Exosome-derived circUPF2 enhances resistance to targeted therapy by redeploying ferroptosis sensitivity in hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) can be treated with sorafenib, which is the primary choice for targeted therapy. Nevertheless, the effectiveness of sorafenib is greatly restricted due to resistance. Research has shown that exosomes and circular RNAs play a vital role in the cancer's malignant advancement. However, the significance of exosomal circular RNAs in the development of resistance to sorafenib in HCC remains uncertain. METHODS: Ultracentrifugation was utilized to isolate exosomes (Exo-SR) from the sorafenib-resistant HCC cells' culture medium. Transcriptome sequencing and differential expression gene analysis were used to identify the targets of Exo-SR action in HCC cells. To identify the targets of Exo-SR action in HCC cells, transcriptome sequencing and analysis of differential expression genes were employed. To evaluate the impact of exosomal circUPF2 on resistance to sorafenib in HCC, experiments involving gain-of-function and loss-of-function were conducted. RNA pull-down assays and mass spectrometry analysis were performed to identify the RNA-binding proteins interacting with circUPF2. RNA immunoprecipitation (RIP), RNA pull-down, electrophoretic mobility shift assay (EMSA), immunofluorescence (IF) -fluorescence in situ hybridization (FISH), and rescue assays were used to validate the interactions among circUPF2, IGF2BP2 and SLC7A11. Finally, a tumor xenograft assay was used to examine the biological functions and underlying mechanisms of Exo-SR and circUPF2 in vivo. RESULTS: A novel exosomal circRNA, circUPF2, was identified and revealed to be significantly enriched in Exo-SR. Exosomes with enriched circUPF2 enhanced sorafenib resistance by promoting SLC7A11 expression and suppressing ferroptosis in HCC cells. Mechanistically, circUPF2 acts as a framework to enhance the creation of the circUPF2-IGF2BP2-SLC7A11 ternary complex contributing to the stabilization of SLC7A11 mRNA. Consequently, exosomal circUPF2 promotes SLC7A11 expression and enhances the function of system Xc- in HCC cells, leading to decreased sensitivity to ferroptosis and resistance to sorafenib. CONCLUSIONS: The resistance to sorafenib in HCC is facilitated by the exosomal circUPF2, which promotes the formation of the circUPF2-IGF2BP2-SLC7A11 ternary complex and increases the stability of SLC7A11 mRNA. Focusing on exosomal circUPF2 could potentially be an innovative approach for HCC treatment.

Neutrophil hitchhiking: Riding the drug delivery wave to treat diseases.

Neutrophils are a crucial component of the innate immune system and play a pivotal role in various physiological processes. From a physical perspective, hitchhiking is considered a phenomenon of efficient transportation. The combination of neutrophils and hitchhikers has given rise to effective delivery systems both in vivo and in vitro, thus neutrophils hitchhiking become a novel approach to disease treatment. This article provides an overview of the innovative and feasible application of neutrophils as drug carriers. It explores the mechanisms underlying neutrophil function, elucidates the mechanism of drug delivery mediated by neutrophil-hitchhiking, and discusses the potential applications of this strategy in the treatment of cancer, immune diseases, inflammatory diseases, and other medical conditions.

Outcomes of Robotic Versus Laparoscopic Pancreatoduodenectomy Following Learning Curves of Surgeons: A Multicenter Study on 2255 Patients.

OBJECTIVE: This study aimed to compare robotic pancreatoduodenectomy (RPD) with laparoscopic pancreatoduodenectomy (LPD) in operative and oncologic outcomes. BACKGROUND: Previous studies comparing RPD with LPD have only been carried out in small, single-center studies with variable quality. METHODS: Consecutive patients from nine centers in China who underwent RPD or LPD between 2015 and 2022 were included. A 1:1 propensity score matching (PSM) was used to minimize bias. RESULTS: Of the 2,255 patients, 1158 underwent RPD and 1097 underwent LPD. Following PSM, 1006 patients were enrolled in each group. The RPD group had significantly shorter operative time (270.0 vs. 305.0 minutes, P<0.001), lower intraoperative blood transfusion rate (5.9% vs. 12.0%, P<0.001), lower conversion rate (3.8% vs. 6.7%, P=0.004), and higher vascular reconstruction rate (7.9% vs. 5.6%, P=0.040) than the LPD group. There were no significant differences in estimated blood loss, postoperative length of stay, perioperative complications, and 90-day mortality. Patients who underwent vascular reconstruction had similar outcomes between the two groups, although they had significantly lower estimated blood loss (300.0 vs. 360.0 mL; P=0.021) in the RPD group. Subgroup analysis on pancreatic ductal adenocarcinoma (PDAC) found no significant differences between the two groups in median recurrence-free survival (14.3 vs. 15.3 mo, P=0.573) and overall survival (24.1 vs. 23.7 mo, P=0.710). CONCLUSIONS: In experienced hands, both RPD and LPD are safe and feasible procedures with similar surgical outcomes. RPD had the perioperative advantage over LPD especially in vascular reconstruction. For PDAC patients, RPD resulted in similar oncological and survival outcomes as LPD.

The TGF-ß/Smad2/3 signaling pathway is involved in Musashi2-induced invasion and metastasis of colorectal cancer.

To identify Musashi2 as an effective biomarker regulated by the TGF-ß/Smad2/3 signaling pathway for the precise diagnosis and treatment of colorectal cancer (CRC) through bioinformatic tools and experimental verification. The Cancer Genome Atlas, Timer, and Kaplan-Meier analyses were performed to clarify the expression of Musashi2 and its influence on the prognosis of CRC. Transforming growth factor beta 1 (TGF-ß1) was used to activate the TGF-ß/Smad2/3 signaling pathway to identify whether it could regulate the expression and function of Musashi2. Western blot analysis and quantitative PCR analyses were conducted to verify the expression of Musashi2. Cell counting kit-8 (CCK8), EdU, wound healing, and Transwell assays were conducted to reveal the role of Musashi2 in the proliferation, migration, and invasion of CRC. Musashi2 was upregulated in CRC and promoted proliferation and metastasis. TGF-ß1 increased the expression of Musashi2, while the antagonist inducer of type II TGF-ß receptor degradation-1 (ITD-1) decreased the expression. CCK8 and EdU assays demonstrated that inhibition of Musashi2 or use of ITD-1 lowered proliferation ability. The Transwell and wound healing assays showed that the migration and invasion abilities of CRC cells could be regulated by Musashi2. The above functions could be enhanced by TGF-ß1 by activating the TGF-ß/Smad2/3 signaling pathway and reversed by ITD-1. A positive correlation was found between Musashi2 and the TGF-ß/Smad2/3 signaling pathway. TGF-ß1 activates the TGF-ß/Smad2/3 pathway to stimulate the expression of Musashi2, which promotes the progression of CRC. Musashi2 might become a target gene for the development of new antitumor drugs.

Quality of life in pregnancy after percutaneous closure of atrial septal defect guided by transthoracic echocardiography.

PURPOSE: We evaluated quality of life (QoL) in pregnant women who underwent transthoracic echocardiography-guided percutaneous closure of atrial septal defect (ASD). METHODS: A total of 45 pregnant women underwent transthoracic echocardiography-guided percutaneous closure of ASD. We assessed QoL using the 36-Item Short Form Survey (SF-36) and compared results between pre- and post-procedure patients, as well as between those with ASD and healthy women in their second and third trimesters of pregnancy. RESULTS: All patients showed improved right ventricular function and were classified as Class I, post-procedure. Mean SF-36 scores of the post-procedure group were better on all sub-scales than those of the pre-procedure group (p < 0.05), with the exception of role-emotional and mental health. Mean SF-36 scores for the pre-procedure group were also lower on all sub-scales than those of healthy pregnant controls (p < 0.05), with the exception of role physical, role emotional, and mental health. There was no difference between the post-procedure group and healthy pregnant controls. In a subgroup analysis, scores were better in some dimensions (social functioning and role emotional) for post-procedure patients in the 31-40 years of age group and the group on their second or third pregnancies than those of the 20-30 years of age group and the group on their first pregnancies (p < 0.05). CONCLUSION: After closure of ASD, QoL in pregnant women was improved. In a subgroup analysis, the younger women and those on their first pregnancy performed more poorly in some dimensions (social functioning and role emotional); this suggested that these groups should receive more proactive intervention.

Limited data was available on the general quality of life (QoL) in pregnant women with atrial septal defect (ASD), even though the condition could produce anxiety over health of the pregnancy and fetus. The percutaneous closure procedure was available for ASD during pregnancy; however, pregnant women were often concerned that the required X-rays would harm the fetus. A safe and effective procedure, percutaneous closure of ASD guided by transthoracic echocardiography, was widely used for this condition. This study used the 36-Item Short Form Survey (SF-36) to assess QoL in pregnant women with ASD pre- and post-procedure and compared the results to those of healthy pregnant women at a similar stage of pregnancy. Post-procedure QoL in pregnant women with ASD was improved; however, the younger women and those on their first pregnancy performed more poorly in some dimensions (social functioning and role emotional). Our results suggested that these groups should receive more proactive intervention.

Emerging Role of Neutrophil Extracellular Traps in Gastrointestinal Tumors: A Narrative Review.

Neutrophil extracellular traps (NETs) are extracellular fibrous networks consisting of depolymerized chromatin DNA skeletons with a variety of antimicrobial proteins. They are secreted by activated neutrophils and play key roles in host defense and immune responses. Gastrointestinal (GI) malignancies are globally known for their high mortality and morbidity. Increasing research suggests that NETs contribute to the progression and metastasis of digestive tract tumors, among them gastric, colon, liver, and pancreatic cancers. This article explores the formation of NETs and reviews the role that NETs play in the gastrointestinal oncologic microenvironment, tumor proliferation and metastasis, tumor-related thrombosis, and surgical stress. At the same time, we analyze the qualitative and quantitative detection methods of NETs in recent years and found that NETs are specific markers of coronavirus disease 2019 (COVID-19). Then, we explore the possibility of NET inhibitors for the treatment of digestive tract tumor diseases to provide a new, efficient, and safe solution for the future therapy of gastrointestinal tumors.

Prognostic thirteen-long non-coding RNAs (IncRNAs) could improve the survival prediction of gastric cancer.

OBJECTIVE: Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) play important regulatory roles in the tumorigenesis and progression of gastric cancer (GC). The aim of this study was to construct the prognostic predictive model of lncRNAs signature and improve the survival prediction of GC. PATIENTS AND METHODS: The expression profiling of lncRNAs in large GC cohorts was performed from The Cancer Genome Atlas (TCGA) databases using the lncRNAs-mining approach, including training data set (N=160) and testing data set (N=159). A 13-lncRNAs signature significantly associated with overall survival (OS) in the training data set was selected. The prognostic value of this 13-lncRNAs signature was then confirmed in the test validation set and the entire validation set, respectively. RESULTS: Based on lncRNA expression profiling of 319 patients with stomach adenocarcinoma (STAD), prognostic 13-lncRNAs signature was found to be significantly associated with the prognosis of GC. Compared to patients with low-risk scores, patients with high-risk scores had a significantly shorter survival time. Moreover, functional enrichment analysis indicated that this 13-lncRNAs signature was potentially involved in multiple biological processes, such as DNA replication and cell cycle signaling pathway. CONCLUSIONS: The prognostic model of the 13-lncRNAs signature established by our study could improve the survival prediction of GC to a greater extent.

Exosome as a crucial communicator between tumor microenvironment and gastric cancer (Review).

Gastric cancer is one of the most common malignancies and has relatively high morbidity and mortality rates. Exosomes are nanoscale extracellular vesicles that originate from a diverse array of cells and may be found throughout various bodily fluids. These vesicles are endogenous nanocarriers in their natural state with the unique ability to transport lipids, proteins, DNA and RNA. Exosomes contain DNA, RNA, proteins, lipids and other bioactive components that have crucial roles in the transmission of information and regulation of cell activities in gastric cancer. This paper begins with an exploration of the composition, formation and release mechanisms of exosomes. Subsequently, the role of exosomes in the tumor microenvironment is reviewed in terms of the immune cell population, nonimmune cell population and other factors. Finally, the current status and challenges of exosome­based research on the progression, diagnosis and therapeutic methods of gastric cancer are summarized. This holistic review offers insight that may guide future research directions for exosomes and potentially pave the way for novel therapeutic interventions in the management of gastric cancer.

The dawn of a new Era: mRNA vaccines in colorectal cancer immunotherapy.

Colorectal cancer (CRC) is a typical cancer that accounts for 10% of all new cancer cases annually and nearly 10% of all cancer deaths. Despite significant progress in current classical interventions for CRC, these traditional strategies could be invasive and with numerous adverse effects. The poor prognosis of CRC patients highlights the evident and pressing need for more efficient and targeted treatment. Novel strategies regarding mRNA vaccines for anti-tumor therapy have also been well-developed since the successful application for the prevention of COVID-19. mRNA vaccine technology won the 2023 Nobel Prize in Physiology or Medicine, signaling a new direction in human anti-cancer treatment: mRNA medicine. As a promising new immunotherapy in CRC and other multiple cancer treatments, the mRNA vaccine has higher specificity, better efficacy, and fewer side effects than traditional strategies. The present review outlines the basics of mRNA vaccines and their advantages over other vaccines and informs an available strategy for developing efficient mRNA vaccines for CRC precise treatment. In the future, more exploration of mRNA vaccines for CRC shall be attached, fostering innovation to address existing limitations.

Targeting the "tumor microenvironment": RNA-binding proteins in the spotlight in colorectal cancer therapy.

Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate among cancers. The development of CRC involves both genetic and epigenetic abnormalities, and recent research has focused on exploring the ex-transcriptome, particularly post-transcriptional modifications. RNA-binding proteins (RBPs) are emerging epigenetic regulators that play crucial roles in post-transcriptional events. Dysregulation of RBPs can result in aberrant expression of downstream target genes, thereby affecting the progression of colorectal tumors and the prognosis of patients. Recent studies have shown that RBPs can influence CRC pathogenesis and progression by regulating various components of the tumor microenvironment (TME). Although previous research on RBPs has primarily focused on their direct regulation of colorectal tumor development, their involvement in the remodeling of the TME has not been systematically reported. This review aims to highlight the significant role of RBPs in the intricate interactions within the CRC tumor microenvironment, including tumor immune microenvironment, inflammatory microenvironment, extracellular matrix, tumor vasculature, and CRC cancer stem cells. We also highlight several compounds under investigation for RBP-TME-based treatment of CRC, including small molecule inhibitors such as antisense oligonucleotides (ASOs), siRNAs, agonists, gene manipulation, and tumor vaccines. The insights gained from this review may lead to the development of RBP-based targeted novel therapeutic strategies aimed at modulating the TME, potentially inhibiting the progression and metastasis of CRC.

Prevalence of anemia in patients with rheumatoid arthritis and its association with dietary inflammatory index: A population-based study from NHANES 1999 to 2018.

Anemia is common in patients with rheumatoid arthritis (RA), and it is unknown whether the dietary inflammatory index (DII) is linked to anemia. This study aimed to clarify the prevalence of anemia in RA patients and its association with the DII. The data utilized in this study were collected from the National Health and Nutrition Examination Survey database from 1999 to 2018. The prevalence of anemia in RA patients was estimated by ethnicity, sex, and age. Weighted multivariate logistic regression was utilized to explore the correlation between anemia risk and DII. The most crucial dietary factors related to the risk of anemia in RA patients were screened by stepwise regression. A nomogram model was established according to key dietary factors. A total of 10.25% (confidence interval, 8.58-11.92%) of RA patients will develop anemia, with the lowest prevalence around the age of 60. In addition, higher DII levels were discovered in anemic patients than in nonanemic patients. In multivariate regression models, an important positive association was revealed between anemia and growing quartiles of DII (Q4 vs Q1: odds ratio = 1.98; confidence interval, 1.25-3.15). In the subgroup analysis, the adjusted relation of DII with anemia in females, Mexicans, smokers, nondrinkers, and age groups ≥ 60 years was statistically significant. The same association was observed in the sensitivity analysis. A nomogram model based on stepwise regression screening of key dietary factors showed good discriminatory power to identify anemic risk in RA patients (area under the curve: 0.707). In patients with RA, high DII levels were associated with the risk of anemia. More attention should be given to controlling dietary inflammation to better prevent and treat anemia.

Identification of SOCS3 and PTGS2 as new biomarkers for the diagnosis of gout by cross-species comprehensive analysis.

Background: Gout is the most common inflammatory arthritis in adults. Gout is an arthritic disease caused by the deposition of monosodium urate crystal (MSU) in the joints, which can lead to acute inflammation and damage adjacent tissue. Hyperuricemia is the main risk factor for MSU crystal deposition and gout. With the increasing burden of gout disease, the identification of potential biomarkers and novel targets for diagnosis is urgently needed. Methods: For the analysis of this subject paper, we downloaded the human gout data set GSE160170 and the gout mouse model data set GSE190138 from the GEO database. To obtain the differentially expressed genes (DEGs), we intersected the two data sets. Using the cytohubba algorithm, we identified the key genes and enriched them through GO and KEGG. The gene expression trends of three subgroups (normal control group, intermittent gout group and acute gout attack group) were analyzed by Series Test of Cluster (STC) analysis, and the key genes were screened out, and the diagnostic effect was verified by ROC curve. The expression of key genes in dorsal root nerve and spinal cord of gout mice was analyzed. Finally, the clinical samples of normal control group, hyperuricemia group, intermittent gout group and acute gout attack group were collected, and the expression of key genes at protein level was verified by ELISA. Result: We obtained 59 co-upregulated and 28 co-downregulated genes by comparing the DEGs between gout mouse model data set and human gout data set. 7 hub DEGs(IL1B, IL10, NLRP3, SOCS3, PTGS2) were screened out via Cytohubba algorithm. The results of both GO and KEGG enrichment analyses indicate that 7 hub genes play a significant role in regulating the inflammatory response, cytokine production in immune response, and the TNF signaling pathway. The most representative hub genes SOCS3 and PTGS2 were screened out by Series Test of Cluster, and ROC analysis results showed the AUC values were both up to 1.000. In addition, we found that PTGS2 expression was significantly elevated in the dorsal root ganglia and spinal cord in monosodium urate(MSU)-induced gout mouse model. The ELISA results revealed that the expression of SOCS3 and PTGS2 was notably higher in the acute gout attack and intermittent gout groups compared to the normal control group. This difference was statistically significant, indicating a clear distinction between the groups. Conclusion: Through cross-species comprehensive analysis and experimental verification, SOCS3 and PTGS2 were proved to be new biomarkers for diagnosing gout and predicting disease progression.

Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.

Tumors employ diverse strategies for immune evasion. Unraveling the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here, we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as a pivotal immune suppressor. FGF21 is upregulated in multiple types of tumors and promotes tumor progression. Tumor-secreted FGF21 significantly disrupts anti-tumor immunity by rewiring cholesterol metabolism of CD8+T cells. Mechanistically, FGF21 sustains the hyperactivation of AKT-mTORC1-sterol regulatory-element-binding protein 1 (SREBP1) signal axis in the activated CD8+T cells, resulting in the augment of cholesterol biosynthesis and T cell exhaustion. FGF21 knockdown or blockade using a neutralizing antibody normalizes AKT-mTORC1 signaling and reduces excessive cholesterol accumulation in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings reveal FGF21 as a "secreted immune checkpoint" that hampers anti-tumor immunity, suggesting that inhibiting FGF21 could be a valuable strategy to enhance the cancer immunotherapy efficacy.

Dysregulated microRNAs participate in the crosstalk between colorectal cancer and atrial fibrillation.

Colorectal cancer and atrial fibrillation share several common risk factors, and the incidence of the two diseases also exhibits a certain correlation. The above facts suggest a potential interaction mechanism between them, which has obtained increasing attention in the scientific community but remains to be further explored. Participating in diverse physiological and pathological processes, miRNAs exert important roles in both occurrence and growth of colorectal cancer and atrial fibrillation. To fill the gap in the understanding of the potential linkage between two diseases, the present study collected dysregulated miRNAs of colorectal cancer and atrial fibrillation from previous studies and then selected the miRNAs with the same change trends in both diseases. Finally, we reviewed the potential crosstalk of two diseases focusing on the roles of 6 dysregulated miRNAs, including 3 co-downregulated miRNAs (hsa-mir-126, hsa-mir-133a and hsa-mir-150) and 3 co-upregulated miRNAs (hsa-mir-106a, hsa-mir-155 and hsa-mir-21). The molecular mechanisms mediated by these miRNAs in colorectal cancer and atrial fibrillation were reviewed, and the possible crosstalk between the two diseases was discussed from the perspective of miRNAs. This study also provides potential common targets for preventive and curative measures against both colorectal cancer and atrial fibrillation.

Immune and inflammatory mechanisms and therapeutic targets of gout: An update.

Gout is an autoimmune disease characterized by acute or chronic inflammation and damage to bone joints induced due to the precipitation of monosodium urate (MSU) crystals. In recent years, with the continuous development of animal models and ongoing clinical investigations, more immune cells and inflammatory factors have been found to play roles in gouty inflammation. The inflammatory network involved in gout has been discovered, providing a new perspective from which to develop targeted therapy for gouty inflammation. Studies have shown that neutrophil macrophages and T lymphocytes play important roles in the pathogenesis and resolution of gout, and some inflammatory cytokines, such as those in the interleukin-1 (IL-1) family, have been shown to play anti-inflammatory or proinflammatory roles in gouty inflammation, but the mechanisms underlying their roles are unclear. In this review, we explore the roles of inflammatory cytokines, inflammasomes and immune cells in the course of gout development and the research status of therapeutic drugs used for inflammation to provide insights into future targeted therapy for gouty inflammation and the direction of gout pathogenesis research.

Application of machine learning algorithm in predicting distant metastasis of T1 gastric cancer.

Distant metastasis (DM) is relatively uncommon in T1 stage gastric cancer (GC). The aim of this study was to develop and validate a predictive model for DM in stage T1 GC using machine learning (ML) algorithms. Patients with stage T1 GC from 2010 to 2017 were screened from the public Surveillance, Epidemiology and End Results (SEER) database. Meanwhile, we collected patients with stage T1 GC admitted to the Department of Gastrointestinal Surgery of the Second Affiliated Hospital of Nanchang University from 2015 to 2017. We applied seven ML algorithms: logistic regression, random forest (RF), LASSO, support vector machine, k-Nearest Neighbor, Naive Bayesian Model, Artificial Neural Network. Finally, a RF model for DM of T1 GC was developed. The AUC, sensitivity, specificity, F1-score and accuracy were used to evaluate and compare the predictive performance of the RF model with other models. Finally, we performed a prognostic analysis of patients who developed distant metastases. Independent risk factors for prognosis were analysed by univariate and multifactorial regression. K-M curves were used to express differences in survival prognosis for each variable and subvariable. A total of 2698 cases were included in the SEER dataset, 314 with DM, and 107 hospital patients were included, 14 with DM. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. A combined analysis of seven ML algorithms in the training and test sets found that the RF prediction model had the best prediction performance (AUC: 0.941, Accuracy: 0.917, Recall: 0.841, Specificity: 0.927, F1-score: 0.877). The external validation set ROCAUC was 0.750. Meanwhile, survival prognostic analysis showed that surgery (HR = 3.620, 95% CI 2.164-6.065) and adjuvant chemotherapy (HR = 2.637, 95% CI 2.067-3.365) were independent risk factors for survival prognosis in patients with DM from stage T1 GC. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. ML algorithms had shown that RF prediction models had the best predictive efficacy to accurately screen at-risk populations for further clinical screening for metastases. At the same time, aggressive surgery and adjuvant chemotherapy can improve the survival rate of patients with DM.

Landscapes and mechanisms of CD8+ T cell exhaustion in gastrointestinal cancer.

CD8+ T cells, a cytotoxic T lymphocyte, are a key component of the tumor immune system, but they enter a hyporeactive T cell state in long-term chronic inflammation, and how to rescue this depleted state is a key direction of research. Current studies on CD8+ T cell exhaustion have found that the mechanisms responsible for their heterogeneity and differential kinetics may be closely related to transcription factors and epigenetic regulation, which may serve as biomarkers and potential immunotherapeutic targets to guide treatment. Although the importance of T cell exhaustion in tumor immunotherapy cannot be overstated, studies have pointed out that gastric cancer tissues have a better anti-tumor T cell composition compared to other cancer tissues, which may indicate that gastrointestinal cancers have more promising prospects for the development of precision-targeted immunotherapy. Therefore, the present study will focus on the mechanisms involved in the development of CD8+ T cell exhaustion, and then review the landscapes and mechanisms of T cell exhaustion in gastrointestinal cancer as well as clinical applications, which will provide a clear vision for the development of future immunotherapies.

Clinical Significance of Fibrinogen and Platelet to Pre-Albumin Ratio in Predicting the Prognosis of Advanced Gastric Cancer.

Objective: The aim of this study was to investigate the clinical significance of Fibrinogen and Platelet to Pre-albumin Ratio(FPAR) in predicting the prognosis of patients with advanced gastric cancer(AGC) and to construct a predictive model. Methods: We collected clinical data from 489 postoperative patients with AGC. FPAR was divided into high and low groups according to the receiver operating characteristic (ROC) curve. The value of FPAR in predicting the prognosis of progressive gastric cancer was analysed using univariate and multivariable Cox regression analysis and its relationship with clinicopathological features. Finally, the Overall Survival(OS) and recurrence-free survival(RFS) prediction models were constructed and validated using FPAR. Results: Univariate and multifactorial cox regression analysis showed that grade (P<0.001), TNM-stage (P<0.001), chemotherapy (P<0.001), and FPAR (OR=3.054,95% CI:2.088-4.467, P<0.001) were independent risk factors for OS; grade (P=0.021), N-stage (P=0.024), TNM-stage (P=0.033), and FPAR (OR=2.215,95% CI:1.634-3.003, P<0.001) were independent risk factors for RFS. Subgroup analysis showed that the FPAR-low group had higher OS and RFS than the FPAR-high group, regardless of the patient's TNM stage (p<0.05). However, OS was instead higher in the the stage III-FPAR-low group than in the the stage II-FPAR-high group (p<0.05), while RFS was not significantly different. Predictive models incorporating FPAR had better predictive performance than those without FPAR, showing wide range of net benefit and AUC. After correction, the 2-year AUC, 3-year AUC and C-index of the OS model were 0.737, 0.756, and 0.746; the 2-year AUC, 3-year AUC, and C-index of the RFS model were 0.738, 0.758, and 0.711. Conclusion: FPAR levels were associated with prognosis in patients with AGC and could independently predict RFS and OS.

Photothermally responsive theranostic nanocomposites for near-infrared light triggered drug release and enhanced synergism of photothermo-chemotherapy for gastric cancer.

Near-infrared (NIR) photothermal therapy plays a critical role in the cancer treatment and diagnosis as a promising carcinoma treatment modalities nowadays. However, development of clinical application has been greatly limited due to the inefficient drug release and low tumor accumulation. Herein, we designed a NIR-light triggered indocyanine green (ICG)-based PCL core/P(MEO2MA-b-HMAM) shell nanocomposites (PPH@ICG) and evaluated their therapeutic effects in vitro and in vivo. The anticancer drug 5-fluorouracil (5Fu) and the photothermal agent ICG were loaded into a thermo-sensitive micelle (PPH@5Fu@ICG) by self-assembly. The nanoparticles formed were characterized using transmission electron microscopy, dynamic light scattering, and fluorescence spectra. The thermo-sensitive copolymer (PPH@5Fu@ICG) showed a great temperature-controlled drug release response with lower critical solution temperature. In vitro cellular uptake and TEM imaging proved that PPH@5Fu@ICG nanoparticles can home into the lysosomal compartments under NIR. Moreover, in gastric tumor-bearing nude mice, PPH@5Fu@ICG + NIR group exhibited excellent improvement in antitumor efficacy based on the NIR-triggered thermo-chemotherapy synergy, both in vitro and in vivo. In summary, the proposed strategy of synergistic photo-hyperthermia chemotherapy effectively reduced the 5Fu dose, toxic or side effect, which could serve as a secure and efficient approach for cancer theranostics.

Analysis and application of RNA binding protein gene pairs to predict the prognosis of gastric cancer.

Background: RNA-binding proteins (RBPs) are closely related to tumors, but little is known about the mechanism of RBPs in tumorigenesis and progression of gastric cancer (GC). As genes do not usually act alone in the pathway deregulation, gene pair combinations are more likely to become stable and accurate biomarkers. The purpose of our research is to establish a novel signature based on RBP gene pairs to predict the prognosis of gastric cancer patients. Methods: We downloaded genetic and clinical information from the TCGA and GEO database. TCGA and GSE13911 were used for screening differentially expressed genes (DEGs). The RBP genes were gathered from previous studies and employed to screen out DE-RBP genes after intersecting with DEGs. Samples were classified according to the relative expression of each pair of DE-RBP genes. The univariate Cox regression analysis and random forest were used to identify hub gene pairs to construct signature for predicting the prognosis of gastric cancer. Time-dependent ROC curves and KM survival curves were performed to evaluate the signature. GSEA was performed in TCGA training cohort and GSE62254 testing cohort to analyze enrichment pathways. Finally, the influence of these gene pairs on the prognosis of GC patients was further elucidated respectively through the combination of high and low expression of the two genes in each hub gene pair. Results: We screened out 6 hub RBP gene pairs (COL5A2/FEN1, POP1/GFRA1, EXO1/PLEKHS1, SLC39A10/CHI3L1, MMP7/PPP1R1 B and SLC5A6/BYSL) to predict the prognosis of patients with gastric cancer. Using the optimal cut-off value to divide patients into high-risk and low-risk groups in the training and testing cohort, we found that the overall survival (OS) of the low-risk group was higher than that of the high-risk group (P < 0.05). The area under the ROC curves for 1, 3, and 5 years were (0.659, 0.744, 0.758) and (0.624, 0.650, 0.653) in two cohorts. Univariate and multivariate Cox regression analysis showed that 6 RBP gene pairs signature were independent prognostic factors for gastric cancer (P < 0.05). In addition, the prognostic survival analysis showed that COL5A2-high/FEN1-low, POP1-low/GFRA1-high, EXO1-low/PLEKHS1-low,SLC39A10-high/CHI3L1-low, MMP7-high/PPP1R1 B-low, SLC5A6-low/BYSL-low had worse OS (P < 0.05). And the gene correlation analysis showed that there was no obvious correlation between the genes in each gene pairs except SLC5A6/BYSL and POP1/GFRA1. Finally, GSEA analysis showed that the high-risk group was enriched in tumor migration, invasion and growth-related pathways. Conclusion: Our study identified a novel 6 RBP gene pairs signature to predict the prognosis of gastric cancer patients and provide potential targets for clinical gene therapy.