Objective： Human epididymis protein 4（HE4） is a promising biomarker of epithelial ovarian cancer（EOC）. But its role in assessing the primary optimal debulking（OD） of EOC remains unknown. The purpose of this stu...Objective： Human epididymis protein 4（HE4） is a promising biomarker of epithelial ovarian cancer（EOC）. But its role in assessing the primary optimal debulking（OD） of EOC remains unknown. The purpose of this study is to elucidate the ability of preoperative HE4 in predicting the primary cytoreductive outcomes in advanced EOC, tubal or peritoneal carcinoma.Methods： We reviewed the records of 90 patients with advanced ovarian, tubal or peritoneal carcinoma who underwent primary cytoreduction at the Department of Obstetrics and Gynecology of Peking University People＇s Hospital between November 2005 and October 2010. Preoperative serum HE4 and CA125 levels were detected with EIA kit. A receiver operating characteristic（ROC） curve was used to determine the most useful HE4 cut-off value. Logistic regression analysis was performed to identify significant preoperative clinical characteristics to predict optimal primary cytoreduction.Results： OD was achieved in 47.7%（43/48） of patients. The median preoperative HE4 level for patients with OD vs. suboptimal debulking was 423 and 820 pmol/L, respectively（P〈0.001）. The areas under the ROC curve for HE4 and CA125 were 0.716 and 0.599, respectively（P=0.080）. The most useful HE4 cut-off value was 473 pmol/L. Suboptimal cytoreduction was obtained in 66.7%（38/57） of cases with HE4 ≥473 pmol/L compared with only 27.3%（9/33） of cases with HE4 〈473 pmol/L. At this threshold, the sensitivity, specificity, positive predictive value（PPV） and negative predictive value（NPV） for diagnosing suboptimal debulking were 81%, 56%, 67%, and 73%, respectively. Logistic regression analysis showed that the patients with HE4 ≥473 pmol/L were less likely to achieve OD（odds ratio =5.044, P=0.002）.Conclusions： Preoperative serum HE4 may be helpful to predict whether optimal cytoreductive surgery could be obtained or whether extended cytoreduction would be needed by an interdisciplinary team.展开更多
Objective:To investigate the value of serum human epididymis protein 4(HE4) in differential diagnosis of patients with low-grade serous(LGSC) and high-grade serous carcinoma(HGSC) serous ovarian cancer.Methods:LGSC an...Objective:To investigate the value of serum human epididymis protein 4(HE4) in differential diagnosis of patients with low-grade serous(LGSC) and high-grade serous carcinoma(HGSC) serous ovarian cancer.Methods:LGSC and HGSC serous ovarian cancer were diagnosed by the two-tier grade system,serum levels of HE4 and carbohydrate antigen 12S(CA125) were measured by ELBA and radioisotope method,respectively in 60 serous ovarian cancer patients. HE4 and TPS3 protein in cancer tissue were measured by immunohistochemical method. Results:The difference in density of HE4 and TP53 protein was significant between LGSC and HGSC tissue,while serum CA12S did not show significant difference between different serum samples.There was significant difference in serum HE4 levels between LGSC and HGSC and the result was different within FIGO(Ⅰ+Ⅱ) stage,suggesting HE4 was not a reliable biomarker for the discrimination between LGSC and HCSC.HE4 had potential as a biomarker for the discrimination between LGSC and HGSC but the role in early diagnosis was limited.Conclusions:HE4 may be a reliable marker for differential diagnosis of LGSC and HGSC.But its role in early diagnosis of LGSC and HGSC need to be confirmed from the perspective of two-tier grade system.展开更多
BACKGROUND Numerous studies have demonstrated that human epididymis protein 4(HE4)is overexpressed in various malignant tissues including ovarian,endometrial,lung,breast,pancreatic,and gastric cancers.However,no study...BACKGROUND Numerous studies have demonstrated that human epididymis protein 4(HE4)is overexpressed in various malignant tissues including ovarian,endometrial,lung,breast,pancreatic,and gastric cancers.However,no study has examined the diagnostic impact of HE4 in patient with esophageal squamous cell carcinoma(ESCC)until now.AIM To analyze the value of four serum tumor markers for the diagnosis of ESCC,and examine the associations of serum levels of HE4 with ESCC patients’clinicopathological characteristics.METHODS The case group consisted of 80 ESCC patients,which were compared to a control group of 56 patients with benign esophageal disease.Serum levels of HE4,carcinoma embryonic antigen(CEA),alpha fetal protein,and carbohydrate antigen 19-9(CA19-9)were detected by ELISA.The associations of serum HE4 levels with ESCC patients’clinicopathological characteristics such as gender,tumor location,and pathological stage were also examined after operation.RESULTS The result of ELISA showed that serum HE4 level was significantly higher in the patients with ESCC than in the controls,and the staining intensity was inversely correlated with the pathological T and N stages.Serum HE4 levels had a sensitivity of 66.2%and specificity of 78.6%when the cutoff value was set at 3.9 ng/mL.Moreover,the combined HE4 and CA19-9 increased the sensitivity to 83.33%,and interestingly,the combination of HE4 with CEA led to the most powerful sensitivity of 87.5%.Furthermore,A positive correlation was observed between HE4 serum levels and pathological T and N stages(P=0.0002 and 0.0017,respectively),but there was no correlation between HE4 serum levels and ESCC patient gender(P=0.4395)or tumor location(P=0.6777).CONCLUSION The results of this study suggest that detection of serum HE4 levels may be useful in auxiliary diagnosis and evaluation of the progression of ESCC.展开更多
BACKGROUND Spermatogonial stem cells(SSCs)are the origin of male spermatogenesis,which can reconstruct germ cell lineage in mice.However,the application of SSCs for male fertility restoration is hindered due to the un...BACKGROUND Spermatogonial stem cells(SSCs)are the origin of male spermatogenesis,which can reconstruct germ cell lineage in mice.However,the application of SSCs for male fertility restoration is hindered due to the unclear mechanisms of proliferation and self-renewal in humans.AIM To investigate the role and mechanism of SPOC domain-containing protein 1(SPOCD1)in human SSC proliferation.METHODS We analyzed publicly available human testis single-cell RNA sequencing(RNAseq)data and found that SPOCD1 is predominantly expressed in SSCs in the early developmental stages.Small interfering RNA was applied to suppress SPOCD1 expression to detect the impacts of SPOCD1 inhibition on SSC proliferation and apoptosis.Subsequently,we explored the target genes of SPOCD1 using RNA-seq and confirmed their role by restoring the expression of the target genes.In addition,we examined SPOCD1 expression in some non-obstructive azoospermia(NOA)patients to explore the correlation between SPOCD1 and NOA.RESULTS The uniform manifold approximation and projection clustering and pseudotime analysis showed that SPOCD1 was highly expressed in the early stages of SSC,and immunohistological results showed that SPOCD1 was mainly localized in glial cell line-derived neurotrophic factor family receptor alpha-1 positive SSCs.SPOCD1 knockdown significantly inhibited cell proliferation and promoted apoptosis.RNA-seq results showed that SPOCD1 knockdown significantly downregulated genes such as adenylate kinase 4(AK4).Overexpression of AK4 in SPOCD1 knockdown cells partially reversed the phenotypic changes,indicating that AK4 is a functional target gene of SPOCD1.In addition,we found a significant downregulation of SPOCD1 expression in some NOA patients,suggesting that the downregulation of SPOCD1 may be relevant for NOA.CONCLUSION Our study broadens the understanding of human SSC fate determination and may offer new theories on the etiology of male infertility.展开更多
Overexpression of receptor-interacting protein 140（RIP140） promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2（ERK1/2） signaling.However,involvement of RIP140 in human neural dif...Overexpression of receptor-interacting protein 140（RIP140） promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2（ERK1/2） signaling.However,involvement of RIP140 in human neural differentiation remains unclear.We found both RIP140 and ERK1/2 expression increased during neural differentiation of H1 human embryonic stem cells.Moreover,RIP140 negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation,and positively correlated with the neural stem cell marker Nestin during later stages.Thus,ERK1/2 signaling may provide the molecular mechanism by which RIP140 takes part in neural differentiation to eventually affect the number of neurons produced.展开更多
Human embryonic stem cells (hESC) can be induced to differentiate to trophoblast by bone morphogenetic proteins (BMPs) and by aggregation to form embryoid bodies (EB), but there are many differences and controversies ...Human embryonic stem cells (hESC) can be induced to differentiate to trophoblast by bone morphogenetic proteins (BMPs) and by aggregation to form embryoid bodies (EB), but there are many differences and controversies regarding the nature of the differentiated cells. Our goals herein were to determine if BG02 cells form trophoblast-like cells (a) in the presence of BMP4-plus-basic fibroblast growth factor (FGF-2) and (b) upon EB formation, and (c) whether the BMP4 antagonist noggin elicits direct effects on gene expression and hormone production in the cells. Transcriptome profiling of hESC incubated with BMP4/FGF-2 showed a down-regulation of pluripotency-associated genes, an up-regulation of trophoblast-associated genes, and either a down-regulation or no change in gene expression for many markers of the three embryonic germ layers. Yet, there was up-regulation of several genes associated with mesoderm, ectoderm, and endoderm, strongly suggesting that differentiation to trophoblast-like cells under the conditions used does not yield a homogeneous cell type. Several genes, heretofore unreported, were identified that are altered in hESC in response to BMP4-mediated differentiation. The production of human chorionic gonadotropin (hCG), progesterone, and estradiol in the differentiated cells confirmed that trophoblast-like cells were obtained. Gene expression by EB was characterized by an up-regulation of a number of genes associated with trophoblast, ectoderm, endoderm, and mesoderm, and the production of hCG and progesterone confirmed that trophoblast-like cells were formed. These results suggest that, in the presence of FGF-2, BG02 cells respond to BMP4 to yield trophoblast-like cells, which are also obtained upon EB formation. Thus, BMP4-mediated differentiation of hESC represents a viable cell system for studying early developmental events post-implantation;however, up-regulation of non-trophoblast genes suggests a somewhat diverse response to BMP4/FGF-2. Noggin altered the transcription of a limited number of genes but, not surprisingly, did not lead to secretion of hormones.展开更多
Objective: To study the correlation of serum mesothelin and human epididymis secretory protein 4 contents with cellular infiltrative growth in patients with ovarian cancer. Methods:Patients with ovarian cancer who und...Objective: To study the correlation of serum mesothelin and human epididymis secretory protein 4 contents with cellular infiltrative growth in patients with ovarian cancer. Methods:Patients with ovarian cancer who underwent surgical resection in West Coast Medical Center of the Affiliated Hospital of Qingdao University between June 2013 and December 2016 were selected as the ovarian cancer group of the study, and healthy women who received physical examination in China University of Petroleum (East China) Hospital during the same period were selected as the control group of the study. Serum was collected from two groups of subjects to detect serum mesothelin and human epididymis secretory protein 4 contents, and the ovarian cancer lesions and adjacent lesions were collected from ovarian cancer group to detect the expression of proliferation, apoptosis and invasion genes. Results: Serum mesothelin and human epididymis secretory protein 4 contents of ovarian cancer group were significantly higher than those of control group;FUNDC1, LSD1, TNFAIP8, CXCR4, β-catenin, CD44, PELP1, Slug, ZEB1 and Snail mRNA expression in ovarian cancer lesions were significantly higher than those in adjacent lesions and positively correlated with serum mesothelin and human epididymis secretory protein 4 contents while MFN2, PTEN, FN14 and E-cadherin mRNA expression were significantly lower than those in adjacent lesions and negatively correlated with serum mesothelin and human epididymis secretory protein 4 contents. Conclusion: Serum mesothelin and human epididymis secretory protein 4 contents abnormally increase in patients with ovarian cancer and are associated with the infiltrative growth of cancer cells.展开更多
基金supported by Natural Science Foundation of China(NSFC-81172454)the Specialized Research Fund for Doctoral Program of Higher Education(SRFDR-20100001110079)
文摘Objective： Human epididymis protein 4（HE4） is a promising biomarker of epithelial ovarian cancer（EOC）. But its role in assessing the primary optimal debulking（OD） of EOC remains unknown. The purpose of this study is to elucidate the ability of preoperative HE4 in predicting the primary cytoreductive outcomes in advanced EOC, tubal or peritoneal carcinoma.Methods： We reviewed the records of 90 patients with advanced ovarian, tubal or peritoneal carcinoma who underwent primary cytoreduction at the Department of Obstetrics and Gynecology of Peking University People＇s Hospital between November 2005 and October 2010. Preoperative serum HE4 and CA125 levels were detected with EIA kit. A receiver operating characteristic（ROC） curve was used to determine the most useful HE4 cut-off value. Logistic regression analysis was performed to identify significant preoperative clinical characteristics to predict optimal primary cytoreduction.Results： OD was achieved in 47.7%（43/48） of patients. The median preoperative HE4 level for patients with OD vs. suboptimal debulking was 423 and 820 pmol/L, respectively（P〈0.001）. The areas under the ROC curve for HE4 and CA125 were 0.716 and 0.599, respectively（P=0.080）. The most useful HE4 cut-off value was 473 pmol/L. Suboptimal cytoreduction was obtained in 66.7%（38/57） of cases with HE4 ≥473 pmol/L compared with only 27.3%（9/33） of cases with HE4 〈473 pmol/L. At this threshold, the sensitivity, specificity, positive predictive value（PPV） and negative predictive value（NPV） for diagnosing suboptimal debulking were 81%, 56%, 67%, and 73%, respectively. Logistic regression analysis showed that the patients with HE4 ≥473 pmol/L were less likely to achieve OD（odds ratio =5.044, P=0.002）.Conclusions： Preoperative serum HE4 may be helpful to predict whether optimal cytoreductive surgery could be obtained or whether extended cytoreduction would be needed by an interdisciplinary team.
基金suuported by Young Researcher Foundation from Education Department of Jiangxi Province(Grand No.GJJ12161)
文摘Objective:To investigate the value of serum human epididymis protein 4(HE4) in differential diagnosis of patients with low-grade serous(LGSC) and high-grade serous carcinoma(HGSC) serous ovarian cancer.Methods:LGSC and HGSC serous ovarian cancer were diagnosed by the two-tier grade system,serum levels of HE4 and carbohydrate antigen 12S(CA125) were measured by ELBA and radioisotope method,respectively in 60 serous ovarian cancer patients. HE4 and TPS3 protein in cancer tissue were measured by immunohistochemical method. Results:The difference in density of HE4 and TP53 protein was significant between LGSC and HGSC tissue,while serum CA12S did not show significant difference between different serum samples.There was significant difference in serum HE4 levels between LGSC and HGSC and the result was different within FIGO(Ⅰ+Ⅱ) stage,suggesting HE4 was not a reliable biomarker for the discrimination between LGSC and HCSC.HE4 had potential as a biomarker for the discrimination between LGSC and HGSC but the role in early diagnosis was limited.Conclusions:HE4 may be a reliable marker for differential diagnosis of LGSC and HGSC.But its role in early diagnosis of LGSC and HGSC need to be confirmed from the perspective of two-tier grade system.
基金National Natural Science Foundation of China,No.81602023.
文摘BACKGROUND Numerous studies have demonstrated that human epididymis protein 4(HE4)is overexpressed in various malignant tissues including ovarian,endometrial,lung,breast,pancreatic,and gastric cancers.However,no study has examined the diagnostic impact of HE4 in patient with esophageal squamous cell carcinoma(ESCC)until now.AIM To analyze the value of four serum tumor markers for the diagnosis of ESCC,and examine the associations of serum levels of HE4 with ESCC patients’clinicopathological characteristics.METHODS The case group consisted of 80 ESCC patients,which were compared to a control group of 56 patients with benign esophageal disease.Serum levels of HE4,carcinoma embryonic antigen(CEA),alpha fetal protein,and carbohydrate antigen 19-9(CA19-9)were detected by ELISA.The associations of serum HE4 levels with ESCC patients’clinicopathological characteristics such as gender,tumor location,and pathological stage were also examined after operation.RESULTS The result of ELISA showed that serum HE4 level was significantly higher in the patients with ESCC than in the controls,and the staining intensity was inversely correlated with the pathological T and N stages.Serum HE4 levels had a sensitivity of 66.2%and specificity of 78.6%when the cutoff value was set at 3.9 ng/mL.Moreover,the combined HE4 and CA19-9 increased the sensitivity to 83.33%,and interestingly,the combination of HE4 with CEA led to the most powerful sensitivity of 87.5%.Furthermore,A positive correlation was observed between HE4 serum levels and pathological T and N stages(P=0.0002 and 0.0017,respectively),but there was no correlation between HE4 serum levels and ESCC patient gender(P=0.4395)or tumor location(P=0.6777).CONCLUSION The results of this study suggest that detection of serum HE4 levels may be useful in auxiliary diagnosis and evaluation of the progression of ESCC.
基金the National Natural Science Foundation for Young Scholars of China,No.82201771National Natural Science Foundation of China,No.32270912+2 种基金Natural Science Foundation of Changsha,No.kq2202491Research Grant of CITIC-Xiangya,No.YNXM202109 and No.YNXM202115Hunan Provincial Grant for Innovative Province Construction,No.2019SK4012。
文摘BACKGROUND Spermatogonial stem cells(SSCs)are the origin of male spermatogenesis,which can reconstruct germ cell lineage in mice.However,the application of SSCs for male fertility restoration is hindered due to the unclear mechanisms of proliferation and self-renewal in humans.AIM To investigate the role and mechanism of SPOC domain-containing protein 1(SPOCD1)in human SSC proliferation.METHODS We analyzed publicly available human testis single-cell RNA sequencing(RNAseq)data and found that SPOCD1 is predominantly expressed in SSCs in the early developmental stages.Small interfering RNA was applied to suppress SPOCD1 expression to detect the impacts of SPOCD1 inhibition on SSC proliferation and apoptosis.Subsequently,we explored the target genes of SPOCD1 using RNA-seq and confirmed their role by restoring the expression of the target genes.In addition,we examined SPOCD1 expression in some non-obstructive azoospermia(NOA)patients to explore the correlation between SPOCD1 and NOA.RESULTS The uniform manifold approximation and projection clustering and pseudotime analysis showed that SPOCD1 was highly expressed in the early stages of SSC,and immunohistological results showed that SPOCD1 was mainly localized in glial cell line-derived neurotrophic factor family receptor alpha-1 positive SSCs.SPOCD1 knockdown significantly inhibited cell proliferation and promoted apoptosis.RNA-seq results showed that SPOCD1 knockdown significantly downregulated genes such as adenylate kinase 4(AK4).Overexpression of AK4 in SPOCD1 knockdown cells partially reversed the phenotypic changes,indicating that AK4 is a functional target gene of SPOCD1.In addition,we found a significant downregulation of SPOCD1 expression in some NOA patients,suggesting that the downregulation of SPOCD1 may be relevant for NOA.CONCLUSION Our study broadens the understanding of human SSC fate determination and may offer new theories on the etiology of male infertility.
基金supported by the National Natural Science Foundation of China,No.31340024
文摘Overexpression of receptor-interacting protein 140（RIP140） promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2（ERK1/2） signaling.However,involvement of RIP140 in human neural differentiation remains unclear.We found both RIP140 and ERK1/2 expression increased during neural differentiation of H1 human embryonic stem cells.Moreover,RIP140 negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation,and positively correlated with the neural stem cell marker Nestin during later stages.Thus,ERK1/2 signaling may provide the molecular mechanism by which RIP140 takes part in neural differentiation to eventually affect the number of neurons produced.
文摘Human embryonic stem cells (hESC) can be induced to differentiate to trophoblast by bone morphogenetic proteins (BMPs) and by aggregation to form embryoid bodies (EB), but there are many differences and controversies regarding the nature of the differentiated cells. Our goals herein were to determine if BG02 cells form trophoblast-like cells (a) in the presence of BMP4-plus-basic fibroblast growth factor (FGF-2) and (b) upon EB formation, and (c) whether the BMP4 antagonist noggin elicits direct effects on gene expression and hormone production in the cells. Transcriptome profiling of hESC incubated with BMP4/FGF-2 showed a down-regulation of pluripotency-associated genes, an up-regulation of trophoblast-associated genes, and either a down-regulation or no change in gene expression for many markers of the three embryonic germ layers. Yet, there was up-regulation of several genes associated with mesoderm, ectoderm, and endoderm, strongly suggesting that differentiation to trophoblast-like cells under the conditions used does not yield a homogeneous cell type. Several genes, heretofore unreported, were identified that are altered in hESC in response to BMP4-mediated differentiation. The production of human chorionic gonadotropin (hCG), progesterone, and estradiol in the differentiated cells confirmed that trophoblast-like cells were obtained. Gene expression by EB was characterized by an up-regulation of a number of genes associated with trophoblast, ectoderm, endoderm, and mesoderm, and the production of hCG and progesterone confirmed that trophoblast-like cells were formed. These results suggest that, in the presence of FGF-2, BG02 cells respond to BMP4 to yield trophoblast-like cells, which are also obtained upon EB formation. Thus, BMP4-mediated differentiation of hESC represents a viable cell system for studying early developmental events post-implantation;however, up-regulation of non-trophoblast genes suggests a somewhat diverse response to BMP4/FGF-2. Noggin altered the transcription of a limited number of genes but, not surprisingly, did not lead to secretion of hormones.
文摘Objective: To study the correlation of serum mesothelin and human epididymis secretory protein 4 contents with cellular infiltrative growth in patients with ovarian cancer. Methods:Patients with ovarian cancer who underwent surgical resection in West Coast Medical Center of the Affiliated Hospital of Qingdao University between June 2013 and December 2016 were selected as the ovarian cancer group of the study, and healthy women who received physical examination in China University of Petroleum (East China) Hospital during the same period were selected as the control group of the study. Serum was collected from two groups of subjects to detect serum mesothelin and human epididymis secretory protein 4 contents, and the ovarian cancer lesions and adjacent lesions were collected from ovarian cancer group to detect the expression of proliferation, apoptosis and invasion genes. Results: Serum mesothelin and human epididymis secretory protein 4 contents of ovarian cancer group were significantly higher than those of control group;FUNDC1, LSD1, TNFAIP8, CXCR4, β-catenin, CD44, PELP1, Slug, ZEB1 and Snail mRNA expression in ovarian cancer lesions were significantly higher than those in adjacent lesions and positively correlated with serum mesothelin and human epididymis secretory protein 4 contents while MFN2, PTEN, FN14 and E-cadherin mRNA expression were significantly lower than those in adjacent lesions and negatively correlated with serum mesothelin and human epididymis secretory protein 4 contents. Conclusion: Serum mesothelin and human epididymis secretory protein 4 contents abnormally increase in patients with ovarian cancer and are associated with the infiltrative growth of cancer cells.
