Objective. The aim of this retrospective multicenter study was to assess whether the pre- chemotherapy hemoglobin levels have any impact on the clinical outcome of patients with advanced epithelial ovarian cancer who ...Objective. The aim of this retrospective multicenter study was to assess whether the pre- chemotherapy hemoglobin levels have any impact on the clinical outcome of patients with advanced epithelial ovarian cancer who received a first- line taxane/platinum- based regimen. Methods. The study was conducted on 315 patients who underwent initial surgery followed by taxane/- platinum- based chemotherapy for FIGO stage IIc- IV epithelial ovarian cancer. All the patients had ECOG performance status 0- 1 at presentation. The median follow- up of survivors was 36 months (range, 6- 120 months). Results. The 25% , 50% , and 75% quantiles of hemoglobin levels before starting first line chemotherapy were 10.2, 11.4, and 12.3 g/dl, respectively. Residual disease after initial surgery (>1cmversus ≤ 1cm, P = 0.0013) was the only independent prognostic variable for overall survival. Conversely, hemoglobin levels (< 10.2 g/dl versus 10.2- 11.4 g/dl versus 11.5- 12.3 g/dl versus >12.3 g/dl)were inversely related to overall survival at univariate (P = 0.03) but not at multivariate analysis. Conclusions. This investigation showed that hemoglobin levels before starting first- line taxane/platinum- based chemotherapy are not an independent prognostic factor for overall survival in patients with advanced epithelial ovarian cancer.展开更多
Macrozoospermia,characterized by the presence of largeheaded spermatozoa usually carrying several flagella,is one of the most severe phenotypes of male infertility.As in most cases,the gametes are chromosomally abnorm...Macrozoospermia,characterized by the presence of largeheaded spermatozoa usually carrying several flagella,is one of the most severe phenotypes of male infertility.As in most cases,the gametes are chromosomally abnormal and cannot be used for assisted reproductive technologies(ART)(Ray et al.,2017).In 2007,subjects from consanguineous families were shown to carry the same homozygous deleterious AURKC variant(NM_001015878.2:c.144delC,later renamed c.145delC,p.Leu49TrpfsTer23),establishing AURKC as the first and main gene associated with macrozoospermia(Dieterich et al.,2007).Using flow cytometry,all spermatozoa from patients homozygous for the c.145delC variant were shown to be tetraploid,highlighting a cytokinesis blockage of the first meiotic divisions thus confirming that ART cannot be successful for these patients(Dieterich et al.,2009).展开更多
Oxidative stress is involved in chronic and acute pathologies: cardiovascular, neurodegenerative, neoplastic, inflammatory and infectious diseases. Clinical trials focused on prevention of cardiovascular and neoplasti...Oxidative stress is involved in chronic and acute pathologies: cardiovascular, neurodegenerative, neoplastic, inflammatory and infectious diseases. Clinical trials focused on prevention of cardiovascular and neoplastic diseases involving antioxidant supplementation have however provided predominantly negative obserations in large-scale studies. Screening of patient cohorts to assess baseline oxidative stress on the basis of a biomarker profile is decisive but lacking. For the first time, we evaluated the level of oxidative stress, testing more than 10 established biomarkers, in a comprehensive initial survey of 617 patients displaying chronic human pathologies. Multiple diseasespecific abnormalities were identified in plasma, whole blood and/or urine. This is the case for vitamins and oligo elements, vitamin C, vitamin E, β-carotene, selenium, zinc and copper;endogenous antioxidants such as reduced and oxidised glutathione, thiols, urate, and glutathione peroxidase activity, and a biomarker of oxidative DNA damage (8-hydroxy-2’-deoxy guanosine). The distinct biomarker profiles suggest the involvment of multiple forms of oxidative insults which arein some way partially specific to each pathological condition. This finding is in favor of the determination of an integrated score to combine contributions of distinct biomarkers, in order to screen patients presenting elevated levels of oxidative stress.展开更多
Asthenoteratozoospermia is a common cause of male infertility.To further define the genetic causes underlying asthenoteratozoospermia,we performed whole-exome sequencing in a cohort of Han Chinese men with asthenotera...Asthenoteratozoospermia is a common cause of male infertility.To further define the genetic causes underlying asthenoteratozoospermia,we performed whole-exome sequencing in a cohort of Han Chinese men with asthenoteratozoospermia.Homozygous deleterious variants of MYCBPAP were first identified in two unrelated Chinese cases.Replication analyses in a French cohort revealed an additional asthenoteratozoospermia-affected case harboring a homozygous nonsense variant in MYCBPAP.All of the identified MYCBPAP variants were absent or extremely rare in the public human genome databases.Further functional assays indicated remarkably reduced abundance of MYCBPAP in the spermatozoa from MYCBPAP-associated cases.Subsequently,we generated a Mycbpap knockout(Mycbpap^(−/−))mouse model,which also exhibited male infertility with reduced sperm motility and abnormal morphologies in sperm heads and flagella.Further investigations demonstrated that Mycbpap^(−/−)male mice presented disrupted acrosome biogenesis and abnormally elongated manchette during spermiogenesis.Intriguingly,proteomic analyses indicated that the proteins related to spermatogenesis,acrosomal and flagellar functions were significantly down-regulated in the testes from Mycbpap^(−/−)male mice.Endogenous immunoprecipitation combined with mass spectrometry revealed interactions of MYCBPAP with a ribosome elimination related protein ARMC3 and central apparatus proteins including CFAP65 and CFAP70.Furthermore,MYCBPAP-associated male infertility in humans and mice could be partially overcome by using intracytoplasmic sperm injections.Collectively,these findings illustrate the essential role of MYCBPAP in normal spermatogenesis and homozygous deleterious variants in MYCBPAP can be considered as a genetic diagnostic indicator for infertile men with asthenoteratozoospermia.Our study will provide effective guidance for genetic counseling,clinical diagnosis and assisted reproduction treatments of MYCBPAP-associated male infertility.展开更多
文摘Objective. The aim of this retrospective multicenter study was to assess whether the pre- chemotherapy hemoglobin levels have any impact on the clinical outcome of patients with advanced epithelial ovarian cancer who received a first- line taxane/platinum- based regimen. Methods. The study was conducted on 315 patients who underwent initial surgery followed by taxane/- platinum- based chemotherapy for FIGO stage IIc- IV epithelial ovarian cancer. All the patients had ECOG performance status 0- 1 at presentation. The median follow- up of survivors was 36 months (range, 6- 120 months). Results. The 25% , 50% , and 75% quantiles of hemoglobin levels before starting first line chemotherapy were 10.2, 11.4, and 12.3 g/dl, respectively. Residual disease after initial surgery (>1cmversus ≤ 1cm, P = 0.0013) was the only independent prognostic variable for overall survival. Conversely, hemoglobin levels (< 10.2 g/dl versus 10.2- 11.4 g/dl versus 11.5- 12.3 g/dl versus >12.3 g/dl)were inversely related to overall survival at univariate (P = 0.03) but not at multivariate analysis. Conclusions. This investigation showed that hemoglobin levels before starting first- line taxane/platinum- based chemotherapy are not an independent prognostic factor for overall survival in patients with advanced epithelial ovarian cancer.
基金funded by the French National Research Agency(ANR)projects MAS FLAGELLA (ANR-14-CE15-0002)+2 种基金FLAGELOME (ANR-19-CE17-0014)the INSERM (Institut National de la Sante et de la Recherche Medicale)Bettencourt Foundation
文摘Macrozoospermia,characterized by the presence of largeheaded spermatozoa usually carrying several flagella,is one of the most severe phenotypes of male infertility.As in most cases,the gametes are chromosomally abnormal and cannot be used for assisted reproductive technologies(ART)(Ray et al.,2017).In 2007,subjects from consanguineous families were shown to carry the same homozygous deleterious AURKC variant(NM_001015878.2:c.144delC,later renamed c.145delC,p.Leu49TrpfsTer23),establishing AURKC as the first and main gene associated with macrozoospermia(Dieterich et al.,2007).Using flow cytometry,all spermatozoa from patients homozygous for the c.145delC variant were shown to be tetraploid,highlighting a cytokinesis blockage of the first meiotic divisions thus confirming that ART cannot be successful for these patients(Dieterich et al.,2009).
文摘Oxidative stress is involved in chronic and acute pathologies: cardiovascular, neurodegenerative, neoplastic, inflammatory and infectious diseases. Clinical trials focused on prevention of cardiovascular and neoplastic diseases involving antioxidant supplementation have however provided predominantly negative obserations in large-scale studies. Screening of patient cohorts to assess baseline oxidative stress on the basis of a biomarker profile is decisive but lacking. For the first time, we evaluated the level of oxidative stress, testing more than 10 established biomarkers, in a comprehensive initial survey of 617 patients displaying chronic human pathologies. Multiple diseasespecific abnormalities were identified in plasma, whole blood and/or urine. This is the case for vitamins and oligo elements, vitamin C, vitamin E, β-carotene, selenium, zinc and copper;endogenous antioxidants such as reduced and oxidised glutathione, thiols, urate, and glutathione peroxidase activity, and a biomarker of oxidative DNA damage (8-hydroxy-2’-deoxy guanosine). The distinct biomarker profiles suggest the involvment of multiple forms of oxidative insults which arein some way partially specific to each pathological condition. This finding is in favor of the determination of an integrated score to combine contributions of distinct biomarkers, in order to screen patients presenting elevated levels of oxidative stress.
基金supported by the National Natural Science Foundation of China(32288101,32100480,32370654,82271638,32322017)the Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212200)+1 种基金Shanghai Hospital Development Center Foundation(SHDC12023121)the outstanding Youth Foundation of Hunan Provincial Natural Science Foundation of China(2023JJ20080).
文摘Asthenoteratozoospermia is a common cause of male infertility.To further define the genetic causes underlying asthenoteratozoospermia,we performed whole-exome sequencing in a cohort of Han Chinese men with asthenoteratozoospermia.Homozygous deleterious variants of MYCBPAP were first identified in two unrelated Chinese cases.Replication analyses in a French cohort revealed an additional asthenoteratozoospermia-affected case harboring a homozygous nonsense variant in MYCBPAP.All of the identified MYCBPAP variants were absent or extremely rare in the public human genome databases.Further functional assays indicated remarkably reduced abundance of MYCBPAP in the spermatozoa from MYCBPAP-associated cases.Subsequently,we generated a Mycbpap knockout(Mycbpap^(−/−))mouse model,which also exhibited male infertility with reduced sperm motility and abnormal morphologies in sperm heads and flagella.Further investigations demonstrated that Mycbpap^(−/−)male mice presented disrupted acrosome biogenesis and abnormally elongated manchette during spermiogenesis.Intriguingly,proteomic analyses indicated that the proteins related to spermatogenesis,acrosomal and flagellar functions were significantly down-regulated in the testes from Mycbpap^(−/−)male mice.Endogenous immunoprecipitation combined with mass spectrometry revealed interactions of MYCBPAP with a ribosome elimination related protein ARMC3 and central apparatus proteins including CFAP65 and CFAP70.Furthermore,MYCBPAP-associated male infertility in humans and mice could be partially overcome by using intracytoplasmic sperm injections.Collectively,these findings illustrate the essential role of MYCBPAP in normal spermatogenesis and homozygous deleterious variants in MYCBPAP can be considered as a genetic diagnostic indicator for infertile men with asthenoteratozoospermia.Our study will provide effective guidance for genetic counseling,clinical diagnosis and assisted reproduction treatments of MYCBPAP-associated male infertility.
