Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions.

At present, diabetes mellitus (DM) has been one of the most endangering healthy diseases. Current therapies contain controlling high blood sugar, reducing risk factors like obesity, hypertension, and so on; however, DM patients inevitably and eventually progress into different types of diabetes complications, resulting in poor quality of life. Unfortunately, the clear etiology and pathogenesis of diabetes complications have not been elucidated owing to intricate whole-body systems. The immune system was responsible to regulate homeostasis by triggering or resolving inflammatory response, indicating it may be necessary to diabetes complications. In fact, previous studies have been shown inflammation plays multifunctional roles in the pathogenesis of diabetes complications and is attracting attention to be the meaningful therapeutic strategy. To this end, this review systematically concluded the current studies over the relationships of susceptible diabetes complications (e.g., diabetic cardiomyopathy, diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy) and inflammation, ranging from immune cell response, cytokines interaction to pathomechanism of organ injury. Besides, we also summarized various therapeutic strategies to improve diabetes complications by target inflammation from special remedies to conventional lifestyle changes. This review will offer a panoramic insight into the mechanisms of diabetes complications from an inflammatory perspective and also discuss contemporary clinical interventions.

The RNA sequencing results revealed the expression of different genes and signaling pathways during chemotherapy resistance in peripheral T-cell lymphoma.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is a subtype of non-Hodgkin's lymphoma that occurs primarily at extranodal sites and is commonly treated using chemotherapy and radiotherapy. PTCL is more malignant than other lymphoid tumors, resulting in a poor prognosis.The 5-year recurrence rate remains high, and there is a lack of standard treatment for patients with relapse-resistant disease. However, the molecular mechanisms underlying the resistance of peripheral T-cell lymphoma cells to chemotherapeutic drugs, as well as identifying strategies to overcome drug resistance remains unclear. In this study, we aimed to identify pivotal genes and signaling pathways associated with chemotherapy resistance in PTCL. METHODS: In this study, a total of 5 healthy controls and 7 clinical patients were enrolled; 4 patients were classified as chemotherapy sensitive, and 3 patients were classified as chemotherapy resistant. Peripheral blood samples were collected from each participant, and total RNA was extracted from the white blood cells. RNA sequencing was conducted on the Illumina HiSeq platform to obtain comprehensive gene expression profiles. Subsequently, the expression patterns of the DEGs associated with the most enriched signaling pathways, with a special focus on cancer-related genes, were validated using quantitative real-time polymerase chain reaction (qRT-PCR) in peripheral TCL patients. RESULTS: RNA sequencing (RNA-seq) analysis revealed 4063 differentially expressed genes (DEGs) in peripheral T-cell lymphoma specimens from patients with chemotherapy resistance, of which 1128 were upregulated and 2935 were downregulated. Subsequent quantitative gene expression analysis confirmed a differential expression pattern in all the libraries, with 9 downregulated genes and 10 upregulated genes validated through quantitative real-time PCR in 6 clinical specimens from patients with chemotherapy resistance. KEGG pathway analysis revealed significant alterations in several pathways, with 6 downregulated pathways and 9 upregulated pathways enriched in the DEGs. Notably, the TNF signaling pathway, which is extensively regulated, was among the pathways that exhibited significant changes. These findings suggest that DEGs and the TNF signaling pathway may play crucial roles in chemotherapy resistance in peripheral T-cell lymphoma. CONCLUSION: Our study revealed that the expression of specific genes, including TNFRSF1B, TRADD2, and MAP3K7, may play an important role in chemotherapy resistance in peripheral T-cell lymphoma. Moreover, we identified the downregulation of the TNF signaling pathway, a crucial pathway involved in cell survival, death, and differentiation, as a potential contributor to the development of chemotherapy resistance in peripheral T-cell lymphoma. These findings provide valuable insights into the molecular mechanisms underlying chemotherapy resistance and highlight potential targets for overcoming treatment resistance in this challenging disease.

Impact of Metastatic Lymph Nodes on Survival of Patients with pN1-Category Esophageal Squamous Cell Carcinoma: A Long-Term Survival Analysis.

BACKGROUND: The morbidity and mortality rates of esophageal squamous cell carcinoma (ESCC) are high in China. The overall survival (OS) of patients with ESCC is related to lymph node (LN) metastasis (LNM). This study aimed to discuss the impact of metastasis in LN stations on the OS of patients with pathologic N1 (pN1) ESCC. METHODS: Data were obtained from the Esophageal Cancer Case Management database of Sichuan Cancer Hospital and Institute (SCCH-ECCM). Additionally, data of patients with pN1-category ESCC collected between January 2010 and December 2017 were retrospectively analyzed. RESULTS: Data from 807 patients were analyzed. The median OS of the patients with one metastatic LN (group 1) was 49.8 months (95 % confidence interval [CI], 30.8-68.9 months), whereas the OS of those with two metastatic LNs (group 2) was only 33.3 months (P = 0.0001). Moreover, group 1 did not show a significantly longer OS than group 2.1 (patients with 2 metastatic LNs in 1 LNM station; P = 0.5736), but did show a significantly longer OS than group 2.2 (patients with 2 metastatic LNs in 2 LNM stations; P < 0.0001). After propensity score-matching, the 5-year survival rate for group 1 was 28 %, whereas that for group 2 was 14 % (P = 0.0027). CONCLUSIONS: The OS for the patients with one metastatic LN in one LNM was not significantly longer than for the patients with two metastatic LNs in one LNM station. Patients with one LNM station had a significantly longer OS than those with two LNM stations. Thus, the number of LNM stations is a significant determinant of OS in pN1 ESCC.

circRNA-CPA4 Regulates Cell Proliferation and Apoptosis of Non-small Cell Lung Cancer via the miR-1183/PDPK1 Axis.

Non-small-cell lung cancer (NSCLC) stands as a prevalent subtype of lung cancer, with circular RNAs emerging as key players in cancer development. This study elucidates the role of circRNA-CPA4 in NSCLC. Elevated circRNA-CPA4 expression in NSCLC lines was confirmed through qRT-PCR. Silencing circRNA-CPA4 with shRNA revealed, through CCK-8, colony formation, and flow cytometry assays, a notable constraint on proliferation and promotion of apoptosis in NSCLC cells. Subcellular localization analysis, RNA immunoprecipitation, and expression level assessments were employed to decipher the intricate interplay among miR-1183, circRNA-CPA4, and PDPK1. Results demonstrated heightened circRNA-CPA4 levels in NSCLC, and its knockdown curtailed NSCLC growth in vivo. Acting as a molecular sponge for miR-1183, circRNA-CPA4 regulated PDPK1 expression. Conversely, inhibiting miR-1183 counteracted the impact of circRNA-CPA4 silencing, reinstating NSCLC cell proliferation, and impeding apoptosis. Overall, this study unveils a novel mechanism: circRNA-CPA4 promotes PDPK1 expression by sequestering miR-1183, fostering NSCLC cell proliferation, and hindering apoptosis.

Preoperative pulmonary nodule localization: A comparison of hook wire and Lung-pro-guided surgical markers.

In minimally invasive thoracoscopic surgery, for solitary pulmonary nodules (SPNs) far from the pleura, it is difficult to resected by only relying on imaging data, and effective preoperative localization can significantly improve the success rate of surgery. Therefore, preoperative localization is particularly important for accurate resection. Here, we compare the value of a novel Lung-pro-guided localization technique with Hook-wire localization in video-assisted thoracoscopic surgery. METHOD: In this study, 70 patients who underwent CT-guided Hook-wire localization and Lung-pro guided surgical marker localization before VATS-based SPNs resection between May 2020 and March 2021 were analyzed, and the clinical efficacy and complication rate of the two groups were compared. RESULT: Thirty-five patients underwent Lung-pro guided surgical marker localization, and 35 patients underwent CT-guided Hook-wire localization. The localization success rates were 94.3% and 88.6%, respectively (p = 0.673). Compared with the puncture group, the locating time in the Lung-pro group was significantly shorter (p = 0.000), and the wedge resection time was slightly shorter than that in the puncture group (P = 0.035). There were no significant differences in the success rate of localization, localization complications, intraoperative blood loss, postoperative hospital stay, and the number of staplers used. CONCLUSION: The above studies show that the Lung-pro guided surgical marker localization and the CT-guided Hook-wire localization have shown good safety and effectiveness. However, the Lung-pro guided surgical marker localization may show more safety than the Hook-wire and can improve the patient's perioperative experience.

Integrated multi-omics analysis for lung adenocarcinoma in Xuanwei, China.

BACKGROUND: Xuanwei lung cancer (XWLC) is well-known for its high incidence and mortality. However, the molecular mechanism is still unclear. METHODS: We performed a comprehensive transcriptomic, proteomic, and phosphoproteomic characterization of tumors and matched normal adjacent tissues from three XWLC patients with lung adenocarcinoma (LUAD). RESULTS: Integrated transcriptome and proteome analysis revealed dysregulated molecules and pathways in tumors and identified enhanced metabolic-disease coupling. Non-coding RNAs were widely involved in post-transcriptional regulatory mechanisms to coordinate the progress of LUAD and partially explained the molecular differences between RNA and protein expression patterns. Phosphoproteome provided evidence support for new phosphate sites, reporting the potential roles of core kinase family members and key kinase pathways involved in metabolism, immunity, and homeostasis. In addition, by comparing with the previous LUAD researches, we emphasized the higher degree of oxidative phosphorylation in Xuanwei LUAD and pointed that VIPR1 deficiency aggravated metabolic dysfunction. CONCLUSION: Our integrated multi-omics analysis provided a powerful resource for a systematic understanding of the molecular structure of XWLC and proposed therapeutic opportunities based on redox metabolism.

Development and validation of an immune-related gene prognostic index for lung adenocarcinoma.

Background: Lung cancer is the most common malignant tumor in the world, and its prognosis is still not optimistic. The aim of this study was to establish an immune-related gene (IRG) prognostic index (IRGPI) for lung adenocarcinoma (LUAD) based on IRGs, and to explore the prognosis, molecular and immune features, and response to immune checkpoint inhibitor (ICI) therapy in IRGPI-classified different subgroups of LUAD. Methods: Based on the LUAD transcriptome RNA-sequencing data in TCGA database, the differentially expressed genes (DEGs) were selected. Subsequently, DEGs were intersected with IRGs to obtain differentially expressed immune-related genes (DEIRGs). Weighted gene co-expression network analysis (WGCNA) identified hub genes in DEIRGs. Finally, univariate and multivariate Cox regression analyses were used to build an IRGPI model. Subsequently, TCGA patients were divided into high- and low-risk groups, and the survival of patients in different groups was further analyzed. Besides, we validated the molecular and immune characteristics, relationship with immune checkpoints, angiogenesis-related genes, and immune subtypes distribution in different subgroups. Meanwhile, we further validated the response to ICI therapy in different subgroups. Results: The IRGPI was constructed based on 13 DEIRGs. Compared with the low-risk group, overall survival (OS) was lower in the high-risk group, and the high-risk score was independently associated with poorer OS. Besides, the high-risk score was associated with cell cycle pathway, high mutation rate of TP53 and KRAS, high infiltration of M0 macrophages, and immunosuppressive state, and these patients had poorer prognosis but the TIDE score of the high-risk group was lower than that of the other group, which means that the high-risk group could benefit more from ICI treatment. In contrast, the low-risk score was related to low mutation rate of TP53 and KRAS, high infiltration of plasma cells, and immunoactive state, and these patients had better prognosis but the low-risk group less benefit from ICI treatment based on the results of TIDE score. Conclusions: IRGPI is a prospective biomarker based on IRGs that can distinguish high- and low-risk groups to predict patient prognosis, help characterize the tumor immune microenvironment, and evaluate the benefit of ICI therapy in LUAD.

[Recent Advances in Diagnosis and Treatment Strategies for Multiple Primary Lung Cancer].

As the utilization of computed tomography in lung cancer screening becomes more prevalent in the post-pandemic era, the incidence of multiple primary lung cancer (MPLC) has surged in various countries and regions. Despite the continued application of advanced histologic and sequencing technologies in this research field, the differentiation between MPLC and intrapulmonary metastasis (IM) remains challenging. In recent years, the specific mechanisms of genetic and environmental factors in MPLC have gradually come to light. Lobectomy still predominates in the treatment of MPLC, but the observation that tumor-specific sublobar resection has not detrimentally impacted survival appears to be a viable option. With the evolution of paradigms, the amalgamated treatment, primarily surgical, is an emerging trend. Among these, stereotactic ablative radiotherapy (SABR) and lung ablation techniques have emerged as efficacious treatments for early unresectable tumors and control of residual lesions. Furthermore, targeted therapies for driver-positive mutations and immunotherapy have demonstrated promising outcomes in the postoperative adjuvant phase. In this manuscript, we intend to provide an overview of the management of MPLC based on the latest discoveries.
.

Molecular subtyping based on immune cell marker genes predicts prognosis and therapeutic response in patients with lung adenocarcinoma.

OBJECTIVE: Lung adenocarcinoma (LA) is one of the most common malignancies and is responsible for the greatest number of tumor-related deaths. Our research aimed to explore the molecular subtype signatures of LA to clarify the correlation among the immune microenvironment, clinical outcomes, and therapeutic response. METHODS: The LA immune cell marker genes (LICMGs) identified by single-cell RNA sequencing (scRNA-seq) analysis were used to discriminate the molecular subtypes and homologous immune and metabolic traits of GSE72094 LA cases. In addition, the model-building genes were identified from 1441 LICMGs by Cox-regression analysis, and a LA immune difference score (LIDscore) was developed to quantify individual differences in each patient, thereby predicting prognosis and susceptibility to immunotherapy and chemotherapy of LA patients. RESULTS: Patients of the GSE72094 cohort were divided into two distinct molecular subtypes based on LICMGs: immune activating subtype (Cluster-C1) and metabolically activating subtype (cluster-C2). The two molecular subtypes have distinct characteristics regarding prognosis, clinicopathology, genomics, immune microenvironment, and response to immunotherapy. Among the LICMGs, LGR4, GOLM1, CYP24A1, SFTPB, COL1A1, HLA-DQA1, MS4A7, PPARG, and IL7R were enrolled to construct a LIDscore model. Low-LIDscore patients had a higher survival rate due to abundant immune cell infiltration, activated immunity, and lower genetic variation, but probably the higher levels of Treg cells in the immune microenvironment lead to immune cell dysfunction and promote tumor immune escape, thus decreasing the responsiveness to immunotherapy compared with that of the high-LIDscore patients. Overall, high-LIDscore patients had a higher responsiveness to immunotherapy and a higher sensitivity to chemotherapy than the low-LIDscore group. CONCLUSIONS: Molecular subtypes based on LICMGs provided a promising strategy for predicting patient prognosis, biological characteristics, and immune microenvironment features. In addition, they helped identify the patients most likely to benefit from immunotherapy and chemotherapy.

[Progress in Diagnosis and Treatment of Lung Cancer Associated with Cystic Airspaces].

Lung cancer associated with cystic airspaces (LCCA) is a type of lung cancer characterized by the presence of cystic cavities in or around the tumor on imaging. Due to its high potential for misdiagnosis or underdiagnosis, the prognosis of LCCA patients is poor, necessitating further large-scale clinical studies to elucidate its characteristics. Currently, four imaging classification systems exist, and there has been a progressive increase in attention towards LCCA, particularly with regard to the study of its imaging features. The results indicate a correlation between the pathological features and imaging findings of LCCA; however, research on driver gene mutations and molecular subtyping associated with lung cancer remains insufficient. Due to the challenges associated with early diagnosis and the poorer prognosis compared to general types of lung cancer, this paper comprehensively reviews the research progress on LCCA, including its definition, etiology, pathogenesis, imaging features, histological and pathological features, treatment, and prognosis, aiming to serve as a valuable resource for clinical decision-making.
.

Survival analysis of patients with advanced non-small cell lung cancer receiving EGFR-TKI treatment of Yunnan in southwestern China: a real-world study.

Importance: Patients with EGFR mutations who have advanced-stage non-small cell lung cancer (NSCLC) already receive tyrosine kinase inhibitors (TKIs) as the standard first-line therapy. Notably, Yunnan is a regional high incidence area of lung cancer in the highlands with a high rate of rare EGFR mutations. Overall, lung cancer patients in Xuanwei may present a distinct subgroup globally. Recent studies suggested that the NSCLC cohort in Xuanwei harbored a significantly higher uncommon mutation rate. However, little was known about the clinicopathological features and treatment efficacy of EGFR-TKI in Yunnan NSCLC patients. Objective: This study aimed to investigate the clinical impact of histologic type on the survival outcomes of patients with stage IIIB and IV NSCLC receiving EGFR-TKI treatment of Yunnan in southwestern China. Methods: In this retrospective study, we enrolled advanced NSCLC patients (IIIB-IV) with EGFR mutations who were first diagnosed and treated at Yunnan Cancer hospital from January 2016 to December 2019. Sociodemographics, lifestyle, survival, and clinicopathological characteristics of the patients were collected. The Kaplan-Meier method was used to assess the OS and PFS of patients. An analysis of prognostic factors was conducted using Cox regression. Results: A total of 468 eligible patients were included. The median progression-free survival (PFS) and overall survival(OS) were 11.30(95% CI, 10.12-12.48) months and 30.30(95% CI, 26.24-34.36) months. Based on survival analysis among all the patients,females(HR=0.815;95% CI:0.671-0.989; P=0.017), Xuanwei origin (HR=0.776; 95% CI: 0.609-0.989; P=0.040), sample types(HR=0.780; 95% CI: 0.642-0.947; P=0.012) had a longer PFS. Multivariable analysis showed that only the sample type was an independent factor on median PFS with EGFR-TKI therapy. Patients less than 60 years old (HR=1.433; 95% CI:1.134-1.812, P=0.003)had better OS, but objectives with BMI≥24kg/m2(HR=0.653; 95% CI: 0.500-0.864; P=0.002), females(HR=0.776; 95% CI:0.613-0.982; P=0.035)and patients with tissue sample type (HR=0.760; 95% CI:0.600-.0961; P=0.022) had better OS. Notably, subgroup analysis of our study also found that PFS was significantly better in patients with G719X, L861Q, S768I, G719X+L861Q, and G719X+S768I in Xuanwei than classical mutation ones, including 19-Del and L858R (median 22.7 vs. 12.0 months, HR=0.523, P=0.010), while PFS was inferior in patients with rare mutations of EGFR in non-Xuanwei than the classical mutation ones (median 5.10 vs. 11.10 months, HR=1.760, P=0.015). Conclusion: NSCLC patients in Yunnan displayed a unique EGFR mutation profile, especially a higher prevalence of EGFR uncommon and compound mutations subtype. This study indicates prognostic factors of NSCLC treated with EGFR-TKI in Yunan and Xuanwei. This study will provide new clinical evidence for EGFR-TKI-targeted therapy in patients with rare EGFR mutations in China and worldwide. More researchs were needed for NSCLC EGFR-TKI therapy and medical insurance policy-making in Yunnan, Xuanwei area and uncommon especially.

Fibrinogen-to-albumin ratio predicts overall survival of hepatocellular carcinoma.

BACKGROUND: Fibrinogen-to-albumin ratio (FAR) has been found to be of prognostic significance for several types of malignant tumors. However, less is known about the association between FAR and survival outcomes in hepatocellular carcinoma (HCC) patients. AIM: To explore the association between FAR and prognosis and survival in patients with HCC. METHODS: A total of 366 histologically confirmed HCC patients diagnosed between 2013 and 2018 in a provincial cancer hospital in southwestern China were retrospectively selected. Relevant data were extracted from the hospital information system. The optimal cutoff for baseline serum FAR measured upon disease diagnosis was established using the receiver operating characteristic (ROC) curve. Univariate and multivariate Cox proportional hazards models were used to determine the crude and adjusted associations between FAR and the overall survival (OS) of the HCC patients while controlling for various covariates. The restricted cubic spline (RCS) was applied to estimate the dose-response trend in the FAR-OS association. RESULTS: The optimal cutoff value for baseline FAR determined by the ROC was 0.081. Multivariate Cox proportional hazards model revealed that a lower baseline serum FAR level was associated with an adjusted hazard ratio of 2.43 (95% confidence interval: 1.87-3.15) in the OS of HCC patients, with identifiable dose-response trend in the RCS. Subgroup analysis showed that this FAR-OS association was more prominent in HCC patients with a lower baseline serum aspartate aminotransferase or carbohydrate antigen 125 level. CONCLUSION: Serum FAR is a prominent prognostic indicator for HCC. Intervention measures aimed at reducing FAR might result in survival benefit for HCC patients.

HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non-Small Cell Lung Cancer.

PURPOSE: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. EXPERIMENTAL DESIGN: We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). RESULTS: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell-mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. CONCLUSIONS: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706.