BACKGROUND The standard treatment of transitional cell carcinoma of the upper urinary tract consists of radical nephroureterectomy with bladder cuff removal,which can be performed either in open or laparoscopy or robo...BACKGROUND The standard treatment of transitional cell carcinoma of the upper urinary tract consists of radical nephroureterectomy with bladder cuff removal,which can be performed either in open or laparoscopy or robot-assisted laparoscopy.Treatment of chronic renal insufficiency patients with upper urothelial tumor is in a dilemma.Urologists weigh and consider the balance between tumor control and effective renal function preservation.European Association of Urology guidelines recommend that select patients may benefit from endoscopic treatment,but laparoscopic treatment is rarely reported.CASE SUMMARY In this case report,we describe a case of 79-year-old female diagnosed with urothelial carcinoma of the renal pelvis and adrenal adenoma with chronic renal insufficiency.The patient was treated with retroperitoneal laparoscopic partial resection of the renal pelvis and adrenal adenoma resection simultaneously.CONCLUSION Retroperitoneal laparoscopic partial resection of the renal pelvis is an effective surgical procedure for the treatment of urothelial carcinoma of the renal pelvis.展开更多
Objective To systematic review and analyze the practices and effects of integrating post-abortion family planning （PAFP） services into existing health system worldwide in order to inform the future interventions to ...Objective To systematic review and analyze the practices and effects of integrating post-abortion family planning （PAFP） services into existing health system worldwide in order to inform the future interventions to deliver PAFP in China. Methods A systematic search for relevant published and unpublished literature was conducted. Based on a set of criteria, citation and full text were screened, related data were extracted. Findings of included studies were reviewed and analyzed using a textual narrative approach to synthesis. Results A total of 28 studies were included in the synthesis. The studies were published between 1995 and 2008 and covered 20 countries. Some countries were in the stage of piloting post-abortion care （PAC）/PAFP intervention, while others were either from piloting to scaling up or examined how well a pilot PAC/PAFP intervention and resulting improvements were able to be maintained over the long term in the same intervention site. Most studies examined initiatives that were implemented at public sectors from tertiary, secondary to primary health facilities, while a few were imple- mented at private sectors. Efforts of integrating PAFP into existing health system from health system perspectives such as funding the programs, training of trainer （TOT） training or on the job training of physicians and mid-level service provider, expan- sion the range of contraceptive methods available including a few free distribution of contraceptives, improving data collection including cost analysis in a few countries,service guidelines provided to health professionals, supportive supervision at program sites to ensure quality of care, and leadership from government to strengthen PAC/ PAFP service by revising or developing a new national policy. Effects of those intervention programs included that 2 studies decreased abortion rates, 7 studies improved modern contraceptive use, 1 study improved women＇s knowledge on sexual ＆ reproductive health, and 5 studies reported women＇s high satisfaction rate with receiving PAC/PAFP services. Conclusion Each study was conducted within a cultural legal social and religious framework. There might be no single set of best practices that can be put forward as a model to integrate PAFP into existing health system in China. These areas should be taken into account in our future intervention including government＇s optimization and complement to the regulations related to abortion, contraception and PAFP, capacity building for service provider, continuous efforts to improve the quality of PAFP service, and accessibility of multiple contraceptive methods for married as well as unmarried youth.展开更多
In this study,we aimed to assess the effect of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection on semenparameters.The study comprised 110 sperm volunteers who self-reported SARS-CoV-2 infection fr...In this study,we aimed to assess the effect of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection on semenparameters.The study comprised 110 sperm volunteers who self-reported SARS-CoV-2 infection from the Human Sperm Bank ofthe Center for Reproductive Medicine,Shandong University(Jinan,China).The volunteers had normal sperm concentration beforeinfection.Each volunteer provided semen samples before and after infection.We selected 90 days after infection as the cutoff point.Semen parameters within 90 days after infection of 109 volunteers(group A)were compared with semen parameters before infection.Moreover,semen parameters on or after 90 days after infection of 36 volunteers(group B)were compared with semen parameters beforeinfection.Furthermore,based on whether the volunteers had completed the three-dose SARS-CoV-2 vaccination booster,volunteersin group A and B were further divided into two subgroups separately.Semen parameters were compared before and after infection ineach subgroup.Our results showed that in this cohort population,the semen quality in volunteers with normal sperm concentrationsbefore infection decreased after SARS-CoV-2 infection within 90 days,while the semen quality returned to preinfection levels after 90days.The completion of a three-dose SARS-CoV-2 vaccination booster may exert a protective effect on semen quality after infection.展开更多
Non-obstructive azoospermia(NOA),the lack of sperm in the ejaculate due to failure of spermatogenesis,can result from a variety of diverse factors,with genetic factors accounting for~30%of NOA cases,including chromoso...Non-obstructive azoospermia(NOA),the lack of sperm in the ejaculate due to failure of spermatogenesis,can result from a variety of diverse factors,with genetic factors accounting for~30%of NOA cases,including chromosomal aberrations,Y-chromosome microdeletions,and monogenic variants(Tang et al.,2022).More than 2000genes are known to participate in spermatogenesis,and>400 genes specifically linked to azoospermia have been identified through studies in mouse models(Krausz and Riera-Escamilla,2018).However,relatively few genes associated with azoospermia in mice have been verified in humans.展开更多
There are many unknown genetic factors that lead to infertility in nonobstructive azoospermia men.Here,we performed whole-exome sequencing in blood samples obtained from 40 azoospermia patients with meiotic arrest and...There are many unknown genetic factors that lead to infertility in nonobstructive azoospermia men.Here,we performed whole-exome sequencing in blood samples obtained from 40 azoospermia patients with meiotic arrest and found a novel c.151_154del(p.D51fs)frame-shift mutation in exon 3 of the testis expressed 11(TEX11)gene in one patient.Sanger sequencing analysis of the patient and 288 fertile men was performed to validate the mutation.Immunohistochemical analysis showed TEX11 expression in late-pachytene spermatocytes and in round spermatids in fertile human testes.In contrast,testes of the patient with TEX11 mutation underwent meiotic arrest and lacked TEX11 expression.Western blotting of human embryonic kidney(HEK293)cells transfected with a vector for the p.D51fs TEX11 variant detected no TEX11 expression.In conclusion,we identified a novel frame-shift mutation in the TEX11 gene in an azoospermia patient,emphasizing that this gene should be included in genetic screening panels for the clinical evaluation of azoospermia patients.展开更多
AIM:To investigate the correlation between the Helicobacter pylori(H.pylori)infection and host genetic background of healthy populations in Indonesia.METHODS:In March 2007,epidemiological studies were undertaken on th...AIM:To investigate the correlation between the Helicobacter pylori(H.pylori)infection and host genetic background of healthy populations in Indonesia.METHODS:In March 2007,epidemiological studies were undertaken on the general population of a city in Indonesia(Mataram,Lombok).The participants included 107 men and 187 women,whose ages ranged from6 to 74 years old,with an average age of 34.0(±14.4)(±SD).The H.pylori of subject by UBT method determination,and through the polymerase chain reaction with confronting two-pair primers(PCR-CTPP)method parsing the single nucleotide polymorphism of interleukin(IL)-8,IL-4,IL-1β,CD14,tumor necrosis factor(TNF-a)and tyrosine-protein phosphates non-receptor type 11(PTPN11)genotypes.The experimental data were analyzed by the statistical software SAS.RESULTS:The H.pylori infection rates in the healthy Indonesian population studied were 8.4%for men and12.8%for women;no obvious differences were noted for H.pylori infection rates by sex or age.TC genotypes of IL-4,TC and CC genotypes of TNF-a,and GA genotypes of PTPN11,were higher in frequency.Both CC and TC genotype of TNF-a T-1031C loci featured higher expressions in the healthy Indonesian population Indonesia studied of(OR=1.99;95%CI:0.67-5.89)and(OR=1.66;95%CI:0.73-3.76),respectively.C allele of IL-1βT-31C gene locus was at a higher risk(OR=1.11;95%CI:0.70-1.73)of H.pylori infection,but no statistical significance was found in our study.CONCLUSION:We reveal that the association between the TNF-a and IL-1βgenotypes may be the susceptibility of H.pylori in the studied population.展开更多
Repairing DNA double-strand breaks(DSBs)with homologous chromosomes as templates is the hallmark of meiosis.The critical outcome of meiotic homologous recombination is crossovers,which ensure faithful chromosome segre...Repairing DNA double-strand breaks(DSBs)with homologous chromosomes as templates is the hallmark of meiosis.The critical outcome of meiotic homologous recombination is crossovers,which ensure faithful chromosome segregation and promote genetic diversity of progenies.Crossover patterns are tightly controlled and exhibit three characteristics:obligatory crossover,crossover interference,and crossover homeostasis.Aberrant crossover patterns are the leading cause of infertility,miscarriage,and congenital disease.Crossover recombination occurs in the context of meiotic chromosomes,and it is tightly integrated with and regulated by meiotic chromosome structure both locally and globally.Meiotic chromosomes are organized in a loop-axis architecture.Diverse evidence shows that chromosome axis length determines crossover frequency.Interestingly,short chromosomes show different crossover patterns compared to long chromosomes.A high frequency of human embryos are aneuploid,primarily derived from female meiosis errors.Dramatically increased aneuploidy in older women is the well-known“maternal age effect.”However,a high frequency of aneuploidy also occurs in young women,derived from crossover maturation inefficiency in human females.In addition,frequency of human aneuploidy also shows other age-dependent alterations.Here,current advances in the understanding of these issues are reviewed,regulation of crossover patterns by meiotic chromosomes are discussed,and issues that remain to be investigated are suggested.展开更多
Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated ...Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that cancerous immunoglobulins play significant roles in the growth and proliferation of cancer cells in vitro and in vivo. RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. Through gene regulation studies, both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell proliferation (such as NFκB-1, IgG, P21, cyclin D1, ribosomal P1, and c-fos). Furthermore, selected toll-like receptor genes (TLR- 2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and anti-antigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and down- regulate TLR-4 and TLR-9 intwo types of cancer cells. Based on these studies, it is reasonable to postulate that cancerous immunoglobulins play important roles in the modulation of the innate immune system to allow the growth and survival of cancer cells within the human body. Consequently, RP215 inits humanized forms may be utilized to target cancer cells for potential therapeutic purposes.展开更多
RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically ...RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically on glycoproteins, known as CA215, from cancer cells. Further molecular analysis by matrix adsorption laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) revealed that CA215 consists mainly of immunoglobulin super-family (IgSF) proteins, including immunoglobulins, T-cell receptors, and cell adhesion molecules, as well as several other unrelated proteins. Peptide mappings and glycoanalysis were performed with CA215 and revealed high-mannose and complex bisecting structures with terminal sialic acid in N-glycans. As many as ten O-glycans, which are structurally similar to those of mucins, were also identified. In addition, two additional O-linked glycans were exclusively detected in cancerous immunoglobulins but not in normal B cell-derived immunoglobulins. Immunizations of mice with purified CA215 resulted in the predominant generation of RP215-related Mabs, indicating the immunodominance of this carbohydrate-associated epitope. Anti-idiotype (anti-id) Mabs of RP215, which were generated in the rat, were shown to contain the internal images of the carbohydrate-associated epitope. Following immunizations of these anti-id Mabs in mice, the resulting anti-anti-id (Ab3) responses in mice were found to be immunologically similar to that of RP215. Judging from these observations, anti-id Mabs, which carry the internal image of the RP215-specific epitope, may be suitable candidates for anticancer vaccine development in humans.展开更多
There continues to be an increase in utilization of assisted reproductive technology(ART), including the use of third party gametes. Specifically, the use of third party oocytes, most recently reported in 2010 by the ...There continues to be an increase in utilization of assisted reproductive technology(ART), including the use of third party gametes. Specifically, the use of third party oocytes, most recently reported in 2010 by the United States(US) Center for Disease Control and Society of Reproductive Medicine, accounted for 15 504 cycles and 7334 live births. This translates into approximately 11% of all the in vitro fertilization cases performed in the US. As utilization increases and the technological tools advance, they have created underappreciated and unforeseen ethical quandaries. As such, many practitioners think they "have heard it all". However, each ART scenario is novel with the potential to pose complex unforeseen issues, potentially creating global challenges that could impact broad social and legal questions and test the moral consciousness' of practitioners, policymakers and patients. While there are published US national guidelines to assist practitioners, we have identified new complex issues in assisted reproduction that present unique challenges, and we give a perspective from oureyes in the Western Hemisphere looking out to a global level. Specifically, this review focuses on some of the more recent and evolving issues that currently are and will be confronting us in the upcoming years. Particular attention focuses on discrepancies between third party legal contracts and ART consents regarding level of information sharing, and oocyte and embryo directives and management; dilemmas and obligations surrounding disclosure of medical outcomes especially in the context of growing access to Direct to Consumer genetic testing and Reproductive Tourism-Exile. Given the complexity of these and other ethical questions, finding answers may be achieved by ending the isolation of reproductive professionals and instead promoting increased and consistent communication among physicians, embryologists, therapists and reproductive attorneys to confront these evolving ethical quandaries.展开更多
During the last two decades, two distinct monoclonal antibodies, RP215 and GHR106 were generated, respectively and extensively characterized, biologically and immunologically. Both antibodies target separately specifi...During the last two decades, two distinct monoclonal antibodies, RP215 and GHR106 were generated, respectively and extensively characterized, biologically and immunologically. Both antibodies target separately specific pan cancer markers and are being evaluated preclinically for potential therapeutic applications in cancer immunotherapy and/or fertility regulations. RP215 was shown to react specifically with carbohydrate-associated epitope located in the heavy chain variable regions of cancer cell expressed specific immunoglobulins, designated as CA215 which are distinct from those of normal B cell origins. The cancerous immunoglobulins may function to react with specific human serum proteins to facilitate growth/proliferation as well as protection of cancer cells in circulations. RP215-based enzyme immunoassays were designed to monitor serum CA215 levels among cancer patients. On the other hand, GHR106 was generated against N1-29 oligopeptide located in the extracellular domains of human GnRH receptor found either in the anterior pituitary or in most of the cancer cells. In vitro culture of cancer cells revealed that either of these two antibodies can induce apoptosis of cancer cells following 24 - 48 hours incubations. Anti-tumor activities of both antibodies were evaluated by typical nude mouse experiments. Either one was shown to effectively reduce the volumes of implanted tumors, dose-dependently. Humanized forms of either antibody were made available in CAR (chimeric antigen receptor)-T cell constructs. They were shown separately to induce cytotoxic killings of cancer cells in vitro by releasing cytokines upon incubations of tumor cells with either of CAR-T cell constructs. In addition, GHR106 also acts as GnRH antagonist by a specific targeting to pituitary GnRH receptor for reversible suppressions of reproductive hormones such as LH, testosterone or estradiol. Based on the above preclinical assessments, it can be generally concluded that both RP215 and GHR106 are restricted in normal tissue expressions and suitable for targeting cancerous immunoglobulins and GnRH receptor, respectively for cancer immunotherapy. Furthermore, specific targeting of pituitary GnRH receptor may suggest that the long acting GHR106 (5 - 21 days half-life) is an adequate GnRH antagonist for numerous gynecological treatments including ovulation inhibition in IVF/ART, endometriosis, premenstrual syndrome, precocious puberty, uterine fibroids and/or polycystic ovarian syndrome.展开更多
To the Editor:Recurrent pregnancy loss(RPL)is defined as two or more consecutive spontaneous pregnancy losses before 24 weeks of gestation;it affects 1-2%of couples.[1]Some causes of RPL are uterine anatomical abnorma...To the Editor:Recurrent pregnancy loss(RPL)is defined as two or more consecutive spontaneous pregnancy losses before 24 weeks of gestation;it affects 1-2%of couples.[1]Some causes of RPL are uterine anatomical abnormalities,abnormal chromosomes in parents or embryos,antiphospholipid syndrome,and certain autoimmune disorders.[2]However,the etiology of 40-50%of RPL couples remains unclear and is defined as unexplained RPL(uRPL).展开更多
Objective:Although consensus on the optimal endometrial preparation protocol for frozen-thawed embryo transfer(FET)is lacking,this is particularly true for patients with infertility and a history of endometrial polyps...Objective:Although consensus on the optimal endometrial preparation protocol for frozen-thawed embryo transfer(FET)is lacking,this is particularly true for patients with infertility and a history of endometrial polyps(EPs).In this study,we aimed to investigate whether a gonadotropin-releasing hormone agonist combined with hormone replacement therapy(GnRHa-HRT)could improve pregnancy outcomes in single euploid FET for patients with a history of EPs.Methods:In this retrospective cohort study,395 women who underwent their first single euploid FET cycle were divided into groups according to endometrial preparation protocols as follows:natural cycle(NC)(n=220),hormone replacement therapy(HRT)(n=122),and GnRHa-HRT groups(n=53).Subsequently,the FET cycles in the three groups were subdivided according to maternal age.All patients underwent hysteroscopic polypectomy before FET,and their EPs were confirmed by pathology.Results:No statistically significant differences were observed in live birth rates among the three groups(58.64%vs.58.20%vs.56.60%,P=0.964).Furthermore,the rates of miscarriage,ectopic pregnancy,premature live birth,and pregnancy complications were comparable among the three groups(P>0.05).After adjusting for potential confounding factors,no significant differences in pregnancy outcomes were reported between the groups(adjusted odds ratios[OR]and 95%credible intervals[CI]for live birth rate,HRTvs.NC:1.119,0.660–1.896,P=0.677;GnRHa-HRTvs.NC:1.165,0.610–2.226,P=0.643).Additionally,the pregnancy outcomes of the FET cycle were not influenced by the endometrial preparation protocols in the subgroups when stratified by maternal age(P>0.05).Conclusion:GnRHa-HRT did not improve the pregnancy outcomes of the single euploid FET in patients with a history of EPs.展开更多
Infertility affects around 8%-12%of couples globally,and in about 50%of these cases,male factors are either the primary cause or contribute significantly to infertility.Any defects during spermiogenesis may result in ...Infertility affects around 8%-12%of couples globally,and in about 50%of these cases,male factors are either the primary cause or contribute significantly to infertility.Any defects during spermiogenesis may result in male subfertility or complete infertility in mammals.1 Previously,we found that CFAP53 is localized in the manchette and sperm tail,and it plays an essential role in sperm flagellum biogenesis.展开更多
The vaginal microbiome is critical for the reproductive health of women,yet the differential impacts exerted by the host and by ambient environmental variables on the vaginal microbiome remain largely unknown.Here,we ...The vaginal microbiome is critical for the reproductive health of women,yet the differential impacts exerted by the host and by ambient environmental variables on the vaginal microbiome remain largely unknown.Here,we conducted a comprehensive cross-sectional study of the relationships between the vaginal microbiome and 81 matched host and environmental variables across 6755 Chinese women.By 16S rRNA sequencing,we identified four core vaginal microbiota with a prevalence of over 90%and a total median abundance of 98.8%.Twenty-four variables,including physiology,lifestyle behaviors,gynecologic history,social and environmental information,were found associated with the microbiome composition,of which bacterial vaginosis(BV)showed the largest effect size.Age was among the strongest explanatory variables and the vaginal microbiome dynamically succeeded with increasing age,especially with a composition turning point at the age of 45.Our mediation analyses indicated that the effects of age on the microbiome could be mediated by variables such as parity number and lifestyles.We further classified the vaginal microbiomes of the population into 13“Vagitypes”.Women with Lactobacillus iners-and Lactobacillus jensenii-dominated Vagitypes had significantly higher live birth rate than those with Vagitype dominated by Fannyhessea vaginae(53.40%,59.09%vs 21.43%;OR[95%CI]:3.62[1.12-14.87],5.39[1.27-27.36];P=0.031,P=0.021).This study provides a comprehensive overview of the associations between identified variables and the vaginal microbiome,representing an important step toward understanding of environment-microbe-host interactions.展开更多
Dear Editor,Assisted Reproductive Technology(ART)refers to the use of medical aids to achieve pregnancy in infertile couples,including Artificial Insemination(AI)and In vitro Fertilization-Embryo Transfer(IVF),of whic...Dear Editor,Assisted Reproductive Technology(ART)refers to the use of medical aids to achieve pregnancy in infertile couples,including Artificial Insemination(AI)and In vitro Fertilization-Embryo Transfer(IVF),of which IVF has been a common option for infertility treatment.展开更多
Objective Premature ovarian insufficiency(POI)is defined as the depletion of ovarian function before 40years of age,affecting approximately 3.7%of women in their reproductive age worldwide.Previous studies revealed se...Objective Premature ovarian insufficiency(POI)is defined as the depletion of ovarian function before 40years of age,affecting approximately 3.7%of women in their reproductive age worldwide.Previous studies revealed several genes involved in the Fanconi anaemia(FA)pathway participate in the pathogenesis of POI,such as FANCA and FANCM.FA pathway maintains rapid proliferation in the developing primordial germ cells by deregulating transcription-replication conflicts,which is crucial for the establishment of sufficient ovarian reserve.FANCJ encodes a DNA helicase located downstream of the FA pathway promoting DNA damage repair and cell proliferation.Recently,two heterozygous FANCJ missense variants have been reported in patients with POI,suggesting haploinsufficiency of FANCJ participates in the pathogenesis of the disease.In this study,to further explore the contribution of FANCJ variants in POI,we reported a rare homozygous FANCJ start-loss variation in one patient with POI and illustrated its pathogenicity by in vitro functional studies.Methods The loss-of-function(LoF)variants of FANCJ were screened in our internal whole-exome sequencing(WES)database of POI.Sanger sequencing and WES analysis were employed on the proband and the patient’s family members to illustrate the origin of the bi-allelic variant.Cycloheximide chase assay was performed to demonstrate the impact of the variant on the protein stability of FANCJ.Protein ubiquitination assay was performed to confirm the accelerated degradation pathway of FANCJ protein.ResultsThrough the variation screening,a bi-allelic variant of FANCJ(NM_032043.3:c.1A>G,p.Met1Val)was identified in one case.The functional study showed that the start-loss variant affected FANCJ protein stability by accelerated protein degradation through the ubiquitinproteasome pathway.Conclusion Our findings provide further genetic evidence of the FANCJ variant participating in the pathogenesis of POI,expand the inherited mode and highlight the essential role of the FA pathway in maintaining ovarian function.展开更多
Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology.However,its genetic basis is largely unrevealed.Geminin,encoded by the GMNN gene,plays an...Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology.However,its genetic basis is largely unrevealed.Geminin,encoded by the GMNN gene,plays an important role in preventing DNA re-replication by inhibiting CDT1.Here,using whole-exome sequencing and Sanger sequencing,we identified three rare missense mutations of GMNN in females with preimplantation arrest,following a dominant inheritance pattern.The RNA sequencing data from both the mouse zygotes and the patient's one-cell embryo demonstrated the altered cell cycle processes.We then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 and DNA damage,resulting in cell cycle disturbance.Our findings uncover a mechanistic understanding of the pathogenesis of human preimplantation embryo arrest,which acts by impairing the correct cell cycle and DNA rereplication procedure,and provides a new molecular target for the diagnosis and treatment of infertile patients.展开更多
The number of growth factors involved in female fertility has been extensively studied, but reluctance to add essential growth factors in culture media has limited progress in optimizing embryonic growth and implantat...The number of growth factors involved in female fertility has been extensively studied, but reluctance to add essential growth factors in culture media has limited progress in optimizing embryonic growth and implantation outcomes, a situation that has ultimately led to reduced pregnancy outcomes. Insulin-like growth factor Ⅱ(IGF-Ⅱ) is the most intricately regulated of all known reproduction-related growth factors characterized to date, and is perhaps the predominant growth factor in human ovarian follicles. This review aims to concisely summarize what is known about the role of IGF-Ⅱ in follicular development, oocyte maturation, embryonic development, implantation success, placentation, fetal growth, and in reducing placental cell apoptosis, as well as present strategies that use growth factors in culture systems to improve the developmental potential of oocytes and embryos in different species. Synthesizing the present knowledge about the physiological roles of IGF-Ⅱ in follicular development, oocyte maturation, and early embryonic development should, on the one hand, deepen our overall understanding of the potential beneficial effects of growth factors in female reproduction and on the other hand support development(optimization) of improved outcomes for assisted reproductive technologies.展开更多
Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection has swept the globe for 3 years(Zhou et al.,2020).With the nationwide relaxation of controls on the coronavirus disease 2019(COVID-19)ep...Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection has swept the globe for 3 years(Zhou et al.,2020).With the nationwide relaxation of controls on the coronavirus disease 2019(COVID-19)epidemic since December 2022 in China,fertility and in vitro fertilization(IVF)centers are receiving increasing numbers of infected patients.展开更多
文摘BACKGROUND The standard treatment of transitional cell carcinoma of the upper urinary tract consists of radical nephroureterectomy with bladder cuff removal,which can be performed either in open or laparoscopy or robot-assisted laparoscopy.Treatment of chronic renal insufficiency patients with upper urothelial tumor is in a dilemma.Urologists weigh and consider the balance between tumor control and effective renal function preservation.European Association of Urology guidelines recommend that select patients may benefit from endoscopic treatment,but laparoscopic treatment is rarely reported.CASE SUMMARY In this case report,we describe a case of 79-year-old female diagnosed with urothelial carcinoma of the renal pelvis and adrenal adenoma with chronic renal insufficiency.The patient was treated with retroperitoneal laparoscopic partial resection of the renal pelvis and adrenal adenoma resection simultaneously.CONCLUSION Retroperitoneal laparoscopic partial resection of the renal pelvis is an effective surgical procedure for the treatment of urothelial carcinoma of the renal pelvis.
基金funded by the European Commission’s Seventh Framework Program[FP7/2007-2013]under grant agreement No.282490
文摘Objective To systematic review and analyze the practices and effects of integrating post-abortion family planning （PAFP） services into existing health system worldwide in order to inform the future interventions to deliver PAFP in China. Methods A systematic search for relevant published and unpublished literature was conducted. Based on a set of criteria, citation and full text were screened, related data were extracted. Findings of included studies were reviewed and analyzed using a textual narrative approach to synthesis. Results A total of 28 studies were included in the synthesis. The studies were published between 1995 and 2008 and covered 20 countries. Some countries were in the stage of piloting post-abortion care （PAC）/PAFP intervention, while others were either from piloting to scaling up or examined how well a pilot PAC/PAFP intervention and resulting improvements were able to be maintained over the long term in the same intervention site. Most studies examined initiatives that were implemented at public sectors from tertiary, secondary to primary health facilities, while a few were imple- mented at private sectors. Efforts of integrating PAFP into existing health system from health system perspectives such as funding the programs, training of trainer （TOT） training or on the job training of physicians and mid-level service provider, expan- sion the range of contraceptive methods available including a few free distribution of contraceptives, improving data collection including cost analysis in a few countries,service guidelines provided to health professionals, supportive supervision at program sites to ensure quality of care, and leadership from government to strengthen PAC/ PAFP service by revising or developing a new national policy. Effects of those intervention programs included that 2 studies decreased abortion rates, 7 studies improved modern contraceptive use, 1 study improved women＇s knowledge on sexual ＆ reproductive health, and 5 studies reported women＇s high satisfaction rate with receiving PAC/PAFP services. Conclusion Each study was conducted within a cultural legal social and religious framework. There might be no single set of best practices that can be put forward as a model to integrate PAFP into existing health system in China. These areas should be taken into account in our future intervention including government＇s optimization and complement to the regulations related to abortion, contraception and PAFP, capacity building for service provider, continuous efforts to improve the quality of PAFP service, and accessibility of multiple contraceptive methods for married as well as unmarried youth.
基金supported by the National Key Research and Development Program of China(No.2022YFC2703200 and No.2021YFC2700600).
文摘In this study,we aimed to assess the effect of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection on semenparameters.The study comprised 110 sperm volunteers who self-reported SARS-CoV-2 infection from the Human Sperm Bank ofthe Center for Reproductive Medicine,Shandong University(Jinan,China).The volunteers had normal sperm concentration beforeinfection.Each volunteer provided semen samples before and after infection.We selected 90 days after infection as the cutoff point.Semen parameters within 90 days after infection of 109 volunteers(group A)were compared with semen parameters before infection.Moreover,semen parameters on or after 90 days after infection of 36 volunteers(group B)were compared with semen parameters beforeinfection.Furthermore,based on whether the volunteers had completed the three-dose SARS-CoV-2 vaccination booster,volunteersin group A and B were further divided into two subgroups separately.Semen parameters were compared before and after infection ineach subgroup.Our results showed that in this cohort population,the semen quality in volunteers with normal sperm concentrationsbefore infection decreased after SARS-CoV-2 infection within 90 days,while the semen quality returned to preinfection levels after 90days.The completion of a three-dose SARS-CoV-2 vaccination booster may exert a protective effect on semen quality after infection.
基金supported by the National Key R&D Program of China(2023YFC2705503)Major Innovation Projects in Shandong Province(2021ZDSYS16)+4 种基金the National Natural Science Foundation of China(82071699 and 82371619)CAMS Innovation Fund for Medical Sciences(2021-I2M-5-001)the Basic Science Center Program of NSFC(31988101)Science Foundation for Distinguished Young Scholars of Shandong(ZR2021JQ27)Taishan Scholars Program for Young Experts of Shandong Province(tsqn202103192)。
文摘Non-obstructive azoospermia(NOA),the lack of sperm in the ejaculate due to failure of spermatogenesis,can result from a variety of diverse factors,with genetic factors accounting for~30%of NOA cases,including chromosomal aberrations,Y-chromosome microdeletions,and monogenic variants(Tang et al.,2022).More than 2000genes are known to participate in spermatogenesis,and>400 genes specifically linked to azoospermia have been identified through studies in mouse models(Krausz and Riera-Escamilla,2018).However,relatively few genes associated with azoospermia in mice have been verified in humans.
基金the Key Research and Development Program of Shandong Province(2019GSF108237)the Young Scholars Program of Shandong University(2016WLJH50)the Natural Science Foundation of Shandong Province(ZR2017MH049).
文摘There are many unknown genetic factors that lead to infertility in nonobstructive azoospermia men.Here,we performed whole-exome sequencing in blood samples obtained from 40 azoospermia patients with meiotic arrest and found a novel c.151_154del(p.D51fs)frame-shift mutation in exon 3 of the testis expressed 11(TEX11)gene in one patient.Sanger sequencing analysis of the patient and 288 fertile men was performed to validate the mutation.Immunohistochemical analysis showed TEX11 expression in late-pachytene spermatocytes and in round spermatids in fertile human testes.In contrast,testes of the patient with TEX11 mutation underwent meiotic arrest and lacked TEX11 expression.Western blotting of human embryonic kidney(HEK293)cells transfected with a vector for the p.D51fs TEX11 variant detected no TEX11 expression.In conclusion,we identified a novel frame-shift mutation in the TEX11 gene in an azoospermia patient,emphasizing that this gene should be included in genetic screening panels for the clinical evaluation of azoospermia patients.
文摘AIM:To investigate the correlation between the Helicobacter pylori(H.pylori)infection and host genetic background of healthy populations in Indonesia.METHODS:In March 2007,epidemiological studies were undertaken on the general population of a city in Indonesia(Mataram,Lombok).The participants included 107 men and 187 women,whose ages ranged from6 to 74 years old,with an average age of 34.0(±14.4)(±SD).The H.pylori of subject by UBT method determination,and through the polymerase chain reaction with confronting two-pair primers(PCR-CTPP)method parsing the single nucleotide polymorphism of interleukin(IL)-8,IL-4,IL-1β,CD14,tumor necrosis factor(TNF-a)and tyrosine-protein phosphates non-receptor type 11(PTPN11)genotypes.The experimental data were analyzed by the statistical software SAS.RESULTS:The H.pylori infection rates in the healthy Indonesian population studied were 8.4%for men and12.8%for women;no obvious differences were noted for H.pylori infection rates by sex or age.TC genotypes of IL-4,TC and CC genotypes of TNF-a,and GA genotypes of PTPN11,were higher in frequency.Both CC and TC genotype of TNF-a T-1031C loci featured higher expressions in the healthy Indonesian population Indonesia studied of(OR=1.99;95%CI:0.67-5.89)and(OR=1.66;95%CI:0.73-3.76),respectively.C allele of IL-1βT-31C gene locus was at a higher risk(OR=1.11;95%CI:0.70-1.73)of H.pylori infection,but no statistical significance was found in our study.CONCLUSION:We reveal that the association between the TNF-a and IL-1βgenotypes may be the susceptibility of H.pylori in the studied population.
基金This work is supported by grants from the National Key R&D Program of China(2018YFC1003700,2018YFC1003400)National Natural Science Foundation of China(31671293,31801203,and 31890782).
文摘Repairing DNA double-strand breaks(DSBs)with homologous chromosomes as templates is the hallmark of meiosis.The critical outcome of meiotic homologous recombination is crossovers,which ensure faithful chromosome segregation and promote genetic diversity of progenies.Crossover patterns are tightly controlled and exhibit three characteristics:obligatory crossover,crossover interference,and crossover homeostasis.Aberrant crossover patterns are the leading cause of infertility,miscarriage,and congenital disease.Crossover recombination occurs in the context of meiotic chromosomes,and it is tightly integrated with and regulated by meiotic chromosome structure both locally and globally.Meiotic chromosomes are organized in a loop-axis architecture.Diverse evidence shows that chromosome axis length determines crossover frequency.Interestingly,short chromosomes show different crossover patterns compared to long chromosomes.A high frequency of human embryos are aneuploid,primarily derived from female meiosis errors.Dramatically increased aneuploidy in older women is the well-known“maternal age effect.”However,a high frequency of aneuploidy also occurs in young women,derived from crossover maturation inefficiency in human females.In addition,frequency of human aneuploidy also shows other age-dependent alterations.Here,current advances in the understanding of these issues are reviewed,regulation of crossover patterns by meiotic chromosomes are discussed,and issues that remain to be investigated are suggested.
文摘Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that cancerous immunoglobulins play significant roles in the growth and proliferation of cancer cells in vitro and in vivo. RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. Through gene regulation studies, both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell proliferation (such as NFκB-1, IgG, P21, cyclin D1, ribosomal P1, and c-fos). Furthermore, selected toll-like receptor genes (TLR- 2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and anti-antigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and down- regulate TLR-4 and TLR-9 intwo types of cancer cells. Based on these studies, it is reasonable to postulate that cancerous immunoglobulins play important roles in the modulation of the innate immune system to allow the growth and survival of cancer cells within the human body. Consequently, RP215 inits humanized forms may be utilized to target cancer cells for potential therapeutic purposes.
文摘RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically on glycoproteins, known as CA215, from cancer cells. Further molecular analysis by matrix adsorption laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) revealed that CA215 consists mainly of immunoglobulin super-family (IgSF) proteins, including immunoglobulins, T-cell receptors, and cell adhesion molecules, as well as several other unrelated proteins. Peptide mappings and glycoanalysis were performed with CA215 and revealed high-mannose and complex bisecting structures with terminal sialic acid in N-glycans. As many as ten O-glycans, which are structurally similar to those of mucins, were also identified. In addition, two additional O-linked glycans were exclusively detected in cancerous immunoglobulins but not in normal B cell-derived immunoglobulins. Immunizations of mice with purified CA215 resulted in the predominant generation of RP215-related Mabs, indicating the immunodominance of this carbohydrate-associated epitope. Anti-idiotype (anti-id) Mabs of RP215, which were generated in the rat, were shown to contain the internal images of the carbohydrate-associated epitope. Following immunizations of these anti-id Mabs in mice, the resulting anti-anti-id (Ab3) responses in mice were found to be immunologically similar to that of RP215. Judging from these observations, anti-id Mabs, which carry the internal image of the RP215-specific epitope, may be suitable candidates for anticancer vaccine development in humans.
文摘There continues to be an increase in utilization of assisted reproductive technology(ART), including the use of third party gametes. Specifically, the use of third party oocytes, most recently reported in 2010 by the United States(US) Center for Disease Control and Society of Reproductive Medicine, accounted for 15 504 cycles and 7334 live births. This translates into approximately 11% of all the in vitro fertilization cases performed in the US. As utilization increases and the technological tools advance, they have created underappreciated and unforeseen ethical quandaries. As such, many practitioners think they "have heard it all". However, each ART scenario is novel with the potential to pose complex unforeseen issues, potentially creating global challenges that could impact broad social and legal questions and test the moral consciousness' of practitioners, policymakers and patients. While there are published US national guidelines to assist practitioners, we have identified new complex issues in assisted reproduction that present unique challenges, and we give a perspective from oureyes in the Western Hemisphere looking out to a global level. Specifically, this review focuses on some of the more recent and evolving issues that currently are and will be confronting us in the upcoming years. Particular attention focuses on discrepancies between third party legal contracts and ART consents regarding level of information sharing, and oocyte and embryo directives and management; dilemmas and obligations surrounding disclosure of medical outcomes especially in the context of growing access to Direct to Consumer genetic testing and Reproductive Tourism-Exile. Given the complexity of these and other ethical questions, finding answers may be achieved by ending the isolation of reproductive professionals and instead promoting increased and consistent communication among physicians, embryologists, therapists and reproductive attorneys to confront these evolving ethical quandaries.
文摘During the last two decades, two distinct monoclonal antibodies, RP215 and GHR106 were generated, respectively and extensively characterized, biologically and immunologically. Both antibodies target separately specific pan cancer markers and are being evaluated preclinically for potential therapeutic applications in cancer immunotherapy and/or fertility regulations. RP215 was shown to react specifically with carbohydrate-associated epitope located in the heavy chain variable regions of cancer cell expressed specific immunoglobulins, designated as CA215 which are distinct from those of normal B cell origins. The cancerous immunoglobulins may function to react with specific human serum proteins to facilitate growth/proliferation as well as protection of cancer cells in circulations. RP215-based enzyme immunoassays were designed to monitor serum CA215 levels among cancer patients. On the other hand, GHR106 was generated against N1-29 oligopeptide located in the extracellular domains of human GnRH receptor found either in the anterior pituitary or in most of the cancer cells. In vitro culture of cancer cells revealed that either of these two antibodies can induce apoptosis of cancer cells following 24 - 48 hours incubations. Anti-tumor activities of both antibodies were evaluated by typical nude mouse experiments. Either one was shown to effectively reduce the volumes of implanted tumors, dose-dependently. Humanized forms of either antibody were made available in CAR (chimeric antigen receptor)-T cell constructs. They were shown separately to induce cytotoxic killings of cancer cells in vitro by releasing cytokines upon incubations of tumor cells with either of CAR-T cell constructs. In addition, GHR106 also acts as GnRH antagonist by a specific targeting to pituitary GnRH receptor for reversible suppressions of reproductive hormones such as LH, testosterone or estradiol. Based on the above preclinical assessments, it can be generally concluded that both RP215 and GHR106 are restricted in normal tissue expressions and suitable for targeting cancerous immunoglobulins and GnRH receptor, respectively for cancer immunotherapy. Furthermore, specific targeting of pituitary GnRH receptor may suggest that the long acting GHR106 (5 - 21 days half-life) is an adequate GnRH antagonist for numerous gynecological treatments including ovulation inhibition in IVF/ART, endometriosis, premenstrual syndrome, precocious puberty, uterine fibroids and/or polycystic ovarian syndrome.
基金supported by grants from the National Key Research and Development Program(No.2021YFC2700604)General Program of National Natural Science Foundation of China(No.82171648)+5 种基金Shandong Provincial Key Research and Development Program(No.2021LCZX02)Youth Program of National Natural Science Foundation of China(No.82101752)Youth Program of Shandong Provincial Natural Science Foundation of China(No.ZR2021QH075)Taishan Scholars Program for Young Experts of Shandong Province(No.tsqn202312388)the Shandong Provincial Medical and Health Science and Technology Development Program(No.2019WS171)the Shandong Provincial Natural Science Foundation(No.ZR2020MH072).
文摘To the Editor:Recurrent pregnancy loss(RPL)is defined as two or more consecutive spontaneous pregnancy losses before 24 weeks of gestation;it affects 1-2%of couples.[1]Some causes of RPL are uterine anatomical abnormalities,abnormal chromosomes in parents or embryos,antiphospholipid syndrome,and certain autoimmune disorders.[2]However,the etiology of 40-50%of RPL couples remains unclear and is defined as unexplained RPL(uRPL).
基金Key R&D Program of Shandong Province(2021LCZX02)National Key Research and Development Program(2021YFC2700604,2022YFC2703202)+4 种基金General Program of National Natural Science Foundation of China(82171648)Taishan Scholars Program for Young Experts of Shandong Province(tsqn201812154)Youth Program of National Natural Science Foundation of China(82101752)Youth Program of Shandong Provincial Natural Science Foundation of China(ZR2021QH075)General Program of Shandong Provincial Natural Science Foundation of China(ZR2022MH087)for data fee(scientific research informed consent,etc.),paper modification,and publication fee,etc.
文摘Objective:Although consensus on the optimal endometrial preparation protocol for frozen-thawed embryo transfer(FET)is lacking,this is particularly true for patients with infertility and a history of endometrial polyps(EPs).In this study,we aimed to investigate whether a gonadotropin-releasing hormone agonist combined with hormone replacement therapy(GnRHa-HRT)could improve pregnancy outcomes in single euploid FET for patients with a history of EPs.Methods:In this retrospective cohort study,395 women who underwent their first single euploid FET cycle were divided into groups according to endometrial preparation protocols as follows:natural cycle(NC)(n=220),hormone replacement therapy(HRT)(n=122),and GnRHa-HRT groups(n=53).Subsequently,the FET cycles in the three groups were subdivided according to maternal age.All patients underwent hysteroscopic polypectomy before FET,and their EPs were confirmed by pathology.Results:No statistically significant differences were observed in live birth rates among the three groups(58.64%vs.58.20%vs.56.60%,P=0.964).Furthermore,the rates of miscarriage,ectopic pregnancy,premature live birth,and pregnancy complications were comparable among the three groups(P>0.05).After adjusting for potential confounding factors,no significant differences in pregnancy outcomes were reported between the groups(adjusted odds ratios[OR]and 95%credible intervals[CI]for live birth rate,HRTvs.NC:1.119,0.660–1.896,P=0.677;GnRHa-HRTvs.NC:1.165,0.610–2.226,P=0.643).Additionally,the pregnancy outcomes of the FET cycle were not influenced by the endometrial preparation protocols in the subgroups when stratified by maternal age(P>0.05).Conclusion:GnRHa-HRT did not improve the pregnancy outcomes of the single euploid FET in patients with a history of EPs.
基金supported by the National Science Fund for Distinguished Young Scholars of China (No.81925015)the National Natural Science Foundation of China (No.91649202)+1 种基金the Shandong Provincial Key Research&Development Program (China) (No.2018YFJH0504)the open fund of the State Key Laboratory of Reproductive Medicine (China) (SKLRM-K202201).
文摘Infertility affects around 8%-12%of couples globally,and in about 50%of these cases,male factors are either the primary cause or contribute significantly to infertility.Any defects during spermiogenesis may result in male subfertility or complete infertility in mammals.1 Previously,we found that CFAP53 is localized in the manchette and sperm tail,and it plays an essential role in sperm flagellum biogenesis.
基金funded by the National Key Research and Development Program of China 2021YFC2700400 and 2021YFC2700701 to H.Z.and S.G.Z.the Basic Science Center Program of NSFC 31988101,Shandong Provincial Key Research and Development Program 2020ZLYS02+4 种基金the Innovative Research Team of Highlevel Local Universities in Shanghai SHSMU-ZLCX20210200,to Z.-J.C.the National Natural Science Foundation of China 82421004,82192874,31871509,82071606,and 82071122 to H.Z.,S.G.Z.and Q.F.the National High-level Young Scientist Project Foundation(2019)and the Excellent Young Scientist Foundation of Shandong Province ZR202102230369 to Q.F.the Taishan Scholars Program of Shandong Province ts20190988 to H.Z.the Fundamental Research Funds of Shandong University 2023QNTDO04 to S.G.Z.
文摘The vaginal microbiome is critical for the reproductive health of women,yet the differential impacts exerted by the host and by ambient environmental variables on the vaginal microbiome remain largely unknown.Here,we conducted a comprehensive cross-sectional study of the relationships between the vaginal microbiome and 81 matched host and environmental variables across 6755 Chinese women.By 16S rRNA sequencing,we identified four core vaginal microbiota with a prevalence of over 90%and a total median abundance of 98.8%.Twenty-four variables,including physiology,lifestyle behaviors,gynecologic history,social and environmental information,were found associated with the microbiome composition,of which bacterial vaginosis(BV)showed the largest effect size.Age was among the strongest explanatory variables and the vaginal microbiome dynamically succeeded with increasing age,especially with a composition turning point at the age of 45.Our mediation analyses indicated that the effects of age on the microbiome could be mediated by variables such as parity number and lifestyles.We further classified the vaginal microbiomes of the population into 13“Vagitypes”.Women with Lactobacillus iners-and Lactobacillus jensenii-dominated Vagitypes had significantly higher live birth rate than those with Vagitype dominated by Fannyhessea vaginae(53.40%,59.09%vs 21.43%;OR[95%CI]:3.62[1.12-14.87],5.39[1.27-27.36];P=0.031,P=0.021).This study provides a comprehensive overview of the associations between identified variables and the vaginal microbiome,representing an important step toward understanding of environment-microbe-host interactions.
基金supported by Key R&D Program of Shandong Province(2021LCZX02)the National Natural Science Foundation of China(82171648,82471701,82471702)+2 种基金the Basic Science Center Program of the National Natural Science Foundation of China(31988101)the Taishan Scholars Program for Young Experts of Shandong Province(tsqn202312388)the Natural Science Foundation of Shandong Province(ZR2020MH071).
文摘Dear Editor,Assisted Reproductive Technology(ART)refers to the use of medical aids to achieve pregnancy in infertile couples,including Artificial Insemination(AI)and In vitro Fertilization-Embryo Transfer(IVF),of which IVF has been a common option for infertility treatment.
基金supported by the National Key Research&Development Program of China(2022YFC2703800,2022YFC2703000)the National Natural Science Foundation of China(82125014,32070847)+5 种基金the Basic Science Center Program of NFSC(31988101)the Key Project of Natural Science Foundation of Shandong Province(ZR202105250005)the Program for Excellent Young Scholars of Shandong Province(ZR2022YQ69)the Taishan Scholars Program for Young Experts of Shandong Provincethe Jinan Shizhong District key Industry Leading Talent ProgramThe Fundamental Research Funds of Shandong University。
文摘Objective Premature ovarian insufficiency(POI)is defined as the depletion of ovarian function before 40years of age,affecting approximately 3.7%of women in their reproductive age worldwide.Previous studies revealed several genes involved in the Fanconi anaemia(FA)pathway participate in the pathogenesis of POI,such as FANCA and FANCM.FA pathway maintains rapid proliferation in the developing primordial germ cells by deregulating transcription-replication conflicts,which is crucial for the establishment of sufficient ovarian reserve.FANCJ encodes a DNA helicase located downstream of the FA pathway promoting DNA damage repair and cell proliferation.Recently,two heterozygous FANCJ missense variants have been reported in patients with POI,suggesting haploinsufficiency of FANCJ participates in the pathogenesis of the disease.In this study,to further explore the contribution of FANCJ variants in POI,we reported a rare homozygous FANCJ start-loss variation in one patient with POI and illustrated its pathogenicity by in vitro functional studies.Methods The loss-of-function(LoF)variants of FANCJ were screened in our internal whole-exome sequencing(WES)database of POI.Sanger sequencing and WES analysis were employed on the proband and the patient’s family members to illustrate the origin of the bi-allelic variant.Cycloheximide chase assay was performed to demonstrate the impact of the variant on the protein stability of FANCJ.Protein ubiquitination assay was performed to confirm the accelerated degradation pathway of FANCJ protein.ResultsThrough the variation screening,a bi-allelic variant of FANCJ(NM_032043.3:c.1A>G,p.Met1Val)was identified in one case.The functional study showed that the start-loss variant affected FANCJ protein stability by accelerated protein degradation through the ubiquitinproteasome pathway.Conclusion Our findings provide further genetic evidence of the FANCJ variant participating in the pathogenesis of POI,expand the inherited mode and highlight the essential role of the FA pathway in maintaining ovarian function.
基金supported by the National Natural Science Foundation of China(82192874,82402161,82071606,82171842,31988101)the National Key Research and Development Program of China(2024YFC3405600)+12 种基金Shandong Provincial Key Research and Development Program(2024CXPT087)Shandong Provincial Key Research and Development Program(2020ZLYS02)Taishan Scholars Program of Shandong Province(ts20190988)Ningxia Hui Autonomous Region Key Research and Developmental Program(2024BEG02019)China National Postdoctoral Program for Innovative Talent(BX20240172)China Postdoctoral Science Foundation(2024M751487)Youth Project of Jiangsu Provincial Natural Science Foundation(BK20240375)Postdoctoral Research Fund of Gusu School in Nanjing Medical University(GSBSHKY202303)Fundamental Research Funds of Shandong University(2023QNTDO04)the Science and Technology Innovation Program of Hunan Province(2023RC3233)the Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC-XIANGYA(YNXM-202202)the Natural Science Foundation of Hunan Province(2024JJ2083)the Specific Research Fund of the Innovation Platform for Academicians of Hainan Province(YSPTZX202310)。
文摘Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology.However,its genetic basis is largely unrevealed.Geminin,encoded by the GMNN gene,plays an important role in preventing DNA re-replication by inhibiting CDT1.Here,using whole-exome sequencing and Sanger sequencing,we identified three rare missense mutations of GMNN in females with preimplantation arrest,following a dominant inheritance pattern.The RNA sequencing data from both the mouse zygotes and the patient's one-cell embryo demonstrated the altered cell cycle processes.We then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 and DNA damage,resulting in cell cycle disturbance.Our findings uncover a mechanistic understanding of the pathogenesis of human preimplantation embryo arrest,which acts by impairing the correct cell cycle and DNA rereplication procedure,and provides a new molecular target for the diagnosis and treatment of infertile patients.
基金the National Key Research and Development Program of China (2017YFC1001500 and 2016YFC1000600)the Scientific Innovation Program of Shenzhen City, China, under basic research program (JCYJ20180305163835455)+1 种基金the Young Scholars Program of Shandong University (2016WLJH50)the Natural Science Foundation of Shandong Province (ZR2017MH049)。
文摘The number of growth factors involved in female fertility has been extensively studied, but reluctance to add essential growth factors in culture media has limited progress in optimizing embryonic growth and implantation outcomes, a situation that has ultimately led to reduced pregnancy outcomes. Insulin-like growth factor Ⅱ(IGF-Ⅱ) is the most intricately regulated of all known reproduction-related growth factors characterized to date, and is perhaps the predominant growth factor in human ovarian follicles. This review aims to concisely summarize what is known about the role of IGF-Ⅱ in follicular development, oocyte maturation, embryonic development, implantation success, placentation, fetal growth, and in reducing placental cell apoptosis, as well as present strategies that use growth factors in culture systems to improve the developmental potential of oocytes and embryos in different species. Synthesizing the present knowledge about the physiological roles of IGF-Ⅱ in follicular development, oocyte maturation, and early embryonic development should, on the one hand, deepen our overall understanding of the potential beneficial effects of growth factors in female reproduction and on the other hand support development(optimization) of improved outcomes for assisted reproductive technologies.
基金supported by the National Natural Science Foundation of China(31988101,82192874,82130046)the National Key Research and Development Program of China(2021YFC2700400)+3 种基金CAMS Innovation Fund for Medical Sciences(2021-I2M-5-001)Shandong Provincial Key Research and Development Program(2020ZLYS02)Taishan Scholars Program of Shandong Province(ts20190988,tsqn201909194)Innovative research team of high-level local universities in Shanghai(SHSMU-ZLCX20210200,SHSMUZLCX20210201)。
文摘Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection has swept the globe for 3 years(Zhou et al.,2020).With the nationwide relaxation of controls on the coronavirus disease 2019(COVID-19)epidemic since December 2022 in China,fertility and in vitro fertilization(IVF)centers are receiving increasing numbers of infected patients.
