Comparison of prediction ability of two extended Cox models in nonlinear survival data analysis / 南方医科大学学报

OBJECTIVE@#To compare the predictive ability of two extended Cox models in nonlinear survival data analysis.@*METHODS@#Through Monte Carlo simulation and empirical study and with the conventional Cox Proportional Hazards model and Random Survival Forests as the reference models, we compared restricted cubic spline Cox model (Cox_RCS) and DeepSurv neural network Cox model (Cox_DNN) for their prediction ability in nonlinear survival data analysis. Concordance index was used to evaluate the differentiation of the prediction results (a larger concordance index indicates a better prediction ability of the model). Integrated Brier Score was used to evaluate the calibration degree of the prediction (a smaller index indicates a better prediction ability).@*RESULTS@#For data that met requirement of the proportion risk, the Cox_RCS model had the best prediction ability regardless of the sample size or deletion rate. For data that failed to meet the proportion risk, the prediction ability of Cox_DNN was optimal for a large sample size (≥500) with a low deletion (< 40%); the prediction ability of Cox_RCS was superior to those of other models in all other scenarios. For example data, the Cox_RCS model showed the best performance.@*CONCLUSION@#In analysis of nonlinear low maintenance data, Cox_RCS and Cox_DNN have their respective advantages and disadvantages in prediction. The conventional survival analysis methods are not inferior to machine learning or deep learning methods under certain conditions.

Advances in genetics and prevention of monogenic global developmental delay and intellectual disability / 中华围产医学杂志

Global developmental delay/intellectual disability (GDD/ID) is an enormous group of neurodevelopmental disorders with diverse clinical and genetic heterogeneity. The estimated prevalence of GDD/ID was 1%-3%, affecting about 150 million people. GDD/ID is one of the leading causes of disability in children worldwide. The causes of GDD/ID are complex, comprising genetic and environmental factors. It is often co-morbid with a variety of psychiatric behavioral disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder. Owing to the improvement of genetic technology, monogenic GDD/ID has been one of the hot-spot research in genomic era, and the relevant preventive measures deserve extensive attention. In this review, we summarized the advances in genetics and prevention of monogenic GDD/ID.

Prenatal diagnosis of abnormal morphology of Sylvian fissure and malformations of cortical development / 中华围产医学杂志

Objective:To investigate the significance of abnormal morphology of Sylvian fissure detected by fetal neurosonogram (NSG) in prenatal diagnosis of malformations of cortical development (MCD).Methods:This retrospective study involved fetuses with abnormal morphology of Sylvian fissure on prenatal NSG in Peking University First Hospital between January 2016 and December 2021. Clinical data including the basic information as well as the results of NSG, genetic examinations and MRI were collected. The diagnosis of MCD could be made when both brain morphological abnormalities and pathogenic/likely pathogenic genetic abnormalities were presented. The association between the abnormal morphology of Sylvian fissure and MCD was analyzed by descriptive analysis.Results:Thirteen participants who had complete genetic information were included in this study [defined as those who were found with pathogenic/likely pathogenic copy number variation (CNV) or those who further underwent whole-exome sequencing (WES) as no pathogenic/likely pathogenic CNV were detected]. Twelve fetuses (12/13) were eventually diagnosed with MCD. Pathogenic CNV were found in seven fetuses and pathogenic point mutations in five, involving six pathogenic genes and four genetic syndromes. Symmetric morphologic abnormality of Sylvian fissure was detected in 10 cases by prenatal NSG with shallow and broad shape in six and abnormal angle of Sylvian fissure in four. The other two fetuses showed asymmetric abnormal morphology of Sylvian fissure that was shallow and broad shape on one side and abnormal angle on the other. The imaging features of MCD present by prenatal NSG and were consistent with those of MRI.Conclusions:Abnormal morphology of Sylvian fissure detected by prenatal NSG is important in MCD diagnosis. Genetic examination are recommended to the fetuses with abnormal morphology of Sylvian fissure. For those requiring for genetic analysis, chromosomal microarray analysis together with WES might be an optimal choice.

Proteomics reveals the protective mechanism of salvianolate injection on early hyperacute myocardial infarction / 药学学报

The hyperacute stage of myocardial infarction refers to a period of time within 30 minutes after the occurrence of myocardial infarction, when the symptoms are not obvious and the diagnosis is difficult, and the related pathophysiological mechanism has received less attention. In this study, proteomics was used to investigate the pathological changes in the early hyperacute phase of myocardial infarction, aiming to provide experimental evidence for pathological mechanism of myocardial infarction hyperacute stage. Meanwhile, the intervention effect and related mechanism of salvianolate injection were discussed based on heat shock protein B6 (HSPB6), aiming to benefit the clinical rational use of salvianolate injection. The protein expression changes before and after myocardial infarction model establishment were detected by label-free proteomics via mass spectrometry and analyzed by bioinformatics method. Then the binding effect of salvianolate injection on the commonly differential protein HSPB6 was evaluated by molecular docking technology, which was finally verified by animal experiments. All animal experimental protocols were approved by the Ethics Committee of Xiyuan Hosptial (2022XLC041). The results of this study showed that a total of 2 166 proteins were quantified by lable-free proteomics, of which 194 shared differential proteins were involved in myocardial injury and body regulation in the hyperacute phase of myocardial infarction, mainly involving molecular functions such as protein homodimerization activity, oxygen binding and transport, and serine endopeptidase inhibitor activity. Among them, HSPB6 protein is involved in the regulation of myocardial function. Molecular docking results indicated that magnesium salvianolate acetate, which is the main component of salvianolate injection, had the lowest binding energy with HSPB6 protein: -14.53 kcal·mol-1. Animal experiments showed that compared with the Sham group, the model group had significantly lower ejection fraction (EF) and fractional shortening (FS) (P < 0.001), cardiac blood perfusion decreased significantly (P < 0.001). There were obvious pathological changes such as myocardial fiber disorder, cardiomyocyte edema and interstitial small blood vessel congestion; the injury of cardiac function of rats in the administration group was attenuated, and the FS of rats in the low-dose group was significantly improved (P < 0.05), the pathological injury of myocardial tissue was markedly mitigated, and the expression of HSPB6 protein was up-regulated to varying degrees (P < 0.01, P < 0.001). In conclusion, salvianolate injection could be able to improve the cardiac function and pathological morphology of rats in the early hyperacute stage of myocardial infarction, and its mechanism may be related to the promotion of expression of HSPB6.

Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses / 中华儿科杂志

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

CIC-rearranged sarcoma: a clinicopathological analysis of four cases / 中华病理学杂志

Objective: To investigate the clinicopathological features and differential diagnosis of CIC-rearranged sarcoma (CRS). Methods: Five CRSs of 4 patients (2 biopsies of pelvic cavity and lung metastasis from case 4) diagnosed in the First Affiliated Hospital of Nanjing Medical University were enrolled from 2019 to 2021. All cases were evaluated by clinical presentation, H&E, immunohistochemical staining and molecular analysis and the related literature was reviewed. Results: There were one male and three females, the age at diagnosis ranged from 18 to 58 (mean 42.5) years. Three cases were from the deep soft tissues of the trunk and one case from the skin of foot. Grossly, the tumor size ranged from 1 to 16 cm. Microscopically, the tumor was arranged in nodules or solid sheets. The tumor cells were typically round or ovoid, with occasional spindled or epithelioid morphology. The nuclei were round to ovoid with vesicular chromatin and prominent nucleoli. Mitotic figures were brisk (>10/10 HPF). Rhabdoid cells were seen in four of five cases. Myxoid change and hemorrhage were observed in all samples and two cases showed geographic necrosis. Immunohistochemically, CD99 was variably positive in all samples, while WT1 and TLE-1 were positive in four of five samples. Molecular analysis showed CIC-rearrangements in all cases. Two patients succumbed within 3 months. One had mediastinal metastasis 9 months after surgery. One underwent adjuvant chemotherapy and remained tumor-free 10 months after diagnosis. Conclusions: CIC-rearranged sarcoma is uncommon and shows aggressive clinical course with dismal prognosis. The morphological and immunohistochemical characteristics can largely overlap with a variety of sarcomas; hence, knowledge of this entity is vital to avoid potential diagnostic pitfalls. Definitive diagnosis requires molecular confirmation of CIC-gene rearrangement.

Diffuse midline glioma with H3K27 alteration in adults: a clinicopathological analysis / 中华病理学杂志

Objective: To investigate the clinicopathological characteristics, pathological diagnosis and prognosis of diffuse midline glioma (DMG) with H3K27 alteration in adults. Methods: Twenty cases of H3K27-altered adult DMG diagnosed in the First Affiliated Hospital of Nanjing Medical University were enrolled from 2017 to 2022. All cases were evaluated by clinical and imaging presentations, HE, immunohistochemical staining and molecular genetics; and the relevant literature was reviewed. Results: The ratio of male to female was 1∶1, and the median age was 53 years (range from 25 to 74 years); the tumors were located in the brainstem (3/20, 15%) and non-brainstem (17/20, 85%; three in thoracolumbar spinal cord and one in pineal region). The clinical manifestations were non-specific, mostly dizziness, headache, blurred vision, memory loss, low back pain, limb sensation and/or movement disorders, etc. Microscopically, the tumors showed infiltrative growth, with WHO grade 2 (3 cases), grade 3 (12 cases), and grade 4 (5 cases). The tumors showed astrocytoma-like and oligdendroglioma-like, pilocytic astrocytoma-like and epithelioid-like patterns. Immunohistochemically, the tumor cells were positive for GFAP, Olig2 and H3K27M, and H3K27me3 expression was variably lost. ATRX expression was lost in four cases, p53 was strongly positive in 11 cases. Ki-67 index was about 5%-70%. Molecular genetics showed p. k27m mutation in exon 1 of H3F3A gene in 20 cases; BRAF mutation in two cases: V600E and L597Q mutation in one case each. Follow up intervals ranged from 1 to 58 months, and the survival time for brainstem (6.0 months) and non-brainstem (30.4 months) tumors was significantly different (P<0.05). Conclusions: DMG with H3K27 alteration is uncommonly found in adults, mostly occurs in non-brainstem, and can present in adults of all ages. Owing to the wide histomorphologic features, mainly astrocytic differentiation, routine detection of H3K27me3 in midline glioma is recommended. Molecular testing should be performed on any suspected cases to avoid missed diagnosis. Concomitant BRAF L597Q mutation and PPM1D mutation are novel findings. The overall prognosis of this tumor is poor, with tumors located in the brainstem showing worse outcome.

Clinicopathological features of ectopic meningothelial hamartoma / 中华病理学杂志

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of ectopic meningothelial hamartoma (EMH). Methods: Three cases of EMH diagnosed in the First Affiliated Hospital of Nanjing Medical University from January 2014 to December 2020 were enrolled. All cases were evaluated by clinical and imaging features, HE and immunohistochemical staining, and the relevant literature was reviewed. Results: There were one male and two female patients, aged 2, 67 and 19 years, respectively. Clinically, they presented as skin masses in the head and face region (two cases) and sacro-coccygeal region (one case). Grossly, the lesions ranged in size from 1.6 cm to 8.9 cm. Microscopically, the lesions were ill-defined, and located in the dermis and subcutis, and showed pseudovascular channels lined by monolayer of cuboidal to flattened epithelium with mild atypia, with variable cystic cavity formation. There was prominent interstitial fibrosis. Concentric, lamellated, onion skin-like arrangement with short spindle or ovoid cells and psammoma bodies were noted. Immunohistochemically, these cells were strongly positive for SSTR2, EMA, vimentin and progesterone receptor. Ki-67 positive index was low, approximately 1%. Conclusions: EMH is uncommon. Definitive diagnosis relies on histopathologic examination. The importance in recognizing the lesions is to differentiate from other more aggressive tumors.

How to write a high-quality case report on the prenatal diagnosis of monogenic diseases / 中华围产医学杂志

With the development of gene detection technology, more and more rare diseases can be diagnosed prenatally, and a growing number of related case reports have been submitted. This article aims to provide guidance for clinicians who are considering writing a case report on the prenatal diagnosis of monogenic diseases from the following aspects: the option of genetic testing methods for prenatal diagnosis, essential components of the report, the importance of phenotype, and discussion of the related case.

Epidemiological characteristics of influenza in Fuling district of Chongqing of China in 2010-2019 / 中国基层医药

Objective:To investigate the characteristics and change law of influenza in Fuling District of Chongqing in 2010-2019, and to provide a scientific basis for the pre-control of influenza.Methods:We performed an epidemiological analysis on the data of influenza-like illness reported by Fuling District influenza surveillance sentinel hospitals in Chongqing in 2010-2019.Results:In 2010-2019, a total of 42 169 cases of influenza-like illness were reported in Fuling District, with an average treatment rate of 1.22%. The activity of influenza-like illness peaked in winter, spring, and summer. There were 22 788 cases in the group of cases aged < 5 years, accounting for 50.4%. In 2010-2019, a total of 8049 pharyngeal swabs were collected to screen for influenza-like illness, with a positive rate of 14.52%. Influenza virus A H3 positive rate was highest, accounting for 37.98%, followed by influenza virus B BV positive rate, accounting for 30.80%. The highest influenza virus-positive rate was reported in January (26.34%), followed by November (24.85%).Conclusion:Influenza in the Fuling district of Chongqing mainly occurs in winter, spring, and summer. Influenza virus A H3 is the dominant strain. Children and school students are prone to develop influenza-like illnesses. We should continue to strengthen the monitoring of influenza strains, greatly promote vaccination, and strengthen the monitoring and prevention of influenza-like illness among susceptible populations.

Analysis on the risk of refracture after osteoporotic vertebral fracture with changes in blood calcium and bone metabolism / 中华内分泌外科杂志

Objective:To study the risk of refracture after osteoporotic vertebral fracture with changes in blood calcium and bone metabolism.Methods:260 patients with osteoporotic vertebral fracture treated in our hospital from Feb. 2018 to Feb. 2020 were selected for study. All patients were treated with kyphoplasty. The clinical curative effect, blood calcium, PINP, and β-CTX level changes were observed, postoperative recurrence was followed up. Clinical data of fracture patients were collected, risk factors of osteoporotic vertebral fractures in patients with postoperative recurrence of fracture were analyzed, receiver-operating characteristic curve was drawn to analyze the predictive value of blood calcium, PINP, andβ-CTX in postoperative recurrence of osteoporotic vertebral fracture.Results:The total clinical response rate was 95.77% (249/260) after treatment. After treatment, serum calcium, PINP, and β-CTX decreased with time, and the difference was significant ( P<0.05) . All patients were followed up for 6 months. There were 81 cases (31.15%) suffering postoperative fracture and 179 cases (68.85%) without fracture. According to univariate analysis, there were no statistically significant differences in age, sex, BMI, history of trauma, underlying disease, site of surgical vertebral body, segment of surgical vertebral body, correction angle of sagittal kyphosis, or amount of bone cement injection between the two groups ( P>0.05) . Long-term history of glucocorticoid use, preoperative fractured vertebra number, surgical vertebra number, blood calcium, PINP, β-CTX, fracture compression rate, vertebra height recovery rate, reinforced vertebra number, and bone cement leakage were correlated with postoperative recurrence of fracture in patients with osteoporotic vertebral fracture ( P<0.05) . Multivariate Logistic analysis showed that long-term history of glucocorticoid use, preoperative number of fractured vertebrae, surgical vertebra number, fracture compression rate, vertebral height recovery rate, enhanced vertebral body number, bone cement leakage, blood calcium, PINP, and β-CTX were all independent risk factors for postoperative recurrence of osteoporotic vertebral fracture ( P<0.05) . ROC curve results showed that AUC, 95%CI and truncation value were 0.820, 0.770-0.871 and 2.12mmol/L vs 0.915, 0.873-0.957 and 45.51 ng/mL vs 0.973, 0.957-0.988, and 463.29 for serum calcium, PINP, and β-CTX respectively in predicting the recurrence of osteoporotic vertebral fracture. Conclusion:Kyphoplasty has a significant effect on osteoporotic vertebral fracture, and it can effectively improve the serum calcium, PINP, and β-CTX, which have a certain monitoring value for postoperative recurrence of fracture.

Black carbon analytical methods for environmental samples and associated perspectives of biomonitoring / 环境与职业医学

Black carbon (BC) is the most strongly light-absorbing component of particulate matter and is largely emitted from the incomplete combustion of fossil and biomass fuels. It has a graphite structure with less carbonized, irregular, microcrystalline, and heterogeneous components, which is determined by pyrolysis conditions. BC can be absorbed by human body via inhalation or ingestion route and then be transported to various organs through the blood circulation system in human body. When crossing different biological barriers (such as blood-brain barrier, placenta barrier, and blood-testis barrier), BC may further act on these targets and induce various toxicities. This review first distinguished between BC and carbon black, and then introduced analytical methods of BC in various environmental samples: microscopic observation, chemothermal oxidation methods, other chemical oxidation methods, and molecular marker analysis. We summarized the principles, technical characteristics, and application to environmental samples of these methods, and discussed the ideas and perspectives of determination of BC in biological samples for human biomonitoring.

Variable Quasi-circular Gait Planning with Smooth Angular Acceleration for Lower Limb Rehabilitation / 中国康复理论与实践

Objective:To solve the problem of leg shaking caused by the sudden change of angular acceleration at the joint of periodic motion during circular gait training of lower limb rehabilitation robot. Methods:A kind of quasi-circular gait was proposed, which divided the periodic motion into three phases: start phase, middle phase and end phase. The time was equal in the start phase and the end phase, and could be adjusted with the parameter ratio. The joint trajectories of the two phases were planned by quintic polynomial, and the middle phase was still the circular gait joint trajectory. The trajectory of the proposed quasi-circular gait was simulated. Results:The angular velocity was continuously differentiable and 0, the angular acceleration was continuous and 0, and the end-effector trajectory became flat with the increase of ratio. The results on the physical prototype of the lower limb rehabilitation robot were principally consistent with the simulation, and the machine worked smoothly. Conclusion:The proposed variable quasi-circular gait had smooth angular acceleration at the junction of periodic motions, which effectively solved the jitter problem when using circular gait for lower limb rehabilitation training and avoided secondary injury to the patients.

Automatic Adjustment Algorithm of Bed Height for Multi-position Lower Limb Rehabilitation Robot / 中国康复理论与实践

Objective:To develop an automatic adjustment algorithm of bed height of multi-position lower limb rehabilitation robot, to meet the variety of leg lengths and training modes to avoid the collision between robot and ground. Methods:Six mathematical models of robot bed body height were established for six training modes of multi-position lower limb rehabilitation robot, which were described with leg length and bed tilt angle. The influence was analyzed that mechanical clearance and deflection as well as the jitter error of leg bracket during movement. Furthermore, a software related to these models was developed to automatically adjust the bed height for training. Volunteers were recruited to test actually. Results:The test data of bed height are consistent with the theoretical calculation of six mathematical models. Clearance and deflection did not affect the theoretical results of bed height. The end of robot's lower limb was always above the safe height during rehabilitation training. Conclusion:The automatic adjustment algorithm of bed height has been established, which can ensure that the rehabilitation robot runs at a safe height.

Identification of a novel mutation of MBD5 gene in a pedigree affected with autosomal dominant mental retardation type 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with mental and motor retardation, language impairment, facial dysmorphism and epilepsy.@*METHODS@#Whole exome sequencing was carried out to detect pathogenic variant in the proband, and candidate variant was selected based on his phenotype. Sanger sequencing was used to verify the variant in the proband, his parents and other family members.@*RESULTS@#The proband was found to carry a frameshifting mutation of MBD5 gene, namely c.2217delT (p.F739Lfs*6), which was inherited from his mother and unreported previously. Sanger sequencing confirmed that his brother carried the same mutation with a similar phenotype. His mother also had poor language expression when she was young, in addition with poor academic performance, though she could do some housework and had no history of convulsion.@*CONCLUSION@#A novel pathogenic variant of the MBD5 gene was discovered, which has enriched the mutational spectrum of the MBD5 gene. Above discovery has enabled genetic counseling and prenatal diagnosis for the family.

Therapeutic effect and mechanism of Shouhui Tongbian Capsules on slow transit constipation model mice / 中国中药杂志

Shouhui Tongbian Capsules was used to explore the therapeutic effect and potential mechanism on slow transit constipation model mice induced by loperamide hydrochloride. In the experiment, loperamide hydrochloride-induced ICR mice were used as the model of slow transit constipation. Fifty ICR mice were divided into the blank group, model group and high, medium and low dose groups of Shouhui Tongbian Capsules extract(100, 200 and 400 mg·kg~(-1)). The model group and the administration groups were then modeled using loperamide hydrochloride intragastrically to obtain slow transit constipation. After successful modeling, high, medium and low doses of drugs were given to each drug group by intragastric administration. After 14 days of administration, the first defecation time, 6 h defecation grain number, 6 h defecation wet weight and dry weight, black feces discharged within 6 h and the fecal water content were measured. Intestinal tissues were taken for c-Kit and SCF immunohistochemical sections to detect the expression of c-Kit and SCF in the blank group, model group and high, medium and low dose groups of the medicinal extract of Shouhui Tongbian Capsules. The tissue changes in the intestinal wall of mice were detected by HE staining. At the same time, partial intestinal tissues were taken to test the activity of ATP synthase and isocitrate dehydrogenase in intestinal tissues of mice. RESULTS:: showed that Shouhui Tongbian Capsules effectively improved the symptoms of slow transit constipation in ICR mice and promoted intestinal movement. Shouhui Tongbian Capsules obviously shortened the time of discharging black stool for the first time, improved the intestinal propulsion rate, increased the water content and amount of feces, and improved the constipation symptoms. Mechanism study revealed that Shouhui Tongbian Capsules increased ATP synthase activity and mitochondrial isocitrate dehydrogenase activity in intestinal tissue, and up-regulated c-Kit/SCF signaling pathway to promote interstitial Cajal cells proliferation, intestinal nerve transmission, intestinal motility and transport capacity.

Parental origin verification through chromosomal microarray analysis to determine the clinical significance of copy number variations / 中华围产医学杂志

Objective:To explore the role of parental origin verification in chromosomal microarray analysis (CMA) on the determination of the clinical significance of copy number variations (CNVs).Methods:This retrospective study collected clinical information from 73 core families who underwent prenatal diagnosis at Peking University First Hospital from November 2017 to December 2019. Indications for prenatal diagnosis included ultrasound abnormality in 54 cases (including 12 with thickened nuchal translucency (≥2.5 mm), four with fetal growth restriction, seven with abnormal pregnancy history, and 31 with isolated ultrasound abnormality), NIPT indicated high-risk in four cases, advanced age in nine cases, abnormal pregnancy history alone in three cases, intrauterine death in two cases and one with maternal mental retardation. Genomic DNA of amniotic fluid sample, chorionic villi, cord blood, fetal tissues, and fetal heart blood were extracted using genomic DNA extraction kit. The CNVs of prenatal samples in 73 subjects were analyzed using array-based comparative genomic hybridization (array-CGH) analysis and single nucleotide polymorphism array (SNP-array). Peripheral blood DNA of the couples, and relevant families if necessary, were collected and analyzed in the same way. The results of parental origin detection in CMA were summarized.Results:A total of 76 CNVs were detected in these 73 samples, out of which nine were pathogenic and parental origin detection revealed that six were de novo, two were maternally, and one was paternally inherited; six CNVs were likely pathogenic, including three de novo, two maternally inherited and one paternally inherited; 20 CNVs were variants of uncertain significance, including five paternally inherited, three maternally inherited and 12 de novo; 41 CNVs were likely benign, among which 38 were inherited from parents with normal phenotype. Conclusions:Parental origin verification plays an important role in explaining the clinical significance of detected fetal CNVs and thereby can help to analyze its clinical effect and reproductive risk.

Serum proteomic approach in patients with Qi deficiency and blood stasis syndrome in coronary heart disease:to explore therapeutic mechanism of Yiqi Huoxue decoction / 中国药理学与毒理学杂志

OBJECTIVE To explore the curative effect and mechanism of Yiqi Huoxue decoction in the treatment of coronary heart disease with Qi deficiency and blood stasis syndrome. METHODS The patients with coronary heart dis?ease of Qi deficiency and blood stasis syndrome were treated with Yiqi Huoxue decoction for 3 months, and the changes of cardiac function were observed. 61 serum samples (including 29 cases of disease group and 32 cases of Yiqi Huoxue expression group) were analyzed by non labeled proteomics. The disease group was used as the control group, and the protein with expression level difference of more than 1.2 folds (P<0.05) was screened. The molecular function, biologi?cal pathway and protein interaction of the different proteins were analyzed by bioinformatics, so as to identify the molecu?lar and biological pathway of Yiqi Huoxue decoction in the treatment of coronary heart disease with Qi deficiency and blood stasis syndrome. RESULTS Clinical treatment found that Yiqi Huoxue decoction can improve TCM syndrome score and left ventricular ejection fraction, regulate blood glucose and blood lipid levels, prolong thrombin time, and improve heart function. The results of proteomic quantitative analysis showed that there were 69 proteins with different expression levels in the disease group. Bioinformatics analysis results showed that Yiqi Huoxue decoction may regulate ApoA1, alpha-2 and other proteins to act on HDL assembly, platelet degradation, PI3K Akt signaling pathway, and then play a therapeutic role in coronary heart disease with Qi deficiency and blood stasis syndrome. CONCLUSION Yiqi Huoxue decoction can effectively improved the heart function decline caused by Qi deficiency and blood stasis syn?drome of coronary heart disease. It mainly act on energy metabolism and platelet activation pathway by activating HDL assembly and platelet degradation signal pathway proteins. This study can provide reference for the follow-up treatment mechanism of Qi deficiency and blood stasis syndrome of coronary heart disease.

Cytokine release assessment:a good de-risk approach to bi-specific T-cell engagers in non-clinical development / 中国药理学与毒理学杂志

Bi-specific T-cell engagers (BiTEs) show great clinical outcomes for anti-cancer purposes. However, potential cytokine release syndrome (CRS) is notorious to all BiTEs. The mechanism underlying CRS is still not fully known, even though such toxicities are considered to be cytokine release related. Assessment of CRS is a key to non-clinical de-risk programs for BiTEs therapeutic development. In the present review, possible mechanisms are discussed, especially factors contributing to CRS develop?ment. T cell activation may be just an initiation of the CRS cascade, and other cell types can greatly contribute to CRS, such as a chain reaction triggered by downstream B-cells, monocytes, and endothe?lium cells. A non-clinical de-risk program can be designed based on these components in the CRS cascade. Combination of in vitro cytokine release assay, and in vivo mouse and non-human primates studies should be reliable enough to predict and mitigate CRS risk in the clinics. Further more, a good de-risk program should be able to provide ranking for candidates for further development and provide enough confidence to select a first-in-human dose.

Prenatal diagnosis of X-linked adrenoleukodystrophy in 20 pedigrees / 中华围产医学杂志

Objective:To summarize the characteristics of genetic variation and prenatal diagnosis in pedigrees with X-linked adrenoleukodystrophy (X-ALD) and elucidate the value of prenatal diagnosis in preventing the birth of children with X-ALD.Methods:Twenty pedigrees, clinically diagnosed with X-ALD in Peking University First Hospital from November 2012 and March 2019, were included in this retrospective study. Genomic DNA was extracted from peripheral blood and amniotic fluid or chorionic villi samples of probands and their families for detecting variants in ATP-binding cassette subfamily D member 1 ( ABCD1) gene using polymerase chain reaction (PCR)-Sanger sequencing. Linkage analysis was also performed on five microsatellite markers near ABCD1 gene to exclude maternal contamination. Characteristics of ABCD1 gene variants and prenatal diagnosis of X-ALD pedigrees were summarized by descriptive statistics. Results:Twenty ABCD1 gene variants were identified in the 20 pedigrees. The variants in three probands that were not detected by next-generation sequencing were identified by PCR-Sanger sequencing. Among the mothers of the 20 probands, 17 carried ABCD1 variants and three did not. We performed 24 prenatal diagnoses on 20 pregnancies (24 fetuses) and identified eight fetuses with variants who were finally terminated. The 16 cases without variants were born alive. The validation results obtained after termination or delivery were consistent with those performed prenatally. Conclusions:No hotspot variants in ABCD1 gene are detected in these X-ALD patients and most variants are maternally inherited. PCR-Sanger sequencing is an effective method for detecting ABCD1 variants. Prenatal diagnosis for mothers who had a body with X-ALD could prevent another one from birth.