Parity and Pancreatic Cancer Risk: A Dose-Response Meta-Analysis of Epidemiologic Studies

<div><p>Background</p><p>Previous epidemiologic studies have reported inconsistent results between parity and pancreatic cancer (PC) risk. To our knowledge, a comprehensive and quantitative assessment of this association has not been conducted.</p><p>Methods</p><p>Relevant published studies of parity and PC were identified using MEDLINE (PubMed) and Web of Science databases until November 2013. Two authors (H-BG and LW) independently assessed eligibility and extracted data. Eleven prospective and 11 case-control studies reported relative risk (RR) estimates and 95% confidence intervals (CIs) of PC associated with parity. Fixed- and random-effects models were used to estimate the summary RR depending on the heterogeneity of effects.</p><p>Results</p><p>The summary RR for PC comparing the highest versus lowest parity was 0.86 (95% CI: 0.73–1.02; <i>Q</i> = 50.49, <i>P</i><0.001, <i>I</i>² = 58.4%). Significant inverse associations were also observed in the studies that adjusted for cigarette smoking (RR = 0.81; 95% CI: 0.68–0.98), Type 2 diabetes mellitus (RR = 0.83; 95% CI: 0.75–0.93), and those that included all confounders or important risk factors (RR = 0.85; 95% CI: 0.76–0.96). Additionally, in the dose-response analysis, the summary RR for per one live birth was 0.97 (95% CI: 0.94–1.01; <i>Q</i> = 62.83, <i>P</i><0.001, <i>I</i>² = 69.8%), which also indicated a borderline statistically significant inverse effect of parity on PC risk. No evidence of publication bias and significant heterogeneity between subgroups were detected by meta-regression analyses.</p><p>Conclusion</p><p>In summary, these findings suggest that higher parity is associated with a decreased risk of PC. Future large consortia or pooled studies are warranted to fully adjust for potential confounders to confirm this association.</p></div

Forest plots (random effect model) of meta-analysis on the relationship between passive maternal smoking and preterm birth by study design.

<p>Squares indicate study-specific risk estimates (size of the square reflects the study-specific statistical weight); horizontal lines indicate 95% CIs; diamond indicates the summary risk estimate with its 95% CI.</p

Summary risk estimates of the association between parity and pancreatic cancer risk.

<p>RR: relative risk; CI: confidence interval; BMI: body mass index; DM: diabetes mellitus.</p><p><i>* P</i> value for heterogeneity within each subgroup.</p><p><i>^** P</i> value for heterogeneity between subgroups with meta-regression analysis.</p

Forest plots (random effect model) of meta-analysis on the relationship between passive maternal smoking and preterm birth by exposure location.

<p>Squares indicate study-specific risk estimates (size of the square reflects the study-specific statistical weight); horizontal lines indicate 95% CIs; diamond indicates the summary risk estimate with its 95% CI.</p

Data_Sheet_1_Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer.docx

BackgroundThe association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown.MethodsFecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins.ResultsNon-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae, and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases.ConclusionWe revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.</p

Table_2_Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer.DOCX

BackgroundThe association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown.MethodsFecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins.ResultsNon-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae, and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases.ConclusionWe revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.</p

Data_Sheet_2_Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer.PDF

BackgroundThe association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown.MethodsFecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins.ResultsNon-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae, and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases.ConclusionWe revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.</p

Data_Sheet_3_Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer.PDF

BackgroundThe association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown.MethodsFecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins.ResultsNon-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae, and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases.ConclusionWe revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.</p

Forest plot (random effects model) of parity (highest versus lowest) and pancreatic cancer risk by study design.

<p>Squares indicate study-specific relative risks (size of the square reflects the study-specific statistical weight); horizontal lines indicate 95% CIs; diamond indicates the summary relative risk estimate with its 95% CI. CI: confidence interval; RR: relative risk.</p

Table_1_Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer.DOCX

BackgroundThe association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown.MethodsFecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins.ResultsNon-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae, and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases.ConclusionWe revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.</p