Background: Surfactant protein D (SFTPD) is a lung specific protein which performs several key regulatory processes to maintain overall lung function. Several infectious and immune mediated diseases have been shown to be associated with SFTPD. Recent findings have suggested the serum concentration of SFTPD can be used as a diagnostic or prognostic marker for chronic obstructive pulmonary disease (COPD) and acute exacerbation COPD (AECOPD). But these findings lack replication studies from different ethnic populations and meta-analysis, to establish SFTPD as reliable diagnostic or prognostic biomarker for COPD and associated conditions.Methods: We performed systematic literature search based on stringent inclusion and exclusion criteria to identify eligible studies to perform a meta-analysis. Our objective was to assess the predictability of serum SFTPD concentration and SFTPD allelic conformation at rs721917 (C > T) with COPD and AECOPD outcome. These variables were compared between COPD and healthy controls, where mean difference (MD), and odds ratio (OR) were calculated to predict the overall effect size. Review manager (RevMan-v5.3) software was used to analyse the data.Results: A total of eight published reports were included in this study. Comparative serum SFTPD concentration data were extracted from six studies and three studies were evaluated for assessment of genetic marker from SFTPD. Our study identified strong association of elevated serum SFTPD with COPD and AECOPD. Significant association of risk was also observed for “T” allele or “TT” genotype of rs721917 from SFTPD with COPD and AECOPD.Conclusion: Serum concentration and alleleic conformation of SFTPD has a significantly high predictive value for COPD and AECOPD. Thus, these can be tested further and could be applied as a predictive or prognostic marker. Chronic Obstructive Pulmonary Disease (COPD) affects lungs and exhibits irreversible airflow conditions that leads to improper respiratory function  is a highly lung specific glycoprotein secreted by type II alveolar cells and non-ciliated clara cells and functionally involved in maintaining the lung functions , compared to SCOPD , and control group  was reported among Pakistanis  higher among AECOPD  than SCOPD  and control subjects   followed by acute exacerbation COPD (AECOPD). AECOPD is characterized by sudden worsening of respiratory conditions including secretion of greenish phlegm . We attempt to establish an association between variation in serum SFTPD concentration and the SFTPD genetic variation rs721917 with COPD and its sub- phenotype(s). The rationale of this study is to increase the power by considering multiple studies in a meta-analysis with similar environmental conditions, thereby evaluating the significance of SFTPD as an important diagnostic biomarker.A search for eligible literature was done till May 12th, 2018. Databases used for the retrieval of eligible articles were PubMed  and Google Scholar. The following keywords were used to retrieve all the publications: “COPD and SFTPD”; “Chronic obstructive pulmonary disease and surfactant protein D”; “COPD and serum SFTPD”; “COPD and SFTPD genotypes.” Publications with the desirable keywords were selected. Further publications were added from the cross-references of the retrieved articles. Details are given in the Scanning of publications with relevant titles and abstracts were done only for case-control studies encompassing COPD, and AECOPD as one of the major sub-phenotypes. No other sub-phenotypes of COPD were included in the study owing to maintain the focus area of the present meta-analysis. Only those studies were included where study participants were aged more than 35 years and all were smokers. We did not keep sex as a selection criteria. While for genetic polymorphisms, studies having information about rs721917 were only selected.Data extraction from the eligible publications was done by two investigators independently and conflicts were resolved through group discussions. Following data was extracted from the finally selected publications:Protein biomarker: author names, number of participants, SFTPD serum/plasma level mean value (cases and controls), diagnostic criteria.Genetic biomarker (rs721917): author names, number of participants, allele distribution among cases and controls, population, and diagnostic criteria.I2 and chi2 tests, where I2 more than 50% and chi2p-value <0.05 was considered significant heterogeneity. Both the analyses were done using fixed effect model. Meta-OR or Meta-MD were calculated using Z-test with 5% level of significance and 95% confidence interval. Possible publication bias was evaluated through visual inspection of funnel plots generated using the same software.For statistical analysis, Review Manager (RevMan-v5.3) Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2014, software was used. As serum biomarker level is a continuous variable mean difference (MD) was calculated. For genetic marker odds ratio (OR) for pooled data was calculated. Different genetic models such as, allelic model, dominant model, recessive model, and additive model were used to analyze the association. Heterogeneity among studies was calculated using SFTPD (rs721917) with overall COPD and acute exacerbation with COPD (AECOPD). Detail characteristics of these studies are presented in the Following online literature search, a total of 97 publications were obtained. Additionally seven publications were found through cross-references. However, based on our study inclusion-exclusion criteria, a total of 96 publications were excluded. Therefore, only eight publications were found eligible and taken forward for the meta-analysis . EligiblSFTPD rs71917 withZ < 0.00001] with overall COPD (Z < 0.00001] (Serum concentration of SFTPD (mean and SD) was available for a total of 2,109 cases and 464 healthy controls reported in eligible studies. Elevated serum SFTPD values were found to be significantly associated  (Z = 0.05] and AECOPD  with marginal significance. Recessive model confirmed the protective role of “CC” genotype for both COPD  and AECOPD . Dominant role and risk confers by the “T” allele was further confirmed by additive models of association  and GOLD Criteria, while the Pakistani population was diagnosed solely on the basis of GOLD criteria . For rs7= 0.009] . Similarociation .Surfactant protein-D is a key innate immunity molecule with significant role in host defense. It has been reported as associated with several health conditions including COPD as well as various associated manifestations, such as AECOPD  compared to COPD  when compared to healthy controls. However, as this study was performed on reported case-control based cross-sectional studies, causal effect relationship between the serum SFTPD level and COPD could not be affirmed. Recent evidences confirmed that elevated serum SFTPD can be used as a prognostic marker for COPD, as its serum concentration has been found significantly elevated among AECOPD compared to COPD  can be made to access the diagnosis and prognosis.Limitations of this study include, less population numbers due to stringent inclusion and exclusion criteria. Population as a whole has been considered and not further stratified on their ethnicities. Studies with larger cohorts need to be conducted to confirm the association of serum SFTPD and its allelic conformation with COPD and AECOPD. Furthermore, to generalize these findings large-scale population based replication studies are warranted.SS conceptualized the study. DN and NS performed the systematic review and meta-analysis. SS, DN, and NS wrote the manuscript. All authors reviewed and finalized the manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


TIM-family proteins are expressed on different immune cells such as dendritic cells, macrophages, type 1 and 2 T helper (Th) cells. Therefore, they have the ability to contribute to the various intracellular signals and immune responses, importantly the regulation of Th1 and Th17 cell differentiation, which plays a remarked role in fight against inflammatory and autoimmune diseases. Association of TIM family gene polymorphisms with rheumatoid arthritis (RA) has been frequently investigated. The findings however are not entirely consistent. Therefore, we carried out the present meta-analysis to examine the association between RA and the following TIM family gene polymorphisms: rs41297579, rs1036199, rs10515746, and rs7700944.A systematic search of Scopus, PubMed, and Web of Science databases was conducted through December 2018. Combined odds ratios (OR) with their corresponding 95% confidence intervals (CI) were calculated under different possible genetic models.A total of eight case-control studies were included in the present meta-analysis. The results demonstrated significant association of RA with TIM-3 rs1036199 polymorphism under dominant  and allelic models . None of the other examined polymorphisms indicated significant association with RA.The present meta-analysis revealed that the TIM-3 rs1036199 polymorphism might confer susceptibility to RA. Further studies are required to reassert our findings. Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive inflammation of the synovial membrane of the joint capsule and tendons (synovitis). Clinical manifestations range from chronic pain, loss of joint function, and deformity, to disability and systemic complications , 2. RA uThe transmembrane immunoglobulin and mucin domain (TIM) family gene was first isolated in 2001 . This noTIM-family proteins belong to the type I transmembrane proteins consisting the N-terminal immunoglobulin (Ig) domain of the variable type, a mucin-like domain, and a C-terminal cytoplasmic tail , 16. TheSeveral studies have investigated the association between RA and TIM family gene polymorphisms. The results are, however, not conclusive. To our knowledge, no meta-analysis has evaluated the association between RA and TIM gene polymorphisms. Therefore the present meta-analysis was conducted to address the issue whether the TIM family gene polymorphisms affect susceptibility to RA.The present meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement  and metaWe searched the Scopus, PubMed, and Web of Science databases through December 2018 by combining the following search terms:  AND (“Hepatitis A virus cellular receptor-1” OR HAVCR-1 OR “T-cell immunoglobulin and mucin domain containing -1” OR TIM-1 OR “Kidney Injury Molecule -1” OR KIM-1 OR “Hepatitis A virus cellular receptor-2” OR HAVCR-2 OR “T-cell immunoglobulin and mucin domain containing -3” OR TIM-3 OR “T-cell immunoglobulin and mucin domain containing-4” OR TIM-4) AND (polymorphism OR genotype OR SNP OR “single nucleotide polymorphisms”). Studies were considered eligible if they investigated the association between RA and the following TIM family gene polymorphisms: rs41297579, rs1036199, rs10515746, and rs7700944. Further, we performed hand-searching of bibliographies from relevant publications to identify potential studies that were not retrieved by the electronic search. The search strategy was not confined to English language articles and any time period.After removing duplicate records, two authors independently screened search results based on title and/or abstract. Then the apparently relevant papers were selected for detailed review. Finally, the authors carefully considered inclusion and exclusion criteria to include or exclude studies. Any disagreement between reviewers were resolved by consensus.Eligible studies should satisfy the following inclusion criteria: a) case–control studies that investigated the association between RA and the aforementioned TIM family gene polymorphism; and b) adequate data including genotype/allele frequency in both case and control groups were provided to calculate the combined odds ratio (OR) and their corresponding 95% confidence intervals (CIs). Book chapters, review articles, duplicate reports, conference abstracts, studies lacking control group, letters to the editor, case reports, and animal studies were all excluded.Two authors independently extracted the following data from each eligible study: the first author’s name, journal’s name, year of publication, ethnicity, country of origin, gender, study design, age of participants, methodology of genotyping, number of genotyped cases and controls, and genotype/allele frequency for in cases and controls. Genotype data were extracted for each ethnic group of people separately if data were available. Any disagreement between two reviewers were discussed and resolved by consensus. To assess the methodological quality of included studies, the Newcastle-Ottawa Scale (NOS) was used . Studiesp value less than 0.1. If heterogeneity was detected, the random-effects model (Der Simonian–Laird approach) was applied. Otherwise, the fixed-effects model (Mantel–Haenszel approach) was used. Publication bias was assessed using the degree of funnel plot asymmetry and also by Begg’s test  [Deviation from Hardy-Weinberg equilibrium (HWE) was analyzed using the Chi-Square test in control groups . For eacificant) , 35. TheAs shown in The TIM-3 rs1036199 polymorphism was demonstrated to associate with RA risk under dominant model  and allelic model  . Due to The pooled results rejected any association between TIM-3 rs10515746 polymorphism and RA under dominant model , allelic model , and GT vs. GG model  . SimilarNo significant association was found between this polymorphism and RA: dominant model , recessive model , allelic model , AA vs. GG model , and GA vs. GG model  .p = 0.24), allelic model (I2 = 95.6%), AA vs GG model (I2 = 91.7%), and GA vs GG model (I2 = 97.1%). Also significant heterogeneity was observed across studies included in the three genetic models applicable for TIM-3 rs10515746: dominant model (I2 = 84.1%), allelic model (I2 = 84%), and GT vs GG model (I2 = 82%). No significant heterogeneity was detected among studies included in the meta-analyses related to other investigated SNPs. As shown in For the TIM-4 rs7700944 polymorphism, there was a significant heterogeneity across included studies under all genetic models, except for recessive model: dominant model (I2 = 97%), recessive model  or anti-citrullinated protein antibodies (ACPAs) . It shouThe TIM1−1454G>A polymorphism occurs in promoter region and therefore it is not expected to affect the function of TIM1 protein. Interestingly, Chae and colleagues reported that neither RF nor CRP were detectable in the sera of patients carrying this polymorphism .The results showed significant association between TIM-3 G>T (+4259) and RA. The human TIM-3 gene coding region is consisted of seven exons. Among the various polymorphisms linked to this gene, the G>T (+4259) is the only SNP that occurs in the exon zone (exon 3). The change of allele at 4259 G>T leads to amino acid substitution from arginine to leucine. Arginine is an ionic amino acid whereas leucine is a non-polarized amino acid. Therefore the 4259 G>T polymorphism might alter the structure and function of gene. More interestingly, the TIM-3 protein is expressed on the surface of Th1 cells that serve to regulate Th1 and Th17 cell differentiation and their respective immune responses. Thus, the TIM-3 G>T (+4259) polymorphism might disturb the balance between Th1 and Th2 cell responses and thereby confer susceptibility to asthma and autoimmune diseases such as RA. Of note, Chae et al observed higher CRP values in the sera of patients harboring TIM1 +4259G>T variant .The SNP rs7700944 is located in the intron region of the TIM-4 gene. The intron regions are comprised of noncoding DNA sequences which lie between coding regions in the genome. The intron regions play important role in the regulation and evolution of gene and control of alternative splicing in human genome. Evidences link polymorphisms that occur in the intron region of genes with different human diseases. For example, IL-1ß +3954 is an intronic polymorphism that has been associated with susceptibility to RA in a Chinese population . After aAlthough the present study was designed in a systematic manner to include all the eligible studies, there are some limitations to be mentioned. First is the concern about few number of included studies, because of which sensitivity and subgroup meta-analyses of studies stratified by sex, ethnicity, and methodology of genotyping could not be performed. Second that most of the included studies were conducted in East-Asians and so the findings are not generalizable to other race/ethnic groups. Third that our meta-analyses were confined to certain SNPs of TIM gene family due to inadequate numbers of publications.In sum, the current meta-analysis provided evidence that TIM-3 G>T (+4259) gene polymorphism might increase the risk of RA. The analyses, however, failed to found significant association between RA and other polymorphisms of TIM family genes. Further studies with larger sample sizes across different race/ethnic groups are warranted to validate the findings.S1 Fig(TIFF)Click here for additional data file.S2 Fig(TIFF)Click here for additional data file.S3 Fig(TIFF)Click here for additional data file.S4 Fig(TIFF)Click here for additional data file.S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file.


Background. The results of previous studies on the association between polymorphisms of CYP1A1 and CYP1B1 and prostate cancer (PCa) susceptibility are inconsistent. The aim of the present study was to conduct a meta-analysis in order to better estimate this association. Methods. A systematic search was carried out on PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases for relevant articles published up to 15 August 2018. Pooled odds ratios (ORs) and 95% confidence intervals were obtained using fixed-effect or random-effect models. Results. A significant association was found between the CYP1A1 rs1048943 polymorphism and PCa in the overall population  = 1.04–1.39, P=0.014; AB vs. AA: OR = 1.24, 95% CI = 1.02–1.51, P=0.029; BB + AB vs. AA: OR = 1.25, 95% CI = 1.04–1.50, P=0.018) and Asian population , but not in the Caucasian population. Moreover, we found that the rs4646903 polymorphism was associated with a significant increase in the risk of PCa in the Asian population  and Caucasian population . Conclusion. This meta-analysis revealed a clear association between rs1048943 and rs4646903 polymorphisms of the CYP1A1 gene but not between CYP1B1 rs10012, rs162549, rs1800440, and rs2551188 polymorphisms and the risk of PCa. Prostate cancer (PCa) is the most common malignant tumor of the urinary system in men in the western world, the second most frequent cancer and the fifth leading cause of tumor-related deaths worldwide ,2. GlobaA single nucleotide polymorphism (SNP) is a single nucleotide variation at the genomic level, which can appear in coding or non-coding sequences. In recent years, third-generation genetic markers have attracted a lot of attention for their potential role in predicting cancer susceptibility. A number of genes including those encoding the androgen receptor (AR), prostate-specific antigen (PSA), 5a-reductase type II (SRD5A2), and cytochrome P450 (CYP) have been confirmed as PCa susceptibility genes . TokizanPrevious meta-analyses investigating the relationship between CYP1A1 and CYP1B1 polymorphisms and the risk of PCa reported inconsistent results. Cui et al.  did not The PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were systematically searched independently by two authors (W.Z. and H.L.) on 15 August 2018 to retrieve eligible articles. The search terms included: ‘cytochrome P450 1A1’, ‘cytochrome P450 1B1’, ‘CYP1A1’, ‘CYP1B1’, ‘prostate cancer’, ‘PCa’, ‘PC’, ‘gene’, ‘polymorphism’, ‘allele’ and ‘variation’. In addition, reference lists of the retrieved papers were manually reviewed to obtain additional studies that met the inclusion criteria.Studies selected for the meta-analysis had to meet the following inclusion criteria: (i) the study investigated the association between CYP1A1, CYP1B1 polymorphism, and risk of PCa, (ii) the design was a case–control study, (iii) sufficient data were reported to determine the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs), and (iv) the full text was published. Meta-analyses, letters, single-case reports, duplicate studies, animal model studies, and studies without available data were excluded.Two authors (W.Z. and X.W.) independently extracted the available data from included papers, and any disagreements were resolved by the third investigator (J.L.). The following information was extracted and recorded: author, year of publication, ethnicity of subjects , the name of gene, the names of SNPs, genotyping method , source of controls , total numbers of cases and controls, and the Newcastle–Ottawa Scale (NOS). Studies which investigated more than one kind of SNP were counted as individual data for the present meta-analysis. The quality of all included studies was assessed independently by the three researchers using the validated NOS, and disagreements were resolved through discussion with another researcher (H.Z.). Studies with scores of >6 were considered as high-quality studies, and those with scores of ≤6 as low-quality studies.Q-test: I2 ≥ 50% or P≤0.05) between studies, a random-effect model was used for analysis; otherwise, a fixed-effect model would be chosen [We utilized Stata 12.0 software  to conduct the meta-analysis and estimate heterogeneity between the included studies. ORs and 95% confidence intervals (CIs) were used to assess any associations between CYP1A1 and CYP1B1 polymorphisms and the risk of PCa. The pooled ORs were calculated in BB vs. AA , BB + AB vs. AA, BB vs. AB + AA, B vs. A, and AB vs. AA genetic models using either the fixed-effects model or the random-effect model. In case of significant heterogeneity . Meanwhile, no association was evident when examining BB vs. AA and BB vs. AA + AB .Overall, analysis of the association between the rs1048943 polymorphism and PCa from nine independent studies revealed no significant heterogeneity by a fixed-effect model. The results, however, showed a significant association between the rs1048943 polymorphism and PCa after comparing the B allele vs. A allele, AB vs. AA and BB + AB vs. AA .The P=0.405; BB + AB vs. AA, OR = 0.97, 95% CI = 0.63–1.49, P=0.883).In the Caucasian population, significant between-study heterogeneity was found when comparing BB vs. AA, AB vs. AA, BB vs. AA + AB by the random-effect model. There was no significant heterogeneity for B allele vs. A allele or BB + AB vs. AA models, and the results showed no association of the rs1048943 polymorphism with PCa susceptibility .Overall, significant between-study heterogeneity was detected for most of the genetic models, except for the BB vs. AA and BB vs. AA + AB models. Fixed-effect model analysis of these two genetic models indicated no significant association , which was not evident when comparing BB vs. AA  or BB vs. AA + AB .In the Asian populations, there was significant between-study heterogeneity in the B allele vs. A allele and BB + AB vs. AA models, and the results showed an association between rs4646903 and PCa when comparing AB vs. AA . Comparing BB vs. AA + AB, however, indicated no association .In the Caucasian populations, significant between-study heterogeneity was found in the B allele vs. A allele, AB vs. AA, and BB + AB vs. AA models. There was a significant association between rs4646903 and PCa when comparing BB vs. AA .Except for AB vs. AA in the overall population, significant between-study heterogeneity was found in all other genetic models. However, the association between the CYP1B1 gene rs1056836 polymorphism and risk of PCa was not significant .The meta-analysis for associations between the rs10012, rs162549, rs1056827, rs1056837, rs1800440, rs2551188, and rs2567206 polymorphisms and PCa risk in the overall population included three, two, five, two, four, four, and four independent studies, respectively. Due to significant between-study heterogeneity indicated by the t = −2.95, P=0.021; BB + AB vs. AA: t = −3.53, P=0.010) and in the Asian populations . Egger’s publication bias plots and Funnel plots for positive results are shown in Egger’s linear regression test was used to evaluate any publication bias by funnel plot asymmetry . The intIn recent years, genetic susceptibility to cancer has been a hotspot of research in the scientific community. Emerging evidence has demonstrated the potential association between gene polymorphisms and cancer risk, particularly in the CYP1 family including CYP1A1 and CYP1B1. For instance, CYP1A1 polymorphisms are known to be associated with susceptibility to a wide variety of cancers including lung , bladderThe present study provides a systematic analysis of all available case–control studies on the CYP1A1 rs1048943 and rs4646903; and CYP1B1 rs1056836, rs10012, rs162549, rs1056827, rs1056837, rs1800440, rs2551188, and rs2567206 polymorphisms and the risk of PCa. Previously, no significant associations have been found between the CYP1B1 rs10012, rs162549, rs1800440, and rs2551188 polymorphisms and PCa risk in the overall population. A possible explanation is that PCa is a multigenic disease, and the effect of a single polymorphism may therefore be limited. On the other hand, our study demonstrated that the rs1048943 polymorphism was associated with PCa susceptibility in the overall population. Results were similar in the Asian populations; however, no effect was detectable in men of Caucasian descent. Furthermore, our meta-analysis provided evidence that the rs4646903 polymorphism in the AB genotype compared with AA, and BB genotype compared with AA were considered as risk factors for PCa in Asian and Caucasian populations, respectively. However, the CYP1A1 rs4646903 polymorphism was not associated with an increased risk of PCa overall. The effect of polymorphisms on PCa susceptibility is influenced by ethnicity. Data from the National Central for Biotechnology Information (NCBI) show that the B allele  of rs4646903 is present in 34.0% of the Asian population, 10.7% of the Caucasian population, and 23.4% of the African-American population. However, African Americans are reported to have the highest incidence of PCa, which not only emphasizes the racial background of the disease , but alsA meta-analysis performed by Zhang et al.  showed tBetween-study heterogeneity is one of the pivotal issues affecting the results of the present meta-analysis. Subgroup analysis based on ethnic groups revealed a decrease in the heterogeneity amongst studies. These results indicate that ethnic subgroups contribute significantly to the high heterogeneity observed in our analysis. Due to the limited studies of hospital-based controls and genotyping methods other than PCR-RFLP, we were unable to conduct subgroup analysis based on the source of the controls and genotyping methods. However, their impact on heterogeneity should not be ignored. It is well known that using different detection methods to determine genotypes increases the heterogeneity between studies. Therefore, additional studies with different sources of control groups and genetic methods are still necessary in order to assess the impact of these polymorphisms on PCa risk. Studies that include hospital-based control groups and genotyping methods other than PCR-RFLP such as AS-PCR, Taqman, and Genechips are particularly important. Publication bias was observed in some comparisons of the present meta-analysis, which may be because the present study only included English and Chinese publications, possibly resulting in selective bias.There are several potential limitations of this meta-analysis that should be considered. First, patients with benign prostatic hyperplasia (BPH) were enrolled as controls in our study, which may have an effect on the final results. Second, accurate determination of the association between the CYP1B1 rs1056836 polymorphism and the risk of PCa was not possible due to significant heterogeneity in the overall, Caucasian, and Asian populations. Third, our results were based on unadjusted estimates. A more reliable estimate could have been achieved if individual data such as age and other environmental factors were available.To summarize, this meta-analysis suggests that the CYP1A1 rs1048943 and rs4646903 polymorphisms are associated with PCa risk, especially in the Asian and Caucasian populations, respectively. No significant associations were detected for the CYP1B1 rs10012, rs162549, rs1800440, or rs2551188 polymorphisms. Larger studies are necessary to verify our findings and elucidate the exact association between CYP1A1 and CYP1B1 polymorphisms and susceptibility to PCa.


Geriatric Nutritional Risk Index (GNRI) has been widely used to assess the nutritional status in a variety of human pathological conditions, but the prognostic value of the GNRI in malignancies has not been evinced.  Relevant studies updated on Jul 27, 2019, were retrieved in available databases, including PubMed, Web of Science, Cochrane library, Chinese CNKI, and Chinese Wan-fang. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled by using STATA 14. p ≤ 0.001), poor CSS , poor DFS , and poor PFS , and the correlation of GNRI with OS was not changed when stratified by possible confounding factors, suggesting that malignancy patients with low GNRI would suffer from reduced survival rate and increased recurrence rate. Moreover, low GNRI was also associated with postoperative complications in malignancies.  A total of 15 studies involving 8,046 subjects were included in this meta-analysis. Meta-analysis results evinced that low GNRI was associated with poor OS (HR = 1.95, 95% CI: 1.49-2.56,  In summary, GNRI is associated poor prognosis in human malignancies, and GNRI should be used as a predictive indicator of adverse outcomes during malignancy treatment. In 2005, Bouillanne et al. created a new index of malnutrition, called the Geriatric Nutritional Risk Index (GNRI), which is based on three parameters: height, body weight, and serum albumin level. The GNRI was calculated as follows: [1.489 × albumin (g/L)] + [41.7 × ]. The ratio of body weight to ideal body weight was set to 1 when the patient's body weight exceeded the ideal body weight , all-cauMalnutrition is a common problem among cancer patients, and cancer-associated malnutrition is associated with increased morbidity and mortality . MeanwhiHowever, the prognostic significance of GNRI on human malignancies has not been thoroughly clarified. Therefore, this meta-analysis was conducted to verify the prognostic role of GNRI in human malignancies based on available evidence.PubMed, Web of Science, Cochrane library, Chinese CNKI, and Chinese Wan-fang. We used the following search words: “Geriatric Nutritional Risk Index,” “GNRI,” and “cancer,” “carcinoma,” “leukemia,” and “lymphoma.” The search strategy in Cochrane was “Geriatric Nutritional Risk Index in Abstract OR GNRI in Abstract.” The search strategy in PubMed was “ OR GNRI[Title/Abstract].” The search strategy in Web of Science was “TS=.” The reference lists of retrieved literatures were also screened to identify more potential studies.Our literature search strategy was performed according to the preferred reporting items for systemic reviews and meta-analysis (PRISMA) statement criteria . We retrStudies included in this meta-analysis were required to meet all of the following criteria: (1) reporting the prognostic role of the GNRI in human malignancy; (2) analyzing prognostic outcomes, including overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), or progression-free survival (PFS); and (3) providing the hazard ratio (HR) and 95% its confidence interval (CI) for prognosis . The studies were excluded if they met any of the following items: (1) case report, (2) review article, (3) redundant publication, and (4) HR and 95% CI unacquirable.st author information, publication year, patient country, cancer species, sample capacity, dividing line for GNRI, HR origin, analytic methodology, and follow-up interval. For studies based on the same study center, we collected data from the study with the largest sample size. Here, we declared that the data extraction method in this part was nearly the same as that used in our team's previously published meta-analysis researches.This procedure was conducted by two authors (Da-wei Sun and Lin An), and disagreements were resolved by consensus among all the participating authors. The hazard ratios (HRs) and 95% confidence intervals (CIs) for prognosis were our main concern. When the prognostic results were provided in the Kaplan-Meier curve, Engauge Digitizer 4.1 was used to read and calculate the number of death/recurrence in each group. Then according to the total numbers of observed deaths/recurrences and the number of samples in each group, we calculated the HR and 95% CI by following Tierney et al.'s method . The othI2 were used to check the interstudy heterogeneity, with significance set at p < 0.1 or I2 > 50%. A random effects model was employed in case of significant heterogeneity; otherwise, a fixed effects model was applied. Publication bias was examined by both Begg's and Egger's tests [p value < 0.05 was considered significant. Meanwhile, we performed a sensitivity analysis by removing each study to evaluate the effect of an individual study on the overall pooled HRs. Here, we also declared that the statistics analysis method in this part was nearly the same as that used in our team's previously published meta-analysis researches.Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare the prognostic outcomes, including OS, CSS, DFS, and PFS. Chi-square test and 's tests , 14. In I2 = 84.2%, p ≤ 0.001), the GNRI was significantly associated with OS   with 3,023 cases. On the basis of random effects model (≤ 0.001) . As a reI2 = 14.4%, p = 0.322), the GNRI was also significantly relevant to CSS  (Five studies (including one study consisting of two subcohorts) with 5,743 cases reported the prognostic role of GNRI for CSS. According to a fixed effects model (≤ 0.001) . That isI2 = 70.5%, p = 0.002) evinced that GNRI was also significantly correlated with DFS  (The correlation of the GNRI with DFS was available in 6 studies (including one study consisting of two subcohorts) with 5,625 cases. Meta-analysis results from a random effects model (≤ 0.001) . That isI2 = 50.8%, p = 0.154); thus, a random effects model was adopted to perform this meta-analysis. Meta-analysis results evinced that low GNRI was associated with PFS  (The association between GNRI and PFS was investigated by only 2 studies with 725 cases. Heterogeneity could be identified among these 2 studies (≤ 0.001) , suggestConsidering that more than ten studies were included in the meta-analysis with OS and heterogeneity was identified in this meta-analysis result, thus, stratification analysis was conducted in this process. As shown in To examine the robustness of our results, sensitivity analysis was performed by removing each individual included study. Omitting any of the included studies did not change the combined meta-analysis effect of GNRI on the HRs for OS, CSS, DFS, or PFS Figures . That isp = 0.155), but publication bias was found by Egger's test (p ≤ 0.05). Publication bias was not examined in the other meta-analysis, since the included study number was less than ten.For the meta-analysis with OS, no publication bias was found by Begg's test  after abdominal surgery , 32. AddThe obvious limitation for our meta-analysis is heterogeneity, especially in the meta-analysis with OS and DFS. However, no heterogeneity could be found in the subgroup meta-analysis using the studies defined by study sample size < 240, GNRI value < 98, HR source from crude origin, or multivariate analysis. Due to the small number of included studies in the meta-analysis with DFS, stratified analysis was not conducted in this part. The minor limitation for our meta-analysis is publication bias, which was found in the meta-analysis with OS. Nevertheless, the combined meta-analysis effect of GNRI on the HRs for OS, CSS, DFS, and PFS was not altered during the sensitivity analysis. Finally, we must declare that the data extraction, statistics analysis, and stratified analysis methods used in this research were nearly the same as those used in our team's previously published meta-analysis researches , 35. TheIn summary, GNRI is associated with poor prognosis in human malignancies, and GNRI should be used as a predictive indicator of adverse outcomes during malignancy treatment.


Resting-state functional magnetic resonance imaging (RS-fMRI) has frequently been used to investigate local spontaneous brain activity in Parkinson's disease (PD) in a whole-brain, voxel-wise manner. To quantitatively integrate these studies, we conducted a coordinate-based (CB) meta-analysis using the signed differential mapping method on 15 studies that used amplitude of low-frequency fluctuation (ALFF) and 11 studies that used regional homogeneity (ReHo). All ALFF and ReHo studies compared PD patients with healthy controls. We also performed a validation RS-fMRI study of ALFF and ReHo in a frequency-dependent manner for a novel dataset consisting of 49 PD and 49 healthy controls.Decreased ALFF was found in the left putamen in PD by meta-analysis. This finding was replicated in our independent validation dataset in the 0.027–0.073 Hz band but not in the conventional frequency band of 0.01–0.08 Hz.Findings from the current study suggested that decreased ALFF in the putamen of PD patients is the most consistent finding. RS-fMRI is a promising technique for the precise localization of abnormal spontaneous activity in PD. However, more frequency-dependent studies using the same analytical methods are needed to replicate these results.Trial registration: NCT NCT03439163. Registered 20 February 2018, retrospectively registered. Parkinson's disease (PD) is a progressive neurological degenerative disorder that is characterized by bradykinesia, rigidity, tremor, and postural instability. The main pathological feature of PD is the progressive loss of dopamine neurons in the substantia nigra and putamen . HoweverWhile task-related fMRI holds the advantage of being able to assess specific activation corresponding to specific tasks, different tasks activate different brain regions and hence the results are less suitable for meta-analysis. Resting-state (RS) fMRI has two intrinsic advantages: it is noninvasive and task free. Task-free RS is a simpler experimental design for PD investigation. Therefore, RS-fMRI design is very similar across studies, and is more suitable for meta-analysis. There have been three published CB meta-analysis investigations of RS-fMRI studies in PD . The CB Frequency-dependent or subfrequency band analysis is drawing more and more attention in RS-fMRI studies since the work by Zuo and colleagues . They obIn the current study, we carried out a CB meta-analysis on previous PD resting-state fMRI studies using ALFF/fALFF and ReHo separately, similar to previous meta-analysis , 5. HoweIt should be noted that both ALFF and ReHo are metrics for measuring local activity. Both methods have been widely used in studies on brain disorders in whole-brain voxel-wise analysis. A study showed that ReHo and ALFF could reveal convergent abnormal local activity in some brain areas , but ReHt value, and sample size. These data were extracted from published articles that used RS-fMRI in PD. Part 2 was for validation purposes and used RS-fMRI data from 80 patients with PD and 52 healthy participants. After quality control , 49 patients with PD and 49 healthy participants were entered into the final analysis. All data in the current study can be used for further validation and exploratory studies.The data for the current study included two parts. Part 1 was for a CB meta-analysis including coordinates, On 28 June 2017, we conducted a PubMed literature search  using thWe also reviewed articles and references to retrieve additional articles. An additional study, using the Kendall coefficient of concordance (KCC) method, was included in the current meta-analysis after carefully reviewing a recent publication of meta-analysis  because t-values from each study; using the files prepared in i) to recreate the effect-size maps (standard stereotactic space) of the original studies with 10 Monte Carlo randomizations and full-width at half maximum (FWHM) 20 mm; and generating the mean map in a voxel-wise manner weighted by the sample size, variance, and between-study heterogeneity. A combined threshold of P < 0.001  with peak height Z value >1 was adopted as recommended in the SDM, together with extent threshold >10 voxels  9) in PD patients. In addition, decreased ReHo was observed in the right putamen and right precentral gyrus (BA 6) in PD patients Fig. , Table 5In the meta-analysis of SDM for combination of ALFF and ReHo, increased spontaneous brain activities in PD patients compared with controls were found in the right inferior temporal gyrus and right brain stem. Decreased spontaneous brain activities were found in the left pallidum/putamen and the right insula (BA 47) Fig. , Table 5Compared with healthy controls, PD patients had decreased ALFF in the bilateral putamen and right fusiform at 0.027–0.073 Hz Fig. , Table 6Using the SDM meta-analysis, we detected some characteristic PD-related neural changes in the resting state. For example, there was altered local activity in the putamen and the pre-SMA. A finding of decreased ALFF in the left putamen from our validation study was very consistent with the results of our CB meta-analysis, which was also consistent with findings from a previous CB meta-analysis . The incCompared with positron emission tomography, RS-fMRI has the advantages of lower cost, better temporal resolution, and no ionizing radiation. Since 2009 when the first PD RS-fMRI article was published , approxiALFF measures the amplitude of fluctuation of every single voxel, while ReHo measures the local synchronization of the nearest neighboring voxels. The two metrics are the two most widely used methods for depicting local activity . Also, i18F-dopa uptake in putamen in PD is associated with the clinical severity of locomotor disability, and 18F-dopa reduction in putamen is associated is associated with the degree of rigidity and bradykinesia [There was decreased ALFF in the left putamen in PD patients in both our validation dataset and CB meta-analysis investigation. These findings align with previous findings that the striatal dysfunction in PD has been consistently reported in previous studies . It has ykinesia , 71. A rykinesia . NotablyThere was decreased ReHo in the right putamen in PD patients in both our CB meta-analysis and a previous CB meta-analysis . Howevert maps is better than coordinate-based meta-analysis [A few limitations should be addressed. First, it has been proposed that at least 20 experiments should be included in a meta-analysis . Althouganalysis . We sugganalysis . It shouWe performed a CB meta-analysis of local activity using RS-fMRI in PD patients and healthy controls and also a validation study using a novel dataset in a frequency-dependent manner. The most consistent result was abnormal ALFF in the left putamen, as evidenced by decreased ALFF in the CB meta-analysis and decreased ALFF of PD in our independent dataset. However, owing to the limited number of original studies that were suitable for CB meta-analysis, our results need to be further validated.The consistent finding in the current study is the abnormally decreased ALFF in the left putamen. The precise localization of abnormal brain activity is helpful to identify new targets of focused stimulation, such as deep brain stimulation, transcranial magnetic stimulation, and focused ultrasound stimulation.GigaScience GigaDB repository [The datasets supporting the results of this article are available in the NeuroImaging Tool & Resources Collaboratory (NITRC) repository, as “PD RS-fMRI meta and validation” , and in pository .ALFF: amplitude of low frequency fluctuation; BA: Brodmann area; CB: coordinate based; fALFF: fractional amplitude of low frequency fluctuation; FDR: false discovery rate; fMRI: functional magnetic resonance imaging; FWHM: full-width at half maximum; KCC: Kendall coefficient of concordance; PD: Parkinson's disease; ReHo: regional homogeneity; RS: resting state; SDM: signed differential mapping; SMA: supplementary motor area;The present investigation was performed according to the Declaration of Helsinki and was approved by the Medical Research Ethics Committee at Xuanwu Hospital, Capital Medical University. All participants gave written informed consent prior to participation.GigaScience. All remaining authors have no competing interests.Y.-F.Z. is an Editorial Board Member of This study was supported by the National Natural Science Foundation of China , the Ministry of Science and Technology (2016YFC1306503 to T.W.), and the Beijing Municipal Commission of Health and Family Planning (PXM 2017_026283_000002 to T.W.).Experimental design: all authors; data collection: J.W., J.R.Z., TW; data analyses: all authors; and writing the article: J.W., Y.F.Z., and T.W.GIGA-D-18-00065_Original_Submission.pdfClick here for additional data file.Reviewer_1_Report_ -- Alejandro De La Vega03/24/2018 ReviewedClick here for additional data file.Reviewer_2_Report_ -- Michael Riedel04/09/2018 ReviewedClick here for additional data file.


AXIN2 variants on overall cancer risks; however, the available results remain inconsistent.Many epidemiological studies have investigated association of AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G polymorphisms and cancer risk. We also used in silico tools to assess the effect of AXIN2 expression on cancer susceptibility and overall survival time.An updated analysis was conducted to ascertain a more accurate estimation of the correlation between AXIN2 148 C/T variant was associated with cancer risk , especially for lung and prostate adenocarcinoma. Similar results were observed in 1365 C/T polymorphism . Moreover, in subgroup analysis by ethnicity, similar findings were obtained for Asian and Caucasian populations. Results from in silico tools suggested that AXIN2 expressions in lung adenocarcinoma were lower than that in normal group.A total of 4281 cases and 3955 control participants were studied. The overall results indicated that AXIN2 148 C/T and 1365 C/T variants may be associated with decreased cancer susceptibility.Our findings indicated that  Cancer is considered as a multifactorial disease and its occurrence is associated with several factors such as lifestyle, environment and single nucleotide polymorphism (SNP) –3. With r (VEGF) , 13.AXIN2 gene has been identified by previous genotyping technologies. This gene is located on human chromosome 17q23-q24 and composed of 10 exons, which encodes a protein consisting of 843 amino acids [AXIN2 polymorphisms and cancer risk among different case–control studies.Mutations of no acids . Loss ofno acids –18. Assono acids –24. Studno acids –27. ThesAXIN2 148 C>T polymorphism, a case–control study observed no statistically significant correlation between controls and prostate adenocarcinoma in Turkish population [AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G polymorphisms and cancer risk [For pulation . Howeverpulation , 22. Thecer risk –33.AXIN2 variants and cancer susceptibility. The following terms were utilized for searching abstracts and titles: “Axin OR AXIN2”, “polymorphism OR SNP OR variant”, and “cancer OR adenocarcinoma OR carcinoma OR tumor”. The latest search was conducted on Jan 31, 2019 with no language restrictions. Furthermore, we also carefully screened and manually searched the review or original publications for more eligible studies.PubMed, Web of Science, Google Scholar, and China Wanfang Databases were systematically searched to identify all eligible published articles on AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G variants and cancer risk; (b) studies that involved available information for measuring odds ratio (OR) with 95% confidence intervals (CIs); (c) genotype distribution in controls must be conformed to Hardy-Weinberg equilibrium (HWE).Two authors independently chose the eligible studies based on the inclusion criteria: (a) case–control studies that evaluated the association between P value for HWE, age range, genotyping data of AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G variants in cases and controls. Disagreement should be resolved by discussion with a third author (W Zhang). If the controversial content still existed, it should be addressed by all investigators to reach a consensus.All related information was independently screened by two investigators (L Shi and B Xu) from each enrolled study, including the name of first author, year of publication, country of origin, ethnicity, source of control, genotyping method, cancer type, total number of participants, AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G polymorphisms and cancer susceptibility was measured by calculating OR with 95% CI. A total of four genetic models were adopted in the current analysis, including allelic comparison model , homozygote contrast model (MM vs. WW), heterozygote model (MW vs. WW), and dominant model (MM + MW vs. WW). The χ2-test-based Q test was performed to investigate P value for heterogeneity among eligible researches. If P < 0.05, indicating that a significant heterogeneity was found, we employed the random-effects model (DerSimonian–Laird method) [http://ihg2.helmholtz-muenchen.de/cgibin/hw/hwa1.pl) [P value more than 0.05 suggested an HWE balance. Moreover, we applied leave-one-out sensitivity analyses to calculate the stability of pooled results [The strength of the relationship between  method) . On the  method) . We adophwa1.pl) . The P v results . All of AXIN2 expression in lung and prostate adenocarcinoma tissues and the paracancerous tissues. (http://gemini.cancer-pku.cn/) [AXIN2 on cancer susceptibility and overall survival time. Moreover, the String online server was applied to assess the gene–gene correlation of AXIN2 (http://string-db.org/).An online gene expression database was adopted to investigate the pku.cn/) . RNA expAXIN2 148 C/T, 1365 C/T, and rs4791171 A/G variants. There were 2909 cancer subjects and 2907 control volunteers for 148 C/T polymorphism, 587 cancer subjects and 605 controls for 1365 C/T variant, 785 cases and 443 controls for rs4791171 A/G variant. Furthermore, we checked the minor allele frequencies (MAF) of three AXIN2 variants by Trans-Omics for Precision Medicine (TOPMed) online (https://www.ncbi.nlm.nih.gov/snp/) , 0.470; Global, 0.474. MAF of AXIN2 1365 C/T were: in Africans, 0.069; East Asians, 0.192; Europeans, 0.114; Americans, 0.100; others, 0.090; Global, 0.104. Finally, MAF of AXIN2 rs4791171 A/G were: in Africans, 0.267; East Asians, 0.370; Europeans, 0.681; Americans, 0.620; others, 0.670; Global, 0.547. In stratified analysis by ethnicity, seven studies were performed in Caucasian populations, twelve studies were in Asian descendants, and two were done in Arabians and one was in Latin descendants. Eight studies were conducted using population based controls and the rest 14 studies were utilizing hospital based controls. The classical genotyping method, PCR-restriction fragment length polymorphism (RFLP) was adopted in nine of these studies.As was shown in Table AXIN2 148 C/T variant and cancer risk   and Caucasians , . In subgroup analysis by source of control, similar results were also observed in population-based studies. Furthermore, we identified notable correlation between AXIN2 1365 C/T variant and cancer risk . For rs4791171 A/G polymorphism, no significant association was indicated .In the overall analysis, we identified a significant correlation between AXIN2 expression in normal group was higher than that in lung adenocarcinoma tissue , AXIN2 1365 C/T variant  and rs4791171 A/G polymorphism . As shown in Fig. Egger’s test and Begg’s funnel plot were utilized to evaluate publication bias in all of enrolled studies. We demonstrated no publication bias for AXIN2 rs2240308 variant may increase the risk of cancer, especially lung cancer in Asian descendants [To date, large quantities of studies have been conducted to explore whether the variants confer individual’s susceptibility to carcinoma. However, results from the previous publications have yielded controversial results , 22. A pcendants . The oveAXIN2 148 C/T variant was associated with decreased cancer risk, especially for lung and prostate adenocarcinoma, which is in line with conclusions identified by Kanzaki et al. Liu et al. and Gune et al. [AXIN2 1365 C/T polymorphism . Moreover, in subgroup analysis by ethnicity, positive findings were obtained for Asian and Caucasian populations. In the stratified analysis by source of control, similar findings were identified in population-based studies for AXIN2 148 C/T variant, which is consistent with the findings reported by Yu et al. [AXIN2 expressions in lung cancer and prostate cancer are lower than that in normal counterpart. High expression of AXIN2 may have longer OS time than low expression group for lung cancer participants, which were consistent with results derived from the present meta-analysis. Nevertheless, we indicated no significant difference between the high expression and low/medium expression of AXIN2 in prostate cancer patients.In the current study, a total of 4281 cases and 3955 control participants were investigated. The overall results showed evidence that e et al. , 26, 28.u et al. . MoreoveAXIN2 1365 C/T and rs4791171 A/G variants. Four articles towards AXIN2 1365 C/T and three articles for rs4791171 A/G polymorphism were eligible based on the selection criteria. Secondly, insufficient original data from the raw articles limited further evaluation of potential interactions, including relationship between the AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G variants and different tumor grade and stage. Thirdly, meta-analysis was based on unadjusted estimates, which may lead to serious confounding bias. Furthermore, gene–gene interaction would also participate in etiological mechanism of carcinoma. As shown in Fig. AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G variants with overall cancer susceptibility is statistically more powerful than single case–control study. All the studies according to the inclusion criteria were accumulated in our analysis. Secondly, genotype distribution of controls is conformed to Hardy–Weinberg equilibrium (HWE) in any of the enrolled studies and no significant publication bias was found, which indicated that conclusions of the present analysis are relatively trustworthy.Some limitations of the above analysis should be mentioned. Firstly, the numbers of enrolled articles in the current analysis were still not large enough for the comprehensive analysis, especially for AXIN2 148 C/T and 1365 C/T variants may be associated with decreased cancer susceptibility, especially for lung and prostate adenocarcinoma. Future large scale studies with standardized unbiased cases and well-matched control subjects are needed to ascertain these finding in more detail.Taken together, the current study showed evidence that


XRCC1, XRCC3, and ERCC2 gene polymorphism and prognosis have been investigated in several cancers. The aim of this meta-analysis was to assess the prognostic value of XRCC1, XRCC3, and ERCC2 gene polymorphism in hepatocellular carcinoma (HCC). Associations between XRCC1, XRCC3, and ERCC2 polymorphisms in HCC were estimated using crude HRs with 95% CIs. A systematic literature search was performed to identify relevant studies in PubMed, Embase, and the Cochrane library up to December 2018. The prognostic values of XRCC1 rs1799782 C>T, XRCC1 rs25487 G>A, and ERCC2 rs1799793 G>A polymorphisms and overall survival (OS). OS was significantly longer for the ERCC2 rs13181 CC genotype than for AA . A significantly lower OS was observed for patients with the CT genotype compared with the CC genotype at XRCC3 rs861539 . Ten studies involving 2687 patients were included in the quantitative analysis. There were no statistically significant associations between ERCC2 rs13181 A>C polymorphism and XRCC3 rs861539 C>T polymorphism may be predictive markers for prognosis in patients with HCC. Well-designed studies with larger sample sizes are needed to verify our findings. The Liver cancer is one of the most common malignancies. It was the sixth most commonly diagnosed cancer and the fourth cause of cancer-related death worldwide in 2018 and accounts for approximately 841,000 new cases and 782,000 deaths annually [XRCC1), X-ray repair cross-complementing group 3 (XRCC3), and excision repair cross-complementation group 2 (ERCC2). Many previous studies have investigated the associations between polymorphisms in these genes and prognosis [ XRCC1 rs25487, ERCC5 rs2018836, ERCC5 rs3818356, and XRCC4 rs1805377 have significant effects on survival. Another study suggested that ERCC2-312 genotypes but not XRCC1-194 were independent risk factors for poor prognosis in HCC [ XRCC1 Gln allele and XRCC3 T allele are related to a poor prognosis in HCC.The development of HCC is a multifactorial process involving an insidious onset, rapid progression, and high mortality rates. The fundamental pathogenic event in carcinogenesis is the accumulation of DNA damage and errors in DNA repair. In response to DNA damage, specific DNA repair mechanisms are activated. The major DNA repair pathways are mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), and double-strand break repair (DSBR) . Polymorrognosis –7. In 20rognosis  found ths in HCC  showed t XRCC1, XRCC3, and ERCC2 gene polymorphisms and prognosis in HCC [Despite a number of recent studies of the relationships betweens in HCC –16, the XRCC1 OR X-ray repair cross-complementing group1 OR XRCC3 OR X-ray repair cross-complementing group 3 OR ERCC1 OR excision repair cross-complementation group 1 OR ERCC2 OR excision repair cross-complementing group 2 OR XPD OR xeroderma pigmentosum group D) AND . The reference lists of the identified studies were examined to identify additional studies. When multiple studies evaluated the same population, the most recent and the largest study was included.The present study was conducted according to the PRISMA guidelines for systematic reviews and meta-analyses . A systeThe following inclusion criteria were applied. (1) Patients in the study were diagnosed with HCC. (2) Genotype frequencies could be extracted for at least one of the five polymorphisms. (3) Studies provided sufficient data for the prognostic effects in patients with HCC. The following exclusion criteria were applied: (1) studies with repeated data, (2) studies lacking sufficient data, and (3) studies of patients with carcinomas other than the liver.Two investigators extracted data independently, including information on authors, year, country, ethnicity, number of patients, SNP sites, quality assessment scores, and HRs with 95% confidence intervals (CIs). If the HR and 95% CI could not be obtained directly, they were extracted using the methods of Parmar , TierneyI2 statistic were utilized to evaluate heterogeneity. When P < 0.10 or I2 > 25% for the Q-test, a random effects model (DerSimonian and Laird method) was used to evaluate the pooled HR. Otherwise, a fixed-effects model (Mantel-Haenszel method) was used [The strength of the associations between five gene polymorphisms and overall survival (OS) in HCC was estimated using crude HRs with 95% CIs. The Chi squared-based Q-test and was used . In addiwas used . All staThe study search and selection strategies are presented in  XRCC1 rs25487 G>A polymorphism and prognosis in HCC, 3 studies reported an association for XRCC1 rs1799782 C>T, 2 studies reported an association for ERCC2 rs13181 A>C, 3 studies reported an association for ERCC2 rs1799793 G>A, and 2 studies reported an association for XRCC3 rs861539 C>T .Three studies with a total of 621 patients with advanced HCC were eligible for analyses of the association between the ERCC2 rs13181 A>C polymorphism and the OS. ERCC2 rs13181 CC genotype carriers had a significantly longer OS than that of AA genotype carriers .Three studies were applicable for analyzing the association between the XRCC3 rs861539 C>T polymorphism and the OS. A significantly lower OS was observed for the CT genotype compared with the CC genotype , NER , and DSBR , may be instrumental in carcinogenesis, drug responses, treatment efficiency, and survival in HCC, thus affecting prognosis.DNA repair systems play a fundamental role in maintaining the integrity of genomic DNA. Polymorphisms in genes related to DNA repair mechanisms, including BER  and TT genotypes  have a significantly higher risk of HCC than that of individuals with the XRCC3 CC genotype. In addition, Avadanei and collaborators [ XRCC3 rs861539 C>T polymorphism and OS. We found a significantly lower OS for the CT genotype than the CC genotype. We suspected that the XRCC3 rs861539 C>T polymorphism is a promising marker for prognosis in HCC. However, we did not perform a systematic literature review to comprehensively evaluate the effects of XRCC3 TT and TC genotypes on prognosis in HCC owing to the lack of data. The relation between XRCC3 and prognosis in HCC should be evaluated in future work. Because only two eligible studies were included in the meta-analysis, our results should be interpreted with caution. Studies with larger sample sizes are needed to obtain more definitive conclusions.Then et al.  found thborators  evaluate ERCC2 and XRCC3 polymorphisms were based on only a few eligible studies. Second, the results of our comprehensive analyses were based on unadjusted estimates owing to the lack of adjusted data. Third, ethnicity, therapeutic regimen, and HBV infection status are very important factors for stratified analyses. However, few studies provided sufficient data for subgroups, making such stratified analyses impossible.Several limitations of our study should be addressed. First, the analyses of ERCC2 rs13181 A>C polymorphism and XRCC3 rs861539 C>T polymorphisms are potential prognostic markers in HCC. The ERCC2 rs13181 CC genotype was associated with a significantly longer OS than that of the AA genotype. The carriers of the CT genotype had a poor prognosis compared with that of the CC genotype carriers. Well-designed studies with larger sample sizes are needed to verify our findings.In conclusion, the


XRCC1 gene polymorphisms are being increasingly explored in cancer epidemiology studies. However, the contribution of XRCC1 gene polymorphisms to neuroblastoma risk remains unclarified. Herein, we conducted a case-control study with 393 neuroblastoma patients and 812 controls to explore the association of XRCC1 gene polymorphisms  with neuroblastoma risk. Results showed that none of the studied polymorphisms was associated with neuroblastoma risk. However, individuals with 2 risk genotypes seemed to be at significantly higher risk for neuroblastoma compared with those without risk genotype . Stratified analysis revealed that the XRCC1 rs25489 CT/TT was strongly associated with reduced risk of neuroblastoma in the children ≤ 18 months of age and subgroup with clinical stage I+II+4s diseases, compared with CC genotypes. We also identified an increased neuroblastoma risk for carrier of 2-3 risk genotypes among children ≤ 18 months of age and subgroup with clinical stage I+II+4s. More evidence of the association between XRCC1 gene polymorphisms and neuroblastoma risk is needed.Neuroblastoma is a common pediatric extra-cranial tumor of the sympathetic nervous system. XRCC1 is a scaffold protein that participates in DNA single-strand break repair by complexing with other proteins.  Neuroblastoma is an extracranial solid tumor of the developing sympathetic nervous system ,2. This MYCN is observed in approximately 20% of neuroblastoma cases and associated with poor prognosis .–36.33–36We then further conducted stratification analysis for rs25489 C>T by age, gender, tumor sites of origin and clinical stages . CompareXRCC1 gene on neuroblastoma susceptibility. We found that XRCC1 polymorphisms might play a low-penetrant role on the neuroblastoma risk.In this two-center Chinese population study, we examined the impact of polymorphisms in the XRCC1 gene is located on chromosome 19q13.2 and encodes a 633 amino acid protein [XRCC1 have been identified. Among them, three common polymorphisms, rs25487 C>T (Arg399Gln), rs25489 C>T (Arg280His), and rs1799782 G>A (Arg194Trp), are mostly investigated. These three polymorphisms could cause amino acid changes in evolutionarily conserved regions [XRCC1 polymorphism 399Gln allele might affect the function of XRCC1 protein, consequently impairing DNA repair capacity [ protein . It cons regions ,38, and 7 C>T Arg9Gln, rs2XRCC1 polymorphisms and cancer risk. Hong et al. observed that rs25487 T allele and the 3 common allele combinations  were associated with an increased risk of colorectal cancer in a study of 209 colorectal cancer cases and 209 controls recruited from Korean [XRCC1 rs25487 TT genotype conferred susceptibility to lung adenocarcinoma at an OR of 2.8 (95% CI=1.2-7.9) in a case-control study [XRCC1 rs1799782 G>A and breast cancer risk in a population-based case-control study in North Carolina [XRCC1 polymorphisms indicates their risk effects may depend on cancer types and ethnic groups.Increasing epidemiological studies have been performed regarding the association between m Korean . Divine ol study . In a pool study . DuelletCarolina . HoweverXRCC1 gene were associated with the risk of neuroblastoma. Failure to detect the association between XRCC1 polymorphisms and neuroblastoma risk might be due to the small sample size and the low-penetrant effect of common polymorphisms. In the combined analysis, subjects carrying 2 risk genotypes tend to have increased neuroblastoma risk, when those without risk genotypes serve as a reference. Stratification analysis revealed that the rs25489 CT/TT is associated with favorable clinical markers such as ≤ 18 months of age and clinical stage I+II+4s. While exploring cumulative effects of risk genotypes, we found that the presence of 2-3 risk genotypes was associated with neuroblastoma risk among children ≤ 18 months of age and those with clinical stage I+II+4s tumors. It is believed that cancer susceptibility results from interactions of genetic and environmental factors and is subjected to modification of clinical markers such as age and clinical stage; in other words, the effect of one SNP on cancer susceptibility maybe modified by other genetic variants, environment exposures, and clinical makers. Single-locus analysis in the current study only focused on one genetic factor. the rs25489. Stratified analysis by age and clinical stage involve the effects of the rs25489 and clinical makers. While SNPs were combined, stratified analysis by age and clinical stage involve interaction of multiple SNPs and clinical makers. It is reasonable that analyses involved in different variables may lead to different results. Therefore, results considering interplays of gene-gene, gene-environmental factors and clinical makers maybe more meaningful in the clinical setting. Alternatively, these results could be chance findings, which calls for larger validation studies.In the present study, we found that none of the four polymorphisms of in vitro data to support a role for these XRCC1 polymorphisms in neuroblastoma, which should be completed in the future.The study was limited by several points. Firstly, the relative small number of participants in the study impaired the statistical power. Therefore, the null association obtained in this study should be cautiously explained. Secondly, the insufficient information about environmental factors limited our ability to analyze gene-environment interactions. Thirdly, only four polymorphisms were investigated in the current study. More polymorphisms should be tested in the future work. Fourthly, due to the restriction to Chinese descent, these findings cannot be directly extrapolated to other ethnicities before validation studies. Last, our work lacks of XRCC1 gene may exert a low-penetrant effect on neuroblastoma risk in Chinese population. Our study helps to provide novel insight into the role of XRCC1 gene polymorphisms in neuroblastoma risk. The findings should be further confirmed in other independent case-control studies.In conclusion, we report that polymorphisms in Details of the selection criteria and characteristics of the study participants were provided elsewhere –36. In bXRCC1 gene were selected using dbSNP database (http://www.ncbi.nlm.nih.gov/) and SNPinfo (http://snpinfo.niehs.nih.gov/) [2<0.8) among these SNPs of XRCC1 .Potentially functional polymorphisms in the ih.gov/) . In finaWe used a TIANamp Blood DNA Kit  for DNA extraction. Polymorphisms were genotyped applying TaqMan platform  without knowing the status of the participants –47. Qual2 test. Two-sided chi-square test was applied to compare the demographic variables between the case group and controls. Tests for association between XRCC1 polymorphisms and neuroblastoma risk were conducted by comparing the genotype frequencies between cases and controls using the χ2 test. We also applied stratified analyses by age, gender, tumor sites, and clinical stages. All analyses were conducted with SAS release 9.4 . P< 0.05 was defined as statistically significant.The Hardy-Weinberg equilibrium (HWE) was performed for each polymorphism among controls using the goodness-of-fit χSupplementary Table 1Supplementary Figure 1


The study performed by Zhou et al.  titled “Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis” attempts to highlight hypoxia-inducible factor-1 alpha as a possible prognostic marker in oral squamous cell carcinoma (OSCC). We would like to underline a few points which may affect such a conclusion. The correlations between HIF-1α expression and tumour size as well as tumour stage are debatable. Further, the subgroup analysis incorporating Australia and Europe into a single subgroup limits the viability of the prognostic analysis of HIF-1α. We also suggest future studies in the same research area to analyse head and neck squamous cell carcinoma instead of OSCC, to ameliorate the limitations encountered by Zhou et al., due to the scarcity of relevant clinical data and a low number of studies about OSCC. Dear Editor,It is well documented and understood that cancer disease progression is intricately linked to the tumour microenvironment . This tuSecondly, we would like to draw attention to the subgroups chosen for meta-analysis of HIF-1α expression and overall survival (OS). Though the reasoning behind cumulating the studies from Australia and Europe into a single group makes sense, considering the scarcity of studies (a limitation of the study as specified by the authors), such a categorisation, is crude and detracts from the purpose of a subgroup analysis. Subgroup analysis is performed to provide a higher resolution of insight into a meta-analysis and requires classification of the subgroups based on common criteria between studies that may influence the overall outcome effect . If we presume that the classification by Zhou et al. was intended to take into account significant hereditary genetic variations, in the form of race or ethnicity, as affecting overall outcome effect, the continental classification is still an imprecise method of doing so. This is due to a lack of information showing the ethnic distribution of the patient samples. Though we may presume that studies from Europe and Australia primarily involve Caucasian population, other ethnic groups such as the Aboriginal Australians and non-Caucasians may also be part of such studies, thereby making a classification which combines Australia and Europe into a single group, erroneous and inapt.We would also like to address the limitation of the study, where the authors cited a small pool of eligible studies. As oral squamous cell carcinoma (OSCC) is a highly specific subset of cancer, it severely narrows down the number of studies in the field. A method of ameliorating this problem could be to choose head and neck squamous cell carcinoma (HNSCC) instead of OSCC to perform such a meta-analysis study. As OSCC is a subset of HNSCC, a much larger pool of viable research can be obtained, and due to etiological similarities between OSCC and other types of HNSCC, it is plausible to assume that establishing HIF-1α as a reliable prognostic indicator in HNSCC would imply its prognostic importance/effect in OSCC, as well.In our opinion, the principal merit of the study is the association achieved between HIF-1α expression and lymph node status and histological differentiation, which provides valuable clinically relevant information. However, we present our remarks not to highlight the limitations of this study but to merely communicate possible improvements in the concept and design to Zhou et al. and other prospective authors in the same discipline, in case of a planned update to this study in a few years, as well as the scientific community at large.


ICAM‐1) rs5498 polymorphism and ischemic stroke (IS) were investigated by several pilot studies, but with inconsistent results. In this study, a meta‐analysis was performed to better assess the relationship between ICAM‐1rs5498 polymorphism and IS.Recently, associations between intercellular adhesion molecule‐1  and 95% confidence intervals (CIs) to evaluate associations between p = 0.009, OR = 1.62, 95% CI 1.13–2.32, I2 = 76%) in overall population. Further subgroup analyses showed that rs5498 polymorphism was significantly associated with IS in Caucasians in AA versus AG + GG , GG versus AA + AG , and A versus G . However, no any positive findings were detected for Asians.Totally 16 studies with 2,596 cases and 11,800 controls were analyzed. A significant association with IS was observed for rs5498 polymorphism in GG versus AA + AG (recessive model, Our findings indicated that rs5498 polymorphism was significantly associated with individual susceptibility to IS in Caucasians, but not in Asians. Studies were excluded if one of the following conditions was fulfilled: (a) not related to ICAM‐1 rs5498 polymorphism and IS; (b) pedigree studies; (c) case reports or case series. In the case of duplicate reports by the same authors, we only included the most complete study.To test the research hypothesis of this meta‐analysis, included studies should meet all the following criteria: (a) case–control study about 2.2ICAM‐1 rs5498 polymorphism in cases and controls. The probability value  of Hardy–Weinberg equilibrium (HWE) was also calculated.We extracted the following information from eligible studies: (a) name of the first author; (b) year of publication; (c) country and ethnicity of participants; (d) type of disease; (e) sample size; and (f) the genotypic distribution of We used the Newcastle‐Ottawa scale (NOS) to evaluate the quality of eligible studies Stang, . The NOSTwo reviewers conducted data extraction and quality assessment independently. When necessary, we wrote to the corresponding authors for extra information. Any disagreement between two reviewers was solved by discussion until a consensus was reached.2.3ICAM‐1 rs5498 polymorphism and IS in dominant (AA vs. AG + GG), recessive (GG vs. AA + AG), over‐dominant (AG vs. AA + GG) and allele (A vs. G) models, and a p value of 0.05 or less was defined as statistically significant. Between‐study heterogeneities were evaluated by I2 statistic. Random‐effect models would be used for analyses if I2 was greater than 50%. Otherwise, analyses would be conducted with fixed‐effect models. Subgroup analyses were subsequently carried out by ethnicity of participants and type of disease. Stabilities of synthetic results were tested in sensitivity analyses. Publication biases were assessed by funnel plots.In the current meta‐analysis, we performed statistical analyses by using Review Manager Version 5.3.3. We calculated ORs and 95% CIs to estimate potential associations between 33.1The initial literature search identified 177 articles. After excluding irrelevant and duplicate articles, 23 articles were retrieved for further evaluation. Another seven articles were subsequently excluded after reading the full text. Ultimately, a total of 16 eligible studies involving 2,596 cases and 11,800 controls were enrolled for analyses  in overall population. Further subgroup analyses showed that rs5498 polymorphism was significantly associated with IS in Caucasians in AA versus AG + GG , GG versus AA + AG , and A versus G . However, no any positive findings were detected for Asians  to lysine (K), which is proved to be associated with alteration in protein structure and binding affinity of ICAM‐1 protein (He et al., Some limitations of this meta‐analysis should also be noted when interpreting our findings. First, our pooled analyses were based on unadjusted estimations due to the lack of raw data, and we have to admit that failure to perform further adjusted analyses may impact the reliability of our findings (Shi, Xie, Jia, & Li, ICAM‐1 rs5498 polymorphism might serve as a genetic biomarker of IS in Caucasians, but not in Asians. However, further well‐designed studies, especially in Caucasian are still warranted to confirm our findings.In summary, our meta‐analysis suggested that This article does not contain any studies with human participants or animals performed by any of the authors.The authors declare that they have no conflict of interest.Hua Gao conceived of the study, participated in its design. Hua Gao and Xinhua Zhang conducted the systematic literature review. Hua Gao and Xinhua Zhang performed data analyses. Hua Gao drafted the manuscript. All authors have read and approved the final manuscript. Click here for additional data file.


It has been suggested that cytokine-mediated inflammation plays a key role for the onset and/or development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). However, clinical studies have yielded inconsistent results for the aberrant cytokine levels in circulation of patients with AD, PD, and ALS. Previous studies have used meta-analysis to address the inconsistent data for blood cytokine levels in the patients with AD, PD, and ALS. Here, we performed a systemic review of cerebrospinal fluid inflammatory cytokine data in patients with AD, PD and ALS, and sought to quantitatively summarize the CSF inflammatory cytokine data with a meta-analytical technique. The systematic search from Pubmed and Web of Science identified 71 articles with 2629 patients and 2049 controls for the meta-analysis. Random-effects meta-analysis demonstrated that CSF TGF-β, MCP-1, and YKL-40 levels were significantly elevated in AD patients when compared with controls. In addition, patients with PD had heightened levels of TGF-β1, IL-6, and IL-1β in CSF. Furthermore, G-CSF, IL-2, IL-15, IL-17, MCP-1, MIP-1α, TNF-α, and VEGF levels were significantly increased in patients with ALS as compared with controls. Taken together, these results not only strengthen the clinical evidence that neurodegenerative diseases are accompanied by the increased inflammatory response, but also reveal the unique inflammatory response profile in the central nervous system of patients with AD, PD and ALS. Given the robust associations between some cytokines and neurodegenerative diseases found in this meta-analysis, CSF inflammatory cytokines may be used as biomarkers for these diseases in the future. Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) are devastating diseases affect millions of people globally –3. Some In the last decade, increasing evidence suggest that inflammation is associated with the onset and development of the neurodegenerative diseases including AD, PD, and ALS –15. ThesIn addition to the significant associations between peripheral blood cytokine levels and the neurodegenerative diseases, studies have also found aberrant cytokine levels in the cerebrospinal fluid (CSF) of patients with AD, PD and ALS , 25, 26.This systematic review and meta-analysis followed the guidelines that are recommended by the PRISMA statement  .n = 15); cytokines were assessed in less than three studies (n = 24), no control group (n = 19); full text was not English (n = 1); sample size was not provided (n = 2). Therefore, a total of 71 studies with 2629 patients and 2049 controls were included in this meta-analysis (Pubmed and Web of science were used to search English language publications by two independent investigators through March 2018. The database search used the following search terms: (inflammation or cytokine or chemokine or tumor necrosis factor or interleukin or interferon or C-reactive protein) and  and , without year restriction. The initial search yielded 805 records from Pubmed and 753 records from Web of Science with the search term. After screening the titles and abstracts, 1426 records were excluded because they were not related to our present subject. The remaining 132 articles were selected for full-text scrutiny. 61 studies were excluded due to: no necessary data  were extracted from all the articles included in this meta-analysis as the main data. Additional data such as average age of patients, percentage of male patients, dementia severity , medication status and assay type were also extracted  was applied for all the statistical analyses. Effective sizes (ESs) were mainly generated by sample size, mean cytokine concentration and s.d, and the rest ESs were calculated by sample size and le sizes . The staP-value < 0.1. I2 index was used to determine the inconsistency across studies which evaluated the impact of heterogeneity, and we used 0.25, 0.50, and 0.75 of I2 to indicate small, medium and high levels of heterogeneity , MCP-1 and YKL-40  levels were significantly increased in AD patients as compared with controls , IL-6  and IL-1β  levels than controls  levels had no significant ES estimate , IL-2 , IL-15 , IL-17 , MCP-1 , MIP-1α , TNF-α  and VEGF  levels were significantly increased in the patients when compared with controls , or DC subjects, and no heterogeneity was found for the HC group , whereas the impact of heterogeneity was slightly increased for the DC group . Furthermore, the impact of heterogeneity was slightly increased , and the significant association between CSF MCP-1 and ALS was retained for the ELISA method . For the non-ELISA method, there was no significant heterogeneity among studies , and the significant association between CSF MCP-1 and ALS was retained . Interestingly, the impact of heterogeneity was reduced to zero , and the significant association between CSF MCP-1 and ALS was slightly increased for the ES generated by sample size and P-value group . However, the significant association between CSF MCP-1 and ALS was lost for the ES generated by mean concentration, s.d. and sample size group , and the heterogeneity increased approximately 10% . These results suggest that assay type, ES generation method and control type may partially explain the between-study heterogeneity in this meta-analysis.The subgroup analysis stratified by control type  suggested that CSF MCP-1 levels were increased in ALS patients as compared to HC subjects . Similarly, age, sex, disease duration and publication year did not confound the outcome of the meta-analysis for the association between CSF MCP-1 and ALS .We then performed meta-regression analyses and demonstrated that sex, age, disease severity, and publication year had no moderating effects on the significant association between CSF YKL-40 and AD  of neurodegenerative diseases, this meta-analysis provided strong clinical evidence with large sample size to validate increased CNS inflammatory response in AD, PD, and ALS.P = 0.095) or PD (p = 0.058), this phenomenon is likely because of the small number of studies included in the meta-analysis, and the high levels of heterogeneity among studies. We hypothesize with increasing number of studies and larger sample size, CSF TNF-α levels would significantly associate with AD and PD. Therefore, future studies are necessary to evaluate whether heightened central TNF-α releases occur in all the three neurodegenerative diseases analyzed in the meta-analysis, and thereby better explain the etiology of AD, PD and ALS. Nevertheless, these results suggested shared and unique CNS inflammatory responses in different neurodegenerative diseases.The level of CSF MCP-1 increased both in patients with AD and ALS, suggesting this chemokine may represent a common inflammatory pathway to affect the two diseases. The same explanation could apply to the increased CSF TGF-β levels in AD and PD. The other cytokines included in this meta-analysis did not show significant associations with at least two neurodegenerative diseases, indicating the unique signature of the CNS inflammatory response of individual neurodegenerative disease. However, the non-significant associations between some CSF cytokines and AD, PD, or ALS may due to the limited number of studies with small sample size, making the observation of significant associations difficult. For example, our results showed significant increase of CSF TNF-α concentration in patients with ALS, but a non-significant association between CSF TNF-α levels and AD 23), and P-value. This phenomenon could be due to the relatively small number of studies (6 studies) for the sub-group analyzing CSF MCP-1 levels in ALS patients. However, the second explanation is that studies with positive results are more likely to report only sample size and P-value.The between-study heterogeneity ranged from zero to high. The advantage of this study is that a meta-analytic technique with subgroup and meta-regression analyses was used to adjust for potential confounders. Although meta-regression analyses did not find any continuous variables that may have moderating effect on the outcome for the meta-analysis, the subgroup analyses suggested that different control type (DC vs HC) and assay type (ELISA vs non-ELISA) partially explained the heterogeneity. However, the small heterogeneity in some subgroups may be due to the limited number of studies, given that data were pooled from four studies comparing CSF MCP-1 levels between ALS patients and HC subjects, and four studies used non-ELISA assay to compare CSF MCP-1 levels between ALS patients and controls. It should be noted that out of the four studies, two studies used bead-based fluorescent method to detect MCP-1 levels. Therefore, another possibility of the low between-study heterogeneity for the non-ELISA method was due to the relatively new technology with potential more consistent results, although future studies are necessary to validate this idea. Furthermore, another interesting finding is the zero between-study heterogeneity for the sub-group generating ES from sample size and Although this meta-analysis provided strong clinical evidence to clarify the CSF cytokine aberrations in AD, PD and ALS, there are several limitations in this study. The first limitation is that most cytokines in AD, PD, or ALS were studied in less than 10 studies, thus it is unclear whether the non-significant associations between some cytokines and neurodegenerative diseases are due to the limited number of studies with small sample size, and it also prevented us from analyzing the potential confounding factors that explained the between-study heterogeneity. The second limitation is that some of the detailed information of clinical variables, these include disease duration, disease severity and medication status, were not reported in the original papers, and therefore precluded us from assessing the effects of these potential moderators on the outcomes of the meta-analysis. Therefore, more clinical studies are needed to address the inflammatory responses in the CNS of AD, PD, and ALS with more controls on the clinical variables, thereby to better understand the etiology of the neurodegenerative diseases. The third limitation of this study is that we only included English-language publications, and this may potentially limit the number of studies in this meta-analysis. However, considering the very small number of non-English publications on cytokine levels in neurodegenerative diseases, this is unlikely to significantly affect the outcomes of the meta-analysis.YC and QL conceived and designed the study, XC and YH collected the data. XC, YH, ZC, QL, and YC analyzed and interpreted the data. YC drafted the manuscript with critial revisons from all the authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.