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OBJECTIVE: To explore the genetic etiology of fetuses with congenital heart disease (CHD) through whole exome sequencing (WES). METHODS: Thirty seven fetuses identified with CHD by prenatal ultrasonography but with negative results by chromosomal microarray analysis (CMA) at Jinhua Maternal and Child Health Care Hospital from January 2020 to June 2022 were selected as the study subjects, for whom WES was carried out. RESULTS: WES and Sanger sequencing had detected 6 pathogenic or likely pathogenic variants, and 6 variants with unknown clinical significance. The variants had involved 15 loci within 11 genes, in addition with one copy number variation. CONCLUSION: WES can increase the detection rate for genetic abnormalities among fetuses with CHD, which can facilitate the prenatal diagnosis, evaluation of prognosis and genetic counseling for the couples.
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Secuenciación del Exoma , Cardiopatías Congénitas , Diagnóstico Prenatal , Humanos , Cardiopatías Congénitas/genética , Femenino , Embarazo , Diagnóstico Prenatal/métodos , Variaciones en el Número de Copia de ADN , Feto/anomalías , Ultrasonografía PrenatalRESUMEN
Background: Current research offers limited clarity on the correlation between waist circumference and chronic pain prevalence. Objective: This investigation seeks to elucidate the potential relationship between waist circumference and chronic pain and their causal association. Methods: An observational study was conducted, leveraging data from the National Health and Nutrition Examination Survey (NHANES) collected between 2001 and 2004. The multivariable logistic regression was used to assess the relationship between waist circumference and chronic pain. Furthermore, a meta-analysis of Mendelian Randomization (MR) was applied to explore a causal relationship between waist circumference and pain. Results: The observational study, post multivariable adjustment, indicated that an increase in waist circumference by 1 dm (decimeter) correlates with a 14% elevation in chronic pain risk (Odds Ratio [OR] = 1.14, 95% Confidence Interval [CI]: 1.04-1.24, p = 0.01). Moreover, the meta-analysis of MR demonstrated that an increased waist circumference was associated with a genetic predisposition to pain risk (OR = 1.14, 95%CI: 1.06-1.23, p = 0.0007). Conclusion: Observational analysis confirmed a significant relationship between increased waist circumference and the incidence of chronic pain, and results based on MR Study identified increased waist circumference as potentially causal for pain.
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BACKGROUND: Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326). METHODS: Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points. RESULTS: Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage. CONCLUSIONS: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC.
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OBJECTIVE: Mercury is one of the heavy metal pollutants causing serious harm to human health. Quercetin was observed to repair kidney damage through the TLR4/TRIM32 pathway, and the detoxification effect of quercetin on heavy metal poisoning was observed. METHODS: For the study, the researchers divided 40 male mice from the KM strain into five groups: control, HgCl2, QU30, HgCl2+QU15, and HgCl2+QU30. The biological effects of those mice in each group were detected by the biochemical experiment, histopathology experiment and protein expression experiment respectively. RESULTS: HgCl2 had effects in increasing the level of malondialdehyde (MDA) and decreasing the activity of antioxidant enzymes (P < 0.05). HgCl2 induced inflammation by increasing tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and Toll Like Receptor 4 (TLR-4) (P < 0.05). The expression of creatinine (CRE) and urea nitrogen (BUN) showed that HgCl2 promoted kidney injury. HgCl2 altered renal tissue integrity and TRIM32 expression which resulted in the increased autophagy associated protein levels of LC3. In contrast, quercetin reduced oxidative stress, autophagy, inflammation and histopathological changes (P < 0.05). CONCLUSION: Quercetin has the renal protection effects of anti-inflammation, anti-oxidation and anti-autophagy.
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Autofagia , Inflamación , Cloruro de Mercurio , Quercetina , Receptor Toll-Like 4 , Animales , Cloruro de Mercurio/toxicidad , Receptor Toll-Like 4/metabolismo , Quercetina/farmacología , Ratones , Masculino , Autofagia/efectos de los fármacos , Inflamación/inducido químicamente , Riñón/efectos de los fármacos , Riñón/patología , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Factores de Transcripción/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Antioxidantes/farmacologíaRESUMEN
The analysis of genomic variations in offspring after implantation has been infrequently studied. In this study, we aim to investigate the extent of de novo mutations in humans from developing fetus to birth. Using high-depth whole-genome sequencing, 443 parent-offspring trios were studied to compare the results of de novo mutations (DNMs) between different groups. The focus was on fetuses and newborns, with DNA samples obtained from the families' blood and the aspirated embryonic tissues subjected to deep sequencing. It was observed that the average number of total DNMs in the newborns group was 56.26 (54.17-58.35), which appeared to be lower than that the multifetal reduction group, which was 76.05 (69.70-82.40) (F = 2.42, P = 0.12). However, after adjusting for parental age and maternal pre-pregnancy body mass index (BMI), significant differences were found between the two groups. The analysis was further divided into single nucleotide variants (SNVs) and insertion/deletion of a small number of bases (indels), and it was discovered that the average number of de novo SNVs associated with the multifetal reduction group and the newborn group was 49.89 (45.59-54.20) and 51.09 (49.22-52.96), respectively. No significant differences were noted between the groups (F = 1.01, P = 0.32). However, a significant difference was observed for de novo indels, with a higher average number found in the multifetal reduction group compared to the newborn group (F = 194.17, P < 0.001). The average number of de novo indels among the multifetal reduction group and the newborn group was 26.26 (23.27-29.05) and 5.17 (4.82-5.52), respectively. To conclude, it has been observed that the quantity of de novo indels in the newborns experiences a significant decrease when compared to that in the aspirated embryonic tissues (7-9 weeks). This phenomenon is evident across all genomic regions, highlighting the adverse effects of de novo indels on the fetus and emphasizing the significance of embryonic implantation and intrauterine growth in human genetic selection mechanisms.
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Feto , Humanos , Femenino , Embarazo , Recién Nacido , Masculino , Adulto , Polimorfismo de Nucleótido Simple/genética , Implantación del Embrión/genética , Genoma Humano/genética , Mutación INDEL/genética , Genómica , Secuenciación Completa del Genoma , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación/genética , Desarrollo Fetal/genéticaRESUMEN
Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6-34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.
The integrity of the human genome is maintained via multiple pathways of DNA repair, one of the most important of which is homologous recombination repair (HRR), which uses a sister chromatid as a template for high-fidelity restoration of altered DNA sequences. This study aimed to determine the prevalence of deleterious mutations, i.e., changes in the genetic code that interfere with proper cellular function, in the breast cancer genes BRCA1 and BRCA2 and in 13 other genes involved in HRR in various types of solid tumors in patients with advanced or metastatic cancer. The researchers found that 4.7% of tumor samples had BRCA1/2 mutations, 13.6% had mutations in any of the HRR genes and 20.6% had genomic loss of heterozygosity (gLOH) of at least 16% i.e., loss of sections of chromosomes affecting 16% or more of the genome. BRCA1/2 mutations were most common in ovarian cancer (13.1%), prostate cancer (9.3%), breast cancer (8.2%) and pancreatic cancer (4.9%). Prevalence for mutations in HRR genes ranges from 2.4 to 26.0% and gLOH ≥16% ranged from 2.6 to 34.4% depending on the tumor type. In conclusion, the prevalence of mutations in the BRCA1/2 genes, HRR genes and gLOH ≥16% varied widely across 15 tumor types.
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In April 2023, the World Health Organization (WHO) reported that 17.5% of the global adult population experience infertility. What may be the contribution of per-and polyfluoroalkyl (PFAS) to this global public health problem? This study explored the associations between in vitro fertilization (IVF) outcomes and plasma concentrations of individual PFAS and PFAS mixtures in women undergoing in vitro fertilization and embryo transfer (IVF-ET) and how these exposures might affect IVF outcomes. We analyzed 8 PFASs in plasma samples from women (N = 259) who underwent IVF treatment. In multivariable generalized linear mixed models, there were statistically significant associations of higher plasma concentrations of PFNA with reduced numbers of total retrieved oocytes [12.486 (95%CI: 0.446,25.418), p trend = 0.017], 2 PN zygotes [6.467(95%CI: 2.034,14.968), p trend = 0.007], and cleavage embryos [6.039(95%CI: 2.162,14.240), p trend = 0.008]. Similarly, there was a continuous decline in the numbers of retrieved 2 PN zygotes and cleavage embryos with increasing concentration of PFOS [6.467(95%CI: 2.034,14.968), p trend = 0.009 and 6.039(95%CI: 2.162,14.240), p trend = 0.031,respectively] and a negative association between PFHxS concentrations and clinical pregnancy during the initial cycles of frozen ET [0.525(95%CI:0.410,0.640), p trend = 0.021]. To investigate the joint effect of PFAS mixtures, a confounder-adjusted BKMR model analysis showed inverse relationship between PFAS mixtures and the number of high-quality embryos, 2 PN zygotes and cleavage embryos, to which the greatest contributors to the mixture effect are PFDeA and PFBS, respectively. It demonstrated that PFAS exposure might exert negative effects on oocyte yield, fertilization and high-quality embryo in women undergoing IVF. These findings suggest that exposure to PFAS may increase the risk of female infertility and further studies are needed to uncover the potential mechanisms underlying the reproductive effects associated with PFAS.
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BACKGROUND: Recent evidence suggests that insulin resistance affects asthma outcomes. However, the effect of the homeostatic measure of insulin resistance (HOMA-IR) on airway inflammation and asthma exacerbations (AEs) is poorly understood. OBJECTIVE: To analyze the relationship between HOMA-IR and clinical and inflammatory characteristics in patients with asthma, and the association between HOMA-IR and AEs in the following year. METHODS: A prospective cohort study recruited participants with asthma, who were classified into the HOMA-IRhigh group and HOMA-IRlow group based on the cutoff value of 3.80 for HOMA-IR and were observed within 12 months. We evaluated the clinical and inflammatory features and conducted a 1-year follow-up to study the exacerbations. We used negative binomial regression models to analyze the association between HOMA-IR and AEs. RESULTS: Compared with patients in the HOMA-IRlow group (n = 564), those in the HOMA-IRhigh group (n = 61) had higher levels of body mass index, a higher waist circumference and waist-hip ratio, higher triglycerides, lower cholesterol high-density lipoproteins, more neutrophils in the peripheral blood, and elevated IL-5 levels in the induced sputum. Furthermore, patients in the HOMA-IRhigh group had a significantly increased risk for moderate to severe AEs (adjusted incidence rate ratio [aIRR] = 2.26; 95% CI, 1.38-3.70), severe AEs (aIRR = 2.42; 95% CI, 1.26-4.67), hospitalization (aIRR = 2.54; 95% CI, 1.20-5.38), and emergency visits (aIRR = 3.04; 95% CI, 1.80-8.53). CONCLUSIONS: The homeostatic measure of insulin resistance was associated with asthma-related clinical features and airway inflammation, and was an independent risk factor for future AEs. Therefore, insulin resistance may have important implications for managing asthma as a potential treatable trait.
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Previous retrospective cohort studies have found that, compared with oxygen tension in the uterus and fallopian tubes (2â¯%-8â¯%), exposure of pre-implantation embryos to atmospheric oxygen tension (AtmO2, 20â¯%) during assisted reproductive technology(ART) can affect embryo quality, pregnancy outcomes and offspring health. However, current research on the effects and mechanisms of AtmO2 on the development of embryos and offspring is mainly limited to animal experiments. Human embryonic stem cells (hESCs) play a special and irreplaceable role in the study of early human embryonic development. In this study, we used hESCs as a model to elucidate the possible effects and mechanisms of AtmO2 exposure on human embryonic development. We found that exposure to AtmO2 can reduce cell viability, produce oxidative stress, increase DNA damage, initiate DNA repair, activate autophagy, and increase cell apoptosis. We also noticed that approximately 50â¯% of hESCs survived, adapted and proliferated through high expression of self-renewal and pluripotency regulatory factors, and affected embryoid body differentiation. These data indicate that hESCs experience oxidative stress, accumulation of DNA damage, and activate DNA damage response under the selective pressure of AtmO2.Some hESCs undergo cell death, whereas other hESCs adapt and proliferate through increased expression of self-renewal genes. The current findings provide in vitro evidence that exposure to AtmO2 during the early preimplantation stage negatively affects hESCs.
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Diferenciación Celular , Supervivencia Celular , Daño del ADN , Desarrollo Embrionario , Células Madre Embrionarias Humanas , Estrés Oxidativo , Oxígeno , Humanos , Diferenciación Celular/efectos de los fármacos , Oxígeno/toxicidad , Células Madre Embrionarias Humanas/efectos de los fármacos , Células Madre Embrionarias Humanas/metabolismo , Desarrollo Embrionario/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Reparación del ADN , Autofagia/efectos de los fármacos , Línea CelularRESUMEN
INTRODUCTION: Hypoxia-inducible factor-2α (HIF-2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF-2α are poorly understood, with limited understanding of the prevalence and clinical prognosis. METHODS: This retrospective observational study used a de-identified nationwide (US-based) clinico-genomic database (CGDB) across 15 available tumor types. RESULTS: Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above-mentioned six genes was observed in 1.8% (95% CI: 1.5-2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF-2α gene mutations in the study population was 0.9% (95% CI: 0.8-1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF-2α gene mutation was 14.5 (95% CI: 11.5-24.2) and 9.3 (95% CI: 6.0-18.1) months, respectively, compared with 13.4 (95% CI: 12.9-13.9) and 9.8 (95% CI: 9.3-10.4) months among patients without HIF-2α gene mutations. DISCUSSION AND CONCLUSIONS: The prevalence of HIF-2α related gene mutations was generally low (<1%) across the 15 solid tumor types, except for VHL in RCC. No significant association between HIF-2α gene mutation status and OS was identified among patients evaluated in this study.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Mutación , Neoplasias , Humanos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neoplasias/genética , Neoplasias/mortalidad , Neoplasias/patología , Neoplasias/epidemiología , Pronóstico , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Prevalencia , Anciano , AdultoRESUMEN
OBJECTIVES: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort. METHODS: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ováricas , Compuestos de Fenilurea , Quinolinas , Humanos , Femenino , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Supervivencia sin Progresión , Anciano de 80 o más Años , Estudios de CohortesRESUMEN
Epoxy resin is extensively applied in the electronics and electrical fields because of its outstanding comprehensive performance. However, the low thermal conductivity (TC) limits its application in thermal interface materials. In the present work, epoxy-based hybrid composites with high TC were prepared by using expanded graphite (EG) and copper (Cu) nanoparticles as thermally conductive hybrid fillers via hot blending and compression-curing processes. Additionally, the influence of the Cu content on the thermal properties, mechanical properties, and morphology of each epoxy/EG/Cu composite was investigated. According to the results, the epoxy/EG/Cu composite showed a maximum TC of 9.74 W/(m·K) at a fixed EG content of 60 wt % owing to the addition of 10 wt % Cu. After the addition of 10 wt % Cu, the flexural strength, flexural modulus, and impact strengths of epoxy/EG/Cu composites were improved from 27.9 MPa, 9.72 GPa, and 0.81 kJ/m2 to 37.5 MPa, 10.88 GPa, and 0.91 kJ/m2, respectively. Hence, this study offers a feasible strategy for the design of epoxy hybrid composites with excellent TC that can be applied to thermal interface materials.
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The protein kinase C (PKC) family of serine/threonine kinases, which consist of three distinctly regulated subfamilies, have long been established as critical for a variety of cellular functions. However, how PKC enzymes are regulated at different subcellular locations, particularly at emerging signaling hubs such as the ER, lysosome, and Par signaling complexes, is unclear. Here, we present a sensitive Excitation Ratiometric (ExRai) C Kinase Activity Reporter (ExRai-CKAR2) that enables the detection of minute changes in subcellular PKC activity. Using ExRai-CKAR2 in conjunction with an enhanced diacylglycerol (DAG) biosensor capable of detecting intracellular DAG dynamics, we uncover the differential regulation of PKC isoforms at distinct subcellular locations. We find that G-protein coupled receptor (GPCR) stimulation triggers sustained PKC activity at the ER and lysosomes, primarily mediated by Ca2+ sensitive conventional PKC (cPKC) and novel PKC (nPKC), respectively, with nPKC showing high basal activity due to elevated basal DAG levels on lysosome membranes. The high sensitivity of ExRai-CKAR2, targeted to either the cytosol or Par-complexes, further enabled us to detect previously inaccessible endogenous atypical PKC (aPKC) activity in 3D organoids. Taken together, ExRai-CKAR2 is a powerful tool for interrogating PKC regulation in response to physiological stimuli.
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BACKGROUND: Chromosomal microarray analysis (CMA) has emerged as a critical instrument in prenatal diagnostic procedures, notably in assessing congenital heart diseases (CHD). Nonetheless, current research focuses solely on CHD, overlooking the necessity for thorough comparative investigations encompassing fetuses with varied structural abnormalities or those without apparent structural anomalies. OBJECTIVE: This study sought to assess the relation of single nucleotide polymorphism-based chromosomal microarray analysis (SNP-based CMA) in identifying the underlying causes of fetal cardiac ultrasound abnormalities. METHODS: A total of 2092 pregnant women who underwent prenatal diagnosis from 2017 to 2022 were included in the study and divided into four groups based on the presence of ultrasound structural abnormalities and the specific type of abnormality. The results of the SNP-Array test conducted on amniotic fluid samples from these groups were analyzed. RESULTS: Findings from the study revealed that the non-isolated CHD group exhibited the highest incidence of aneuploidy, overall chromosomal abnormalities, and trisomy 18, demonstrating statistically significant differences from the other groups (p < 0.001). Regarding the distribution frequency of copy number variation (CNV) segment size, no statistically significant distinctions were observed between the isolated CHD group and the non-isolated CHD group (p > 0.05). The occurrence rates of 22q11.2 and 15q11.2 were also not statistically different between the isolated CHD group and the non-isolated congenital heart defect group (p > 0.05). CONCLUSION: SNP-based CMA enhances the capacity to detect abnormal CNVs in CHD fetuses, offering valuable insights for diagnosing chromosomal etiology and facilitating genetic counseling. This research contributes to the broader understanding of the utility of SNP-based CMA in the context of fetal cardiac ultrasound abnormalities.
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Variaciones en el Número de Copia de ADN , Cardiopatías Congénitas , Embarazo , Femenino , Humanos , Diagnóstico Prenatal/métodos , Aberraciones Cromosómicas , Ultrasonografía/efectos adversos , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/genética , Análisis por Micromatrices/métodosRESUMEN
NKAP mutations are associated with Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD, MIM: #301039). Here, we elucidate the potential prenatal manifestation of NKAP mutation-associated disorder for the first time, alongside revealing the relationship between NKAP mutations and congenital heart defect (CHD) in the Chinese population. An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD. Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level. Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1. Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3. Summarily, our study strengthens NKAP mutations as a cause of CHD and prompts the reclassification of NKAP p.R330C as likely pathogenic, thereby establishing a prospective prenatal phenotypic spectrum that provides new insight into the prenatal diagnosis of CHD. Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD.
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Cardiopatías Congénitas , Mutación , Fenotipo , Humanos , Cardiopatías Congénitas/genética , Mutación/genética , Femenino , Células HEK293 , Predisposición Genética a la Enfermedad , Masculino , EmbarazoRESUMEN
PURPOSE: To investigate the prevalence of Y chromosome polymorphisms in Chinese men and analyze their associations with male infertility and female adverse pregnancy outcomes. METHODS: The clinical data of 32,055 Chinese men who underwent karyotype analysis from October 2014 to September 2019 were collected. Fisher's exact test, chi-square test, or Kruskal-Wallis test was used to analyze the effects of Y chromosome polymorphism on semen parameters, azoospermia factor (AZF) microdeletions, and female adverse pregnancy outcomes. RESULTS: The incidence of Y chromosome polymorphic variants was 1.19% (381/32,055) in Chinese men. The incidence of non-obstructive azoospermia (NOA) was significantly higher in men with the Yqh- variant than that in men with normal karyotype and other Y chromosome polymorphic variants (p < 0.050). The incidence of AZF microdeletions was significantly different among the normal karyotype and different Y chromosome polymorphic variant groups (p < 0.001). The detection rate of AZF microdeletions was 28.92% (24/83) in the Yqh- group and 2.50% (3/120) in the Y ≤ 21 group. The AZFb + c region was the most common AZF microdeletion (78.57%, 22/28), followed by AZFc microdeletion (7.14%,2/28) in NOA patients with Yqh- variants. There was no significant difference in the distribution of female adverse pregnancy outcomes among the normal karyotype and different Y chromosome polymorphic variant groups (p = 0.528). CONCLUSIONS: Patients with 46,XYqh- variant have a higher incidence of NOA and AZF microdeletions than patients with normal karyotype and other Y chromosome polymorphic variants. Y chromosome polymorphic variants do not affect female adverse pregnancy outcomes.
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Azoospermia , Infertilidad Masculina , Oligospermia , Humanos , Masculino , Femenino , Azoospermia/epidemiología , Azoospermia/genética , Estudios Retrospectivos , Deleción Cromosómica , Infertilidad Masculina/genética , Cromosomas Humanos Y/genética , China/epidemiología , Oligospermia/genéticaRESUMEN
In this study, to improve the electrical properties and impact strength of phenolic formaldehyde (PF) resin, PF-based composites were prepared by mixing graphene and the ionic liquid 3-decyl-bis(1-vinyl-1H-imidazole-3-ium-bromide) (C10[VImBr]2) via hot blending and compression-curing processes. The graphene surface was modified using a silane coupling agent. The synergistic effect of graphene and C10[VImBr]2 on the electrical properties, electromagnetic shielding efficiency, thermal stability, impact strength, and morphology of PF/graphene and PF/graphene/C10[VImBr]2 composites was then investigated. It was found that the electrical conductivity of the composites significantly increased from 2.3 × 10-10 to 4.14 × 10-3 S/m with an increase in the graphene content from 0 to 15 wt %, increasing further to 0.145 S/m with the addition of 5 wt % C10[VImBr]2. The electromagnetic shielding efficiency of the composite increased from 4.70 to 28.64 dB with the addition of 15 wt % graphene, while the impact strength of the composites rose significantly from 0.59 to 1.13 kJ/m2 with an increase in the graphene content from 0 to 15 wt %, reaching 1.53 kJ/m2 with the addition of 5 wt % C10[VImBr]2. Scanning electron microscopy images of the PF/GNP/C10[VImBr]2 composites revealed a rough morphology with numerous microcracks.
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INTRODUCTION: Defects in the homologous recombination repair (HRR) pathway can include mutations in BRCA1 and BRCA2 (BRCAm) and other HRR genes (HRRm). These mutations are associated with a homologous recombination deficiency (HRD) phenotype. We evaluated testing journey and treatment patterns by BRCAm, HRRm, and HRD status in a real-world dataset. METHODS: Deidentified data for patients who had undergone comprehensive genomic profiling using FoundationOne®CDx were collected through December 31, 2020, from a real-world multi-tumor clinico-genomic database (CGDB) capturing data from clinics in the United States. Patients eligible for inclusion in this analysis had a confirmed diagnosis with advanced or metastatic disease between January 1, 2018, and December 31, 2019, for 1 of 15 solid tumor types. Objectives were to evaluate patient treatment patterns by BRCAm, HRRm, and HRD status and to describe the timing of when (throughout disease course) comprehensive genomic profiling was performed. RESULTS: Among 9457 patients included in the overall population with evaluable biomarker status, 7856 (83.1%) received ≥ 1 systemic therapy. Among the 7856 patients who received systemic therapy, 2324 (30.0%) underwent testing before first-line therapy, 4114 (52.4%) were tested after receiving first-line therapy and before receiving subsequent therapy (if any), 970 (12.3%) were tested after second-line therapy and before receiving subsequent therapy (if any), and 447 (5.7%) patients underwent testing after receiving third-line therapy. A higher proportion of patients with BRCAm, HRRm, or HRD-positive status were treated with poly(ADP-ribose) polymerase (PARP) inhibitors across all lines of therapy. There was no evidence of a meaningful difference in the proportion of patients who received other treatment (including chemotherapy and immunotherapy) by BRCAm, HRRm, or HRD status. CONCLUSION: The majority of patients from this real-world dataset underwent FoundationOne®CDx testing after initiation of first-line treatment. Testing appeared to influence treatment patterns, with a higher proportion of patients with BRCAm, HRRm, and HRD-positive disease receiving PARP inhibitors.
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Neoplasias , Neoplasias Ováricas , Humanos , Femenino , Reparación del ADN por Recombinación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Mutación , Biomarcadores , Genómica , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: Breast-conserving surgery combined with oncoplastic breast surgery has become the standard surgical treatment for early breast cancer. OBJECTIVE: The purpose of this study was to investigate the safety and efficacy of the thoracodorsal artery perforator flap (TDAPF) in breast-conserving reconstruction of T2 breast cancer. METHODS: Thirty patients with T2 breast cancer admitted to our hospital from January 2019 to December 2020 were enrolled to receive pedicled TDAPF for repairing breast defects after breast-conserving surgery. Intraoperative conditions, postoperative complications, and shape satisfaction after breast reconstruction were recorded. RESULTS: The operation was successfully completed in all 30 patients, with an operation time of 177.77 ± 24.39 min, bleeding of 44.17 ± 7.67 mL, and length of hospital stay of 5.23 ± .97 d. There was no deformity or seroma at the donor site. Breast shape recovered well after operation. After operation, one patient had fat liquefaction in the recipient site, which healed well after wound treatment. The incidence of postoperative complications was 3.33%. Postoperative follow-up lasted 16-28 months, with a median of 22 months. The Breast-Q score for breast satisfaction was 61.83 ± 12.87 at 6 months after operation, compared to 62.07 ± 11.78 before operation (P > .05). CONCLUSIONS: TDAPF, featuring a high survival rate, moderate flap area, fewer postoperative complications, and high satisfaction with breast shape after operation. For east asian women with moderate breast size, TDAPF is a safe, effective choice for repairing defects in breast-conserving surgery for T2 breast cancer.
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Neoplasias de la Mama , Mamoplastia , Colgajo Perforante , Traumatismos de los Tejidos Blandos , Humanos , Femenino , Neoplasias de la Mama/cirugía , Colgajo Perforante/irrigación sanguínea , Colgajo Perforante/cirugía , Mamoplastia/efectos adversos , Arterias/cirugía , Complicaciones Posoperatorias/epidemiología , Resultado del Tratamiento , Trasplante de Piel , Traumatismos de los Tejidos Blandos/cirugíaRESUMEN
In recent years, the increase in high-calorie diets and sedentary lifestyles has made obesity a global public health problem. An unbalanced diet promotes the production of proinflammatory cytokines and causes redox imbalance in the body. Phenolics have potent antioxidant activity and cytoprotective ability. They can scavenge free radicals and reactive oxygen species, and enhance the activity of antioxidant enzymes, thus combating the body's oxidative stress. They can also improve the body's inflammatory response, enhance the enzyme activity of lipid metabolism, and reduce the contents of cholesterol and triglyceride. Most phenolics are biotransformed and absorbed into the blood after the action by gut microbiota; these metabolites then undergo phase I and II metabolism and regulate oxidative stress by scavenging free radicals and increasing expression of antioxidant enzymes. Phenolics induce the expression of genes encoding antioxidant enzymes and phase II detoxification enzymes by stimulating Nrf2 to enter the nucleus and bind to the antioxidant response element after uncoupling from Keap1, thereby promoting the production of antioxidant enzymes and phase II detoxification enzymes. The absorption rate of phenolics in the small intestine is extremely low. Most phenolics reach the colon, where they interact with the microbiota and undergo a series of metabolism. Their metabolites will reach the liver via the portal vein and undergo conjugation reactions. Subsequently, the metabolites reach the whole body to exert biological activity by traveling with the systemic circulation. Phenolics can promote the growth of probiotics, reduce the ratio of Firmicutes/Bacteroidetes (F/B), and improve intestinal microecological imbalance. This paper reviews the nutritional value, bioactivity, and antioxidant mechanism of phenolics in the body, aiming to provide a scientific basis for the development and utilization of natural antioxidants and provide a reference for elucidating the mechanism of action of phenolics for regulating oxidative stress in the body. © 2023 Society of Chemical Industry.