Double-sided microstructured flexible iontronic pressure sensor with wide linear sensing range.

Iontronic pressure sensors have garnered significant attention for their potential in wearable electronic devices. While simple microstructures can enhance sensor sensitivity, the majority of them predominantly amplify sensitivity at lower pressure ranges and fail to enhance sensitivity at higher pressure ranges, leading to nonlinearity. In the absence of linear sensitivity in a pressure sensor, users are unable to derive precise information from its output, necessitating further signal processing. Hence, crafting a linearity flexible pressure sensor through a straightforward approach remains a formidable task. Herein, a double-sided microstructured flexible iontronic pressure sensor is presented with wide linear sensing range. The ionic gel is made by 1-Ethyl-3-methylimidazolium bis(tri-fluoromethylsulfonyl)imide (EMIM:TFSI) into the matrix of poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), which acts as active layer, featuring irregular microstructures (IMS) and pyramid microstructures (PMS) on both sides. Unlike previous complex methods, IMS and uniform PMS are easily and achieved through pattern transfer from a sandpaper mold and micro-pyramid template. The iontronic pressure sensor exhibits exceptional signal linearity with R2 values of 0.9975 and 0.9985, in the wide pressure range from 100 to 760 kPa and 760 kPa to 1000 kPa, respectively. This outstanding linearity and wide sensing range stem from a delicate balance between microstructure compression and mechanical alignment at the ionic gel interface. This study provides valuable insights into achieving linear responses by strategically designing microstructures in flexible pressure sensors, with potential applications in intelligent robots and health monitoring.

Adjuvant therapy provides no additional recurrence-free benefit for esophageal squamous cell carcinoma patients after neoadjuvant chemoimmunotherapy and surgery: a multi-center propensity score match study.

Purpose: The need for adjuvant therapy (AT) following neoadjuvant chemoimmunotherapy (nICT) and surgery in esophageal squamous cell cancer (ESCC) remains uncertain. This study aims to investigate whether AT offers additional benefits in terms of recurrence-free survival (RFS) for ESCC patients after nICT and surgery. Methods: Retrospective analysis was conducted between January 2019 and December 2022 from three centers. Eligible patients were divided into two groups: the AT group and the non-AT group. Survival analyses comparing different modalities of AT (including adjuvant chemotherapy and adjuvant chemoimmunotherapy) with non-AT were performed. The primary endpoint was RFS. Propensity score matching(PSM) was used to mitigate inter-group patient heterogeneity. Kaplan-Meier survival curves and Cox regression analysis were employed for recurrence-free survival analysis. Results: A total of 155 nICT patients were included, with 26 patients experiencing recurrence. According to Cox analysis, receipt of adjuvant therapy emerged as an independent risk factor(HR:2.621, 95%CI:[1.089,6.310], P=0.032), and there was statistically significant difference in the Kaplan-Meier survival curves between non-AT and receipt of AT in matched pairs (p=0.026). Stratified analysis revealed AT bring no survival benefit to patients with pathological complete response(p= 0.149) and residual tumor cell(p=0.062). Subgroup analysis showed no significant difference in recurrence-free survival between non-AT and adjuvant chemoimmunotherapy patients(P=0.108). However, patients receiving adjuvant chemotherapy exhibited poorer recurrence survival compared to non-AT patients (p= 0.016). Conclusion: In terms of recurrence-free survival for ESCC patients after nICT and surgery, the necessity of adjuvant therapy especially the adjuvant chemotherapy, can be mitigated.

Effectiveness and safety of camrelizumab-containing neoadjuvant therapy in patients with esophageal squamous cell carcinoma: a prospective multicenter observational cohort study.

Background: Camrelizumab has been demonstrated to be a feasible treatment option for locally advanced esophageal squamous cell carcinoma (ESCC) when combined with neoadjuvant chemotherapy. This trial was conducted to investigate the effectiveness and safety of camrelizumab-containing neoadjuvant therapy in patients with ESCC in daily practice. Methods: This prospective multicenter observational cohort study was conducted at 13 tertiary hospitals in Southeast China. Patients with histologically or cytologically confirmed ESCC [clinical tumor-node-metastasis (cTNM) stage I-IVA] who had received at least one dose of camrelizumab-containing neoadjuvant therapy were eligible for inclusion. Results: Between June 1, 2020 and July 13, 2022, 255 patients were enrolled and included. The median age was 64 (range, 27 to 82) years. Most participants were male (82.0%) and had clinical stage III-IVA diseases (82.4%). A total of 169 (66.3%) participants underwent surgical resection; 146 (86.4%) achieved R0 resection, and 36 (21.3%) achieved pathological complete response (pCR). Grades 3-5 adverse events (AEs) were experienced by 14.5% of participants. Reactive cutaneous capillary endothelial proliferation occurred in 100 (39.2%) of participants and all were grade 1 or 2. Conclusions: Camrelizumab-containing neoadjuvant therapy has acceptable effectiveness and safety profiles in real-life ESCC patients.

PTMA binds to HMGB1 to regulate mitochondrial oxidative phosphorylation and thus affect the malignant progression of esophageal squamous cell carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the digestive tract with complex pathogenesis. There is a pressing need to search for ESCC targeted therapy sites and explore its pathogenesis. Prothymosin alpha (PTMA) is abnormally expressed in numerous tumors and has a significant regulatory effect on tumor malignant progression. However, the regulatory role and mechanism of PTMA in ESCC have not yet been reported. Methods: We first detected the PTMA expression in ESCC patients, subcutaneous tumor xenograft models of ESCC, and ESCC cells. Subsequently, PTMA expression in ESCC cells was inhibited by cell transfection, and cell proliferation and apoptosis were detected by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry, and Western blot. A dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect reactive oxygen species (ROS) level in cells, and MitoSOX fluorescent probe, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolyl carbocyanine iodide (JC-1) staining, mitochondrial complex kit, and Western blot were used to detect the expression of mitochondrial oxidative phosphorylation. Next, the combination between PTMA and high mobility group box 1 (HMGB1) was detected using Co-immunoprecipitation (co-IP) and immunofluorescence (IF) techniques. Finally, the expression of PTMA was inhibited and the expression of HMGB1 was overexpressed in cells via cell transfection, and the regulatory effect of PTMA and HMGB1 binding on mitochondrial oxidative phosphorylation in ESCC was determined through related experiments. Results: The expression of PTMA in ESCC was abnormally elevated. The inhibition of PTMA expression in ESCC cells significantly decreased the activity of ESCC cells and increased their apoptosis. Moreover, interference with PTMA can induce ROS aggregation in ESCC cells by inhibiting mitochondrial oxidative phosphorylation, which may be achieved by binding to HMGB1. Conclusions: PTMA binds to HMGB1 to regulate mitochondrial oxidative phosphorylation, thereby affecting the malignant progression of ESCC.

PHLDA3 activated by BARX2 transcription, suppresses the malignant development of esophageal squamous cell carcinoma by downregulating PI3K/AKT levels.

BACKGROUND: Low pleckstrin homology-like domain family A, member 3 (PHLDA3) expression has been reported to be associated with cancer specificity and disease-free survival in esophageal squamous cell carcinoma (ESCC), and was an independent predictor of postoperative recurrence. However, the specific mechanisms involved are still unclear. This paper aimed to explore the role and its mechanisms of PHLDA3 in ESCC. MATERIALS AND METHODS: PHLDA3 and BarH-like homeobox 2 (BARX2) expressions in ESCC were predicted by Gene Expression Profiling Interactive Analysis (GEPIA) analysis and determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western Blot. Western blot detected the expression of proteins associated with migration, angiogenesis and phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway. The University of California Santa Cruz Genomics Institute (UCSC) database predicted that the relationship of BARX2 and PHLDA3 promoter and JASPAR identified the possible binding sites. Dual luciferase gene reporter verified PHLDA3 promoter activity, and the relationship of both was determined by chromatin immunoprecipitation (CHIP). Cell counting kit (CCK)-8, 5-ethynyl-2'-deoxyuridine (EDU) and colony formation were used to assess cell proliferation. Wound healing and transwell were used to detect cell migration and invasion ability. Tube formation assay was applied to assess angiogenesis. Mice were injected with transfected KYSE30 cells under the right axilla. Body weight and tumor volume and mass were recorded for each group of mice. Immunohistochemistry was performed to detect KI67 level in tumor tissues. RESULTS: Both PHLDA3 and BARX2 were downregulated in ESCC. The upregulated PHLDA3 suppressed PI3K/AKT expression. In addition, BARX2 bound to the PHLDA3 promoter and transcriptionally activated PHLDA3. PHLDA3 overexpression inhibited ESCC cell proliferation, migration, invasion and angiogenesis, but this effect was reversed by BARX2 knockdown. In addition, BARX2 overexpression inhibited ESCC cell proliferation, migration, invasion and angiogenesis, but this effect was reversed by PHLDA3 knockdown. CONCLUSION: PHLDA3 was transcriptionally activated by BARX2 and inhibited malignant progression of ESCC by downregulating PI3K/AKT levels.

MicroRNA-30a-5p Promotes Chronic Heart Failure in Rats by Targeting Sirtuin-1 to Activate the Nuclear Factor-κB/NOD-Like Receptor 3 Signaling Pathway.

OBJECTIVE: MicroRNA-30a-5p (miR-30a-5p) has been identified as a marker of heart failure; however, its functional mechanisms in chronic heart failure (CHF) remain unknown. We aim to investigate the role of miR-30a-5p targeting sirtuin-1 (SIRT1) in myocardial remodeling in CHF via the nuclear factor-κB/NOD-like receptor 3 (NF-κB/NLRP3) signaling pathway. METHODS: CHF rat models were established using aortic coarctation. The expression of miR-30a-5p, SIRT1, and the NF-κB/NLRP3 signaling pathway-related factors in CHF rats was determined. The CHF rats were then respectively treated with altered miR-30a-5p or SIRT1 to explore their roles in cardiac function, myocardial function, inflammatory response, pathological changes, and cardiomyocyte apoptosis. The binding relation between miR-30a-5p and SIRT1 was confirmed. RESULTS: MiR-30a-5p was upregulated whereas SIRT1 was downregulated in myocardial tissues of CHF rats. MiR-30a-5p inhibition or SIRT1 overexpression improved cardiac and myocardial function, and suppressed the inflammatory response, alleviated pathological changes and inhibited cardiomyocyte apoptosis in CHF rats. MiR-30a-5p targeted SIRT1 to regulate the NF-κB/NLRP3 signaling pathway. In CHF rats, downregulated miR-30a-5p and silenced SIRT1 could reverse the beneficial effects of downregulated miR-30a-5p. CONCLUSION: Inhibited miR-30a-5p inhibits CHF progression via the SIRT1-mediated NF-κB/NLRP3 signaling pathway.

IGHG1 upregulation promoted gastric cancer malignancy via AKT/GSK-3ß/ß-Catenin pathway.

BACKGROUND: Despite current advances in gastric cancer treatment, disease metastasis and chemo-resistance remain as major hurdles against better overall prognosis. Previous studies indicated that IGHG1 as well as -Catenin serve as important regulators of tumor cellular malignancy. Therefore, understanding detailed molecular mechanism and identifying druggable target will be of great potentials in future therapeutic development. METHODS: Surgical tissues and gastric cancer cell lines were retrieved to evaluate IGHG1 expression for patients with or without lymph node/distal organ metastasis. Functional assays including CCK8 assay, Edu assay, sphere formation assay and transwell assay, wound healing assay, etc. were subsequently performed to evaluate the impact of IGHG1/-catenin axis on tumor cell proliferation, migration and chemo-resistance. RESULTS: Gastric cancer tissues and tumor cell lines demonstrated significantly higher level of IGHG1. Functional study further demonstrated that IGHG1 promoted proliferative and migration as well as chemo-resistance of gastric cancer tumor cells. Further experiments indicated that IGHG1 activated AKT/GSK-3/-Catenin axis, which played crucial role in regulation of proliferative and chemo-resistance of gastric cancer cells. CONCLUSION: This study provided novel evidences that IGHG1 acted as oncogene by promotion of gastric cancer cellular proliferation, migration and chemo-resistance. Our research further suggested that IGHG1/AKT/GSK-3ß/ß-Catenin axis acted as novel pathway which regulated gastric cancer cellular malignant behavior. Our research might inspire future therapy development to promote overall prognosis of gastric cancer patients.

M2 Macrophage-Derived Exosomal lncRNA AFAP1-AS1 and MicroRNA-26a Affect Cell Migration and Metastasis in Esophageal Cancer.

Exosomes from cancer cells or immune cells, carrying bio-macromolecules or long non-coding RNAs (lncRNAs), participate in tumor pathogenesis and progression by modulating the microenvironment. This study aims to explore the function of M2 macrophage-derived exosomes on the invasion and metastasis of esophageal cancer (EC) with the involvement of the lncRNA AFAP1-AS1/microRNA-26a (miR-26a)/activating transcription factor 2 (ATF2) axis. We found that lncRNA AFAP1-AS1 could specifically bind to miR-26a, thus affecting the expression of miR-26a, and ATF2 was the direct target of miR-26a. Compared with M1 macrophage-derived exosomes, M2 macrophage-derived exosomes exhibited higher AFAP1-AS1 and ATF2 expression and lower miR-26a expression. Moreover, extracellular AFAP1-AS1 could be moved to KYSE410 cells via being incorporated into M2 macrophage-derived exosomes. M2 macrophage-derived exosomes could downregulate miR-26a and promote the expression of ATF2 through high expression of AFAP1-AS1, thus promoting the migration, invasion, and lung metastasis of EC cells; M2-exosomes upregulating AFAP1-AS1 or downregulating miR-26a ameliorated this effect. In summary, M2 macrophage-derived exosomes transferred lncRNA AFAP1-AS1 to downregulate miR-26a and upregulate ATF2, thus promoting the invasion and metastasis of EC. Targeting M2 macrophages and the lncRNA AFAP1-AS1/miR-26a/ATF2 signaling axis represents a potential therapeutic strategy for EC.

The Long Non-Coding RNA-RoR Promotes the Tumorigenesis of Human Colorectal Cancer by Targeting miR-6833-3p Through SMC4.

BACKGROUND: Long non-coding RNA regulator of reprogramming (LINC-RoR) has shown different expressions in a variety of tumors as a stem cell inducer through reprogramming regulation. However, its role and regulation mechanisms in colorectal cancer (CRC) are still unclear. MATERIALS AND METHODS: Quantitative real-time PCR and Western blot were performed to examine LINC-RoR expression in paired CRC samples and cell lines. The relationship of LINC-RoR expression with clinicopathological characteristics and clinical outcomes was analyzed. The biological functions of LINC-RoR were studied by MTS and colony formation in vitro. Cell apoptosis was analysed by the flow cytometry. The Dual-luciferase reporter assays and RIP assays were performed to explore the regulatory relationship of LINC-RoR. RESULTS: In this study, we found that LINC-RoR was upregulated in CRC cell lines and tissues. High expression of LINC-RoR was associated with poorer survival time and multivariate analysis results showed that LINC-RoR was an independent risk factor of tumor malignancy progression. Overexpression of LINC-RoR promoted the cell proliferation and knocked down it can reverse the effect in vitro. The regulatory network of LINC-ROR/miR-6833-3p/SMC4 was predicted with bioinformatics analysis tools and validated via dual-luciferase reporter assays and RIP. Further study revealed that in overexpression LINC-RoR cell lines the expression of miR-6833-3p was downregulated and miR-6833-3p can inhibit its target gene SMC4, the apoptosis-related protein. CONCLUSION: We concluded that LINC-RoR functions as an oncogene in CRC through the miR-6833-3p/SMC4 pathway.

[Serum Level of MiR-609 and Its Clinical Prognostic Value in Patients with Thalassemia].

OBJECTIVE: To investigate the level of serum microRNA-609 and its clinical prognostic value in patients with thalassemia. METHODS: One hundred and twenty-seven patients with thalassemia treated in our hospital from April 2017 to April 2018 were selected, 100 healthy persons were selected as control group. The changes of miR-609 were analyzed by RT-PCR, the relationship between miR-609 and clinical indicators of thalassemia was analyzed, and the prognostic risk factors of thalassemia were evaluated by multivariate logistic regression analysis. RESULTS: The relative expression level of miR-609 in thalassemia patients was 3.17±0.24, which was significantly higher than that in control group (P<0.05). The levels of ALT, Plt and MCH in patients with high expression of miR-609 were significantly higher than those in patients with low expression of miR-609 (P<0.05). The levels of Hb and sICAM-1 in patients with high expression of miR-609 were significantly lower than those in patients with low expression of miR-609 (P<0.05). There was no correlation between the level of miR-609 and the patient's sex, age and AST (P>0.05). The incidence rate of mild anemia in high expression group was significantly lower than that in low expression group (P<0.05). There was no correlation between the level of miR-609 and the incidence rate of moderate anemia (P>0.05). The number of patients with severe anemia in the miR-609 high expression group was higher than that in miR-609 low expression group (P<0.05). The incidence rate of dizziness, fatigue and fever in patients with miR-609 high expression group was significantly higher than those in patients with miR-609 low expression (P<0.05). There was no correlation between the level of miR-609 and the incidence rate of nausea in patients with thalassemia. ROC curve showed that the AUC value of microRNA-609 was 0.862, the sensitivity was 83.6%, and the specificity was 84.1%, which suggested that miR-609 had a high diagnostic value for thalassemia. Multivariate logistic regression analysis showed that MCH and mir-609 were risk factors for poor prognosis of thalassemia patients. CONCLUSION: The increased level of serum miR-609 in patients with thalassemia is a risk factor for poor prognosis and can be used as a reference index for evaluating the efficacy for patients.

Survival based radiographic-grouping for esophageal squamous cell carcinoma may impact clinical T stage.

Most patients diagnosed with thoracic esophageal squamous cell carcinoma (ESCC) have progressed beyond surgical resection as a therapeutic option. Difficulties in the proper assessment of tumor invasion depth before treatment complicate determination of the type and extent of therapy. Therefore, accurate tumor clinical staging is a necessity for identifying treatment options and aiding in patient prognosis. We investigated radiographic factors as prognostic indicators for survival in ESCC. Between July 2006 - July 2010, 324 thoracic ESCC patients who underwent surgery were selected. All patients received contrast enhanced preoperative chest CT scans and esophageal barium swallow examinations. Measurement of maximal lesion cross-sectional area, the largest long diameter, largest short diameter, CT-indicated lesion length, barium-indicated lesion length and the length of pericardial fat reduction were performed. Relationships between these indicators and post-surgical survival time and the cutoff values of related factors were analyzed. Maximum long diameter, maximum lesion area and lesion length, as measured by CT imaging, were correlated with survival. Survival effects were clearly associated with group intervals, calculated by a genetic algorithm, and tumor stages. Risk-stratification intervals of esophageal lesions from radiographic imaging included: maximum long diameter < 28.7, 28.7-34.6mm, 34.6-41.4mm and >41.4mm; maximum lesion area < 355.8mm2, 355.8-568.0mm2, 568.0-907.3mm2 and >907.3mm2; and CT-indicated lesion length <30.9mm, 30.9-57.3mm, 57.3-70.6mm and > 70.6mm. The reasonable stratification of maximum esophageal lesion area, largest long diameter and lesion length measured in CT is valuable for clinical T staging of ESCC. Radiographic parameters may have prognostic clinical value in the staging of esophageal carcinoma.

Open three-stage transthoracic oesophagectomy versus minimally invasive thoraco-laparoscopic oesophagectomy for oesophageal cancer: protocol for a multicentre prospective, open and parallel, randomised controlled trial.

INTRODUCTION: Oesophageal cancer is the eighth most common cause of cancer worldwide. In 2009 in China, the incidence and death rate of oesophageal cancer was 22.14 per 100 000 person-years and 16.77 per 100 000 person-years, respectively, the highest in the world. Minimally invasive oesophagectomy (MIO) was introduced into clinical practice with the aim of reducing the morbidity rate. The mechanisms of MIO may lie in minimising the reaction to surgical injury and inflammation. There are some randomised trials regarding minimally invasive versus open oesophagectomy, with 100-850 subjects enrolled. To date, no large randomised controlled trial comparing minimally invasive versus open oesophagectomy has been reported in China, where squamous cell carcinoma predominated over adenocarcinoma of the oesophagus. METHODS AND ANALYSIS: This is a 3 year multicentre, prospective, randomised, open and parallel controlled trial, which aims to compare the effectiveness of minimally invasive thoraco-laparoscopic oesophagectomy to open three-stage transthoracic oesophagectomy for resectable oesophageal cancer. Group A patients receive MIO which involves thoracoscopic oesophagectomy and laparoscopic gastric mobilisation with cervical anastomosis. Group B patients receive the open three-stage transthoracic oesophagectomy which involves a right thoracotomy and laparotomy with cervical anastomosis. Primary endpoints include respiratory complications within 30 days after operation. The secondary endpoints include other postoperative complications, influences on pulmonary function, intraoperative data including blood loss, operative time, the number and location of lymph nodes dissected, and mortality in hospital, the length of hospital stay, total expenses in hospital, mortality within 30 days, survival rate after 2 years, postoperative pain, and health-related quality of life (HRQoL). Three hundred and twenty-four patients in each group will be needed and a total of 648 patients will finally be enrolled into the study. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Ethics Committees of all participating institutions. The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations. TRIAL REGISTRATION NUMBER: NCT02355249.

Upregulation of sex-determining region Y-box 9 (SOX9) promotes cell proliferation and tumorigenicity in esophageal squamous cell carcinoma.

Sex-determining region Y-box 9 (SOX9), a vital transcription factor, play important roles in numerous biological and pathological processes. However, the clinical significance and biological role of SOX9 expression has not been characterized in human esophageal squamous cell cancer (ESCC). Herein, we found that SOX9 was markedly upregulated, at both mRNA and protein level, in ESCC cell lines and ESCC tissues and that SOX9 expression was significantly correlated with tumor clinical stage, T classification, N classification, M classification, pathological differentiation, and shorter overall survival. The proliferation and tumorigenicity of ESCC cells were dramatically induced by SOX9 overexpression but were inhibited by SOX9 knockdown both in vitro and in vivo. Moreover, we demonstrated that upregulation of SOX9 increased the expression of phosphorylated Akt, the cyclin-dependent kinase (CDK) regulator cyclin D1, phosphorylated forkhead box O (FOXO)1, and phosphorylated FOXO3, but SOX9 downregulation decreased their expression, whereas the levels of the CDK inhibitors p21Cip1 and p27Kip1 were attenuated in SOX9-transduced cells. Taken together, our results suggest that SOX9 plays an important role in promoting the proliferation and tumorigenesis of ESCC and may represent a novel prognostic marker for the disease.