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Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy. [ABSTRACT FROM AUTHOR]

Objective: Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. Methods: Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. Results: A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). Conclusions: As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups. [ABSTRACT FROM AUTHOR]

Objective: The prognosis of patients with advanced cancers of the upper gastrointestinal (UGI) tract is poor. Systemic chemotherapy forms the basis for their treatment, with limited efficacy. Biomarkers have been introduced into clinical practice for cancer management. This study aimed to investigate the predictive and prognostic values of circulating biomarkers in patients with advanced esophageal and gastric cancers receiving chemotherapy. Design: Overall, 92 patients with advanced esophageal squamous cell carcinoma (ESCC; n = 38) and gastric adenocarcinoma (GAC; n = 54) were enrolled. We analyzed the association of circulating lymphocyte subsets, inflammatory markers, and blood cell counts with treatment efficacy and patient survival. Results: Significant differences were identified in peripheral blood parameters between the groups with different clinicopathological features. Hemoglobin (Hb, p = 0.014), eosinophil counts (p = 0.028), CD4+CD28+T/CD4+T percentage (p = 0.049), CD8+CD38+T/CD8+T percentage (p = 0.044), memory CD4+T (p = 0.007), and CD4+CD28+T (p = 0.007) were determined as predictors for achieving non-PD (progression disease) in the ESCC cohort. High levels of eosinophils (p = 0.030) and memory CD4+T cells (p = 0.026) and high eosinophil-to-lymphocyte ratio (ELR, p = 0.013) were predictors of non-PD in patients with GAC. The combined detection models exhibited good ability to distinguish between partial response (PR)/non-PR and PD/non-PD in patients with ESCC and GAC, respectively. Using the multivariate Cox model, the Eastern Cooperative Oncology Group (ECOG) score status (hazard ratio [HR]: 4.818, 95% confidence intervals [CI]: 2.076-11.184, p < 0.001) and eosinophil count (HR: 0.276, 95% CI: 0.120-0.636, p = 0.003) were independent prognostic factors of progression-free survival (PFS) in patients with ESCC. Metastatic sites (HR: 2.092, 95% CI: 1.307-3.351, p = 0.002) and eosinophil-to-lymphocyte ratio (ELR; HR: 0.379, 95% CI: 0.161-0.893, p = 0.027) were independent prognostic factors for overall survival (OS) in patients with ESCC. Differentiation (HR: 0.041, 95% CI: 0.200-0.803, p = 0.010), memory CD4+T (HR: 0.304, 95% CI: 0.137-0.675, p = 0.003), NK cells (HR: 2.302, 95% CI: 1.044-3.953, p = 0.037), and C-reactive protein-to-lymphocyte ratio (CLR; HR: 2.070, 95% CI: 1.024-4.186, p = 0.043) were independent prognostic factors for PFS in patients with GAC. Total lymphocyte counts (HR: 0.260, 95% CI: 0.086-0.783, p = 0.017), CD8+T (HR: 0.405, 95% CI: 0.165-0.997, p = 0.049), NK cells (HR: 3.395, 95% CI: 1.592-7.238, p = 0.002), and monocyte-to-lymphocyte ratio (MLR; HR: 3.076, 95% CI: 1.488-6.360, p = 0.002) were identified as independent prognostic factors associated with OS of GAC. Conclusion: Lymphocyte subsets, blood cell counts, and inflammatory parameters may predict the chemotherapeutic response and prognosis in ESCC and GAC. A combination of these markers can be used to stratify patients into risk groups, which could improve treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Studies have demonstrated a close association between connective tissue diseases (CTDs) and lung cancer (LC). Evidence supports that poor survival may be associated with the presence of CTDs in patients with LC. Methods: This retrospective cohort study investigated 29 patients with LC with CTDs, and 116 patients with LC without CTDs were enrolled as case-matched control cohorts. Medical records, therapeutic efficacy of cancer, and outcomes were analyzed. Results: The median duration from the diagnosis of CTDs to LC was 17 years. The Eastern Cooperative Oncology Group (ECOG) performance score for LC-CTD patients was worse than that for matched non-CTD LC patients. The median progression-free survival (mPFS) and overall survival (mOS) of first-line chemotherapy did not differ between patients with lung adenocarcinoma (AC) with and without CTDs. A significant difference was observed in mPFS [4 months vs. 17 months; hazard ratio (HR), 9.987; p = 0.004] and mOS (6 months vs. 35 months; HR, 26.009; p < 0.001) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment between patients with AC with and without CTDs. The presence of CTD, sex, ECOG performance status, and tumor-node-metastasis clinical stage were the independent prognostic factors in all patients with non–small cell LC (NSCLC). ECOG performance status was determined to be an independent prognostic factor in patients with LC-CTD. In patients with NSCLC with CTD (n = 26), sex (male) and worse ECOG score were the independent poor prognostic factors. Conclusions: CTDs were associated with poor survival in patients with LC. The therapeutic efficacy of first-line EGFR-TKI therapy was significantly worse in patients with lung AC with CTDs than in those without CTDs. ECOG performance status was determined as an independent prognostic factor for patients with LC and CTDs. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors works by reactivating immune cells. Considering the accessibility of noninvasive liquid biopsies, it is advisable to employ peripheral blood lymphocyte subsets to predict immunotherapy outcomes. Methods: We retrospectively enrolled 87 patients with available baseline circulating lymphocyte subset data who received first-line PD-1/PD-L1 inhibitors at Peking Union Medical College Hospital between May 2018 and April 2022. Immune cell counts were determined by flow cytometry. Results: Patients who responded to PD-1/PD-L1 inhibitors had significantly higher circulating CD8+CD28+ T-cell counts (median [range] count: 236 [30-536] versus 138 [36-460]/mL, p < 0.001). Using 190/mL as the cutoff value, the sensitivity and specificity of CD8+CD28+ T cells for predicting immunotherapy response were 0.689 and 0.714, respectively. Furthermore, the median progression-free survival (PFS, not reached versus 8.7 months, p < 0.001) and overall survival (OS, not reached versus 16.2 months, p < 0.001) were significantly longer in the patients with higher CD8+CD28+ T-cell counts. However, the CD8 +CD28+ T-cell level was also associated with the incidence of grade 3-4 immune-related adverse events (irAEs). The sensitivity and specificity of CD8 +CD28+ T cells for predicting irAEs of grade 3-4 were 0.846 and 0.667, respectively, at the threshold of CD8+CD28+ T cells = 309/mL. Conclusions: High circulating CD8+CD28+ T-cell levels is a potential biomarker for immunotherapy response and better prognosis, while excessive CD8+CD28+ T cells (= 309/mL) may also indicate the emergence of severe irAEs. [ABSTRACT FROM AUTHOR]

Several physiological changes occur during fruit storage, which include the regulation of genes, metabolisms and transcription factors. In this study, we compared 'JF308' (a normal tomato cultivar) and 'YS006' (a storable tomato cultivar) to determine the difference in accumulated metabolites, gene expression, and accessible chromatin regions through metabolome, transcriptome, and ATAC-seq analysis. A total of 1006 metabolites were identified in two cultivars. During storage time, sugars, alcohols and flavonoids were found to be more abundant in 'YS006' compared to 'JF308' on day 7, 14, and 21, respectively. Differentially expressed genes, which involved in starch and sucrose biosynthesis were observed higher in 'YS006'. 'YS006' had lower expression levels of CesA (cellulose synthase), PL (pectate lyase), EXPA (expansin) and XTH (xyglucan endoglutransglucosylase/hydrolase) than 'JF308'. The results showed that phenylpropanoid pathway, carbohydrate metabolism and cell wall metabolism play important roles in prolonging the shelf life of tomato (Solanum lycopersicum) fruit. The ATAC-seq analysis revealed that the most significantly up-regulated transcription factors during storage were TCP 2,3,4,5, and 24 in 'YS006' compared to 'JF308' on day 21. This information on the molecular regulatory mechanisms and metabolic pathways of post-harvest quality changes in tomato fruit provides a theoretical foundation for slowing post-harvest decay and loss, and has theoretical importance and application value in breeding for longer shelf life cultivars. [ABSTRACT FROM AUTHOR]

Tomato is one of the most important vegetable crops in the world and is a model plant used to study the ripening of climacteric fleshy fruit. During the ripening process of tomato fruit, flavor and aroma metabolites, color, texture and plant hormones undergo significant changes. However, low temperatures delayed the ripening process of tomato fruit, inhibiting flavor compounds and ethylene production. Metabolomics and transcriptomics analyses of tomato fruit stored under low temperature (LT, 5 °C) and room temperature (RT, 25 °C) were carried out to investigate the effects of storage temperature on the physiological changes in tomato fruit after harvest. The results of transcriptomics changes revealed that the differentially expressed genes (DEGs) involved in tomato fruit ripening, including several kinds of transcription factors (TFs) (TCP, WRKY, MYB and bZIP), enzymes involved in cell wall metabolism [beta-galactosidase (ß-GAL), pectinesterase (PE) and pectate lyase (PL), cellulose and cellulose synthase (CESA)], enzymes associated with fruit flavor and aroma [acetyltransferase (AT), malic enzyme (ME), lipoxygenase(LOX), aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH) and hexokinase (HK) ], genes associated with heat stress protein 70 and genes involved in the production of plant hormones such as Ethylene responsive factor 1 (ERF1), Auxin/indoleacetic acids protein (AUX/IAA), gibberellin regulated protein. Based on the above results, we constructed a regulatory network model of the effects of different temperatures during the fruit ripening process. According to the analysis of the metabolomics results, it was found that the contents of many metabolites in tomato fruit were greatly affected by storage temperature, including, organic acids (L-tartaric acid, a-hydroxyisobutyric acid and 4-acetamidobutyric acid), sugars (melezitose, beta-D - lactose, D -sedoheptulose 7-phosphate, 2-deoxyribose 1-phosphate and raffinose) and phenols (coniferin, curcumin and feruloylputrescine). This study revealed the effects of storage temperature on postharvest tomato fruit and provided a basis for further understanding of the molecular biology and biochemistry of fruit ripening. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the risk of colon cancer is greatly increased in people with obesity, and fat content in colorectal cancer tissue is increased in people with obesity. As an important part of tumor microenvironment, adipose-derived mesenchymal stem cells (MSCs) are also another important source of cancer-associated fibroblasts (CAFs), which may be one of the important mechanisms of affecting tumor progression. However, the mechanism is poorly defined. In the present study, CAFs were transformed from MSCs [MSC-transformed CAFs (MTCAFs)] by co-culturing with HCT116 cells. Bioinformatics and Western blotting analysis indicated a positive correlation between intercellular adhesion molecule-1(ICAM-1) and the progression of colon cancer. In clinical colon cancer specimens, we found that ICAM-1 was highly expressed and related to shorter disease-free survival, which might act as an indication for the progression of clinical colon cancer. Our data showed that ICAM-1 secreted from MTCAFs could positively promote the proliferation, migration, and invasion of colon cancer cells by activating signal transducer and activator of transcription 3 (STAT3) and Serine/threonineprotein kinase (AKT) signaling and that blocking ICAM-1 in MTCAFs reversed these effects. We further verified that ICAM-1 secreted from MTCAFs promoted tumor progression in vivo. Taken together, ICAM-1 plays a critical role in regulating tumor growth and metastasis, which could be a potential therapeutic target in colon cancer. [ABSTRACT FROM AUTHOR]

Metastasis is the major cause of death in colorectal cancer (CRC) patients. Inhibition of metastasis will prolong the survival of patients with CRC. Cancer cells bring their own soil, cancer-associated fibroblasts (CAFs), to metastasize together, promoting the survival and colonization of circulating cancer cells. However, the mechanism by which CAFs metastasize remains unclear. In this study, CAFs were derived from adipose mesenchymal stem cells (MSCs) after co-culture with CRC cell lines. Transwell assays showed that CAFs have stronger migration and invasion abilities than MSCs. In a nude mouse subcutaneous xenograft model, CAFs metastasized from the primary tumour to the lung and promoted the formation of CRC metastases. The expression of HIF-1α was upregulated when MSCs differentiated into CAFs. Inhibition of HIF-1α expression inhibited the migration and invasion of CAFs. Western blot and ChIP assays were used to identify the genes regulated by HIF-1α. HIF-1α regulated the migration and invasion of CAFs by upregulating miR-210 transcription. Bioinformatics analysis and luciferase reporter assays revealed that miR-210 specifically targeted the 3'UTR of VMP1 and regulated its expression. Downregulation of VMP1 enhanced the migration and invasion of CAFs. In vivo, inhibition of miR-210 expression in CAFs reduced the metastasis of CAFs and tumour cells. Therefore, the HIF-1α/miR-210/VMP1 pathway might regulate the migration and invasion of CAFs in CRC. Inhibition of CAF metastasis might reduce CRC metastasis. [ABSTRACT FROM AUTHOR]

Objective: In this post-hoc analysis, we evaluated anlotinib treatment-induced hypertension as a potential predictive factor of efficacy in esophageal squamous cell carcinoma (ESCC) patients. Methods: A total of 109 patients enrolled in the anlotinib group in a phase 2 trial were included. The tumor response was assessed by computed tomography at week 3, week 6, and then every 6 weeks until progressive disease was observed. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints included overall survival (OS) and objective response rate (ORR). Results: In all patients, the median PFS was 3.02 months [95% confidence interval (CI): 2.63–3.65 months] and the OS was 6.11 months (95% CI: 4.40–7.79 months). The ORR was 7.34% (95% CI: 3.22%–13.95%). A total of 59 (54%) patients were diagnosed with treatment-induced hypertension (Group A), and the remaining patients (n = 50, 46%) were in Group B. Baseline prognostic factors were similar between the 2 groups. Patients in Group A had a longer PFS and OS and higher ORR. When stratifying patients using a previously known history of hypertension, treatment-induced hypertension was a predictor only for patients without previous hypertension, who had longer PFS [hazard ratio (HR): 0.40, 95% CI: 0.24–0.68] and OS (HR: 0.37, 95% CI: 0.21–0.67). Conclusions: We showed, for the first time, a correlation between treatment-induced hypertension and better prognoses in recurrent or metastatic ESCC patients treated with anlotinib, without a previously known history of hypertension. Treatment-induced hypertension may be a simple and low cost predictor for anlotinib antitumor efficacy in these patients, which may also reflect the intended target inhibition. [ABSTRACT FROM AUTHOR]

Q235 steel is widely used in engineering and construction. Therefore, it is important to identify the damage mechanism and the acoustic emission (AE) response of the material to ensure the safety of structures. In this study, an AE monitor system and an in situ tensile test with an optical microscope were used to investigate the AE response and insight into the damage process of Q235 steel. The surface of the specimen was polished and etched before the test in order to improve the quality of micrographs. Two kinds of AE responses, namely a burst and a continuous signal, were recorded by the AE monitor system during the test. Based on the in situ test, it was observed that the damage of Q235 steel was induced by the crystal slip and the inclusion fracture. Since the crystal slip was an ongoing process, continuous AE signals were produced, while burst AE signals were possibly produced by the inclusion fracture which occurred suddenly with released higher energy. In addition, a great number of AE signals with high amplitude were observed during the yielding stage and then the number and amplitude decreased. [ABSTRACT FROM AUTHOR]

Detecting genetic mutations in circulating cell-free DNA (cfDNA) is a promising approach of liquid biopsy. Between June 2014 and May 2015, 168 plasma samples were collected monthly from 20 patients with metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation receiving gefitinib therapy. Clinically relevant EGFR mutations, including exon 19 deletion, L858R and T790M, were quantified using droplet digital polymerase chain reaction. In baseline samples, 19 (95.0%) patients had the same mutation with the matched tumors, and pretreatment T790M mutations were also detected in 3 (15.0%) patients. The dynamics of EGFR mutations were generally associated with treatment response for patients with or without measurable disease. For patients with immeasurable tumor deposits, monitoring disease evolution using cfDNA-based mutation quantification appeared to be more reliable compared with measuring the diameters of target tumor lesions. In addition, molecular progressive disease, defined as a =20% increase of EGFR mutation concentration compared with the lowest concentration recorded during treatment, was tracked up to 8 months prior to objective progression. In survival analysis, sex (P=0.005), pretreatment T790M mutation status (P=0.006), T790M mutation status at the disease progression (P=0.043) and growth rate of EGFR mutations (P=0.023), had a significant impact on median progression-free survival. In conclusion, dynamic monitoring of EGFR mutations in cfDNA is feasible and appears to be useful in early prediction of drug resistance for patients with lung cancer receiving EGFR tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Background: The aberrant expression of microRNAs has been demonstrated to play a crucial role in the initiation and progression of hepatocarcinoma. miR-1246 expression in High invasive ability cell line than significantly higher than that in low invasive ability cell line. Methods: Transwell chambers (8-uM pore size; Costar) were used in the in vitro migration and invison anssay. Dual luciferase reporter gene construct and Dual luciferase reporter assay to identify the target of miR-1246. CADM1 expression was evaluated by immunohistochemistric staining. The clinical manifestations, treatments and survival were collected for statistical analysis. Results: Inhibition of miR-1246 effectively reduced migration and invasion of hepatocellular carcinoma cell lines. Bioinformatics and luciferase reporter assay revealed that miR-1246 specifically targeted the 3'-UTR of Cell adhesion molecule 1 and regulated its expression. Down-regulation of CADM1 enhanced migration and invasion of HCC cell lines. Furthermore, in tumor tissues obtained from liver cancer patients, the expression of miR-1246 was negatively correlated with CADM1 and the high expression of miR-1246 combined with low expression of CADM1 might serve as a risk factor for stage1 liver cancer patients. Conclusions: Our study showed that miR-1246, by down-regulation CADM1, enhances migration and invasion in HCC cells. [ABSTRACT FROM AUTHOR]