BackgroundLiver cancer (LC) is well known for its prevalence as well as its poor prognosis. The aberrant expression of lysyl oxidase (LOX) family is associated with liver cancer, but their function and prognostic value in LC remain largely unclear. This study aimed to explore the function and prognostic value of LOX family in LC through bioinformatics analysis and meta-analysis.ResultsThe expression levels of all LOX family members were significantly increased in LC. Area under the receiver operating characteristic curve (AUC) of LOXL2 was 0.946 with positive predictive value (PPV) of 0.994. LOX and LOXL3 were correlated with worse prognosis. Meta-analysis also validated effect of LOX on prognosis. Nomogram of these two genes and other predictors was also plotted. There was insufficient data from original studies to conduct meta-analysis on LOXL3. The functions of LOX family members in LC were mostly involved in extracellular and functions and structures. The expressions of LOX family members strongly correlated with various immune infiltrating cells and immunomodulators in LC.ConclusionsFor LC patients, LOXL2 may be a potential diagnostic biomarker, while LOX and LOXL3 have potential prognostic and therapeutic values. Positive correlation between LOX family and infiltration of various immune cells and immunomodulators suggests the need for exploration of their roles in the tumor microenvironment and for potential immunotherapeutic to target LOX family proteins.

Background: The occurrence and development of solid tumors depend on the blood supply in the tumor microenvironment (TME). Blocking angiogenesis is a new therapeutic strategy to inhibit tumor growth. The anti-angiogenic drug bevacizumab has been approved for gynecological malignancies, especially for advanced recurring cervical cancers and recurring ovarian cancers (OC). Studies in OC have shown a limited effect of bevacizumab in the general population, with a slight improvement in progression-free survival (PFS) and no effect on overall survival (OS). This might be related to the bevacizumab’s role in aggravating the hypoxia in the TME, which helps maintain the stemness of ovarian cancer stem cells (CSCs) and promotes the invasion and metastasis of cancer cells. Drugs that target CSCs, such as metformin, may enhance the efficacy of anti-vascular therapies. Therefore, this study aimed to evaluate the effect of metformin combined with bevacizumab on the proliferation of OC cells both in vitro and in vivo, as well as on tumor hypoxia and tumor stem cell markers of human ovarian cancer SKOV3 cells.Methods: The OC cell model SKOV3 was treated with metformin, bevacizumab, and cisplatin alone or in combinations. Cell Counting Kit-8 (CCK-8) was used to measure the rate of cell proliferation. Metformin and bevacizumab were studied in vivo in nude mice. SKOV3 cells were transplanted subcutaneously in nude mice, and different drug interventions were performed after tumor formation, including blank control, bevacizumab alone, metformin alone, cisplatin alone, bevacizumab + metformin, bevacizumab + cisplatin, metformin + cisplatin, and bevacizumab + metformin + cisplatin treatments. The growth of transplanted tumors was routinely monitored and visualized by the tumor growth curve. We used flow cytometry to examine the proportion of CD44+/CD117+ CSCs in each group. The immunohistochemistry (IHC) method was applied to detect expressions of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), and microvascular density-associated factor CD34 in tumor cells. The limit dilution method was used to re-inject tumor cells in nude mice to examine the tumor recurrence rate.Results: Combination therapy of metformin and bevacizumab significantly reduced the proliferation rate of SKOV3 cells and the growth rate of transplanted tumors in nude mice compared with the monotherapy effects. In vivo results showed that metformin significantly reduced the proportion of CD44+/CD117+ CSCs (p < 0.01). Although bevacizumab increased the proportion of CD44+/CD117+ CSCs, the addition of metformin did offset this fluctuating trend. The combination of bevacizumab, metformin, and cisplatin efficiently decreased the proportion of CSCs in the OC animal model. IHC results exhibited that expressions of VEGF, CD34, and HIF-1α in transplanted tumors were decreased by metformin alone compared with the control (p < 0.05). In the bevacizumab treatment, VEGF, and CD34 expressions were decreased, while that of HIF-1α was increased, suggesting that the degree of hypoxia was differentially aggravated after the bevacizumab treatment. The VEGF, CD34, and HIF-1α expressions in the bevacizumab + metformin + cisplatin group were the lowest among all other treatment groups (p < 0.05). Subcutaneous statistics of nude mice reseeded by the limit dilution method showed that the tumor recurrence rate in the bevacizumab + metformin + cisplatin group was relatively lower.Conclusion: Metformin, bevacizumab combined with platinum-based chemotherapy can significantly inhibit the growth of ovarian cancer cells and transplanted tumors, which is due to the reduction of the proportion of CD44+/CD117+ CSCs and the alleviation of hypoxia in the tumor microenvironment. Therefore, this may be a reasonable and promising treatment regimen.

Gastric cancer (GC) is the fifth most common cancer globally. Secreted frizzled-related proteins (SFRP) are important elements associated with the Wnt signaling pathway, and its dysregulated expression is found in multiple cancers. However, the function of distinct SFRPs in GC remains poorly understood. We investigated the differential expression, prognostic value, and immune cell infiltration of SFRPs in gastric cancer patients from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan–Meier plotter, cBioPortal, STRING, Gene-MANIA, DAVID, MethSurv, and TIMER databases. We found that the expression levels of SFRP2 and SFRP4 were significantly increased in GC tissues, whereas the SFRP1 and SFRP5 expressions were reduced. SFRP1, SFRP2, and SFRP5 were significantly correlated with the clinical cancer stage in GC patients. Higher expression of SFRPs was associated with short overall survival (OS) in GC patients. Besides, high SFRPs methylation showed favorable OS in GC patients. The functions of SFRPs were primarily related to the Wnt signaling pathway, immune system development, and basal cell carcinoma. The expression of SFRPs was strongly correlated with immune infiltrating cells, including CD4+ T cells and macrophages in GC. Our study indicated that SFRPs could be potential targets of precision therapy and prognostic biomarkers for the survival of GC patients.

BACKGROUND Previous studies had shown endoscopic retrograde appendicitis therapy (ERAT) is an effective treatment for acute appendicitis. However, different studies reported conflicting outcomes regarding the effectiveness of ERAT in comparison with laparoscopic appendectomy (LA). AIM To compare the effectiveness of ERAT with LA. METHODS Randomized controlled trials (RCTs) and retrospective studies of ERAT for acute uncomplicated appendicitis were searched in PubMed, Cochrane Library, Web of Science, Embase database, China National Knowledge Infrastructure (CNKI), the WanFang Database, and Chinese Scientific Journals Database (VIP) from the establishment date to March 1 2021. Heterogeneity was assessed using the I-squared statistic. Pooled odds ratios (OR), weighted mean difference (WMD), and standard mean difference (SMD), with 95% confidence intervals (CI) were calculated through either fixed-effects or random-effects model. Sensitivity analysis was also performed. Publication bias was tested by Egger's test, and Begg’s test. The quality of included RCT were evaluated by the Jadad scale, while Newcastle-Ottawa scale is adopted for assessing the methodological quality of case-control studies. All statistical analysis was performed using Stata 15.1 statistical software. All statistical analysis was performed using Stata 15.1 statistical software. This study is registered with PROSPERO, CRD42021243955. RESULTS After screening, 10 RCTs and 2 case-control studies were included in the current systematic review. Firstly, the length of hospitalizations [WMD = -1.15, 95%CI: -1.99, -0.31; P = 0.007] was shorter than LA group. Secondly, the level of post-operative CRP [WMD = -10.06, 95%CI: (-17.39, -2.73); P = 0.007], TNF-α [WMD = -7.70, 95%CI: (-8.47, -6.93); P < 0.001], and IL-6 Levels [WMD = -9.78, 95%CI: (-10.69, -8.88); P < 0.001; P < 0.001] in ERAT group was significantly lower than LA group. Thirdly, ERAT group had a lower incidence of intestinal obstruction than LA group. [OR = 0.19, 95%CI: (0.05, 0.79); P = 0.020]. Moreover, the quality of 10 RCTs were low with 0-3 Jadad scores, while the methodological quality of two case-control studies were fair with a score of 2 (each). CONCLUSION Compared with LA, ERAT reduces operation time, the level of postoperative inflammation, and results in fewer complications and shorter recovery time, with preserving the appendix and its immune and biological functions.

Background: Gastric cancer (GC) is a common cancer with high mortality. This study aimed to identify its differentially expressed genes (DEGs) using bioinformatics methods.Methods: DEGs were screened from four GEO (Gene Expression Omnibus) gene expression profiles. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. A protein–protein interaction (PPI) network was constructed. Expression and prognosis were assessed. Meta-analysis was conducted to further validate prognosis. The receiver operating characteristic curve (ROC) was analyzed to identify diagnostic markers, and a nomogram was developed. Exploration of drugs and immune cell infiltration analysis were conducted.Results: Nine up-regulated and three down-regulated hub genes were identified, with close relations to gastric functions, extracellular activities, and structures. Overexpressed Collagen Type VIII Alpha 1 Chain (COL8A1), Collagen Type X Alpha 1 Chain (COL10A1), Collagen Triple Helix Repeat Containing 1 (CTHRC1), and Fibroblast Activation Protein (FAP) correlated with poor prognosis. The area under the curve (AUC) of ADAM Metallopeptidase With Thrombospondin Type 1 Motif 2 (ADAMTS2), COL10A1, Collagen Type XI Alpha 1 Chain (COL11A1), and CTHRC1 was &gt;0.9. A nomogram model based on CTHRC1 was developed. Infiltration of macrophages, neutrophils, and dendritic cells positively correlated with COL8A1, COL10A1, CTHRC1, and FAP. Meta-analysis confirmed poor prognosis of overexpressed CTHRC1.Conclusion: ADAMTS2, COL10A1, COL11A1, and CTHRC1 have diagnostic values in GC. COL8A1, COL10A1, CTHRC1, and FAP correlated with worse prognosis, showing prognostic and therapeutic values. The immune cell infiltration needs further investigations.