Efficacy and Safety of Neoadjuvant Subcutaneous Envafolimab in dMMR/MSI-H Locally Advanced Colon Cancer.

BACKGROUND: Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently. OBJECTIVE: This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer. METHODS: Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate. RESULTS: Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a "watch and wait" strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up. CONCLUSIONS: Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.

Transcriptional and post-transcriptional regulation of chloroplast development by nuclear-localized XAP5 CIRCADIAN TIMEKEEPER.

Chlorophyll biosynthesis and breakdown, important cellular processes for photosynthesis, occur in the chloroplast. As a semi-autonomous organelle, chloroplast development is mainly regulated by nuclear-encoded chloroplast proteins and proteins encoded by itself. However, the knowledge of chloroplast development regulated by other organelles is limited. Here, we report that the nuclear-localized XAP5 CIRCADIAN TIMEKEEPER (XCT) is essential for chloroplast development in Arabidopsis. In this study, significantly decreased chlorophyll content phenotypes of cotyledons and subsequently emerging organs from shoot apical meristem were observed in xct-2. XCT is constitutively expressed in various tissues and localized in the nuclear with speckle patterns. RNA-seq analysis identified 207 differently spliced genes and 1511 differently expressed genes, in which chloroplast development-, chlorophyll metabolism- and photosynthesis-related genes were enriched. Further biochemical assays suggested that XCT was co-purified with the well-known splicing factors and transcription machinery, suggesting dual functions of XCT in gene transcription and splicing. Interestingly, we also found that the chlorophyll contents in xct-2 significantly decreased under high temperature and high light condition, indicating XCT integrates temperature and light signals to fine-tune the chlorophyll metabolism in Arabidopsis. Therefore, our results provide new insights into chloroplast development regulation by XCT, a nuclear-localized protein, at the transcriptional and post-transcriptional level.

Elevated circulating BMP9 aggravates pulmonary angiogenesis in hepatopulmonary syndrome rats through ALK1-Endoglin-Smad1/5/9 signalling.

BACKGROUND: Bone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS. METHODS: We profiled the circulating BMP9 levels in common bile duct ligation-induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells. RESULTS: Our data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor-like kinase1 (ALK1)-Endoglin-Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1-Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro-angiogenic monocytes in the microvasculature in HPS rats. CONCLUSIONS: This study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1-Endoglin-Smad1/5/9 pathway. In addition, BMP9-regulated pathways are also involved in accumulation of pro-angiogenic monocytes in the pulmonary microvasculature in HPS rats.

Reversal of cholestatic liver disease by the inhibition of sphingosine 1-phosphate receptor 2 signaling.

Aims: The objective of this study is to examine the impact of inhibiting Sphingosine 1-phosphate receptor 2 (S1PR2) on liver inflammation, fibrogenesis, and changes of gut microbiome in the context of cholestasis-induced conditions. Methods: The cholestatic liver injury model was developed by common bile duct ligation (CBDL). Sprague-Dawley rats were randomly allocated to three groups, sham operation, CBDL group and JTE-013 treated CBDL group. Biochemical and histological assessments were conducted to investigate the influence of S1PR2 on the modulation of fibrogenic factors and inflammatory infiltration. We conducted an analysis of the fecal microbiome by using 16S rRNA sequencing. Serum bile acid composition was evaluated through the utilization of liquid chromatography-mass spectrometry techniques. Results: In the BDL rat model, the study findings revealed a significant increase in serum levels of conjugated bile acids, accompanied by an overexpression of S1PR2. Treatment with the specific inhibitor of S1PR2, known as JTE-013, resulted in a range of specific effects on the BDL rats. These effects included the improvement of liver function, reduction of liver inflammation, inhibition of hepatocyte apoptosis, and suppression of NETosis. These effects are likely mediated through the TCA/S1PR2/NOX2/NLRP3 pathway. Furthermore, the administration of JTE-013 resulted in an augmentation of the diversity of the bacterial community's diversity, facilitating the proliferation of advantageous species while concurrently inhibiting the prevalence of detrimental bacteria. Conclusions: The results of our study suggest that the administration of JTE-013 may have a beneficial effect in alleviating cholestatic liver disease and restoring the balance of intestinal flora.

Perioperative Enteral Immunonutrition Support for the Immune Function and Intestinal Mucosal Barrier in Gastric Cancer Patients Undergoing Gastrectomy: A Prospective Randomized Controlled Study.

OBJECTIVE: The impact of perioperative immunonutrition on patients undergoing radical gastrectomy remains undetermined. This study aimed to assess the influence of enteral immunonutrition support on postoperative immune function and intestinal mucosal barrier function following radical gastrectomy, contrasting findings with a control group to furnish evidence for perioperative enteral nutrition support. METHODS: In this prospective randomized trial, 65 patients who underwent radical gastrectomy between June 2022 and June 2023 were included. Participants were allocated to either the study group (receiving enteral immunonutrition) or the control group (not receiving enteral immunonutrition). We compared postoperative rehabilitation and complications between the groups, analyzed the intestinal mucosal barrier function markers on the 3rd and 7th postoperative days, and delved deeper into peripheral blood cell immunity, inflammation, and nutritional indicators. RESULTS: The cohort consisted of 30 patients in the study group and 35 in the control group, with no significant differences in demographic attributes between the two groups. On the 3rd postoperative day, the diamine oxidase, D-lactic acid, and endotoxin levels in the study group were significantly lower than those in the control group (p = 0.029, p = 0.044, and p = 0.010, respectively). By the 7th postoperative day, these levels continued to be significantly diminished in the study group (p = 0.013, p = 0.033, and p = 0.004, respectively). The times to first flatus (p = 0.012) and first bowel movement (p = 0.012) were significantly shorter in the study group. Moreover, postoperative complications in the study group were fewer than in the control group (p = 0.039). On the 7th postoperative day, the study group had lower peripheral white blood cell (WBC) levels (p = 0.020) and neutrophil-lymphocyte ratios (NLR) (p = 0.031), but displayed elevated albumin levels (p = 0.006). One month post-surgery, the CD4+T and CD8+T counts were significantly greater in the study group (p = 0.003 and p = 0.012, respectively). Correlation analyses indicated that NLR and complications were associated with endotoxin levels. CONCLUSION: Administering perioperative enteral immunonutrition enhances postoperative immune and intestinal mucosal barrier functions in patients undergoing radical gastrectomy. This effect leads to diminished inflammatory responses, a decreased rate of postoperative complications, and accelerated patient recovery.

Extrahepatic Angiogenesis: A Potential Common Pathophysiological Basis of Multiple Organ Dysfunction in Rats with Cholestasis Cirrhosis.

BACKGROUND: In addition to intrahepatic angiogenesis, patients with cholestasis cirrhosis develop extrahepatic vasculature disorders and functional disturbances of multiple organ systems. Without effective intervention, these vascular disorders will eventually turn into multiple organs vascular syndromes, including the brain, lung and other organ systems. However, studies on the pathogenesis of vascular alterations among extrahepatic organ disturbances are still carried out separately, which hampered the successful translation of preclinical studies to the human setting and required further mechanistic insight into these complications. This study aims to investigate the relationship between extrahepatic angiogenesis and multiple organ impairment, and whether the vascular endothelial growth factor (VEGF) family members and their receptors are involved in this process. METHODS: Pathological changes of the multiple organs were determined by histopathological and immunohistochemical staining in the established common bile duct ligation (CBDL) rats, and angiogenesis was estimated by microvessel density (MVD). Levels of the VEGF family members and their receptors in the serum and organ tissues were also measured by using enzyme-linked immunosorbent assays. RESULTS: The MVD and VEGF family members and their receptors were significantly increased in CBDL rats with multiple organ injury, especially in the liver, lung and cerebral cortex. Meanwhile, we noticed moderate elevation of soluble receptor of the vascular endothelial growth factor-1 (sFlt-1) in the liver, lung, and cerebral cortex, whereas the levels of placental growth factor (PLGF) increased significantly. CONCLUSIONS: Extrahepatic angiogenesis may represent a common pathophysiological basis for multiple organ dysfunction and the sFlt-1/PLGF ratio could offer an avenue for further studies to target extrahepatic angiogenesis in cholestatic cirrhosis.

Tumour-associated macrophages in gastric cancer: From function and mechanism to application.

BACKGROUND: Gastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic changes in tumour cells and the influence of the surrounding tumour microenvironment (TME). Accumulative evidence shows that tumour-associated macrophages (TAMs) play a vital role in GC, acting as plentiful and active infiltrating inflammatory cells in the TME. MAIN BODY: In this review, the different functions and mechanisms of TAMs in GC progression, including the conversion of phenotypic subtypes; promotion of tumour proliferation, invasion and migration; induction of chemoresistance; promotion of angiogenesis; modulation of immunosuppression; reprogramming of metabolism; and interaction with the microbial community are summarised. Although the role of TAMs in GC remains controversial in clinical settings, clarifying their significance in the treatment selection and prognostic prediction of GC could support optimising TAM-centred clinicaltherapy. CONCLUSION: In summary, we reviewed the the phenotypic polarisation, function and molecular mechanism of TAMs and their potential applications in the treatment selection and prognostic prediction of GC.

Comprehensive analysis of cuproptosis-related immune biomarker signature to enhance prognostic accuracy in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a malignant tumor with high prevalence and fatality. Cuproptosis is a recently identified copper-dependent programmed cell death mechanism. Multiple studies have demonstrated the profound impact of the immune microenvironment on tumor development. Hence, we decided to excavate the potential functional roles of cuproptosis-related immune genes (CRIGs) in GC and their values as biomarkers. METHODS: Cuproptosis- and immune-related genes were curated from top published studies on cell cuproptosis and cellular immunity. Transcriptome data and clinical information were obtained from TCGA, GTEx, and GEO databases. Cox and LASSO analyses were used to establish a prognostic signature for GC. Long-term prognosis, immune infiltration, immune checkpoint, and drug response were compared between signature groups. CRIG expression in GC scRNA-seq was analyzed. Immunohistochemistry was used to evaluate CRIG and cuproptosis regulator FDX1 in GC tissues. RESULTS: Seven CRIGs (ANOS1, CTLA4, ITGAV, CXCR4, NRP1, FABP3, and LGR6) were selected to establish a potent signature to forecast the long-term prognosis of patients. GC patients had worse prognosis and poor responses to chemotherapeutic drugs (5-Fluorouracil and paclitaxel) in the high-risk group. scRNA-seq revealed that CTLA4, ITGAV, CXCR4, and NRP1 enrichment in specific cell types regulated the progression of GC. Moreover, NRP1, CXCR4, LGR6, CTLA4, and FDX1 were elevated in GC tissues, with a positive correlation between their expression and FDX1. CONCLUSIONS: To conclude, this study first provides insights into the functions of CRIGs in GC. Furthermore, a robust cuproptosis-related immune biomarker signature was established to forecast the long-term survival of GC patients accurately.

Integrated analysis from multicentre studies identities m7G-related lncRNA-derived molecular subtypes and risk stratification systems for gastric cancer.

Introduction: Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Due to the lack of effective chemotherapy methods for advanced gastric cancer and poor prognosis, the emergence of immunotherapy has brought new hope to gastric cancer. Further research is needed to improve the response rate to immunotherapy and identify the populations with potential benefits of immunotherapy. It is unclear whether m7G-related lncRNAs influence tumour immunity and the prognosis of immunotherapy. Methods: This study evaluated 29 types of immune cells and immune functions in gastric cancer patients, and m7G-related lncRNAs and their molecular subtypes were identified. In addition, we also studied the biological function characteristics of m7G-related lncRNA molecular subtypes. Finally, the patient's risk score was calculated based on m7G-related lncRNAs, and a nomogram of staging and risk groups was established to predict the prognosis. For experimental verification, RT-qPCR were preformed from the native cohort. Results: After identifying m7G-related lncRNAs and their molecular subtypes, we found three molecular subtypes, the B subtype had the highest level of infiltration, and the B subtype may benefit more from immunotherapy. We divided GC patients into two regulator subtypes based on biological function. The two subtypes have significant immunological differences and can be used to judge ICI treatment. We established a risk score formula based on five lncRNAs, including LINC00924, LINC00944, LINC00865, LINC00702, and ZFAS1. Patients with poor prognoses were closely related to patients in the high-risk group. After comprehensive analysis of different risk groups, the efficacy of the high-risk group on bleomycin, cisplatin, docetaxel, doxorubicin and etoposide was better than that of the low-risk group, suggesting that risk subgroups based on risk scores play a guiding role in chemotherapy and that the high-risk group may benefit more from immunotherapy. RT-qPCR results showed that LINC00924, LINC00944, and LINC00865 were highly expressed in tumour tissues, while LINC00702 and ZFAS1 were expressed at low levels in tumour tissues. Discussion: In conclusion, we were the first to discover that m7G-related lncRNAs play a vital role in the tumour immune microenvironment of gastric cancer, and a risk prediction model was established to identify patients with potential benefits from immunotherapy and predict the prognosis of GC patients.

Comparisons of nutritional status and complications between patients with and without postoperative feeding jejunostomy tube in gastric cancer: a retrospective study.

Background: Feeding jejunostomy tube (FJT) enables early postoperative nutritional supply for gastric cancer patients undergoing surgery. However, the nutritional benefit of FJT may be accompanied by potential risk of increased complications, so both the nutritional improvement and the complication rates associated with FJT should be assessed. Methods: From January 2009 to December 2014, 715 consecutive patients underwent gastric cancer resection at the Peking Union Medical College Hospital in China. The perioperative nutritional index and incidence of complications in patients with FJT placement were retrospectively compared to those in patients without FJT placement. Nutritional data including albumin, prealbumin, hemoglobin, and high sensitivity C-reactive protein, the neutrophil-to-lymphocyte ratio (NLR), and Onodera's prognostic nutrition index (OPNI) were recorded at the following 3 timepoints: preoperatively, 1-week postoperatively, and 1-month postoperatively. Postoperative complications including surgical site infection, intra-abdominal infections, anastomotic leaks and gastroparesis were assessed. Multivariate logistic regression was used to study the association between FJT and complications. Results: A total of 715 patients were included in the study. The mean age was 60.4 years and 72.2% were male. The overall characteristics between FJT and no-FJT groups were comparable. Of the 247 total gastrectomy cases, 98 (39.7%) had a FJT placed. Compared to the total gastrectomy patients without a FJT, the 98 patients with a FJT had a lower hemoglobin level (P=0.048) and NLR (P=0.030) preoperatively, and higher albumin (P=0.005), prealbumin (P<0.001), and hemoglobin (P=0.014) levels, a higher OPNI (P=0.027), and a lower NLR (P=0.005) 1-month postoperatively. Of the 468 subtotal gastrectomy cases, 87 (18.6%) had a FJT placed. Compared to the subtotal gastrectomy patients without a FJT, these 87 patients had a lower NLR (P=0.006) 1-week postoperatively, and a higher albumin level (P=0.009) 1-month postoperatively. In the multivariate analysis, FJT placement was not associated with postoperative adverse outcomes, including surgical site infection [odds ratio (OR) =1.21, P=0.79], intra-abdominal infection (OR =0.38, P=0.11), anastomotic leak (OR =0.58, P=0.53), reoperation (OR =0.22, P=0.23), gastroparesis (OR =6.35, P=0.08), or hospitalization for more than 30 days (OR =0.58, P=0.32). Conclusions: Early enteral nutritional support by FJT after gastrectomy tended to improve the nutritional status of patients, while it did not appear to increase the incidence rate of postoperative complications.

Reduced neural responses to reward reflect anhedonia and inattention: an ERP study.

An inhibited neural response to reward is typical of clinical depression and can predict an individual's overall depressive symptoms. However, the mechanism underlying this are unclear. Previous studies have found that anhedonia and inattention may mediate the relationship between reward sensitivity and depressive symptoms. Therefore, this study aimed to verify the relationship between reward sensitivity and overall depressive symptoms in a depressive tendency sample as well as to explore the mechanism underlying the ability of neural responses to reward to predict overall depressive symptoms via a mediation model. Sixty-four participants (33 with depressive tendencies and 31 without; dichotomized by BDI-II) finished simple gambling tasks while their event-related potential components (ERPs) were recorded and compared. Linear regression was conducted to verify the predictive effect of ERPs on overall depressive symptoms. A multiple mediator model was used, with anhedonia and distractibility as mediators reward sensitivity and overall depressive symptoms. The amplitude of reward positivity (ΔRewP) was greater in healthy controls compared to those with depressive tendencies (p = 0.006). Both the gain-locked ERP component (b = - 1.183, p = 0.007) and the ΔRewP (b = - 0.991, p = 0.024) could significantly negatively predict overall depressive symptoms even after controlling for all anxiety symptoms. The indirect effects of anhedonia and distractibility were significant (both confidence intervals did not contain 0) while the direct effect of reward sensitivity on depressive symptom was not significant (lower confidence interval = - 0.320, upper confidence interval = 0.065). Individuals with depressive tendencies display impaired neural responses to reward compared to healthy controls and reduced individual neural responses to reward may reflect the different biotypes of depression such as anhedonia and inattention.

Comparison of prognosis between neoadjuvant imatinib and upfront surgery for GIST: A systematic review and meta-analysis.

Background: Significant survival benefit of adjuvant imatinib therapy has been observed in gastrointestinal stromal tumor (GIST). However, the impact of neoadjuvant imatinib on prognosis of GIST remains unclear. This meta-analysis aimed to compare the prognostic impact between upfront surgery and neoadjuvant imatinib plus surgery on GIST. Methods: A comprehensive literature search was performed to identify eligible studies up to 30 Sep 2021, through PubMed, Embase, Web of Science, and Cochrane Library. Studies compared the impact of upfront surgery and neoadjuvant imatinib plus surgery on disease-free (DFS) or overall survival (OS) in patients with GIST were selected. Results: Seven eligible studies with 17,171 patients were included. The reduction rates of tumor size in rectal and mixed site GIST were 33% and 29.8%, respectively. Neoadjuvant imatinib was not significantly associated with DFS compared with no-neoadjuvant therapy in rectal GIST (HR: 0.71, 95% CI: 0.35-1.41). The OS of rectal GIST was significantly improved by neoadjuvant imatinib compared with no-neoadjuvant therapy (HR: 0.36, 95% CI: 0.17-0.75). Conclusion: Neoadjuvant imatinib therapy contributed to tumor shrinkage and R0 resection of rectal GIST. Neoadjuvant imatinib plus surgery significantly improved overall survival of rectal GIST in comparison with upfront surgery.

The Role and Mechanism of microRNA-1224 in Human Cancer.

microRNAs (miRNAs) are a type of small endogenous non-coding RNAs composed of 20-22 nucleotides, which can regulate the expression of a gene by targeting 3' untranslated region (3'-UTR) of mRNA. Many studies have reported that miRNAs are involved in the occurrence and progression of human diseases, including malignant tumors. miR-1224 plays significant roles in different tumors, including tumor proliferation, metastasis, invasion, angiogenesis, biological metabolism, and drug resistance. Mostly, it serves as a tumor suppressor. With accumulating proofs of miR-1224, it can act as a potential bio-indicator in the diagnosis and prognosis of patients with cancer. In this article, we review the characteristics and research progress of miR-1224 and emphasize the regulation and function of miR-1224 in different cancer. Furthermore, we conclude the clinical implications of miR-1224. This review may provide new horizons for deeply understanding the role of miR-1224 as biomarkers and therapeutic targets in human cancer.

The Correlation of Prediabetes and Type 2 Diabetes With Adiposity in Adults.

Background: Fat metabolism is associated with prediabetes and type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate the detailed correlation of diabetes status with adiposity among adults. Methods: Briefly, 28,429 adults aged ≥18 years from both sexes in the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Multivariable linear regression models were used to examine associations of prediabetes and diabetes status, disease duration of T2DM, serum glucose, glycohemoglobin (HbA1c) with total percent fat (TPF), and fat mass distribution. Results: After adjusting for sociodemographic covariates, health behaviors, hypertension, hypercholesterolemia, there were direct associations of prediabetes and T2DM status with TPF, trunk fat mass, android fat mass, gynoid fat mass and android to gynoid ratio compared with non-diabetes. But the fat mass decreased with the increase of the disease duration in patients with T2DM. Besides, when stratifying by diabetes status, we found direct associations of serum glucose and HbA1c with TPF, trunk fat mass, android fat mass, gynoid fat mass, and android to gynoid ratio in non-diabetic and prediabetic participants. But in patients with T2DM, inverse associations of serum glucose and HbA1c with fat mass were observed. Conclusions: This study indicated that adults with prediabetes and T2DM had significantly higher TPF, trunk fat mass, android fat mass, gynoid fat mass, and android to gynoid ratio compared with those without diabetes. Moreover, fat mass decreased as the disease duration increased in patients with T2DM. The associations of serum glucose and HbA1c with TPF and fat mass distribution in patients with T2DM were opposite to the relationships observed in non-diabetic and prediabetic participants.

The Immune Microenvironment in Gastric Cancer: Prognostic Prediction.

Although therapeutic methods have been developed, gastric cancer (GC) still leads to high rates of mortality and morbidity and is the fourth leading cause of cancer-associated death and the fifth most common cancer worldwide. To understand the factors associated with the prognostic prediction of GC and to discover efficient therapeutic targets, previous studies on tumour pathogenesis have mainly focused on the cancer cells themselves; in recent years, a large number of studies have shown that cancer invasion and metastasis are the results of coevolution between cancer cells and the microenvironment. It seems that studies on the tumour microenvironment could help in prognostic prediction and identify potential targets for treating GC. In this review, we mainly introduce the research progress for prognostic prediction and the immune microenvironment in GC in recent years, focusing on cancer-associated fibroblasts (CAFs), tumour-associated macrophages (TAMs), and tumour-infiltrating lymphocytes (TILs) in GC, and discuss the possibility of new therapeutic targets for GC.

Comparison of Prognosis Between Microscopically Positive and Negative Surgical Margins for Primary Gastrointestinal Stromal Tumors: A Systematic Review and Meta-Analysis.

Background: This meta-analysis aimed to determine the prognostic impact of microscopically positive margins (R1) on primary gastrointestinal stromal tumors. Methods: A literature search was performed using PubMed, Embase, Web of Science, and Cochrane Library for studies up to 23 November 2020. The pooled disease-free survival (DFS) and overall survival (OS) between R1 and negative margins (R0) were estimated using a random-effects model. Results: Twenty studies with 6,465 patients were included. Compared with R0 resection, R1 was associated with poor DFS in patients who did not receive adjuvant Imatinib (HR: 1.62, 95% CI: 1.26-2.09; P = 0.48, I2 = 0%; reference: R0). This negative impact of R1 disappeared with the use of adjuvant Imatinib (HR: 1.23, 95% CI: 0.95-1.60; P = 0.38, I2 = 6%; reference: R0). R1 was related to poor DFS in gastric GISTs (HR: 2.15, 95% CI: 1.15-5.02, I2 = 0%; reference: R0), which was attenuated in the subgroup of adjuvant Imatinib (HR: 2.24, 95% CI: 0.32-15.60; P = 0.84, I2 = 0%; reference: R0). Rectal GIST with R1 margin who even received adjuvant Imatinib still had poor DFS (HR: 3.79, 95% CI: 1.27-11.31; P = 0.54, I2 = 0%; reference: R0). Patients who underwent R1 resection had similar OS compared with those underwent R0 resection regardless of the use of adjuvant Imatinib. Conclusion: R1 was associated with poor DFS for primary GISTs, which was attenuated by adjuvant therapy with Imatinib. Similar result was observed in the gastric GISTs subgroup. Rectal GIST patients with R1 resection had poor DFS even when they received adjuvant Imatinib. The R1 margin did not influence the OS of GISTs.

The Roles of Non-Coding RNAs in Radiotherapy of Gastrointestinal Carcinoma.

Radiotherapy (RT), or radiation therapy, has been widely used in clinical practice for the treatment of local advanced gastrointestinal carcinoma. RT causes DNA double-strand breaks leading to cell cytotoxicity and indirectly damages tumor cells by activating downstream genes. Non-coding RNA (including microRNAs, long non-coding RNAs (ncRNAs), and circular RNAs) is a type of RNA that does not encode a protein. As the field of ncRNAs increasingly expands, new complex roles have gradually emerged for ncRNAs in RT. It has been shown that ncRNAs can act as radiosensitivity regulators in gastrointestinal carcinoma by affecting DNA damage repair, cell cycle arrest, irradiation-induced apoptosis, cell autophagy, stemness, EMT, and cell pyroptosis. Here, we review the complex roles of ncRNAs in RT and gastrointestinal carcinoma. We also discuss the potential clinical significance and predictive value of ncRNAs in response to RT for guiding the individualized treatment of patients. This review can serve as a guide for the application of ncRNAs as radiosensitivity enhancers, radioresistance inducers, and predictors of response in RT of gastrointestinal carcinoma.

PDK4 Constitutes a Novel Prognostic Biomarker and Therapeutic Target in Gastric Cancer.

Gastric cancer (GC) is one of the most prevalent and deadly malignancies worldwide. We aimed to assess the functional role and clinical significance of pyruvate dehydrogenase kinase (PDK) in GC and explored the underlying mechanisms. The bioinformatics method was used to investigate the expression of PDKs in GC, the effect on clinical outcomes, enriched pathways, interactive network, and the correlation between PDK4 and immune infiltration. Next, PDK expression in the GC cells and tissues were verified by qRT-PCR and western blotting. A Cell Counting Kit-8 (CCK8), colony-formation, Flow cytometry, Transwell and wound healing assays were carried out to evaluate the influence of PDK4 on cell proliferation, invasion and migration. Among PDKs, PDK4 expression was aberrant in GC and identified as an independent prognostic factor. GO analysis, GSEA, and PPI showed that PDK4 expression may regulate cell adhesion, metal ion transport, synaptic activity, and cancer cell metabolism in GC. Analyses of immune infiltration showed that PDK4 correlated with the abundant expression of various immunocytes. Finally, we verified that upregulation of PDK4 expression enhanced the ability of GC cells to proliferate, migrate, and invade. In conclusion, PDK4 was identified as a potential candidate diagnostic biomarker and therapeutic target for GC patients.