The clinical predictive value of geriatric nutritional risk index in elderly rectal cancer patients received surgical treatment after neoadjuvant therapy

ObjectiveThe assessment of nutritional status has been recognized as crucial in the treatment of geriatric cancer patients. The objective of this study is to determine the clinical predictive value of the geriatric nutritional risk index (GNRI) in predicting the short-term and long-term prognosis of elderly rectal cancer (RC) patients who undergo surgical treatment after neoadjuvant therapy.MethodsBetween January 2014 and December 2020, the clinical materials of 639 RC patients aged ≥70 years who underwent surgical treatment after neoadjuvant therapy were retrospectively analysed. Propensity score matching was performed to adjust for baseline potential confounders. Logistic regression analysis and competing risk analysis were conducted to evaluate the correlation between the GNRI and the risk of postoperative major complications and cumulative incidence of cancer-specific survival (CSS). Nomograms were then constructed for postoperative major complications and CSS. Additionally, 203 elderly RC patients were enrolled between January 2021 and December 2022 as an external validation cohort.ResultsMultivariate logistic regression analysis showed that GNRI [odds ratio = 1.903, 95% confidence intervals (CI): 1.120–3.233, p = 0.017] was an independent risk factor for postoperative major complications. In competing risk analysis, the GNRI was also identified as an independent prognostic factor for CSS (subdistribution hazard ratio = 3.90, 95% CI: 2.46–6.19, p < 0.001). The postoperative major complication nomogram showed excellent performance internally and externally in the area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analysis (DCA). When compared with other models, the competing risk prognosis nomogram incorporating the GNRI achieved the highest outcomes in terms of the C-index, AUC, calibration plots, and DCA.ConclusionThe GNRI is a simple and effective tool for predicting the risk of postoperative major complications and the long-term prognosis of elderly RC patients who undergo surgical treatment after neoadjuvant therapy

Real-world analysis of survival benefit of surgery and adjuvant therapy in elderly patients with colorectal cancer

Abstract Treatment guidelines for colorectal cancer (CRC) in elderly patients remain unclear. This study aimed to investigate whether elderly patients (≥ 70 years) with CRC benefit from surgery and adjuvant therapy. A total of 90,347 eligible CRC patients older than 70 years were collected from the Surveillance, Epidemiology, and End Results (SEER) database and divided into a surgery group and a no-surgery group. After being matched by propensity score matching at a 1:1 ratio, 23,930 patients were included in our analysis. The Kaplan‒Meier method and log-rank test were applied to compare overall survival (OS) and cancer-specific survival (CSS). Univariate and multivariate Cox regression analyses were utilized to confirm independent prognostic factors for OS and CSS. In age-stratified analysis (70–74; 75–79; 80–84; ≥ 85), the OS and CSS rates of patients in the surgery group were significantly higher than those of patients in the no-surgery group (all P < 0.001). Adjuvant therapy was an independent prognostic factor for OS and CSS in elderly patients with CRC (all P < 0.001). Further analysis showed that elderly colon cancer patients with stage III and stage IV disease gained a survival benefit from adjuvant chemotherapy. Adjuvant chemoradiotherapy can significantly improve OS and CSS in elderly rectal cancer patients with stage II, III, and IV disease. In conclusion, among CRC patients aged ≥ 70 years reported in the SEER database, treatment with surgical resection is significantly associated with improved OS and CSS. Moreover, adjuvant therapy led to a significant prognostic advantage for elderly advanced CRC patients who underwent surgery

Pontin Acts as a Potential Biomarker for Poor Clinical Outcome and Promotes Tumor Invasion in Hilar Cholangiocarcinoma

Hilar cholangiocarcinoma (HC) is a devastating malignancy that carries a poor overall prognosis. As a member of the AAA+ superfamily, Pontin becomes highly expressed in several malignant tumors, which contributes to tumor progression and influences tumor prognosis. In our research, Pontin expression in tumor specimens resected from 86 HC patients was detected by immunohistochemistry. Interestingly, high expression of Pontin was significantly associated with lymph node metastasis (p=0.011) and tumor node metastasis (TNM) stage (p=0.005). The Kaplan–Meier overall survival rate and multivariate analyses were performed to evaluate the prognosis of patients with HC. Patients with high Pontin expression had significantly poorer overall survival outcomes. Multivariate analyses found that Pontin was an independent prognostic factor (p=0.001). Moreover, bioinformatics analysis confirmed the increase in Pontin mRNA expression levels in cholangiocarcinoma tissues. In addition, in vitro experiments showed that Pontin expression was inhibited at the mRNA as well as protein levels after transfection with Pontin siRNA in human cholangiocarcinoma cell lines. Moreover, significant suppression of cell invasion was observed after the downregulation of Pontin. Taken together, the present study suggested that Pontin could act as a potential prognostic predictor, which might be a new valuable molecular candidate for the prevention and treatment of HC

Integrin β3 Promotes Resistance to EGFR-TKI in Non-Small-Cell Lung Cancer by Upregulating AXL through the YAP Pathway

Integrin β3 plays a key role in the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), but the development of integrin β3 inhibitors has been stalled due to the failure of phase III clinical trials for cancer treatment. Therefore, it is imperative to find a potentially effective solution to the problem of acquired resistance to EGFR-TKI for patients with integrin-β3 positive non-small-cell lung cancer (NSCLC) by exploring novel downstream targets and action mechanisms of integrin β3. In the present study, we observed that the expression of integrin β3 and AXL was significantly upregulated in erlotinib-resistant NSCLC cell lines, which was further confirmed clinically in tumor specimens from patients with NSCLC who developed acquired resistance to erlotinib. Through ectopic expression or knockdown, we found that AXL expression was positively regulated by integrin β3. In addition, integrin β3 promoted erlotinib resistance in NSCLC cells by upregulating AXL expression. Furthermore, the YAP pathway, rather than pathways associated with ERK or AKT, was involved in the regulation of AXL by integrin β3. To investigate the clinical significance of this finding, the current well-known AXL inhibitor R428 was tested, demonstrating that R428 significantly inhibited resistance to erlotinib, colony formation, epithelial–mesenchymal transformation and cell migration induced by integrin β3. In conclusion, integrin β3 could promote resistance to EGFR-TKI in NSCLC by upregulating the expression of AXL through the YAP pathway. Patients with advanced NSCLC, who are positive for integrin β3, might benefit from a combination of AXL inhibitors and EGFR-TKI therapy

Establish a novel tumor budding-related signature to predict prognosis and guide clinical therapy in colorectal cancer

Abstract Tumor budding is a long-established independent adverse prognostic marker for colorectal cancer (CRC), yet assessment of tumor budding was not reproducible. Therefore, development of precise diagnostic approaches to tumor budding is in demand. In this study, we first performed bioinformatic analysis in our single-center CRC patients’ cohort (n = 84) and identified tumor budding-associated hub genes using the weighted gene co-expression network analysis (WGCNA). A machine learning methodology was used to identify hub genes and construct a prognostic signature. Nomogram model was used to identified hub genes score for tumor budding, and the receiver operating characteristic (ROC) curve and calibration plot indicated high accuracy and stability of hub gene score for predicted the prognosis of CRC. The association between budding-associated hub genes and score and prognosis of CRC were further verified in TCGA CRC cohort (n = 342). Then gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore the signaling pathways related to the tumor budding and validated by immunohistochemistry (IHC) of our clinical samples. Subsequently, immune infiltration analysis demonstrated that there was a high correlation between hub genes score and M2-like macrophages infiltrated in tumor tissue. In addition, somatic mutation and chemotherapeutic response prediction were analyzed based on the risk signature. In summary, we established a tumor budding diagnostic molecular model, which can improve tumor budding assessment and provides a promising novel molecular marker for immunotherapy and prognosis of CRC

Proteolysis and multimerization regulate signaling along the two-component regulatory system AdeRS

International audienceBacterial two-component regulatory systems are ubiquitous environment-sensing signal transducers involved in pathogenesis and antibiotic resistance. The Acinetobacter baumannii two-component regulatory system AdeRS is made up of a sensor histidine kinase AdeS and a cognate response regulator AdeR, which together reduce repression of the multidrug-resistant efflux pump AdeABC. Herein we demonstrate that an N-terminal intrinsically disordered tail in AdeR is important for the upregulation of adeABC expression, although it greatly increases the susceptibility of AdeR to proteasome-mediated degradation. We also show that AdeS assembles into a hexameric state that is necessary for its full histidine kinase activity, which appears to occur via cis autophosphorylation. Taken together, this study demonstrates new structural mechanisms through which two-component systems can transduce environmental signals to impact gene expression and enlightens new potential antimicrobial approach by targeting two-component regulatory systems

Frequent amplification of <i>PTP1B</i> is associated with poor survival of gastric cancer patients

<p>The protein tyrosine phosphatase 1B (<i>PTP1B</i>), a non-transmembrane protein tyrosine phosphatase, has been implicated in gastric pathogenesis. Several lines of recent evidences have shown that <i>PTP1B</i> is highly amplified in breast and prostate cancers. The aim of this study was to investigate <i>PTP1B</i> amplification in gastric cancer and its association with poor prognosis of gastric cancer patients, and further determine the role of <i>PTP1B</i> in gastric tumorigenesis. Our data demonstrated that <i>PTP1B</i> was significantly up-regulated in gastric cancer tissues as compared with matched normal gastric tissues by using quantitative RT-PCR (qRT-PCR) assay. In addition, copy number analysis showed that <i>PTP1B</i> was amplified in 68/131 (51.9%) gastric cancer cases, whereas no amplification was found in the control subjects. Notably, <i>PTP1B</i> amplification was positively associated with its protein expression, and was significantly related to poor survival of gastric cancer patients. Knocking down <i>PTP1B</i> expression in gastric cancer cells significantly inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrested and apoptosis. Mechanically, <i>PTP1B</i> promotes gastric cancer cell proliferation, survival and invasiveness through modulating Src-related signaling pathways, such as Src/Ras/MAPK and Src/phosphatidylinositol-3-kinase (PI3K)/Akt pathways. Collectively, our data demonstrated frequent overexpression and amplification <i>PTP1B</i> in gastric cancer, and further determined the oncogenic role of <i>PTP1B</i> in gastric carcinogenesis. Importantly, <i>PTP1B</i> amplification predicts poor survival of gastric cancer patients.</p