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1.
Future Oncol ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665002

RESUMO

Heterogeneity in breast cancer leads to diverse morphological features and different clinical outcomes. There are inherent differences in breast cancer between the populations in Asia and in western countries. The use of immune-based treatment in breast cancer is currently in the developmental stage. The VGH-TAYLOR study is designed to understand the genetic profiling of different subtypes of breast cancer in Taiwan and define the molecular risk factors for breast cancer recurrence. The T-cell receptor repertoire and the potential effects of immunotherapy in breast cancer subjects is evaluated. The favorable biomarkers for early detection of tumor recurrence, diagnosis and prognosis may provide clues for the selection of individualized treatment regimens and improvement in breast cancer therapy.

2.
Epigenetics ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652256

RESUMO

DNA methylation (DNAm) that occurs on promoter regions is primarily considered to repress gene expression. Previous studies indicated that DNAm could also show positive correlations with gene expression. Both DNAm and gene expression profiles are known to be tissue- and development-specific. This study aims to investigate how DNAm and gene expression are coordinated across different human tissues and developmental stages, as well as the biological significance of such correlations. By analyzing 2,239 samples with both DNAm and gene expression data in the same human subjects obtained from six published datasets, we evaluated the correlations between gene and CpG pairs (GCPs) at cis-regions and compared significantly correlated GCPs (cGCPs) across different tissues and brains at different age groups. A total of 37,363 cGCPs were identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (>90%) of cGCPs were tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlighted the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, early developmental brain possessed a highly unique set of cGCPs that were associated with neurogenesis and psychiatric disorders. By assessing the epigenetic factors involved in cGCPs, we discovered novel regulatory mechanisms of positive cGCPs distinct from negative cGCPs, which were related to multiple factors, such as H3K27me3, CTCF, and JARD2. The catalog of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.

3.
LGBT Health ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34558972

RESUMO

Purpose: Emerging studies indicate that sexual minority youths experience worse health than their heterosexual peers, but few studies have examined the intervening mechanisms linking sexual orientation and health status. This study hypothesizes that interpersonal relationships, moderated by household socioeconomic status (HSES), are important mediators in the association between sexual orientation and health status. Methods: A total of 49,084 youths, consisting of 9499 youths who identified as sexual minority individuals and 39,585 youths who identified as heterosexual, were sampled from a national study on sexual and reproductive health conducted in China. Logistic regression analyses were performed to estimate the association between sexual orientation and self-rated health. Causal mediation and moderated mediation analyses were performed to analyze the mediating and moderating effects of interpersonal relationships and HSES, respectively. Results: Self-rated health was significantly poorer for sexual minority youths compared with heterosexual youths (p < 0.01). From 7.90% to 25.74% of the association between sexual orientation and self-rated health was mediated through poor interpersonal relationships with both parents and peers. A poor relationship with the father accounted for the highest percentage. HSES was found to moderate the mediation effect of interpersonal relationships, with the greatest effect found for sexual minority youths with lower HSES. Conclusion: HSES moderated the indirect effects of interpersonal relationships on the association between sexual orientation and self-rated health. Interventions focused on improving interpersonal relationships for sexual minority youths, especially those with low HSES, merit attention.

4.
J Chin Med Assoc ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34561409

RESUMO

BACKGROUND: To assess the clinical outcomes and metastatic behavior between de novo versus recurrent HER2-positive metastatic breast cancer (MBC) based on a single-institution database in Taiwan. METHODS: We retrospectively identified patients diagnosed between January 2000 and December 2017 with de novo stage IV or recurrent HER2-positive MBC. Several variables were recorded in patients with recurrent disease: age at diagnosis, metastatic site, hormone receptor status, HER2 status, and disease-free interval (DFI). Treatments and metastatic patterns were compared between de novo stage IV and recurrent MBC cohorts. Post-metastasis survival (PMS) was estimated using the Kaplan-Meier method with log-rank tests. Hazard ratios and 95% confidence intervals were estimated using Cox regression analysis. RESULTS: In total, 1,360 patients were diagnosed with breast cancer with HER2 overexpression. At baseline, de novo stage IV patients were older than recurrent MBC patients (median age 58 vs. 53). The majority of the de novo stage IV patients were diagnosed after 2010, while most of the recurrent MBC patients were diagnosed during 2000-2009. An increased number of de novo stage IV patients underwent targeted therapy than recurrent MBC patients was also noted. PMS in patients with de novo stage IV and recurrent MBC was 79.2 months and 61.8 months, respectively, which indicated significant better survival in de novo stage IV than those with recurrent MBC disease. Longer survival was also noted in de novo stage IV and recurrent MBC with DFI >24 months than in those with recurrent MBC with DFI <24 months, and in patients receiving HER2-targeted therapy after MBC diagnosis than in those not receiving the therapy. However, median PMS showed no significant difference between patients with the luminal B2 (HR-positive, HER2-negative) and HER2-enriched (HR-negative, HER2-positive) subtypes. After adjustment in multivariate analysis, a low risk of BC-specific death was observed in patients aged >50 years, those receiving HER2-targeted therapy for MBC, and those with oligo-metastasis, while patients with first metastases to the liver or brain showed a higher risk of BC-specific death than those without metastases. CONCLUSION: De novo and recurrent MBC have distinct characteristic, metastatic patterns and outcomes in Asian HER2-positive breast cancer patients. The age distribution and survivals between HR+/- status were different to non-Asian group. These differences should be further investigated in the future considering ethnic factor.

5.
Mol Med Rep ; 24(5)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34490480

RESUMO

Non­coding RNAs serve essential roles in regulating mRNA and protein expression and dysregulation of non­coding RNAs participates in a variety of types of cancer. microRNAs (miRNAs/miRs), which are 21­24 nucleotides non­coding RNAs, have been shown to be important for the development of gastric cancer (GC). However, the role of miR­486­5p in GC remains to be elucidated. The present study found that miR­486­5p was downregulated in GC tissues. Comparing with gastric normal cells GES­1, GC cells, including MKN­45, AGS, HGC27 and MKN74, had reduced abundance of miR­486­5p transcript. CCK8 and colony formation assays demonstrated that GC cell growth and proliferation were enhanced by miR­486­5p inhibitors and were suppressed by miR­486­5p mimics. miR­486­5p also suppressed cell cycle process and migration and promoted apoptosis in GC cells, as verified by propidium iodide (PI) staining, Transwell assay and PI/Annexin V staining. miR­486­5p downregulated fibroblast growth factor 9 (FGF9) through combining to its 3'untranslated region. Overexpression of FGF9 accelerated the growth and proliferation of GC cells. The expression of miR­486­5p was negatively associated with FGF9 mRNA expression in GC samples. These results revealed that miR­486­5p was a tumor suppressor in GC. Downregulation of FGF9 contributed to the role of miR­486­5p in GC.

6.
Cancer Control ; 28: 10732748211043665, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34569315

RESUMO

BACKGROUND: It is inconclusive whether R1 margin determined by postoperative pathological examination indicates worse long-term survival in gastric cancer (GC) patients after curative intent resection (CIR). Hence, we aimed to systematically pool the conflicting evidence to fill this gap. METHODS: The present study was performed according to the published protocol and Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Published studies examining the impact of microscopic margin status on overall survival (OS) and 5-year OS rate in GC were systematically searched in PubMed, Embase, and Cochrane Library databases. RevMan 5.3 was used to conduct statistical analysis, and the Grading of Recommendations, Assessment, Development, and Evaluations approach was used to assess the certainty of evidence for each outcome. RESULTS: Twenty-three retrospective cohort studies including 19 992 patients were analyzed. The pooled hazard ratio for OS of 14 studies was 2.06 (95% confidence interval [CI]: 1.61-2.65, low certainty), indicating that R1 margin predicted inferior OS. Subgroup and sensitivity analyses upheld the statistical stability of this finding. The pooled odds ratio (OR) of 14 studies was .21 (95% CI: .17-.26, moderate certainty), demonstrating that the presence of R1 margins was associated with a poorer 5-year OS rate. Sensitivity analyses and most of the subgroup analyses confirmed this finding, except the "esophagogastric junction (EGJ) cancers" subgroup, which included two studies with a pooled OR of .41 (95% CI: .10-1.61). CONCLUSION: R1 margin detected by pathological examination might exhibit a high correlation with poorer OS and 5-year OS rate in GC (except EGJ cancers) patients who underwent CIR. To figure out the effect of R1 margin on survival of different stages and histological types need prospective studies with large sample sizes and standardized methods. What is the best treatment for R1 margin patients also need more in-depth and special research.

7.
Int Immunopharmacol ; 100: 108112, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34521023

RESUMO

More than 100 monoclonal antibodies (mAbs) have been approved by FDA. The mechanism of action (MoA) involves in neutralization of a specific target via the Fab region and Fc effector functions through Fc region, while the latter include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). ADCP has been recognized one of the most important MoAs, especially for anti-cancer mAbs in recent years. However, traditional bioassays measuring ADCP always introduced primary macrophages and flow cytometry, which are difficult to handle and highly variable. In this study, we engineered a monoclonal Jurkat/NFAT/CD32a-FcεRIγ effector cell line that stably expresses CD32a-FcεRIγ chimeric receptor and NFAT-controlled luciferase. The corresponding mAb could bind with the membrane antigens on the target cells with its Fab fragment and CD32a-FcεRIγ on the effector cells with its Fc fragment, leading to the crosslinking of CD32a-FcεRIγ and the resultant expression of subsequent NFAT-controlled luciferase, which represents the bioactivity of ADCP based on the MoA of the mAb. With rituximab as the model mAb, Raji cells as the target cells, and Jurkat/NFAT/CD32a-FcεRIγ cells as the effector cells, we adopted the strategy of Design of Experiment (DoE) to optimize the bioassay. Then we fully validated the established bioassay according to ICH-Q2(R1), which proved the good assay performance characteristics of the bioassay, including specificity, accuracy, precision, linearity, stability and robustness. This RGA can be applied to evaluate the -ADCP bioactivity for anti-CD20 mAbs in lot release, stability testing as well as biosimilar comparability. The engineered cells may also potentially be used to evaluate the ADCP bioactivity of mAbs with other targets.

8.
Eur J Pharm Sci ; 167: 106003, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34517106

RESUMO

Three-dimensional (3D) culture of neural progenitor cells (NPCs) in hydrogels represents a powerful means for recapitulating neurodevelopment, disease modelling and drug discovery. However, the differentiation of NPCs to oligodendrocytes in 3D scaffolds remains a great challenge. In this study, polyvinyl alcohol (PVA) - sodium alginate (SA) composite hydrogels intended for NPC culture in 3D were fabricated by ionic crosslinking between SA and calcium ions. It was demonstrated that adding PVA to the composite hydrogels resulted in increases in pore size and swelling rate and decreases in elastic moduli as the PVA proportion was enhanced. In addition, the composite hydrogels were biocompatible with mouse NPCs and improved the proliferation of the encapsulated NPCs compared with SA hydrogels. Moreover, when velvet antler polypeptides (VAPs), which were capable of facilitating the differentiation of NPCs to oligodendrocyte fate in 2D, were loaded into PVA-SA hydrogels, NPCs differentiated into neurons, astrocytes and oligodendrocytes, with the presence of VAPs promoting oligodendrogenesis in a dose-dependant manner. The present composite hydrogels provide a suitable scaffold for the construction of neural tissue engineering and neurological disease modelling.

9.
Hum Mol Genet ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34415308

RESUMO

We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10-7), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, p = 4 x 10-8) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.

10.
J Med Genet ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348960

RESUMO

BACKGROUND: Oligoasthenoteratozoospermia is a typical feature of sperm malformations leading to male infertility. Only a few genes have been clearly identified as pathogenic genes of oligoasthenoteratozoospermia. METHODS AND RESULTS: Here, we identified a homozygous frameshift variant (c.731dup, p.Asn244Lysfs*3) in CCDC34, which is preferentially expressed in the human testis, using whole-exome sequencing in a cohort of 100 Chinese men with multiple morphological abnormalities of the sperm flagella (MMAF). In an additional cohort of 167 MMAF-affected men from North Africa, Iran and France, we identified a second subject harbouring a homozygous CCDC34 frameshift variant (c.799_817del, p.Glu267Lysfs*72). Both affected men presented a typical MMAF phenotype with an abnormally low sperm concentration (ie, oligoasthenoteratozoospermia). Transmission electron microscopy analysis of the sperm flagella affected by CCDC34 deficiency further revealed dramatic disorganisation of the axoneme. Immunofluorescence assays of the spermatozoa showed that CCDC34 deficiency resulted in almost absent staining of CCDC34 and intraflagellar transport-B complex-associated proteins (such as IFT20 and IFT52). Furthermore, we generated a mouse Ccdc34 frameshift mutant using CRISPR-Cas9 technology. Ccdc34-mutated (Ccdc34mut/mut ) male mice were sterile and presented oligoasthenoteratozoospermia with typical MMAF anomalies. Intracytoplasmic sperm injection has good pregnancy outcomes in both humans and mice. CONCLUSIONS: Our findings support that CCDC34 is crucial to the formation of sperm flagella and that biallelic deleterious mutations in CCDC34/Ccdc34 cause male infertility with oligoasthenoteratozoospermia in humans and mice.

11.
Medicine (Baltimore) ; 100(32): e26708, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397873

RESUMO

ABSTRACT: Laparoscopic donor hepatectomy (LDH), accepted as a minimally invasive approach, has become increasingly popular for living donor liver transplant. However, the outcomes of LDH remain to be fully clarified when compared with open living donor hepatectomy. Thus, our meta-analysis was designed to assess the efficacy of laparoscopic in comparison with conventional open donor hepatectomy.The PubMed, Cochrane, and Embase electronic databases were searched to identify the articles concerning the comparison of the efficacy of laparoscopic versus open surgery in treatment of living donor liver transplantation updated to March, 2020. The main search terms and medical Subject Heading terms were: "living donor," "liver donor," "minimally invasive," "laparoscopic surgery," and "open surgery." After rigorous evaluation on quality, the data was extracted from eligible publications. The outcomes of interest included intraoperative and postoperative results.The inclusion criteria were met by a total of 20 studies. In all, 2001 subjects involving 633 patients who received laparoscopic surgery and 1368 patients who received open surgery were included. According to the pooled result of surgery duration, the laparoscopic surgery was associated with shorter duration of hospital stay (MD = -1.07, 95% CI -1.85 to -0.29; P = .007), less blood loss (MD = -57.57, 95% CI -65.07 to -50.07; P < .00001), and less postoperative complications (OR = 0.61, 95% CI 0.44-0.85; P = .003). And the open donor hepatectomy achieved a trend of shorter operation time (MD = 30.31, 95% CI 13.93-46.69; P = .0003) than laparoscopic group. Similar results were found in terms of ALT (P = .52) as well as the AST (P = .47) peak level between the 2 groups.LDH showed the better perioperative outcomes as compared with open donor hepatectomy. The findings revealed that LDH may be a feasible and safe procedure for the living donor liver transplantation.


Assuntos
Hepatectomia/métodos , Laparoscopia/métodos , Transplante de Fígado/métodos , Doadores Vivos , Humanos , Duração da Cirurgia , Coleta de Tecidos e Órgãos/métodos
12.
Neurobiol Aging ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34392980

RESUMO

Somatic mutations arise randomly or are induced by environmental factors, which may increase the risk of Alzheimer's disease (AD). Identifying somatic mutations in sporadic AD (SAD) may provide new insight of the disease. To evaluate the potential contribution of somatic single nucleotide variations (SNVs), particularly that of well-known AD-candidate genes, we investigated sequencing data sets from four platforms: whole-genome sequencing (WGS), deep whole-exome sequencing (WES) on paired brain and liver samples, RNA sequencing (RNA-seq), and single-cell whole-genome sequencing (scWGS) of brain samples from 16 AD patients and 16 non-AD individuals. We found that the average number, mean variant allele fractions (VAFs) and mutational signatures of somatic SNVs have similar distributions between AD brains and non-AD brains. We did not identify any somatic SNVs within coding regions of the APP, PSEN1, PSEN2, nor in APOE. This study shows that somatic SNVs within the coding region of AD-candidate genes are unlikely to be a common causal factor for SAD.

13.
Pharmacol Res ; 172: 105808, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34389457

RESUMO

BACKGROUND: We aimed to evaluate comparative safety and tolerability of the approved PARP inhibitors in people with cancer. METHODS: Eligible studies included randomized controlled trials comparing an approved PARP inhibitor (fluzoparib, olaparib, rucaparib, niraparib, or talazoparib) with placebo or chemotherapy in cancer patients. Outcomes of interest included: serious adverse event (SAE), discontinuation due to adverse event (AE), interruption of treatment due to AE, dose reduction due to AE, and specific grade 1-5 AEs. RESULTS: Ten trials including 3763 participants and six treatments (olaparib, rucaparib, niraparib, talazoparib, placebo, and protocol-specified single agent chemotherapy) were identified. SAE and discontinuation of treatment did not differ significantly among the four approved PARP inhibitors. Regarding interruption of treatment and dose reduction due to AE, statistically significant differences and statistically non-significant trend were observed. Talazoparib is associated with a higher risk of interruption of treatment and dose reduction (excluding rucaparib) due to AE as compared with the other drugs. Niraparib showed a trend of lower risk of AE related dose reduction as compared with the other drugs. Furthermore, there were significant differences in specific grade 1-5 AE among the four drugs. CONCLUSION: The safety profile of the four approved PARP inhibitors is comparable in terms of SAE and AE-related discontinuation of treatment. Statistically significant differences in the AEs spectrum and AEs related dose interruption and dose reduction demonstrated the prompt identification of AE and dose personalization seem mandatory to obtain maximal benefit from PARP inhibitors.

14.
Am J Hum Genet ; 108(8): 1466-1477, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34237282

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF)-induced asthenoteratozoospermia is a common cause of male infertility. Previous studies have identified several MMAF-associated genes, highlighting the condition's genetic heterogeneity. To further define the genetic causes underlying MMAF, we performed whole-exome sequencing in a cohort of 643 Chinese MMAF-affected men. Bi-allelic DNAH10 variants were identified in five individuals with MMAF from four unrelated families. These variants were either rare or absent in public population genome databases and were predicted to be deleterious by multiple bioinformatics tools. Morphological and ultrastructural analyses of the spermatozoa obtained from men harboring bi-allelic DNAH10 variants revealed striking flagellar defects with the absence of inner dynein arms (IDAs). DNAH10 encodes an axonemal IDA heavy chain component that is predominantly expressed in the testes. Immunostaining analysis indicated that DNAH10 localized to the entire sperm flagellum of control spermatozoa. In contrast, spermatozoa from the men harboring bi-allelic DNAH10 variants exhibited an absence or markedly reduced staining intensity of DNAH10 and other IDA components, including DNAH2 and DNAH6. Furthermore, the phenotypes were recapitulated in mouse models lacking Dnah10 or expressing a disease-associated variant, confirming the involvement of DNAH10 in human MMAF. Altogether, our findings in humans and mice demonstrate that DNAH10 is essential for sperm flagellar assembly and that deleterious bi-allelic DNAH10 variants can cause male infertility with MMAF. These findings will provide guidance for genetic counseling and insights into the diagnosis of MMAF-associated asthenoteratozoospermia.


Assuntos
Astenozoospermia/complicações , Modelos Animais de Doenças , Dineínas/genética , Infertilidade Masculina/patologia , Mutação , Fenótipo , Espermatozoides/patologia , Alelos , Animais , Homozigoto , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Espermatozoides/metabolismo , Sequenciamento Completo do Exoma
15.
Sensors (Basel) ; 21(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202575

RESUMO

Nighttime light remote sensing has unique advantages on reflecting human activities, and thus has been used in many fields including estimating population and GDP, analyzing light pollution and monitoring disasters and conflict. However, the existing nighttime light remote sensors have many limitations because they are subject to one or more shortcomings such as coarse spatial resolution, restricted swath width and lack of multi-spectral data. Therefore, we propose an optical system of imaging spectrometer based on linear variable filter. The imaging principle, optical specifications, optical design, imaging performance analysis and tolerance analysis are illustrated. The optical system with a focal length of 100 mm, F-number 4 and 43° field of view in the spectrum range of 400-1000 nm is presented, and excellent image quality is achieved. The system can obtain the multi-spectral images of eight bands with a spatial resolution of 21.5 m and a swath width of 320 km at the altitude of 500 km. Compared with the existing nighttime light remote sensors, our system possesses the advantages of high spatial and high spectral resolution, wide spectrum band and wide swath width simultaneously, greatly making up for the shortage of the present systems. The result of tolerance analysis shows our system satisfy the requirements of fabrication and alignment.


Assuntos
Poluição Ambiental , Tecnologia de Sensoriamento Remoto , Humanos
16.
BMJ Open ; 11(7): e043416, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226211

RESUMO

OBJECTIVE: This study aimed to explore the association between famine exposure in early life and the odds of rheumatoid arthritis (RA) in adulthood. DESIGN: A population-based retrospective cohort study. SETTING: China. PARTICIPANTS: A total of 111 706 participants (1775 with RA) born from 1956 to 1964 were selected from the baseline survey of a large cohort in China. PRIMARY AND SECONDARY OUTCOME MEASURES: Four famine exposure groups were generated based on dates of birth, namely prenatal-exposed, infant-exposed, preschool-exposed and non-exposed groups. Logistic regressions were used to explore the association between famine exposure and self-reported RA in adulthood, adjusting for sex, region, monthly income, highest education, alcohol consumption, tobacco use, body mass index (BMI) and metabolic equivalent tasks. Analyses were also performed with stratification for sex (female or male), residing region (urban or rural), famine severity (severe or non-severe) and BMI (≥24 or <24). RESULTS: The study included 1775 (1.59%) RA cases and 109 931 (98.41%) non-RA controls. Among them, 22 413 (20.06%) were prenatal-exposed, 14 899 (13.34%) were infant-exposed and 34 356 (30.76%) were preschool-exposed. Prenatal exposure to famine was not associated with onset of RA in adulthood. Infant-exposed group and preschool-exposed group had significantly elevated odds of getting RA compared with non-exposed group (infant-exposed: OR=1.44, 95% CI 1.24 to 1.67; preschool-exposed: OR=1.38, 95% CI 1.22 to 1.57, p<0.001), and the relationship was stronger among women, urban residents and participants with BMI ≥24. Similar results were additionally observed when an age-balanced control group was used. CONCLUSIONS: Exposure to the Great Chinese Famine in early life after birth especially in infancy may be associated with a higher risk of RA in adulthood. Strengthening early-life nutrition could be an implication to prevent future RA.


Assuntos
Artrite Reumatoide , Efeitos Tardios da Exposição Pré-Natal , Adulto , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/etiologia , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Fome Epidêmica , Feminino , Humanos , Lactente , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Prevalência , Estudos Retrospectivos
17.
Hum Mol Genet ; 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34231842

RESUMO

Asthenoteratospermia is a common cause of male infertility. Recent studies have revealed that CFAP65 mutations lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations. However, the molecular mechanism underlying CFAP65-associated sperm malformation is largely unclear. Here, we initially examined the role of CFAP65 during spermiogenesis using Cfap65 knockout (Cfap65-/-) mice. The results showed that Cfap65-/- male mice exhibited severe asthenoteratospermia characterized by morphologically defective sperm heads and flagella. In Cfap65-/- mouse testes, hyper-constricted sperm heads were apparent in step 9 spermatids accompanied by abnormal manchette development, and acrosome biogenesis was abnormal in the maturation phase. Moreover, subsequent flagellar elongation was also severely affected and characterized by disrupted assembly of the mitochondrial sheath (MS) in Cfap65-/- male mice. Furthermore, the proteomic analysis revealed that the proteostatic system during acrosome formation, manchette organization, and MS assembly was disrupted when CFAP65 was lost. Importantly, endogenous immunoprecipitation and immunostaining experiments revealed that CFAP65 may form a cytoplasmic protein network comprising MNS1, RSPH1, TPPP2, ZPBP1, and SPACA1. Overall, these findings provide insights into the complex molecular mechanisms of spermiogenesis by uncovering the essential roles of CFAP65 during sperm head shaping, acrosome biogenesis, and MS assembly.

18.
Hum Genet ; 140(9): 1367-1377, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34255152

RESUMO

Spermatozoa are polarized cells with a head and a flagellum joined together by the connecting piece. Flagellum integrity is critical for normal sperm function, and flagellum defects consistently lead to male infertility. Multiple morphological abnormalities of the flagella (MMAF) is a distinct sperm phenotype consistently leading to male infertility due to a reduced or absent sperm motility associated with severe morphological and ultrastructural flagellum defects. Despite numerous genes recently described to be recurrently associated with MMAF, more than half of the cases analyzed remain unresolved, suggesting that many yet uncharacterized gene defects account for this phenotype. By performing a retrospective exome analysis of the unsolved cases from our initial cohort of 167 infertile men with a MMAF phenotype, we identified one individual carrying a homozygous frameshift variant in CFAP206, a gene encoding a microtubule-docking adapter for radial spoke and inner dynein arm. Immunostaining experiments in the patient's sperm cells demonstrated the absence of WDR66 and RSPH1 proteins suggesting severe radial spokes and calmodulin and spoke-associated complex defects. Using the CRISPR-Cas9 technique, we generated homozygous Cfap206 knockout (KO) mice which presented with male infertility due to functional, structural and ultrastructural sperm flagellum defects associated with a very low rate of embryo development using ICSI. Overall, we showed that CFAP206 is essential for normal sperm flagellum structure and function in human and mouse and that bi-allelic mutations in CFAP206 cause male infertility in man and mouse by inducing morphological and functional defects of the sperm flagellum that may also cause ICSI failures.


Assuntos
Proteínas do Citoesqueleto , Mutação da Fase de Leitura , Homozigoto , Infertilidade Masculina , Cauda do Espermatozoide/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Camundongos
19.
Mitochondrion ; 60: 33-42, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303007

RESUMO

We investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in 6745 maternal pairs of European (EA, n = 4718 pairs) and African (AA, n = 2027 pairs) Americans in whole blood. Mother-offspring pairs displayed the highest concordance rate, followed by sibling-sibling and more distantly-related maternal pairs. The allele fractions of concordant heteroplasmies exhibited high correlation (R2 = 0.8) between paired individuals. Discordant heteroplasmies were more likely to be in coding regions, be nonsynonymous or nonsynonymous-deleterious (p < 0.001). The number of deleterious heteroplasmies was significantly correlated with advancing age (20-44, 45-64, and ≥65 years, p-trend = 0.01). One standard deviation increase in heteroplasmic burden (i.e., the number of heteroplasmies carried by an individual) was associated with 0.17 to 0.26 (p < 1e - 23) standard deviation decrease in mtDNA copy number, independent of age. White blood cell count and differential count jointly explained 0.5% to 1.3% (p ≤ 0.001) variance in heteroplasmic burden. A genome-wide association and meta-analysis identified a region at 11p11.12 (top signal rs779031139, p = 2.0e - 18, minor allele frequency = 0.38) associated with the heteroplasmic burden. However, the 11p11.12 region is adjacent to a nuclear mitochondrial DNA (NUMT) corresponding to a 542 bp area of the D-loop. This region was no longer significant after excluding heteroplasmies within the 542 bp from the heteroplasmic burden. The discovery that blood mtDNA heteroplasmies were both inherited and somatic origins and that an increase in heteroplasmic burden was strongly associated with a decrease in average number of mtDNA copy number in blood are important findings to be considered in association studies of mtDNA with disease traits.

20.
Cells ; 10(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202084

RESUMO

Male infertility is a multifactorial disease with a strong genetic background. Abnormal sperm morphologies have been found to be closely related to male infertility. Here, we conducted whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Two novel hemizygous mutations were identified in USP26, an X-linked gene preferentially expressed in the testis and encoding a deubiquitinating enzyme. These USP26 variants are extremely rare in human population genome databases and have been predicted to be deleterious by multiple bioinformatics tools. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring hemizygous USP26 variants showed a highly aberrant morphology and ultrastructure of the sperm heads and flagella. Real-time quantitative PCR and immunoblotting assays revealed obviously reduced levels of USP26 mRNA and protein in the spermatozoa from men harboring hemizygous deleterious variants of USP26. Furthermore, intracytoplasmic sperm injections performed on infertile men harboring hemizygous USP26 variants achieved satisfactory outcomes. Overall, our study demonstrates that USP26 is essential for normal sperm morphogenesis, and hemizygous USP26 mutations can induce X-linked asthenoteratozoospermia. These findings will provide effective guidance for the genetic and reproductive counseling of infertile men with asthenoteratozoospermia.

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