Identification of Malassezia globosa as a Gastric Fungus Associated with PD-L1 Expression and Overall Survival of Patients with Gastric Cancer.

Background: Microbiotas affected the prognosis of cancer patients by regulating programmed death ligand-1 (PD-L1) expression. However, the relationship between gastric fungi and PD-L1 expression is still unclear in gastric cancer (GC). We aimed at exploring the association of gastric fungi with PD-L1 expression and overall survival in GC. Methods: A total of 61 GC patients were divided into the two groups based on the PD-L1 combined positive scores (CPS). Fungal profiling was performed by internal transcribed spacer rDNA sequencing, and the survival analyses were performed by Kaplan-Meier curves. Results: We observed a taxonomic difference of fungi between the PD-L1-High (CPS ≥ 10) and PD-L1-Low group (CPS < 10) by principal coordinates analysis (PCoA) (P = 0.014 for Bray-Curtis and P = 0.042 for Jaccard). Malassezia had a higher abundance in the PD-L1-High group compared to the PD-L1-Low group (P = 0.045). Malassezia globosa elevated significantly in the PD-L1-High group. GC patients with PD-L1 low expression and low abundance of Malassezia globosa had a longer overall survival (OS) than others (P = 0.047). Malassezia globosa was associated with PD-L1 expression (Odds Ratio = 3.509, 95% Confidence Interval: 1.056-11.656, P = 0.040). Malassezia globosa was associated with the tumor size (P = 0.031) and PD-L1 status (P = 0.024). GC patients with a high abundance of Malassezia globosa had shorter OS than others (P = 0.028). Malassezia globosa was an independent factor (Hazard Ratio = 3.080, 95% Confidence Interval: 1.140-8.323, P = 0.027) for OS after adjusting for tumor stage. Malassezia globosa was figured out to be associated with- fatty acid and lipid biosynthesis and degradation via LIPASYN pathway. Conclusions. Malassezia globosa was identified as a PD-L1 expression-associated gastric fungus and associated with OS of GC patients, which calls for more studies to further explore its potential in PD-L1/PD-1 targeted immunotherapy.

Effect of Perioperative Interleukin-6 and Tumor Necrosis Factor-α on Long-Term Outcomes in Locally Advanced Gastric Cancer: Results from the CLASS-01 Trial.

Background: Little is known about the relation between perioperative inflammatory changes and long-term survival in cancer patients. The aim of the study was to assess the association of perioperative serum interleukin-6 (IL6) and tumor necrosis factor-α (TNFα) levels with the 5-year overall survival in locally advanced gastric cancer. Methods: The 135 eligible patients in one center of Nanfang Hospital were retrieved from CLASS-01 trial (NCT01609309), an open-label, multicenter, randomized clinical noninferiority trial conducted at 14 centers in China. Serum IL6 and TNFα levels were tested before surgery, and on postoperative day (POD) 1, POD3, and POD5, respectively, referring to IL6_0, IL6_1, IL6_3, and IL6_5 and TNFα_0, TNFα_1, TNFα_3, and TNFα_5. Kaplan-Meier methods and COX models were used for survival analysis. Results: High levels of IL6_0 (≥3.67 pg/mL) and TNFα_0 (≥14.8 pg/mL) presented worse disease-free survival (DFS) (P = 0.0057 for IL6_0 and P = 0.0014 for TNFα_0) and overall survival (OS) (P = 0.0021 for IL6_0 and P = 0.0019 for TNFα_0). Both high IL6_0 and high IL6_5 levels indicated worse prognosis than other combinations (P = 0.0045 for DFS and P = 0.0022 for OS). In multivariate analysis, both high IL6_0 and high IL6_5 levels were significantly associated with poor DFS (HR = 4.29, 95% CI: 1.42-12.95, P = 0.01) and OS (HR = 4.11, 95% CI: 1.35-12.49, P = 0.013) after adjustment of tumor stage and TNFα_0. Also, high IL6_5 level was identified as the independent-related factor for postoperative infectious complications (OR = 2.69, 95% CI: 1.03-7.01, P = 0.043). Conclusions: Perioperative high serum IL6 and TNFα levels are negatively associated with 5-year survival outcomes in patients with locally advanced gastric cancer, indicating the potential survival benefits from perioperative anti-inflammatory treatment.

Sodium-glucose co-transporter 1 (SGLT1) differentially regulates gluconeogenesis and GLP-1 receptor (GLP-1R) expression in different diabetic rats: a preliminary validation of the hypothesis of "SGLT1 bridge" as an indication for "surgical diabetes".

Background: Sodium-glucose co-transporter 1 (SGLT1) may play a synergistic role in gluconeogenesis (GNG) and glucagon-like peptide-1 (GLP-1) expression. We proposed the hypothesis of a "SGLT1 bridge" as an indication for "surgical diabetes" that was preliminary validated in the present study. Methods: We selected nonobese diabetic Goto-Kakizaki (GK) rats and Zuker diabetic fat (ZDF) rats to represent advanced and early diabetes, respectively. Based on glucose gavage with or without SGLT1 inhibitor phlorizin, the rats were divided into 4 groups: Gk-Glu, GK-P, ZDF-Glu, and ZDF-P. The expressions of SGLT1, GLP-1 receptor (GLP-1R), glucose-6 phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase-1 (Pck1) were determined by immunohistochemistry (IHC) or quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the effects of phlorizin were analyzed. Results: Glucose tolerance was worse in GK rats and the homeostasis model assessment-insulin resistance (HOMA-IR) was higher in ZDF rats, indicating different pathophysiological conditions between the different diabetic rats. GK rats showed higher activity of duodenal SGLT1 (P=0.022) and jejunal SGLT1 mRNA expression (P=0.000) and lower SGLT1 mRNA expression in the liver (P=0.000) and pancreas (P=0.000). Phlorizin effectively inhibited the activity of duodenal SGLT1 in both GK rats (P=0.000) and ZDF rats (P=0.000). In ZDF rats, the expression of GLP-1R mRNA was downregulated in the jejunum (P=0.001) and upregulated in the pancreas (P=0.021) by phlorizin, but there were no regulatory effects on GLP-1R mRNA in the jejunum and pancreas of GK rats. As for the regulatory effects on GNG, phlorizin upregulated Pck1 mRNA in the duodenum (P=0.000) and the jejunum (P=0.038), whereas it downregulated hepatic G6Pase mRNA in ZDF rats (P=0.005) and Pck1 mRNA expression in GK rats (P=0.001), suggesting that SGLT1 inhibitor may have upregulated intestinal GNG in ZDF rats and downregulated hepatic GNG in both ZDF and GK rats. Conclusions: SGLT1 showed synergistic regulatory effects on the entero-insular axis (EIA) and the gut-brain-liver axis (GBLA), preliminarily validating the hypothesis of a "SGLT1 bridge". The distinct expression of SGLT1 and its differentially regulatory effects on diabetic rats with different pathophysiological conditions may provide probable potential indications involved in the "Surgical Diabetes" that is supposed as the inclusion for diabetic surgery.

Dysbiosis of Gastric Mucosal Fungal Microbiota in the Gastric Cancer Microenvironment.

Background: Microbes have been shown to contribute to gastric cancer (GC), gastric bacteria and viruses are associated with gastric carcinogenesis. However, the relationship between gastric fungi and GC is still unclear. Our aim was to evaluate the gastric fungal microbiota in the GC microenvironment. Methods: Gastric fungal microbiome profiling was performed with internal transcribed spacer (ITS) rDNA sequencing in primary tumor and corresponding paired normal mucosal tissues from 61 GC patients. Differences in microbial composition, taxa diversity, and predicted function were further analyzed. Results: Dysbiosis of gastric mucosal fungal microbiome was observed between the tumor and normal groups in GC. The tumor group had a higher abundance of certain taxa than the normal group. In the taxa classification, the abundances of Pezizomycetes, Sordariales, Chaetomiaceae, and Rozellomycota were lower in the tumor group than in the normal group. At the genus level, Solicoccozyma (P = 0.033) was found in higher abundance and was differentially enriched in the tumor group with Lefse analysis. Additionally, Solicoccozyma accounted for 0.3% of gastric fungi in the GC microenvironment. Twenty-seven of the 61 GC patients showed positive Solicoccozyma expression in tumors. Solicoccozyma-positive expression in tumors was associated with the Bormann classification and nerve invasion. Solicoccozyma was considered a gastric fungal marker to classify stage I and stage II-IV GC patients with an area under the receiver-operating curve (AUC) of 0.7061, as well as to classify the nerve invasive and nonnerve invasive tumors from GC patients with an AUC of 0.6978. Functional prediction indicated that the positive expression of Solicoccozyma in tumors was associated with the amino acid- and carbohydrate-related metabolic pathways in GC. Conclusions: This study revealed a novel perspective on the role of Solicoccozyma in tumors and a theoretical basis for therapeutic targets against GC.

Circulating tumor cell-associated white blood cell cluster is associated with poor survival of patients with gastric cancer following radical gastrectomy.

INTRODUCTION: The prognostic implication of circulating tumor cell (CTC) -associated white blood cell clusters (CTC-WBC clusters) in patients with gastric cancer (GC) after radical gastrectomy is not well defined. METHODS: The prognostic value of the CTC-WBC clusters was evaluated retrospectively in an independent cohort of GC patients with radical gastrectomy from Nanfang Hospital, Southern Medical University, China, between March 1, 2018, and September 31, 2019. The cohort was grouped into two groups: CTC-WBC group and CTC group. The CTC-WBC clusters and CTCs in blood were detected by technology of Canapatrol™ CTC filtration system. The Kaplan-Meier method was used to generate survival curve and compare the disease-free survival and OS. Cox regression model was used for multivariate analyses. RESULTS: Two hundred and seventeen patients were included for analyses, 29 patients presenting CTC-WBC clusters positive (CTC-WBC group) and 188 patients presenting exclusively CTCs (CTC group). Depth of tumor invasion was statistically different between two groups (P = 0.043), and the other clinicopathological features between the two groups were similar. Kaplan-Meier analysis showed that positive CTC-WBC cluster patients had significantly shorter OS than patients with exclusively CTC (P = 0.037). Cox regression analysis revealed that CTC-WBC cluster was an independent factor (Hazard Ratio = 2.553, 95% Confidence Interval: 1.008-6.465, P = 0.048) for OS after adjustment of age, gender, number of CTCs, type of CTCs, and tumor stage. CONCLUSION: The presence of CTC-WBC clusters is associated with poor OS in the GC patients after radical surgery regardless of tumor stage. Our data suggest alternative prognostic model needs to be further investigated.

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling.

BACKGROUND: Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients' survival prognosis. The resistance to chemoradiotherapy in rectal cancer is difficult to predict. This study was aimed at evaluating the role of V-set and transmembrane domain containing 2 like protein (VSTM2L) in resistance to chemoradiotherapy in rectal cancer. METHODS: Analysis of the GEO profiling datasets of rectal cancer patients receiving pCRT disclosed that VSTM2L as a candidate gene was significantly upregulated in nonresponders of rectal cancer with pCRT. The mRNA and protein expression of VSTM2L was detected by quantitate real-time PCR, western blotting, and immunohistochemistry in six rectal cancer biopsy tissues before pCRT. Furthermore, the rectal cancer patient-derived organoids were cultured to evaluate the association of VSTM2L expression and tumor response to CRT. Overexpression of VSTM2L in cancer cells treated with CRT was analyzed for the function of cell proliferation and viability, clone formation, DNA damage repair, and apoptosis ability. The GSEA and RNA-sequence analysis were used to find the downstream mechanism of VSTM2L overexpression in cells treated with CRT. RESULTS: The mRNA levels of VSTM2L were significantly downregulated in normal rectal tissues compared to tumor tissues and were upregulated in nonresponders of rectal cancer patients receiving pCRT and positively correlated with poor survival prognosis from GEO datasets. High expression of VSTM2L was significantly associated with tumor regression after pCRT (P = 0.030). Moreover, high expression of VSTM2L reduced γ-H2AX expression in rectal cancer patient-derived organoids treated with CRT. The overexpression of VSTM2L in colorectal cancer cells induced resistance to CRT via promoting cell proliferation and inhibiting apoptosis. The molecular mechanism revealed that the overexpression of VSTM2L induced resistance to CRT through downstream IL-4 signaling affecting the progress of cell proliferation and apoptosis. CONCLUSION: The high expression of VSTM2L induced resistance to CRT, and adverse survival outcomes served as a prognostic factor in patients with rectal cancer receiving pCRT, suggesting that VSTM2L high expression may be a potential resistant predictable biomarker for LARC patients receiving pCRT.

Drug Repurposing in Oncology: Current Evidence and Future Direction.

BACKGROUND: Drug repurposing, the application of known drugs and compounds with a primary non-oncology purpose, might be an attractive strategy to offer more effective treatment options to cancer patients at a low cost and reduced time. METHODS: This review described a total of 10 kinds of non-oncological drugs from more than 100 mechanical studies as well as evidence from population-based studies. The future direction of repurposed drug screening is discussed by using patient-derived tumor organoids. RESULTS: Many old drugs showed previously unknown effects or off-target effects and can be intelligently applied for cancer chemoprevention and therapy. The identification of repurposed drugs needs to combine evidence from mechanical studies and population-based studies. Due to the heterogeneity of cancer, patient-derived tumor organoids can be used to screen the non-oncological drugs in vitro. CONCLUSION: These identified old drugs could be repurposed in oncology and might be added as adjuvants and finally benefit patients with cancers.

High expression of COL10A1 is associated with poor prognosis in colorectal cancer.

BACKGROUND: High expression of collagen type X alpha 1 chain (COL10A1), a member of the collagen family, had been observed in various human cancers, but the detailed function and molecular mechanism of COL10A1 were largely unclear. AIM: The aim of this study was to investigate the expression of COL10A1 in colorectal cancer (CRC) tissues and cells and to reveal its biological function and mechanism in CRC. MATERIALS AND METHODS: Immunohistochemistry (IHC), real-time quantitative polymerase chain reaction (QPCR) and Western blot experiments were used to determine the clinical relevance between expression levels of COL10A1 and CRC. RESULTS: Compared with normal tissues, COL10A1 expression was significantly higher in CRC tissues. Biological functional experiments showed that overexpression of COL10A1 enhanced proliferation, migration, and invasion of CRC cells, and knockdown of COL10A1 inhibited tumorigenesis in vivo. Western blot assays showed that COL10A1 promoted the process of epithelial-mesenchymal transition (EMT). The overexpression of COL10A1 was associated with adverse prognosis in CRC by tissue microarray (TMA) analysis. CONCLUSION: Our findings had provided evidences to support the fact that COL10A1 was abnormally up-expressed in CRC and involved in the progression of CRC and the process of EMT. Furthermore, we demonstrated that the high-level expression of COL10A1 was an independent risk factor of prognosis and overall survival in CRC patients. These suggested that COL10A1 might be a new potential target for cancer therapy in the future.

Optimal Extent of Transhiatal Gastrectomy and Lymphadenectomy for the Stomach-Predominant Adenocarcinoma of Esophagogastric Junction: Retrospective Single-Institution Study in China.

Background: The optimal extent of gastrectomy and lymphadenectomy for esophagogastric junction (EGJ) cancer is controversial. Our study aimed to compare the long-term survival of transhiatal proximal gastrectomy with extended periproximal lymphadenectomy (THPG with EPL) and transhiatal total gastrectomy with complete perigastric lymphadenectomy (THTG with CPL) for patients with the stomach-predominant EGJ cancer. Methods: Between January 2004, and August 2015, 306 patients with Siewert II tumors were divided into the THTG group (n = 148) and the THPG group (n = 158). Their long-term survival was compared according to Nishi's classification. The Kaplan-Meier method and Cox proportional hazards models were used for survival analysis. Results: There were no significant differences between the two groups in the distribution of age, gender, tumor size or Nishi's type (P > 0.05). However, a significant difference was observed in terms of pathological tumor stage (P < 0.05). The 5-year overall survival rates were 62.0% in the THPG group and 59.5% in the THTG group. The hazard ratio for death was 0.455 (95% CI, 0.337 to 0.613; log-rank P < 0.001). Type GE/E = G showed a worse prognosis compared with Type G (P < 0.05). Subgroup analysis stratified by Nishi's classification, Stage IA-IIB and IIIA, and tumor size ≤ 30 mm indicated significant survival advantages for the THPG group (P < 0.05). However, this analysis failed to show a survival benefit in Stage IIIB (P > 0.05). Conclusions: Nishi's classification is an effective method to clarify the subdivision of Siewert II tumors with a diameter ≤ 40 mm above or below the EGJ. THPG with EPL is an optimal procedure for the patients with the stomach-predominant EGJ tumors ≤30 mm in diameter and in Stage IA-IIIA. For more advanced and larger EGJ tumors, further studies are required to confirm the necessity of THTG with CPL.