Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors.

The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ markers than lean adipose tissue Mφ (ATMφ) physiologically. (3) Pro-adipogenic TFs C/EBPα and PPARγ and proinflammatory adipokine leptin upregulate the expression of M1 Mφ markers. (4) Among 10 immune checkpoint receptors (ICRs), LLSI-Mφ and bone marrow (BM) Mφ express higher levels of CD274 (PDL-1) than ATMφ, presumably to counteract the M1 dominant status via its reverse signaling behavior. (5) Among 24 intercellular communication exosome mediators, LLSI- and BM- Mφ prefer to use RAB27A and STX3 than RAB31 and YKT6, suggesting new inflammatory exosome mediators for propagating inflammation. (6) Mφ in peritoneal tissue and LLSI-Mφ upregulate higher levels of immunometabolism enzymes than does ATMφ. (7) Mφ from peritoneum and LLSI-Mφ upregulate more trained immunity enzyme genes than does ATMφ. Our results suggest that multiple new mechanisms including the cell surface, intracellular immunometabolism, trained immunity, and TFs may be responsible for disease group-specific and shared pathways. Our findings have provided novel insights on the pathophysiological regulation of tissue Mφ, the disease group-specific and shared pathways of Mφ, and novel therapeutic targets for cancers and inflammations.

Prognostic Value of Pretreatment Serum Transthyretin Level in Patients with Gastrointestinal Cancers.

BACKGROUND: Many studies have shown the link between the pretreatment serum transthyretin and prognosis in gastrointestinal (GI) cancers. However, based on the conclusion, the initial findings were inconsistent. Hence, this meta-analysis was performed to identify the prognostic values of the pretreatment serum transthyretin in GI cancers. METHODS: Previous studies published before November 2018 were collected from a comprehensive literature search of several databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were applied in the assessment of the intensity of associations. Also, the publication bias and the robustness of merged data were assessed. All statistical analyses were undertaken using STATA/SE 14.1. RESULTS: The combined data indicated that the pretreatment serum transthyretin level was related to the prognosis in GI cancers. The group with reduced pretreatment transthyretin had a significantly worse overall survival (OS) (HR = 1.71, 95% CI: 1.37-2.05). The subgroup analysis for OS further showed the predictive value of transthyretin. In addition, the low serum transthyretin level could be an unfavorable factor for recurrence-free survival (RFS) or progression-free survival (PFS) (HR = 1.66, 95% CI: 1.14-2.18) in GI cancers. CONCLUSION: The low pretreatment serum transthyretin level implies an unfavorable prognosis for patients with GI cancers. The monitoring of pretreatment transthyretin level could contribute to the risk stratification and individualized therapy in GI cancers.

Effect of docetaxel-loaded lipid microbubble in combination with ultrasound-triggered microbubble destruction on the growth of a gastric cancer cell line.

Although gastric cancer therapy has been improved, more efficient treatment strategies still need to be developed. In the present study, a docetaxel (DOC)-loaded lipid microbubble (DLLD) was prepared and the effect of DLLD combined with ultrasound-triggered microbubble destruction (UTMD) on the growth of a gastric cancer cell line was investigated. The following four groups were included in the present study: Control, DOC, DLLD and DLLD plus UTMD. The determined entrapment efficiency of DLLD is 76±3.5%. The present study demonstrated that treatment with DLLD plus UTMD could significantly inhibit the growth of the cultured gastric cancer cell line BGC-823 via arresting the cell cycle in G2/M phase, inhibiting cell DNA synthesis, promoting cell apoptosis and disrupting mitochondrial membrane potential, as compared with treatment with DOC or DLLD alone. Furthermore, the expression of p53, p21 and Bax were identified to be significantly upregulated, while that of Bcl-2 was significantly downregulated in the DLLD plus UTMD group. Therefore, treatment with DLLD plus UTMD was more efficient in inhibiting cell proliferation and inducing cell apoptosis in the gastric cancer cell line, when compared with treatment with DOC or DLLD alone, suggesting that DLLD plus UTMD could serve as a promising strategy for the treatment of gastric cancer.

Prognostic significance of peripheral blood-derived neutrophil/lymphocyte ratio in patients with digestive cancer.

Accumulating studies reported the clinical value of derived neutrophil/lymphocyte ratio (dNLR) regarding the prediction of survival outcomes in digestive cancers, however, the prognostic significances of dNLR in these cancers were inconsistent. This study was carried out to clarify the relationship between circulating dNLR and prognosis in gastrointestinal (GI) cancers. Eligible publications were collected and extracted by searching Pubmed, Embase, Web of Science, and Google Scholar up to November 21, 2018. The prognostic impact of dNLR in subjects with GI cancers was assessed with the overall hazard ratios (HRs). A total of 26 studies with up to 13,945 participants were recruited. Our findings showed that peripheral blood dNLR before treatment could be a useful prognostic predictor in digestive cancers, an elevated dNLR indicated a shorter overall survival (OS) in GI tumors (HR, 1.44; 95% confidence interval [CI], 1.36-1.51). Furthermore, its significant prognostic value for OS was also confirmed in subgroup analyses stratified by disease type, publication year, type of research, detection method, geographic location, cut-off value, treatment, analysis type, follow-up time and disease stage. In addition, high dNLR was significantly associated with worse cancer-specific survival (HR, 1.25; 95% CI, 1.04-1.47) and inferior event-free survival (HR, 1.22; 95% CI, 1.11-1.33) in patients with digestive cancers. Our study showed elevated peripheral blood dNLR may indicate unfavorable outcomes in digestive cancer.

Association of the HOTAIR rs4759314 polymorphism with cancer risk: a meta-analysis.

PURPOSE: To explore the association between HOTAIR rs4759314 and cancer risk. METHODS: A comprehensive online search was conducted using PubMed, EMBASE, and CNKI databases to identify relevant studies. The case-control studies related to HOTAIR rs4759314 polymorphism and cancer risk were selected according to the inclusion and exclusion criteria. The retrieval time was until November 2015. After extracting the basic data information and performing an evaluation of the quality of the literature, the meta-analysis was performed using STATA 12.0 software, by calculating the odds ratio (OD) and 95% confidence interval (95% CI), and further subgroup analysis, literature publication bias testing, and sensitivity analysis. RESULTS: The studies included a total of 5025 patients with cancer and 5657 controls. The results found no significant association between the HOTAIR rs4759314 polymorphism and cancer risk in a Chinese population (G vs A, OR=1.06, 95% CI :0.87-1.30 ; GG/GA vs AA, OR=1.07, 95% CI: 0.87-1.32; GG vs GA/AA, OR=0.75, 95% CI:0.39-1.43; GA vs AA, OR=1.08, 95% CI: 0.88-1.33; GG vs AA, OR=0.76, 95% CI:0.39-1.45) (all p<0.05). However, A allelic gene was associated with lower risk of gastric cancer, while G allelic gene may act as a genetic susceptibility factor for gastric cancer in Chinese population. CONCLUSION: No significant association was noted between the HOTAIR rs4759314 polymorphism and cancer risk in a Chinese population.

Intrathecal Administration of Flavopiridol Promotes Regeneration in Experimental Model of Spinal Cord Injury.

AIM: Spinal cord injury (SCI) is a serious condition of the central nervous system and it affects the quality of life and even hampers the day-to-day activity of the patient. In the current study, we investigated the efficacy of intrathecal administration of flavopiridol in an experimental animal model of SCI. The study also aimed at exploring the physiological effects of flavopiridol on neurons, astrocytes and cell cycle regulatory proteins. MATERIAL AND METHODS: In vitro scratch wound experiments were performed on female Sprague-Dawley rats (n=23). A complete hemisection to the right of T10 was made, and flavopiridol solution (200 mM, 0.8 nmol flavopiridol/animal) was delivered topically to the lesion site. Cell viability assay, in vitro scratch injury assay, cell cycle analysis using flow cytometry and behavioural assessments were performed. RESULTS: The local delivery of flavopiridol reduced cavity formation and improved regeneration of neurons with improvement in physiological performance. Flavopiridol also inhibited the migration and proliferation of astrocytes, and at the same time, promoted the survival of neurons. CONCLUSION: Intrathecal administration of flavopiridol can be a promising treatment strategy in patients with SCI and it needs to be validated in patient setting.

Prognostic value of long non-coding RNA UCA1 in human solid tumors.

BACKGROUND: Numerous studies have shown that the expression of UCA1 was aberrantly upregulated in various cancer types. High expression of UCA1 was reported to be associated with unfavorable prognosis in cancer patients. RESULTS: A total of 1240 patients from 15 articles were included. The results indicated that a significantly shorter OS was observed in patients with high expression level of UCA1 (HR = 1.71, 95% CI: 1.43-1.99), in the subgroup analysis, the association was also observed in patients with cancers of digestive system (HR = 2.12, 95% CI: 1.59-2.66). Statistical significance was also observed in subgroup meta-analysis stratified by the cancer type, cut-off value, analysis type and sample size. Furthermore, poorer DFS was observed in patients with high expression level of UCA1 (HR = 2.54; 95% CI: 1.09-4.00). Additionally, the pooled odds ratios (ORs) showed that increased UCA1 was also related to positive lymph node metastasis (OR = 2.98, 95% CI: 2.06-4.30), distant metastasis (OR = 3.14, 95% CI: 1.77-5.58) and poor clinical stage (OR = 2.76, 95% CI: 2.08-3.68). MATERIALS AND METHODS: A comprehensive retrieval was conducted in multiple databases, including PubMed, Embase, Web of Science and CNKI. We collected relevant articles to explore the association between the expression levels of UCA1 and prognosis. CONCLUSIONS: High expression level of UCA1 was associated with poor clinical outcome. UCA1 could serve as a novel biomarker for prognosis and might be a potential predictive factor for clinicopathological characteristics in various cancers. Further studies should be performed to verify the clinical utility of UCA1 in human solid tumors.

Long noncoding RNA AFAP1-AS1, a potential novel biomarker to predict the clinical outcome of cancer patients: a meta-analysis.

A number of studies have demonstrated that the expression level of actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) was upregulated in various cancers. High expression of AFAP1-AS1 is associated with an increased risk of metastasis and a poor prognosis in cancer patients. The electronic search was conducted in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang database. We collected relevant articles to explore the association between the expression levels of AFAP1-AS1 and lymph node metastasis, distant metastasis, overall survival, relapse-free survival, and progression-free survival. A total of 1,017 patients from eight studies were finally included. The results showed that cancer patients with high AFAP1-AS1 expression suffered an increased risk of developing lymph node metastasis (odds ratio =3.19, 95% confidence interval [CI]: 2.11-4.83, P<0.00001) and distant metastasis (odds ratio =3.05, 95% CI: 1.84-5.04, P<0.0001). Moreover, we found that patients with high AFAP1-AS1 expression also had a poorer overall survival (hazard ratio [HR]: 1.98, 95% CI: 1.57-2.38, P=0.000), a worse progression-free survival (HR: 1.73, 95% CI: 1.11-2.35, P=0.000), and a shorter recurrence-free survival (HR: 1.96, 95% CI: 1.02-2.90, P=0.000) than those with low AFAP1-AS1 expression. High expression of AFAP1-AS1 was associated with poor clinical outcome. AFAP1-AS1 might serve as a potential novel biomarker for indicating the clinical outcomes in human cancers.

HOXB7 as a promising molecular marker for metastasis in cancers: a meta-analysis.

Numerous studies on carcinoma have revealed that the expression level of HOXB7 in cancerous tissues was significantly higher than that in noncancerous tissues. Elevated expression of HOXB7 is associated with the susceptibility to lymph node metastasis and distant metastasis in various tumors. In this study, a meta-analysis was performed to involve majority of relevant articles and explore the association of HOXB7 expression level with metastasis in cancer patients. Literature retrieval was conducted by searching in a number of electronic databases (up to December 1, 2015). The meta-analysis was conducted with RevMan 5.3 software and Stata SE12.0. A total of 1,532 patients with carcinoma from 14 studies were included in analysis. The results of meta-analysis demonstrated that lymph node metastasis was observed more frequently in the patients group with high expression level of HOXB7 than in the patients group with low expression level of HOXB7 (odds ratio =2.17, 95% CI: 1.74-2.71, P<0.00001, fixed-effects model). In addition, a similar result was observed in the association between HOXB7 expression and distant metastasis; the odds ratio was 1.77 (95% CI: 1.09-2.88, P=0.02, fixed-effects model). This meta-analysis demonstrated that the overexpression of HOXB7 was significantly associated with metastasis in cancer patients, which may be served as a common molecular marker for indicating cancer metastasis.

Long noncoding RNA ANRIL: a potential novel prognostic marker in cancer: a meta-analysis.

INTRODUCTION: Numerous researches have showed that the dysregulation of lncRNA ANRIL play a significant role in cancer progression, and high expression of ANRIL may have important clinical value. This meta-analysis aims to investigate potential clinical application role of ANRIL as a biomarker for cancer prognosis. EVIDENCE ACQUISTION: The electronic search was conducted in Pubmed, EMBASE, Web of Science, CNKI and Wanfang database (up to January 27, 2016). We collected relevant articles to explore the association between the expression levels of ANRIL and overall survival (OS). EVIDENCE SYNTHESIS: A total of 519 cancer patients from six studies were finally included. The results showed that cancer patients with high ANRIL expression may have a poorer OS (HR=1.95, 95%CI:1.37-2.53, P=0.000, fixed-effect model) than those with low ANRIL expression. CONCLUSIONS: High expression of ANRIL is associated with poor clinical outcome. ANRIL might be act as a novel potential prognostic biomarker in various cancers.

Long non-coding RNA-LET can indicate metastasis and a poor prognosis: a meta-analysis.

INTRODUCTION: Recent studies have reported that long non-coding RNA low expression in tumor (lncRNA-LET) was down-regulated in several cancers. The current meta-analysis aims to determine whether lncRNA-LET can be used as a potential biomarker for metastasis and prognosis. EVIDENCE ACQUISITION: We collected all relevant papers by searching multiple electronic databases (PubMed, EMBASE, Google Scholar, CNKI, Wanfang Database) and explored the association between the expression levels of lncRNA-LET and lymph node metastasis (LNM), distant metastasis (DM) and overall survival (OS). EVIDENCE SYNTHESIS: A total of 383 patients from four studies were finally included. The meta-analysis results showed that LNM occurred more frequently in patients from the lncRNA-LET low expression group than in patients from the lncRNA-LET overexpression group (OR=4.56, 95% CI 2.92-7.12, P<0.00001), and a similar result was observed between lncRNA-LET expression and DM (OR=4.77, 95% CI 2.29-9.94, P<0.0001). Additionally, we found that patients with low expression of lncRNA-LET had a poorer OS than those with lncRNA-LET overexpression (HR=2.39, 95% CI 1.57-3.21, P=0.000). CONCLUSIONS: lncRNA-LET may serve as a common molecular marker for metastasis and prognosis in human cancers.

Positive association between IL-16 rs1131445 polymorphism and cancer risk: a meta-analysis.

INTRODUCTION: The association between IL-16 rs1131445 polymorphism and cancer risk is not consistent or even contradictory, this meta-analysis aims to investigate the role of IL-16 gene rs1131445 polymorphisms in the risk of cancer. EVIDENCE ACQUISITION: A comprehensive online search was conducted in PubMed, EMBASE and CNKI databases to identify eligible studies. The case-control studies related IL-16 rs1131445 C/T polymorphism with the cancer susceptibility were selected according to the inclusion and exclusion criteria. After extracting the basic data information and quality of literature evaluation, the meta-analysis was performed by using STATA 12.0 software, with calculating odds ratio and 95% confidence interval, and further subgroup analysis, literature publication bias test and sensitivity analysis. EVIDENCE SYNTHESIS: There are totally 1677 cases and 1989 non-tumor controls finally involved. Meta-analysis showed that there are statistical correlations between the IL-16 rs1131445 C/T polymorphism and the cancer risk in Asian populations (TS vs. C, OR=0.80, 95%CI: 0.73-0.88; TT vs. TC, OR=0.75, 95%CI: 0.65-0.87; TT vs. CC, OR=0.69, 95% CI: 0.56-0.84; CC+TC vs. TT, OR=1.36, 95%CI: 1.19-1.55; CC vs. TC+TT, OR=1.27, 95%CI: 1.05-1.53) (all P<0.05). CONCLUSIONS: IL-16 rs1131445 C/T polymorphism is related to the susceptibility to cancer in Asians, suggesting that the C allelic gene of rs1131445 is significantly associated with an increasing cancer risk.

Long Non-Coding RNA HOXA Transcript at the Distal Tip as a Putative Biomarker of Metastasis and Prognosis: a Meta-Analysis.

BACKGROUND: Many studies demonstrated that the expression level of HOTTIP in cancerous tissues was significantly higher than that in adjacent normal tissues. Increased expression of HOTTIP was associated with metastasis and a poor prognosis. METHODS: The current meta-analysis collected all relevant articles and explored the association of HOTTIP expression levels with lymph node metastasis (LNM), distant metastasis (DM), and overall survival (OS) in multiple cancers. Literature collections were conducted by searching a number of electronic databases (up to December 31, 2015). The Meta-analysis was conducted using RevMan5.3 software and Stata SE12.0. RESULTS: A total of 602 patients with cancer from seven studies were included. The Meta-analysis results showed that lymph node metastasis occurred more frequently in patients with high HOTTIP expression than in patients with low HOTTIP expression (OR = 2.22, 95% CI: 1.47 - 3.37, p = 0.0002, fixed-effects model), and a similar result was observed between HOTTIP expression and distant metastasis (OR = 3.30 (95% CI: 1.78 - 6.12, p = 0.0001, fixed-effects model). Moreover, we found that cancer patients with high HOTTIP expression had a poorer overall survival than those with low HOTTIP expression (HR = 2.23, 95% CI: 1.64 - 2.83, p = 0.000, fixed-effects model). CONCLUSIONS: HOTTIP may serve as an independent biomarker for predicting the clinical outcome of cancer patients.

Selection of anti-cancer-associated gene single-chain variable fragments derived from gastric cancer patients using ribosome display.

The aim of this study was to construct a human single-chain variable fragment (scFv) gene library for gastric cancer, from which human anti-cancer-associated gene (CAGE) scFvs are selected. Human lymphocytes were isolated from the peripheral blood of 10 gastric cancer patients and whole human heavy and light chain genes were cloned by reverse transcription-polymerase chain reaction (RT-PCR). VH and VL were rearranged randomly by splicing by overlap extension PCR. The ribosome complexes were enriched against the recombinant CAGE protein conjugated to magnetic beads. scFv antibodies were evaluated by western blot analysis, and affinity constants in a solution of antigen-antibody complexes were determined by enzyme-linked immunosorbent assay. An scFv library was constructed using the peripheral blood lymphocytes. The expressed scFv proteins from the ternary ribosome complexes were analyzed by western blot analysis and the affinity [equilibrium dissociation constant (KD)] of scFv for CAGE was determined to be 7.6x10-8 M. The ribosome display technique is efficient for selecting a fully human antibody fragment from a patient-derived gene pool.

Meta-analysis of the association between VEGF-634 G>C and risk of malignancy based on 23 case-control studies.

PURPOSE: The association between polymorphism of vascular endothelial growth factor (VEGF)-634 G>C and malignancy risk has been widely studied, and no conclusive result was available up to now. METHODS: Twenty-three case-control studies with 21,917 individuals were included in this meta-analysis through searching the databases of Medline, Embase, and CNKI (up to October 1st, 2010). The odds ratio (OR) and 95% confidence interval (95%CI) were used to investigate the strength of the association. RESULTS: Overall, the pooled analysis showed that there was no association between VEGF-634 G>C and risk of malignancy, and the ORs (95%CIs) were 0.98 (0.85-1.12) for GG versus CC, 1.03 (0.90-1.17) for GC versus CC, 1.00 (0.89-1.13) for G carrier versus CC, and 1.08 (0.94-1.23) for C carrier versus GG. Subgroup analyses according to ethnicity, source of control, type of cancer, and sample size were also performed, and results indicated that VEGF-634 G>C was not associated with risk of malignancy for neither Asians [1.06 (0.81-1.38) for GG vs. CC and 1.08 (0.84-1.39) for GC vs. CC] nor Caucasians [0.93 (0.83-1.05) for GG vs. CC and 0.98 (0.87-1.10) for GC vs. CC]. It was also not associated with risk of breast cancer [0.95 (0.81-1.12) for GG vs. CC], gastric cancer [0.93 (0.47-1.84) for GG vs. CC], and colorectal cancer [1.17 (0.93-1.47) for GG vs. CC]. CONCLUSIONS: This meta-analysis suggests that VEGF-634 G>C may be not associated with risk of malignancy. More studies with larger sample size were needed to provide more precise evidence.