Prenatal ultrasound findings and prenatal diagnosis of fetal skeletal dysplasia.

OBJECTIVE: To analyze the value of prenatal ultrasound and molecular testing in diagnosing fetal skeletal dysplasia (SD). METHODS: Clinical data, prenatal ultrasound data, and molecular results of pregnant women with fetal SD were collected in the ultrasound department of our clinic from May 2019 to December 2021. RESULTS: A total of 40 pregnant women with fetal SD were included, with 82.5% exhibiting short limb deformity, followed by 25.0% with central nervous system malformations, 17.50% with facial malformations, 15% with cardiac malformations, and 12.5% with urinary system malformations. The genetic testing positive rate was 70.0% (28/40), with 92.8% (26/28) being single-gene disorders due to mutations in FGFR3, COL1A1, COL1A2, EVC2, FLNB, LBR, and TRPV4 genes. The most common SD subtypes were osteogenesis imperfecta (OI), thanatophoric dysplasia (TD), and achondroplasia (ACH). The gestational age (GA) at initial diagnosis for TD, OI, and ACH was 16.6, 20.9, and 28.3 weeks, respectively (p < 0.05), with no significant difference in femoral shortening between the three groups (p > 0.05). Of the OI cases, 5 out of 12 had a family history. CONCLUSION: Short limb deformity is the most prevalent phenotype of SD. When fetal SD is suspected, detailed ultrasound screening should be conducted, combined with GA at initial diagnosis, family history, and molecular evidence, to facilitate more accurate diagnosis and enhance prenatal counseling and perinatal management.

Genomic analysis of 9 infants with hypermethioninemia by whole-exome sequencing among in Henan, China.

BACKGROUND: Hypermethioninemia is an inborn error of metabolism with elevated plasma methionine (Met) caused by methionine adenosyltransferase deficiency. Methionine adenosyltransferase (MAT) I/III deficiency is the most common cause of hypermethioninemia. Except for increased blood Met, most patients have no symptoms, but a small number have nervous system complications, including cognitive impairment and mental retardation. OBJECTIVE: To investigate the gene variation of patients with hypermethioninemia in newborns in Henan province. METHODS: 9 cases of hypermethioninemia were screened for amino acids profile and acyl carnitine by tandem mass spectrometric (MS/MS) among 245 054 newborns. We performed whole-exome sequencing on 9 families of infants with hypermethioninemia. We identified mutated genes under different models of inheritance and further assessed these mutations through Sanger sequencing and association analysis. RESULTS: The incidence of neonatal hypermethioninemia was 1:27 228 in Henan province. A total of ten mutations in the MAT1A gene in the 9 patients were identified, including nine reported mutations (c.1070C > T, c.895C > T, c.100 T > A, c.315C > A, c.529C > T, c.623A > C, c.407G > T, c.1066C > T, 867G > T) and one novel mutations (c.772G > C). c.772G > C was detected in 2 families and is the most common variant. 7 infants (7/9) with hypermethioninemia were genetically autosomal dominant, and 2 infants (2/9) with hypermethioninemia were genetically autosomal recessive. CONCLUSION: Our findings expand the mutational spectrum of hypermethioninemia, with the description of one new mutation. They improve the understanding of the genetic background and clinical manifestation of MAT1A in Chinese patients.

The Landscape of Clinical Implementation of Pharmacogenetic Testing in Central China: A Single-Center Study.

PURPOSE: Pharmacogenetic testing is recognized as the major method for the individualized pharmacotherapy in clinical pharmacy practice, but information about the clinical implementation of pharmacogenetic testing in China is limited. The present study aimed to determine the situation of clinical implementation for pharmacogenetic testing in central China. METHODS: The study is conducted in the department of clinical pharmacy in The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. We collected and analyzed pharmacogenetic testing results from November 1, 2013 to November 2, 2018 in our hospital, which were checked in the electronic medical record system. The main outcome measures were the number and type of pharmacogenetic testing across five years. RESULTS: A total of 47,265 (56.9% male, mean age = 51.5 years) pharmacogenetic testing results were obtained with an average annual rate of growth of 63.0% across five years. A 50.2% (23,748/47,265) of all the pharmacogenetic testing results were for the determination of cytochrome P450 2C19 (CYP2C19) *2, *3 genotypes, and 41.7% were for the methylene tetrahydrofolate reductase (MTHFR) C677T genotype. The number of departments performing the pharmacogenetic testing was 35, 63, 55, 52, 52 and 39 for 2013-2018, respectively, and the main top five departments were cardiology, psychiatry, ICU, cardiac surgery and intervention. CONCLUSION: Clinical implementation of pharmacogenetic testing in China is growing rapidly, but the types and implementing departments of pharmacogenetic testing were limited. Our present study reported the real-world implementation modality of pharmacogenomic tests in China. It will help us to understand the testing of pharmacogenetics in China in order to promote the rational development of pharmacogenetics.

PPM1D Knockdown Suppresses Cell Proliferation, Promotes Cell Apoptosis, and Activates p38 MAPK/p53 Signaling Pathway in Acute Myeloid Leukemia.

OBJECTIVES: This study was to explore the effect of protein phosphatase, Mg2+/Mn2+ dependent 1D knockdown on proliferation and apoptosis as well as p38 MAPK/p53 signaling pathway in acute myeloid leukemia. METHODS: The expression of protein phosphatase, Mg2+/Mn2+ dependent 1D was detected in acute myeloid leukemia cell lines including SKM-1, KG-1, AML-193, and THP-1 cells, and normal bone marrow mononuclear cells isolated from healthy donors. The knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D was conducted by transfecting small interfering RNA into AML-193 cells and KG-1 cells. RESULTS: The relative messenger RNA/protein expressions of protein phosphatase, Mg2+/Mn2+ dependent 1D were higher in SKM-1, KG-1, AML-193, and THP-1 cells compared with control cells (normal bone marrow mononuclear cells). After transfecting protein phosphatase, Mg2+/Mn2+ dependent 1D small interfering RNA into AML-193 cells and KG-1 cells, both messenger RNA and protein expressions of protein phosphatase, Mg2+/Mn2+ dependent 1D were significantly reduced, indicating the successful transfection. Most importantly, knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D suppressed cell proliferation and promoted cell apoptosis in AML-193 cells and KG-1 cells. In addition, knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D enhanced the expressions of p-p38 and p53 in AML-193 cells and KG-1 cells. The above observation suggested that protein phosphatase, Mg2+/Mn2+ dependent 1D knockdown suppressed cell proliferation, promoted cell apoptosis, and activated p38 MAPK/p53 signaling pathway in acute myeloid leukemia cells. CONCLUSION: Protein phosphatase, Mg2+/Mn2+ dependent 1D is implicated in acute myeloid leukemia carcinogenesis, which illuminates its potential role as a treatment target for acute myeloid leukemia.

Exosomal miR-125a-5p derived from silica-exposed macrophages induces fibroblast transdifferentiation.

Silica particles can cause a systemic disease in workers termed lung silicosis, characterized by diffuse fibrosis. The development of lung silicosis involves various signaling pathway networks comprising numerous cell types and cytokines. As an important medium for communication between cells, exosomes have emerged as a hot research topic; however, the role of exosomal microRNAs (miRNAs) in silicosis remains unclear. In this study, we conducted high-throughput sequencing to generate exosomal miRNAs profiles from macrophages that were either exposed to silica or not. A total of 298 miRNAs were differentially expressed, with 155 up-regulated and 143 down-regulated. Highly conserved differentially expressed miRNAs were functionally annotated and analyzed to predict target genes. Among target interactions associated with the TGF-ß signaling pathway, miR-125a-5p and its putative target gene, Smurf1, were subjected to further research. As expected, levels of miR-125a-5p were upregulated in human serous exosomes and vitro, and inhibit the exosomal miR-125a-5p suppressed the expression of the fibrosis hallmarks. Besides, high levels of the miRNA led to upregulation of smooth muscle actin alpha and repression of Smurf1 in NIH-3T3 and MRC-5 cells. ID1 and SMAD1, downstream of TGF-ß signaling, were upregulated, indicating potential activation of this signaling pathway. These results contribute to understanding of the intercellular communication mediated by exosomal miRNAs and its critical role in fibroblast to myofibroblast transition and silicosis.

Potentiality of Protein phosphatase Mg2+ /Mn2+ dependent 1D as a biomarker for predicting prognosis in acute myeloid leukemia patients.

OBJECTIVE: The present study aimed to investigate the correlation of protein phosphatase Mg2+ /Mn2+ dependent 1D (PPM1D) with the risk stratification, treatment response, and survival profile in acute myeloid leukemia (AML) patients. METHODS: Totally 221 de novo AML patients and 50 healthy donors were enrolled. The bone marrow samples were collected before treatment from AML patients and acquired after enrollment from healthy donors. And bone marrow mononuclear cells were separated for detecting the mRNA/protein expressions of PPM1D by reverse transcription-quantitative polymerase chain reaction and Western blot. Complete remission (CR) was assessed after induction treatment, and event-free survival (EFS) and overall survival (OS) were calculated in AML patients. RESULTS: PPM1D mRNA (P < .001)/protein (P < .001) relative expressions were increased in AML patients compared with healthy donors, and receiver operating characteristic curve presented that PPM1D mRNA (AUC: 0.728, 95% CI: 0.651-0.806)/protein (AUC: 0.782, 95% CI: 0.707-0.857) relative expressions could differentiate AML patients from healthy donors. In AML patients, PPM1D mRNA (P < .001)/protein (P < .001) high relative expressions were correlated with poor-risk stratification. As for its association with prognosis, PPM1D mRNA (P < .001)/protein (P = .010) relative expressions were elevated in CR patients compared with non-CR patients. Patients with PPM1D mRNA (P < .001 for EFS; P = .004 for OS)/protein (P < .001 for EFS; P = .006 for OS) high relative expressions exhibited reduced EFS and OS compared with those with low expressions. CONCLUSION: PPM1D high expression correlates with poor-risk stratification and might serve as a potential biomarker for worse prognosis in AML patients, suggesting its potential to guide AML management.

Silica promotes the transdifferentiation of rat circulating fibrocytes in vitro.

To investigate the effects of silica on circulating fibrocytes (cFbs), the present study established a primary culture model of rat alveolar macrophages and cFbs in vitro. Macrophages were treated with free silica, and their supernatant was used to stimulate cFbs. The mRNA expression levels of collagen I, collagen III and α­smooth muscle actin (SMA) in cFbs were analyzed by reverse transcription­quantitative polymerase chain reaction. The intracellular and extracellular protein expression levels of collagen I, collagen III and α­SMA were detected by ELISA and immunofluorescence staining. The results indicated that in the cell model, the free silica effectively increased the protein and mRNA expression levels of collagen­I, collagen­III and α­SMA. The free silica significantly promoted the transdifferentiation of cFbs into myofibroblasts in a dose­and time-dependent manner.

[The expression of vascular endothelial growth factor antibody in serum of coal workers with pneumoconiosis].

OBJECTIVE: To determine the role of serum VEGF-Ab in pneumoconiosis of coal workers. METHODS: Four groups of participants were recruited for this study, including 230 with early stage (less serious than stage one) changes in relation to pneumoconiosis, 328 with confirmed coal worker pneumoconiosis, 309 workers exposed to coal dust, and 393 healthy people. All participants completed a questionnaire, and have their peripheral venous blood sample taken. Serum VEGF-Ab was detected by ELISA. RESULTS: Compared with healthy controls and those with early stage changes, the participants with pneumoconiosis and those exposed to coal dust had higher levels of serum VEGF-Ab (P < 0.05). The level of serum VEGF-Ab increased with the progression of stages of pneumoconiosis but without statistical significance (P > 0.05). In those with early stage pneumoconiosis, higher levels of serum VEGF-Ab were found in their 20 yr. - and 40 yr. - compared with those in their 60 yr. - (P < 0.05). By contrast, in those with confirmed pneumoconiosis and the healthy controls, lower levels of serum VEGF-Ab were found in their 20 yr. - and 40 yr. - compared with those in their 60 yr. - (P < 0.05). In those with early stage or first-stage pneumoconiosis, longer than 25 years work experience was associated with higher levels of serum VEGF-Ahb (P < 0.05). In those with confirmed pneumoconiosis, coal mining workers had a higher level of serum VEGF-Ab than their colleagues involving in assistance tasks (P < 0.05). In those exposed to coal dust, tunnelling workers had a higher level of serum VEGF-Ab than their coal mining colleagues (P < 0.05). CONCLUSION: Serum VEGF-Ab is associated with the occurrence and development of coal worker pneumoconiosis. The level of serum VEGF-Ab increases with age and length of exposure to dust.