Development of a novel hypoxia-immune-related LncRNA risk signature for predicting the prognosis and immunotherapy response of colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common digestive system tumors worldwide. Hypoxia and immunity are closely related in CRC; however, the role of hypoxia-immune-related lncRNAs in CRC prognosis is unknown. Methods: Data used in the current study were sourced from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) databases. CRC patients were divided into low- and high-hypoxia groups using the single-sample gene set enrichment analysis (ssGSEA) algorithm and into low- and high-immune groups using the Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm. Differentially expressed lncRNAs (DElncRNAs) between low- and high-hypoxia groups, low- and high-immune groups, and tumor and control samples were identified using the limma package. Hypoxia-immune-related lncRNAs were obtained by intersecting these DElncRNAs. A hypoxia-immune-related lncRNA risk signature was developed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses. The tumor microenvironments in the low- and high-risk groups were evaluated using ssGSEA, ESTIMATE, and the expression of immune checkpoints. The therapeutic response in the two groups was assessed using TIDE, IPS, and IC50. A ceRNA network based on signature lncRNAs was constructed. Finally, we used RT-qPCR to verify the expression of hypoxia-immune-related lncRNA signatures in normal and cancer tissues. Results: Using differential expression analysis, and univariate Cox and LASSO regression analyses, ZNF667-AS1, LINC01354, LINC00996, DANCR, CECR7, and LINC01116 were selected to construct a hypoxia-immune-related lncRNA signature. The performance of the risk signature in predicting CRC prognosis was validated in internal and external datasets, as evidenced by receiver operating characteristic curves. In addition, we observed significant differences in the tumor microenvironment and immunotherapy response between low- and high-risk groups and constructed a CECR7-miRNA-mRNA regulatory network in CRC. Furthermore, RT-qPCR results confirmed that the expression patterns of the six lncRNA signatures were consistent with those in TCGA-CRC cohort. Conclusion: Our study identified six hypoxia-immune-related lncRNAs for predicting CRC survival and sensitivity to immunotherapy. These findings may enrich our understanding of CRC and help improve CRC treatment. However, large-scale long-term follow-up studies are required for verification.

A better overall survival (OS) for total (ipsilateral) retroperitoneal lipectomy than standard complete resection in patients with retroperitoneal liposarcoma: a comparative multi-institutional study.

Background: Complete resection (CR) serves as the standard of surgical treatment for retroperitoneal liposarcoma (RPLS). Unfortunately, even at referral centers, recurrence rates are high, and CR may not address multifocal diseases, which are a common phenomenon in RPLS. We sought to retrospectively compare the clinical outcomes of RPLS patients treated with total (ipsilateral) retroperitoneal lipectomy (TRL) and CR. Because TRL remove potentially multifocal tumors in the fat, patients may have a better prognosis than CR. Methods: Patients with primary/first-recurrent RPLS who had been treated at 5 referral centers were recruited from December 2014 to June 2018. Multivariable Cox regression analyses were conducted to determine the effects of demographic, operative, and clinicopathological variables on the following primary endpoints: local recurrence (LR), local recurrence-free survival (LRFS), and overall survival (OS). Results: A total of 134 patients were enrolled in this retrospective study, 53 of whom underwent TRL, and 81 of whom underwent CR. The 2 groups were comparable in terms of age, gender, presentation (primary vs. first-recurrent RPLS), number of tumors (unifocal vs. multifocal) at presentation, and Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade. The TRL group had higher levels of preoperative hemoglobin (Hb) (13 vs. 12.5 g/dL; P=0.008) and a lower amount of intraoperative blood loss (400 vs. 500 mL; P=0.034), but there were no significant differences in the length of hospital stay (23 vs. 22 d; P=0.47) or complications (32 vs. 30; P=0.82) between the 2 groups. In a subset of patients with multifocal tumors at initial presentation, OS was more prolonged in those treated with TRL than those treated with CR (P=0.0272). Based on the multivariable analysis, primary liposarcoma and a low FNCLCC grade were associated with decreased LR and improved OS. Conclusions: TRL is a safe procedure that positively affects the OS of patients with multifocal RPLS. This novel strategy deserves further investigation in prospective studies.

Targeting the lncRNA FGD5-AS1/miR-497-5p/PD-L1 Axis Inhibits Malignant Phenotypes in Colon Cancer (CC).

Long noncoding RNAs (lncRNAs) regulate cancer progression and drug resistance. However, the role of lncRNA FGD5-AS1 in regulating colon cancer (CC) progression is still largely unknown. Hence, this study investigated the role of lncRNA FGD5-AS1 in regulating colon cancer (CC) progression and found that lncRNA FGD5-AS1 regulated miR-497-5p/PD-L1 axis to promote cancer progression in CC cells in vitro and in vivo. Specifically, we found that lncRNA FGD5-AS1 and PD-L1 tended to be high-expressed, while miR-497-5p was low-expressed in CC tissues and cell lines compared to the normal adjacent tissues and cells. Next, we found that lncRNA FGD5-AS1 positively regulated PD-L1 in CC cells by sponging miR-497-5p. Finally, our gain- and loss-of-function experiments evidenced that the lncRNA FGD5-AS1/miR-497-5p/PD-L1 axis regulates CC progression. Functionally, the data suggested that lncRNA FGD5-AS1 positively regulated while miR-497-5p negatively modulated malignant phenotypes, including cell proliferation, viability, invasion, migration, epithelial-mesenchymal transition (EMT), and tumorigenesis in CC cells. Interestingly, the inhibiting effects of lncRNA FGD5-AS1 ablation on CC development were abrogated by both silencing miR-497-5p and upregulating PD-L1. This study found that lncRNA FGD5-AS1 sponged miR-497-5p to upregulate PD-L1, resulting in CC progression, and provided novel agents for CC diagnosis and prognosis.

Pretreatment Contrast-Enhanced Computed Tomography Radiomics for Prediction of Pathological Regression Following Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer: A Preliminary Multicenter Study.

BACKGROUND: Sensitivity to neoadjuvant chemotherapy in locally advanced gastric cancer patients varies; however, an effective predictive marker is currently lacking. We aimed to propose and validate a practical treatment efficacy prediction method based on contrast-enhanced computed tomography (CECT) radiomics. METHOD: Data of l24 locally advanced gastric carcinoma patients who underwent neoadjuvant chemotherapy were acquired retrospectively between December 2012 and August 2020 from three different cancer centers. In total, 1216 radiomics features were initially extracted from each lesion's pretreatment portal venous phase computed tomography image. Subsequently, a radiomics predictive model was constructed using machine learning software. Clinicopathological data and radiological parameters of the enrolled patients were collected and analyzed retrospectively. Univariate and multivariate logistic regression analyses were performed to screen for independent predictive indices. Finally, we developed an integrated model combining clinicopathological predictive parameters and radiomics features. RESULT: In the training set, 10 (14.9%) patients achieved a good response (GR) after preoperative neoadjuvant chemotherapy (n = 77), whereas in the testing set, seven (17.5%) patients achieved a GR (n = 47). The radiomics predictive model showed competitive prediction efficacy in both the training and independent external validation sets. The areas under the curve (AUC) values were 0.827 (95% confidence interval [CI]: 0.609-1.000) and 0.854 (95% CI: 0.610-1.000), respectively. Similarly, when only the single hospital data were included as an independent external validation set (testing set 2), AUC values of the models were 0.827 (95% CI: 0.650-0.952) and 0.889 (95% CI: 0.663-1.000) in the training set and testing set 2, respectively. CONCLUSION: Our study is the first to discover that CECT radiomics could provide powerful and consistent predictions of therapeutic sensitivity to neoadjuvant chemotherapy among gastric cancer patients across different hospitals.

MicroRNA-139-5p regulates chronic inflammation by suppressing nuclear factor-κB activity to inhibit cell proliferation and invasion in colorectal cancer.

The inflammatory microenvironment, which mediates the initiation and malignant development of tumors, has been reported to be associated with microRNA (miRNA) dysregulation. In the present study, the expression of miR-139-5p was analyzed in colorectal cancer (CRC) cell lines SW480, HT29, HCT-8, LoVo and HCT116, aiming to investigate the function and mechanism of miR-139-5p in the regulation of the malignant phenotypes of CRC. miR-139-5p expression was found to be considerably downregulated in CRC cell lines compared with the human normal colon mucosal epithelial cell line NCM460. Subsequently, it was demonstrated that overexpression of miR-139-5p in colon cancer cell lines significantly suppressed the cell proliferation in vitro and in vivo. In addition, overexpression of miR-139-5p further inhibited the invasion ability of colon cancer cells in vitro, concomitantly with downregulation of key invasion-associated proteins, including matrix metalloproteinase 9 (MMP9) and MMP7. Furthermore, it was demonstrated that overexpression of miR-139-5p decreased the expression levels of inflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α), by suppressing nuclear factor (NF)-κB activity. Therefore, these findings collectively indicated that miR-139-5p regulated chronic inflammation by suppressing NF-κB activity in order to inhibit cell proliferation and invasion in CRC, thereby indicating a novel molecular mechanism in CRC therapy.

A Case of Complete Remission from Advanced Gastric Adenocarcinoma with Synchronous Liver Metastasis in Response to EOX Chemotherapy.

Gastric cancer is a malignant tumor with a high degree of malignancy. Multiple liver metastases from gastric cancer (LMGCs) are common. However, the treatment of LMGCs is very difficult. It is rare to achieve complete remission (CR) and long-term survival after treatment. We present the case of a patient with gastric adenocarcinoma and multiple liver metastases who showed CR for more than 33 months after perioperative EOX (epirubicin, oxaliplatin, and capecitabine) combination chemotherapy with radical distal gastrectomy and resection of liver metastases. The patient is still in follow-up without tumor recurrence. These findings suggest that LMGC does not necessarily mean a poor prognosis; preoperative chemotherapy combined with surgery may be a good treatment option for LMGC in selected patients. Further studies are needed to support this treatment approach.

Computed tomography-based radiomics for prediction of neoadjuvant chemotherapy outcomes in locally advanced gastric cancer: A pilot study.

OBJECTIVE: The standard treatment for patients with locally advanced gastric cancer has relied on perioperative radio-chemotherapy or chemotherapy and surgery. The aim of this study was to investigate the wealth of radiomics for pre-treatment computed tomography (CT) in the prediction of the pathological response of locally advanced gastric cancer with preoperative chemotherapy. METHODS: Thirty consecutive patients with CT-staged II/III gastric cancer receiving neoadjuvant chemotherapy were enrolled in this study between December 2014 and March 2017. All patients underwent upper abdominal CT during the unenhanced, late arterial phase (AP) and portal venous phase (PP) before the administration of neoadjuvant chemotherapy. In total, 19,985 radiomics features were extracted in the AP and PP for each patient. Four methods were adopted during feature selection and eight methods were used in the process of building the classifier model. Thirty-two combinations of feature selection and classification methods were examined. Receiver operating characteristic (ROC) curves were used to evaluate the capability of each combination of feature selection and classification method to predict a non-good response (non-GR) based on tumor regression grade (TRG). RESULTS: The mean area under the curve (AUC) ranged from 0.194 to 0.621 in the AP, and from 0.455 to 0.722 in the PP, according to different combinations of feature selection and the classification methods. There was only one cross-combination machine-learning method indicating a relatively higher AUC (>0.600) in the AP, while 12 cross-combination machine-learning methods presented relatively higher AUCs (all >0.600) in the PP. The feature selection method adopted by a filter based on linear discriminant analysis + classifier of random forest achieved a significantly prognostic performance in the PP (AUC, 0.722±0.108; accuracy, 0.793; sensitivity, 0.636; specificity, 0.889; Z=2.039; P=0.041). CONCLUSIONS: It is possible to predict non-GR after neoadjuvant chemotherapy in locally advanced gastric cancers based on the radiomics of CT.

Downregulation of tetrahydrobiopterin inhibits tumor angiogenesis in BALB/c-nu mice with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly vascular tumor, and treatment options for patients of advanced-stage are limited. Nitric oxide (NO), which is derived from endothelial nitric oxide synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an essential cofactor eNOS and represents a critical determinant of NO production. To examine whether treatment of 2,4-diamino-6-hydroxypyrimidine (DAHP) inhibits angiogenesis of HCC, BALB/c-nu mice were injected with HepG-2 cells with DAHP. Supplemental DAHP treatment decreased K-ras mRNA transcripts, inhibition of phosphorylation of eNOS and Akt, inhibition of guanosine triphosphate cyclohydrolase (GTPCH), and decreased significantly NO synthesis, and then inhibited angiogenesis, compared with the results observed in the saline group. Histopathology demonstrated angiogenesis and tumor formation were significantly inhibited in HCC. DAHP downregulates GTPCH protein expression, corresponding to decreased levels of BH4 and the contents of NO. In addition, DAHP downregulates eNOS and Akt protein expression, corresponding to decreased eNOS phosphorylation at Ser1177 and Akt phosphorylation, compared with the saline control. We suggest that DAHP, recognized as a specific competitive inhibitor of GTPCH, can decrease tumor BH4 and NO by the inhibition of the wild-type Ras-PI3K/Akt pathway, and then inhibiting angiogenesis, and may provide a novel and promising way to target BH4 synthetic pathways to inhibit angiogenesis and to control potential progression of HCC. Whether DAHP has a therapeutic potential will require more direct testing in humans.

Tetrahydrobiopterin ameliorates hepatic ischemia-reperfusion Injury by coupling with eNOS in mice.

BACKGROUND: In the liver, eNOS appears to have a central role in protecting against ischemia/reperfusion (I/R) injury. We hypothesized that tetrahydrobiopterin (BH4) would protect livers subjected to I/R injury by coupling with eNOS. METHODS: Chinese Kun Ming (KM) mice were subjected to 60 min of 70% hepatic ischemia 30 min after the administration of BH4 or saline. After reperfusion, survival was evaluated. The histologic appearance and ALT, BH4, nitrite/nitrate, 8-isoprostane, and eNOS protein expression levels were measured. RESULTS: The 1-wk survival rate was 66.67% in the BH4 group and 33.33% in the saline group. The serum ALT values in the BH4 group 1, 3, 6, 12, and 24 h after reperfusion were significantly lower than those of the saline group. A histologic examination of the liver revealed only a small necrotic area in the BH4 group as opposed to massive necrosis in the saline group. The percentage values of the hepatic necrotic area 24 h after reperfusion were significantly less for the BH4 group than for the saline group. The nitrite/nitrate levels in the liver tissue were significantly increased by ~2-fold in the BH4 group compared with the saline group. The free radical indicator 8-isoprostane was reduced approximately 50% in the BH4 group compared with the saline group. Western blotting showed that the level of eNOS protein between the groups was not significantly different. CONCLUSIONS: BH4 significantly improved the survival rate by reducing liver failure. This was supported by the histologic findings, and the mechanism was explored. According to the results, we suggest that BH4 prevents liver damage from I/R injury by attenuating reactive oxygen species and increasing NO synthesis, and might provide a novel and promising therapeutic option for preventing I/R injury.

[Development of the system of quality of life instruments for cancer patients: stomach cancer (QLICP-ST)].

BACKGROUND & OBJECTIVE: We have previously developed and reported the general module of the system of quality of life instruments for cancer patients (QLICP-GM). This study was to develop and evaluate the quality of life instrument for patients with stomach cancer (QLICP-ST). METHODS: The QLICP-ST was developed using the structured group methods applicable to Chinese populations. The system of QLICP-ST was evaluated by analyzing data from 86 stomach cancer patients using statistical description, Pearson's correlation, exploratory factor analysis, and paired student's t test. RESULTS: The test-retest reliability of the overall scale was 0.98 and that of each domain was greater than 0.90. The internal consistency coefficient alpha of the overall scale was 0.91 and that of each domain was higher than 0.65. Correlation analysis and the exploratory factor analysis revealed good construct validity of the QLICP-ST. Differences of the quality of life scores before and after the treatment in physical domain, psychological domain, common symptom and side effect domain, specific domain and the overall scale were significant. Moreover, the standardized response mean(SRM) of these domains were greater than 0.30. CONCLUSION: The system of QLICP-ST can be used in clinical evaluation of the quality of life for stomach cancer patients with sound validity, reliability and responsiveness.