientific basis for the development and utilization of P. tomentella Hand. -Mazz. and the establishment of its quality standard. [ABSTRACT FROM AUTHOR]

The isomers of conducting polymers usually have different properties, however, there are still few studies on the isomeric effect of conducting polymers in supercapacitors field. In this work, four isomers (4-nitroindole, 5-nitroindole, 6-nitroindole, and 7-nitroindole) were selected as the research objects to study the positional isomeric effect of nitro group substituted indoles on the electropolymerization and the capacitance performances of their polymers. The results show that the prepared poly(5-nitroindole) (5-PNI) and poly(6-nitroindole) (6-PNI) are in nanowires structure, poly(7-nitroindole) (7-PNI) is in dense structure, while poly(4-nitroindole) (4-PNI) fails to be prepared. In addition, the as-prepared 5-PNI, 6-PNI nanowires and dense 7-PNI exhibit very different electrochemical properties and capacitance performances. Taking into account the specific capacitance (364 F g-1 at 5 mV s-1), rate capability (58.5%) and cyclic stability (94% capacitance retention after 1000 cycles test), it can be concluded that 5-PNI is the most suitable electrode material in the field of supercapacitors. [ABSTRACT FROM AUTHOR]