ObjectiveTo explore the association between the concentration of maternal serum biomarkers， including free beta-human chorionic gonadotropin （fβ-hCG）， alpha fetoprotein （AFP）， unconjugated estriol （uE3）， and inhibin A （INH A） during the second trimester pregnancy and the risk of fetal presenting with copy number variation （CNV）. MethodsA retrospective analysis was conducted on the diagnostic results of pregnant women who were identified as high risk in the second trimester quadruple serological screening. These pregnant women underwent the interventional prenatal diagnosis and performed amniotic fluid karyotype analysis and comparative genomic hybridization array （aCGH） or CNV sequencing （CNV-seq） simultaneously.The detection rates of different diagnostic methods were calculated. The concentration of serum biomarkers， fβ-hCG， AFP， uE3， and INH A were divided into three levels： abnormally low， normal， and abnormally high. The prevalence of these serum biomarkers concentration in pregnant women with aberrant aCGH/CNV-seq results compared to normal controls was statistically calculated. ResultsAmong the 1 516 cases with high-risk quadruple serological screening in the second trimester， 59 chromosomal abnormalities were revealed by karyotype analysis， while 87 abnormalities were detected by aCGH/CNV-seq， indicating a significant statistical difference in detection rate. In comparison to the result of karyotype analysis， aCGH/CNV-seq identified an additional 46 cases of fetal CNV abnormalities， whereas it failed to detect 18 cases of chromosomal structural abnormalities. Among the 1 457 cases with normal karyotype results， the most frequent abnormality was observed in the concentration of fβ-hCG， followed by abnormalities in INH A and uE3 concentrations， yet the least common abnormality was noted in AFP concentration. When the maternal serum uE3 concentration was less than 0.5 multiples of median （MoM）， there was a significant difference in the risk of fetal CNV compared to the CNV results corresponding to normal concentration of uE3. No significant differences were found in the levels of fβ-hCG， AFP， and INH A between the two groups. ConclusionLow serum uE3 concentration （<0.5 MoM） is associated with an increased risk of fetal presenting with aberrant CNV.

The tumor microenvironment (TME) is a critical determinant of tumor initiation, progression, and therapeutic response, and serves as the basis for designing precise delivery strategies. Its marked heterogeneity underscores the need for a more comprehensive understanding of its composition and function. In addition to the extensively studied classical TME, emerging evidence highlights the significant roles of the tumor mechanical microenvironment and the tumor microbial microenvironment in modulating treatment efficacy. These non-classical dimensions not only independently influence tumor behavior but also interact dynamically with classical TME components. Mechanical cues within the TME, including matrix stiffness and solid stress, significantly affect drug distribution and treatment efficacy, suggesting that mechanical remodeling represents a potential strategy to enhance therapeutic outcomes. Concurrently, tumor-associated microbiota and their metabolites participate in immune regulation and metabolic reprogramming, contributing to tumor development and offering novel therapeutic targets. Moreover, recent advances have broadened our understanding on the multilayered regulatory landscape of the TME through the investigation of previously underappreciated factors such as neural regulation, metabolic niche dynamics, spatiotemporal heterogeneity, and epigenetic modulation. This review systematically summarizes the characteristics of these diverse TME dimensions and highlights recent progress in targeted delivery strategies, to facilitate the development of more personalized and effective anticancer therapies.
Humans ; Tumor Microenvironment ; Neoplasms/pathology* ; Drug Delivery Systems ; Antineoplastic Agents/administration & dosage*

Self-limiting epilepsy syndrome（SeLES）can be classified into two types based on age of onset：one occurring in the neonatal to infant period and the other in the childhood period.These diseases can exhibit complete remission within a specific age range，or be completely controlled with anti-seizure drugs.Children with SeLES typically have normal cognition or only mild cognitive impairment.In recent years，advancements in genetic testing technology have led to a better understanding of the genetic etiologies of SeLES，offering more possibilities for precision treatment.This article aims to explore the role of genetic factors in SeLES，providing reference for the diagnosis，precise drug selection，and prognosis of this type of hereditary epilepsy syndrome，in order to provide theoretical support for the long-term management of patients，and improve their quality of life.

In 2023, new diagnostic criteria were proposed to distinguish myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) from other inflammatory diseases of the central nervous system.With typical clinical presentation and neuroimaging features, the seropositive status of anti-myelin oligodendrocyte glycoprotein-IgG (MOG-IgG) is essential for the diagnosis of MOGAD.Advances in cell transfection immunofluorescence assays have improved diagnostic accuracy in the last few years, but there are differences in the positive predictive value of serum MOG-IgG titers in the context of different MOGAD prevalence.Therefore, alternative diagnostic methods need to be further explored, and the clinical significance of low MOG-IgG titers should be carefully interpreted.In this review, the main clinical features, current understanding and challenges of MOGAD were discussed, including uncertainties about the specificity and pathogenicity of myelin oligodendrocyte glycoprotein autoantibodies and the need to identify immunopathological targets for future therapies.Moreover, it is necessary to search for and validate biomarkers that can help diagnose and detect disease activity, and it is important to identify MOGAD patients who need long-term immunotherapy.

In 2023, new diagnostic criteria were proposed to distinguish myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) from other inflammatory diseases of the central nervous system.With typical clinical presentation and neuroimaging features, the seropositive status of anti-myelin oligodendrocyte glycoprotein-IgG (MOG-IgG) is essential for the diagnosis of MOGAD.Advances in cell transfection immunofluorescence assays have improved diagnostic accuracy in the last few years, but there are differences in the positive predictive value of serum MOG-IgG titers in the context of different MOGAD prevalence.Therefore, alternative diagnostic methods need to be further explored, and the clinical significance of low MOG-IgG titers should be carefully interpreted.In this review, the main clinical features, current understanding and challenges of MOGAD were discussed, including uncertainties about the specificity and pathogenicity of myelin oligodendrocyte glycoprotein autoantibodies and the need to identify immunopathological targets for future therapies.Moreover, it is necessary to search for and validate biomarkers that can help diagnose and detect disease activity, and it is important to identify MOGAD patients who need long-term immunotherapy.

OBJECTIVE: To investigate the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Cohen syndrome. METHODS: A proband who was admitted to Zhengzhou People's Hospital on June 2, 2021 due to intellectual disability and developmental delay, in addition with her younger sister and other family members, were selected as the study subjects. Clinical data of the proband and her younger sister were collected. Genomic DNA was extracted from peripheral venous blood and chorionic villi samples. Chromosomal abnormalities were detected with chromosomal microarray analysis (CMA). Whole exome sequencing (WES) and Sanger sequencing were carried out to detect candidate variants in the proband. With RNA extracted from the peripheral blood samples, VPS13B gene transcripts and expression were analyzed by PCR and real-time quantitative PCR. Prenatal diagnosis was carried out at 12 weeks' gestation. RESULTS: The proband was a 10-year-old female with clinical manifestations including development delay, obesity, severe myopia and peculiar facial features. Her sister was 3 years old with a similar phenotype. CMA revealed no chromosomal abnormality in the proband, while WES results revealed that the proband and her sister had both harbored compound heterozygous variants of the VPS13B gene, namely c.10076_10077delCA (p.T3359fs*29) and c.6940+1G>T, which were respectively inherited from their mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PS4+PM4+PP1; PVS1+PM2_Supporting+PM3+PP1). In vivo splicing assay confirmed that the c.6940+1G>T variant has produced a frameshift transcript with skipping of exon 38. Compared with the control group, the expression of RNA in the peripheral blood of the proband's parents has decreased to 65% ~ 70% (P < 0.01), whilst that in the proband and her sister has decreased to 40% (P < 0.001). Prenatal diagnosis at 12 weeks of gestation has found that the fetus only harbored the heterozygous c.10076_ 10077delCA variant. CONCLUSION The c.10076_10077delCA (p.T3359fs*29) frameshift variant and c.6940+1G>T splicing variant probably underlay the Cohen syndrome in this pedigree. Genetic testing has facilitated the diagnosis of this disease.
Female ; Humans ; East Asian People ; Intellectual Disability/genetics* ; Mutation ; Myopia/genetics* ; Pedigree ; Vesicular Transport Proteins/genetics* ; Child, Preschool ; Child

OBJECTIVE: To explore the genetic characteristics of a fetus with a high risk by maternal serum screening during the second trimester. METHODS: Genetic counseling was provided to the pregnant woman on March 22, 2020 at Henan Provincial People's Hospital. G-banded chromosomal karyotyping and array comparative genomic hybridization (aCGH) were carried out on the amniotic fluid sample and peripheral blood samples from the couple. RESULTS: The fetus and the pregnant woman were respectively found to have a 46,XX,der(6)t(6;14)(q27;q31.2) and 46,XX,t(6;14)(q27;q31.2) karyotype, whilst the husband was found to have a normal karyotype. aCGH analysis has identified a 6.64 Mb deletion at 6q26q27 and a 19.98 Mb duplication at 14q31.3q32.33 in the fetus, both of which were predicted to be pathogenic copy number variations. No copy number variation was found in the couple. CONCLUSION The unbalanced chromosome abnormalities in the fetus have probably derived from the balanced translocation carried by the pregnant woman. aCGH can help to determine the types of fetal chromosome abnormalities and site of chromosomal breakage, which may facilitate the prediction of fetal outcome and choice for subsequent pregnancies.
Pregnancy ; Female ; Humans ; Comparative Genomic Hybridization ; DNA Copy Number Variations ; Translocation, Genetic ; Chromosome Aberrations ; Fetus ; Prenatal Diagnosis

Objective:To investigate the association between prenatal genotype and phenotype of 16p13.11 microdeletion syndrome, aiming to provide a reference for prenatal diagnosis and genetic counseling.Methods:This retrospective study analyzed the results of comparative genomic hybridization microarray and low-coverage whole genome sequencing performed on 4 230 pregnant women in the Henan Provincial People's Hospital from July 2018 to July 2021. Indications for prenatal diagnosis, pedigree information and pregnancy outcomes of 17 fetuses with 16p13.11 microdeletion were described.Results:Prenatal diagnostic indications in the 17 fetuses were ultrasound abnormalities in five cases (increased nuchal translucency in four and cerebral ventriculomegaly with 10.7 mm in one), inter-twin weight discordance over 20% in one case, high risk in five cases and marginal risk in one in trisomy-21 serum screening, advanced maternal age in three cases (one with echogenic intracardiac focus in the left ventricle and two with normal ultrasound images) and adverse pregnancy history in two cases with normal ultrasound images. Pedigree verification that performed on 12 cases revealed that five were caused by de novo mutations and seven were inherited from their parents. The follow-up results showed that five cases were terminated, two lost to follow-up and 10 born alive (inheritance patterns were de novo mutations in three cases, parental inheritance in six and unknown pattern in one). These 10 infants were followed up from age 7 months to 3 years and 2 months and the results showed that one case was born with choroid plexus cyst of the left ventricle and presented instability of gait at 1 year and 3 months; one was a premature infant with 33 gestational weeks whose parents reported his language ability was not well at 2 years and 1 month old but without other abnormalities; one case had low muscle tone and was unable to keep head upright at 3 months who recovered at 5 months old after rehabilitation treatment according to the parents' report; all seven parents in the remaining seven cases reported no abnormalities. Conclusions:There was no specific prenatal diagnostic indication for 16p13.11 microdeletion syndrome. Genetic tracing, pregnancy outcome analysis and follow-up surveillance would provide reference for genetic counseling of 16p13.11 microdeletion syndrome.

Background Tricresyl phosphate (TCP) is mainly used as a flame retardant. Studies have confirmed that it has cytotoxicity and neurotoxicity, but its reproductive toxicity is not clear. Objective To investigate the reproductive toxicity and potential mechanism of TCP subacute exposure on Caenorhabditis elegans. Methods Caenorhabditis elegans were exposed to solvent control and 0.1, 1, 10, 100, and 1000 μg·L⁻¹ TCP respectively for 72 h. Brood size and number of fertilized eggs in the uterus were detected to evaluate reproductive ability. The number of total germline cells and the relative area of gonad arm were measured to evaluate the development of gonads. The body length and body width of Caenorhabditis elegans were detected to evaluate growth and development. The activities of reactive oxygen species (ROS) and superoxide dismutase (SOD) in Caenorhabditis elegans, and the mitochondrial active oxygen metabolism genes (mev-1 and gas-1) of N2 nematodes were detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) to evaluate oxidative stress. WS1433 transgenic nematodes and wild-type nematodes N2 were exposed to solvent control or TCP (0.1, 1, 10, 100, and 1000 μg·L⁻¹) respectively. DNA damage in germ cells of WS1433 transgenic nematodes was detected, the relative expressions of DNA damage-related genes (hus-1, clk-2, cep-1, and egl-1) in N2 nematodes were detected by qRT-PCR to evaluate the effect of TCP exposure on genetic damage. Results Compared with the solvent control group (217.00 ± 12.20), the brood size of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (170.80 ± 11.51, 169.60 ± 10.52, P < 0.05). Compared with the solvent control group (18.43 ± 1.69), the number of fertilized eggs of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (13.47 ± 0.81, 11.95 ± 0.90, P < 0.05). Compared with the solvent control group (312.46 ± 77.4), the number of total germline cells of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (281.80 ± 12.98, 273.50 ± 8.53, P < 0.05). Compared with the solvent control group, the relative area of gonads of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased by 13.83% and 17.25% respectively (P<0.05). Compared with the solvent control group [(1058.10±80.12) μm, (78.21±14.69) μm], the body length and body width of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (P<0.05). Compared with the solvent control group, the relative fluorescence intensity of ROS in nematodes in the 10, 100, and 1000 μg·L⁻¹ TCP groups increased significantly (107.60%±1.02%, 105.90%±1.40%, and 106.40%±1.85%, respectively, P<0.05), and the activities of SOD were reduced (by 20.66%, 15.88%, and 16.44%, respectively, P<0.05). Compared with the solvent control group (1.3±1.3), the number of DNA-damaged germ cells of WS1433 nematodes in the 100 and 1000 μg·L⁻¹ TCP groups increased significantly (2.4±0.3, 2.7±0.3, P<0.05); the expressions of mev-1 and gas-1 genes in N2 nematodes in the 10, 100 and 1000 μg·L⁻¹ TCP groups decreased significantly (P<0.05); the expressions of hus-1 in the 0.1-1000 μg·L⁻¹ TCP groups significantly increased (P<0.05); the expressions of clk-2 and egl-1 in the 100 and 1000 μg·L⁻¹ TCP groups increased significantly (P<0.05); the expressions of cep-1 in the 1, 10, and 100 μg·L⁻¹ TCP groups increased significantly (P<0.05). Conclusion TCP may cause reproductive damage to nematodes through oxidative stress and germ cell DNA damage.

Objective:To analyze the clinical and genetic characteristics of a 27-year-old male patient with intellectual disability and his pedigree to provide a reference for genetic counseling and prenatal diagnosis.Methods:G-banding and array comparative genomic hybridization (aCGH) were performed to analyze the karyotypes and genomic copy number variations of the proband (Ⅲ-1) and his family members. Based on the results, prenatal diagnosis was performed for one pregnant woman (Ⅲ-2) in the pedigree who is the sister of the proband.Results:All karyotyping were normal in the family members, while aCGH results showed a 1 533 kb microduplication in the Xq25 region of the proband, his mother (Ⅱ-3), his uncle (Ⅱ-2), and his sister (Ⅲ-2), which was confirmed to be pathogenic. The proband and his uncle presented with intellectual disability, bradylalia, and facial dysmorphism. In contrast, his mother and sister showed normal phenotypes. His sister's fetal karyotype and aCGH results were normal, and the pregnancy continued. A male baby (Ⅳ-1) was delivered vaginally at term and showed no physical or intellectual abnormalities during a 46-month follow-up.Conclusions:Xq25 microduplication might be the cause of intellectual disability in the proband. STAG2 is probably the essential gene in Xq25 region.