Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study.

BACKGROUND: Evidence from observational studies and clinical trials suggests that the gut microbiota is associated with cancer. However, the causal association between gut microbiota and cancer remains to be determined. METHODS: We first identified two sets of gut microbiota based on phylum, class, order, family, and genus level information, and cancer data were obtained from the IEU Open GWAS project. We then performed two-sample Mendelian randomisation (MR) to determine whether the gut microbiota is causally associated with eight cancer types. Furthermore, we performed a bi-directional MR analysis to examine the direction of the causal relations. RESULTS: We identified 11 causal relationships between genetic liability in the gut microbiome and cancer, including those involving the genus Bifidobacterium. We found 17 strong associations between genetic liability in the gut microbiome and cancer. Moreover, we found 24 associations between genetic liability in the gut microbiome and cancer using multiple datasets. CONCLUSIONS: Our MR analysis revealed that the gut microbiota was causally associated with cancers and may be useful in providing new insights for further mechanistic and clinical studies of microbiota-mediated cancer.

Tumor buster - where will the CAR-T cell therapy 'missile' go?

Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies' clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized.

Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts.

The discovery of immune checkpoint inhibitors (ICIs) has now been universally acknowledged as a significant breakthrough in tumor therapy after the targeted treatment of checkpoint molecules: anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on several cancer types achieved satisfying results. However, there are still quite a lot of patients suffering from severe side effects and ineffective treatment outcomes. Although the current ICI therapy is far from satisfying, a series of novel immune checkpoint molecules with remarkable preclinical and clinical benefits are being widely investigated, like the V-domain Ig suppressor of T cell activation (VISTA), which can also be called PD-1 homolog (PD-1H), and ectonucleotidases: CD39, CD73, and CD38, which belong to the ribosyl cyclase family, etc. In this review, we systematically summarized and discussed these molecules' biological structures, molecular features, and the corresponding targeted drugs, aiming to help the in-depth understanding of immune checkpoint molecules and promote the clinical practice of ICI therapy.

Construction of Molecular Subtypes and Related Prognostic and Immune Response Models Based on M2 Macrophages in Glioblastoma.

OBJECTIVES: To identify the molecular subtypes of glioblastoma multiforme (GBM) related to M2 macrophage-based prognostic genes, then to preliminarily explore their biological functions and construct immunotherapy response gene models. MATERIAL AND METHODS: We used R language to analyze GBM microarray data, and other tools, including xCell and CIBERSORTx, to identify subtypes of GBM that related to M2 macrophages. The process started with the exploration of biological functions of the two subtypes by pathway analyses and GSEA, and continued with a combined procedure of constructing an M2 macrophage-related prognostic gene model and exploring the immune treatment response for GBM. RESULTS: A high abundance of M2 macrophages in GBM was associated with poor prognosis. According to M2 macrophage-related prognostic genes, GBM was divided into two subtypes (cluster A and cluster B). The differential gene enrichment analysis of the two clusters showed that cluster A was less enriched in M2 macrophages and had immunopotential. The M2score, which was constructed based on M2 macrophage-related prognostic genes, was not only related to the survival and prognosis of patients with GBM, but also predictive of the effectiveness of immunotherapy in these patients. This result has been effectively verified in an external data set. CONCLUSION: GBM was successfully divided into two subtypes according to M2-macrophage-related prognostic genes. In GBM, a high M2score may indicate better clinical outcome and enhancement of the immunotherapy response.

Atezolizumab compared to chemotherapy for first-line treatment in non-small cell lung cancer with high PD-L1 expression: a cost-effectiveness analysis from US and Chinese perspectives.

BACKGROUND: The IMpower110 trial revealed that atezolizumab treatment had significantly longer overall survival (OS) than chemotherapy in non-small cell lung cancer (NSCLC) patients with high-programmed death ligand 1 (PD-L1) expression. The purpose of the present study was to estimate the cost-effectiveness of atezolizumab versus platinum-based chemotherapy for first-line treatment in metastatic NSCLC with high PD-L1 expression, from the perspective of US and Chinese payers. METHODS: A partitioned survival model was constructed based on information from the IMpower110 clinical trial to estimate cost-effectiveness of atezolizumab versus chemotherapy as first-line treatment of metastatic NSCLC. Costs were estimated from US and Chinese payer perspectives. The impact of uncertainty was explored by performing one-way and probabilistic sensitivity analyses. RESULTS: In the United States, treatment with atezolizumab was estimated to increase 0.87 quality adjusted life years (QALYs) at a cost of $123,424/QALY. In China, the use of atezolizumab cost an additional $68,489 compared with chemotherapy, yielding an incremental cost-effectiveness ratio (ICER) of $78,936/QALY. Sensitivity analysis indicated that the cost of atezolizumab was the most influential factor in both countries. CONCLUSIONS: In the United States, which had a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per QALY, atezolizumab was a cost-effective strategy for first-line treatment in metastatic NSCLC patients with high PD-L1 expression when compared to chemotherapy. For China, with a WTP threshold of $33,210 per QALY, atezolizumab was not considered good-value treatment for NSCLC, and a price reduction of 52% appeared to be justified.

Association between long non-coding RNA (lncRNA) GAS5 polymorphism rs145204276 and cancer risk.

OBJECTIVE: The long non-coding RNA (lncRNA) growth arrest­specific transcript 5 (GAS5) plays an important role in various tumors, and an increasing number of studies have explored the association of the GAS5 rs145204276 polymorphism with cancer risk with inconclusive results. METHODS: PubMed, Medline, EMBASE, Cochrane databases, and Web of Science were searched, and nine studies involving 6107 cases and 7909 controls were deemed eligible. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the relationship between rs145204276 and cancer risk in six genetic models. RESULTS: The pooled results suggest that the variant allele del was not associated with overall cancer risk. However, the subgroup analysis showed that allele del was significantly associated with a 22% decreased risk of gastrointestinal cancer (OR = 0.78, 95% CI: 0.72-0.85). Both sensitivity analyses and trial sequential analyses (TSA) demonstrated that the subgroup results were reliable and robust. Moreover, False-Positive Report Probability (FPRP) analysis indicated that the results had true significant correlations. CONCLUSION: These findings provide evidence that the GAS5 rs145204276 polymorphism is associated with the susceptibility to gastrointestinal cancer. Further studies with different ethnicities and larger sample sizes are warranted to confirm these results.

miR-125a-5p-targeted regulation of TRA2ß expression inhibits proliferation and metastasis of hepatocellular carcinoma cells.

OBJECTIVE: To explore the regulation of miR-125a-5p in hepatocellular carcinoma (HCC) and its mechanisms. METHODS: By transfecting a miR-125a-5p sequence and an interfering sequence of miR-125a-5p-s into human HCC cell lines HCC-LM3 and HepG2, miR-125a-5p-related levels were assesed by Western blot. The abilities of cell proliferation and migration were assessed by cell culture and Transwell assay, respectively. RESULTS: HepG2 cells showed increased miR-125a-5p levels compared with HCC-LM3 cells (P < 0.01). However, compared with QZG cells, the level of miR-125a-5p in HepG2 and HCC-LM3 cells was down-regulated. Compared with miR-125a-5p groups, miR-125a-5p-s groups showed increased colony formation rate and mobility (P < 0.01). After being transfected with miR-125a-5p, the transformation factor 2ß (TRA2ß) and mRNA levels were decreased, whereas 5p-s expression was increased (P < 0.01). Inhibition of TRA2ß by small interfering RNA (siRNA) diminished the ability of cells. CONCLUSION: miR-125a-5p inhibits the invasive capacity of HCC cells through targeting the TRA2ß pathway.

Cost-Effectiveness Analysis of First-Line FOLFIRI Combined With Cetuximab or Bevacizumab in Patients With RAS Wild-Type Left-Sided Metastatic Colorectal Cancer.

BACKGROUND: The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. METHODS: A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. RESULTS: In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. CONCLUSIONS: Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.

The relationship between miR-302b and EphA2 and their clinical significance in gastric cancer.

Introduction: EphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, and miR-302b can target EphA2 in gastric cancer. This study plans to investigate their relationship and clinical significance in clinical samples. Materials and Methods: We explored the correlation of the expression of EphA2 and miR-302b, and their clinical significance in the training (n=226) cohort of GC patients, and then validated the results in the validation (n=128) cohort. Results: miR-302b was remarkably downregulated in GC tissues, while high EphA2 expression were detected, and they were inversely correlated both in mRNA and protein, (r=-0.4209, P<0.0001; r=-0.336, P <0.001, respectively). Furthermore, the pattern of high EphA2 and low miR-302b expression were found to be associated with poor overall survival in stage IV GC patients in both training and validation cohort. Conclusions: The expression of miR-302b and EphA2 was inversely correlated, and had prognostic significance on GC in clinic.

CXCR4-mediated osteosarcoma growth and pulmonary metastasis is suppressed by MicroRNA-613.

Osteosarcoma is the most common primary bone malignancy. Recently, studies showed chemokine receptor 4 (CXCR4) played a critical role in osteosarcoma. However, the regulation of CXCR4 is not fully understood. microRNAs are short, non-coding RNAs that play an important roles in post-transcriptional regulation of gene expression in a variety of diseases including osteosarcoma. miR-613 is a newly discovered miRNA and has been reported to function as a tumor suppressor in many cancers. In this study, we confirmed that both Stromal Cell-Derived Factor (SDF-1) and CXCR4 could be prognostic markers for osteosarcoma. Meanwhile this study found that SDF-1/CXCR4 pathway regulated osteosarcoma cells proliferation, migration and reduced apoptosis. Besides, we demonstrated that miR-613 was significantly downregulated in osteosarcoma patients. Elevated expression of miR-613 directly suppressed CXCR4 expression and then decreased the proliferation, migration and induced apoptosis of osteosarcoma cells. Moreover, our study found that CXCR4 promoted the development of lung metastases and inhibition of CXCR4 by miR-613 reduced lung metastases. These data indicated that CXCR4 mediated osteosarcoma cell growth and lung metastases and this effect can be suppressed by miR-613 through directly downregulating CXCR4.

miR-302b inhibits tumorigenesis by targeting EphA2 via Wnt/ ß-catenin/EMT signaling cascade in gastric cancer.

BACKGROUND: EphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, this study aims to identify microRNAs that target it and serve as key regulators of gastric carcinogenesis. METHODS: We identified several potential microRNAs targeting EphA2 by bioinformatics websites and then analyzed the role of miR-302b in modulating EphA2 in vitro and in vivo of GC, and it's mechanism. RESULTS: Our analysis identified miR-302b, a novel regulator of EphA2, as one of the most significantly downregulated microRNA (miRNA) in GC tissues. Overexpression of miR-302b impaired GC cell migratory and invasive properties robustly and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro. miR-302b exhibited anti-tumor activity by reversing EphA2 regulation, which relayed a signaling transduction cascade that attenuated the functions of N-cadherin, ß-catenin, and Snail (markers of Wnt/ß-catenin and epithelial-mesenchymal transition, EMT). This modulation of EphA2 also had distinct effects on cell proliferation and migration in GC in vivo. CONCLUSIONS: miR-302b serves as a critical suppressor of GC cell tumorigenesis and metastasis by targeting the EphA2/Wnt/ß-catenin/EMT pathway.

Low plasma PDGF-BB levels are associated with estradiol in postmenopausal osteoporosis: PDGF-BB mediated by estradiol in women.

Objective This study aimed to investigate the association between low plasma Platelet-derived growth factor-BB (PDGF-BB) levels and oestradiol in Postmenopausal osteoporosis (PMOP). Methods This prospective study measured plasma PDGF-BB and oestradiol levels in outpatients who were admitted to our hospital. Participants were screened and then allocated to three groups: normal young women, postmenopausal control, and PMOP. Additionally, Sprague-Dawley rats underwent either sham surgery or bilateral ovariectomy (OVX), and were divided into the following groups: sham, OVX, OVX + oestradiol, and OVX + PDGF-BB. Plasma oestradiol and PDGF-BB levels were measured using commercially available ELISA kits. Results A total of 121 participants, including 69 normal young women, 28 patients with primary PMOP, and 24 age-matched postmenopausal women were enrolled. Plasma oestradiol and PDGF-BB levels were lower in postmenopausal women, especially in PMOP ( P < 0.01). Pearson correlations analysis showed that PDGF-BB levels were positively correlated with oestradiol levels and inversely correlated with age ( P < 0.01). The OVX rat model showed that oestradiol replacement increased plasma PDGF-BB levels, while PDGF-BB systematic treatment had no effect on plasma oestradiol levels. Conclusions Plasma PDGF-BB levels are maintained by oestrogen in normal young women and play a major role in PMOP.

Association of nonsteroidal anti-inflammatory drugs and aspirin use and the risk of head and neck cancers: a meta-analysis of observational studies.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have emerged as the potential chemopreventive agents for a number of cancer types, however, previous studies of head and neck cancers (HNC) have yielded inconclusive results. We performed a meta-analysis of observational studies to quantitatively assess the association between NSAIDs use and the risk for HNC. METHODS: We searched Pubmed, Embase, Google scholar, and Cochrane library for relevant studies that were published in any language, from January 1980 to April 2016. We pooled the odds ratio (OR) from individual studies and performed subgroup, heterogeneity, and publication bias analyses. RESULTS: A total of eleven studies (eight case-control studies and three cohort studies), involving 370,000 participants and 10,673 HNC cases contributed to this meta-analysis. The results of these studies suggested that neither use of overall NSAIDs (OR=0.95; 95% CI, 0.81-1.11), aspirin (OR=0.93; 95% CI, 0.79-1.10), nor nonsteroidal NSAIDs (OR=0.92; 95% CI, 0.76-1.10) were associated with HNC risk. Similar nonsteroidal results were observed when stratified by HNC sites, study design, sample size, and varied adjustment factors. However, we found significant protective effect of ibuprofen (OR=0.85; 95% CI, 0.72-0.99) and long-term aspirin use (≧5years) (OR=0.75; 95% CI, 0.65-0.85) on HNC risk, with low heterogeneity and publication bias. CONCLUSIONS: Our meta-analysis results do not support the hypothesis that overall use of NSAIDs significant reduces the risk of HNC. Whereas, we cannot rule out a modest reduction in HNC risk associated with ibuprofen and long-term aspirin use.

Diagnostic accuracy of circulating tumor cells detection in gastric cancer: systematic review and meta-analysis.

BACKGROUND: Circulating tumor cells (CTCs) detection has previously been used for diagnosing gastric cancer. However, the previous studies failed to make an agreement whether the detection of CTCs contributes to the diagnosis of gastric cancer. METHODS: A systematic review and meta-analysis was performed to evaluate the overall accuracy of CTCs detection for diagnosing gastric cancer. PubMed, Embase and the Wanfang database were searched in all languages published up to Oct 2012. The pooled sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (PLR and NLR, respectively), diagnostic odds ratio (DOR) and summary receiver operating characteristic (sROC) curve were calculated to evaluate the overall test performance. RESULTS: Twenty studies were included in this systematic review and meta-analysis. The diagnostic value of CTCs detection for the gastric cancer was calculated to evaluate the overall test performance. The summary estimates of The pooled sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio were 0.42 (95% confidence interval (CI), 0.21-0.67), 0.99 (95% CI, 0.96-1.00), 58.2 (95% CI, 9.8-345.9), 0.58 (95% CI, 0.38-0.89), and 100 (95% CI, 15-663), respectively. The summary receiver operating characteristic curve was 0.97 (95% CI, 0.95-0.98). Deek's funnel plot asymmetry test found no evidence of study publication bias in the current study (P = 0.49). CONCLUSION: This systematic review suggests that CTCs detection alone cannot be recommended as a screening test for gastric cancer. However, it might be used as a noninvasive method for the confirmation of the gastric cancer diagnosis.