Inborn errors of immunity and its clinical significance in children with lymphoma in China: a single-center study

Abstract Objective: To investigate the incidence, clinical and genetic characteristics of pediatric lymphoma patients of China with inborn errors of immunity (IEI)-related gene mutations, which have not been fully studied. Method: From Jan. 2020 to Mar. 2023, IEI-related genetic mutations were retrospectively explored in 108 children with lymphomas admitted to Beijing Children's Hospital by NGS. Genetic rule and clinical characteristics as well as treatment outcomes were compared between patients with or without IEI-related gene mutations. Results: A total of 17 patients (15.7 %) harbored IEI-associated mutations, including 4 cases with X-linked lymphoproliferative syndrome (XLP), 3 cases had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), 2 cases with Activated p110 syndrome (APDS). Patients with IEI all had alteration of immunocompetence with decreased levels of immunoglobulin and lymphocyte subsets. Recurrent infection existed in 41.2 % of patients. The 18-month event-free survival (EFS) and the overall response rate (ORR) of patients with IEI are significantly lower than those without IEI (33.86% vs. 73.26 %, p = 0.011; 52.94% vs. 87.91 %, p = 0.002, respectively). In addition, patients with IEI had a higher progression disease (PD) rate of 23.5 % than those without IEI of 4.4% (p = 0.006). Conclusion: The present study demonstrated that IEI-associated lymphomas were much more common than originally appreciated in pediatric lymphomas, and those were insensitive to treatment and more likely to progress or relapse. The genomic analysis and a thorough review of the medical history of IEI can be used to distinguish them from pediatric lymphomas without IEI, which are beneficial for the early diagnosis and direct intervention.

Perfil molecular de cáncer de endometrio en mujeres de Bogotá DC, Colombia / Molecular profile of endometrial cancer in women from Bogota DC, Colombia

Introducción: El cáncer de endometrio ocupa el sexto lugar en incidencia del cáncer en mujeres. La caracterización molecular de este cáncer permite optimizar la estratificación de riesgo para mejorar el tratamiento de las pacientes. Objetivo: Determinar el perfil molecular TCGA de pacientes con cáncer de endometrio en Bogotá, D.C., Colombia. Método: Estudio descriptivo en una cohorte de pacientes con cáncer de endometrio. Las mutaciones en los exones 9 a 14 del gen POLE fueron identificadas mediante amplificación por reacción en cadena de la polimerasa, seguida de secuenciación Sanger y análisis bioinformático. La expresión de las proteínas MMR y p53 se identificó mediante inmunohistoquímica. Resultados: Se incluyeron 40 pacientes con una mediana de edad de 66 años. El 15% presentaron mutaciones en el dominio exonucleasa de POLE. El 32% de las pacientes que no presentaron mutaciones manifestaron deficiencia en el sistema MMR. El 43,47% de las pacientes sin mutaciones en POLE ni alteración del sistema MMR presentaron alteración de la proteína p53. Conclusiones: La población de cáncer de endometrio analizada presenta un perfil molecular TCGA similar a lo reportado para otras poblaciones.

Introduction: Endometrial cancer ranks sixth in cancer incidence among women. Its molecular characterization allows for a more precise risk stratification with the aim of improving patient treatment. Objective: To determine the TCGA molecular profile of patients with endometrial cancer in Bogota, Colombia. Method: A descriptive study of a cohort of patients with endometrial cancer. The expression of MMR proteins and p53 was identified through immunohistochemistry. Mutations in exons 9 to 14 of the POLE gene were identified through polymerase chain reaction amplification, followed by Sanger sequencing and bioinformatic analysis. Results: Forty patients were included in the study, with a median age of 66 years, 15% of them exhibited mutations in the exonuclease domain of POLE, while 32% of patients without mutations showed deficiency in the MMR system. Forty three percent of patients without mutations in POLE or MMR alterations showed aberrant p53 protein expression. Conclusions: The analyzed population of endometrial cancer presents a TCGA molecular profile similar to that reported for other populations.

Síndrome de Aarskog: um relato de caso / Aarskog syndrome: a case report

Introdução: A Síndrome de Aarskog-Scott (AAS) é uma rara displasia faciogenital ligada ao gene FGD1, afetando principalmente meninos. Relato de caso: Descreve-se um caso de um menino de 4 anos com AAS, destacando sua importância científica devido à raridade, escassez de descrições e morbidade associada. Ele apresentou fenda sacral, criptorquidia bilateral, atrasos no crescimento e histórico familiar semelhante. A AAS é caracterizada por estatura baixa, anomalias faciais e diversos comprometimentos. Este caso ressalta a importância do acompanhamento médico especializado. Considerações finais: A escassez de estudos comparáveis destaca a relevância dos relatos de casos para aprofundar a compreensão de condições clínicas singulares.

Introduction: Aarskog-Scott Syndrome (AAS) is a rare faciogenital dysplasia linked to the FGD1 gene, primarily affecting boys. Case report: We describe a case of a 4-year-old boy with AAS, highlighting its scientific importance due to its rarity, scarcity of descriptions, and associated morbidity. He presented with sacral cleft, bilateral cryptorchidism, growth delays, and similar family history. AAS is characterized by short stature, facial anomalies, and various impairments. Final considerations: This case underscores the importance of specialized medical care, and the scarcity of comparable studies highlights the relevance of case reports in deepening the understanding of unique clinical conditions.

Alteraciones genéticas asociadas a la enfermedad de Parkinson y Alzheimer: evolución y respuesta al tratamiento / Genetic Alterations Associated with Parkinson's and Alzheimer's Disease: Evolution and Response to Treatment

La enfermedad de Parkinson y Alzheimer son las enfermedades neurodegenerativas más frecuentes a nivel mundial. Tienen etiología multifactorial, entre ellas, la genética; y son motivo de interés en la investigación científica actual. Se realizó una revisión narrativa con el objetivo de determinar las alteraciones genéticas asociadas a estas patologías, además su influencia en la evolución y respuesta al tratamiento de ellas. Se consultaron artículos originales, revisiones bibliográficas, sistemáticas, metaanálisis en inglés y español, con fecha de publicación entre el 1 enero de 2018 y el 20 de mayo de 2023, en bases como PubMed y Medline. Se utilizaron los términos MeSH «Alzheimer Disease¼, «Parkinson Disease¼, «Drug Therapy¼ y «Mutations¼. El riesgo hereditario para la enfermedad de Parkinson suele ser poligenético, sin embargo, existen genes relacionados con mutaciones monogénicas. Se identifican alteraciones en genes de α-sinucleína, glucocerebrosidasa y quinasa 2 rica en leucina que se relacionan con mayor riesgo de desarrollar Parkinson, además de variaciones en el cuadro clínico y edad de inicio de síntomas. En cuanto a la enfermedad de Alzheimer, las alteraciones en los genes de la proteína precursora amiloide, presenilina 1 y 2 se relacionan con la forma familiar de la enfermedad; por otra parte, las de apolipoproteína E4 se han identificado en la forma esporádica, por lo que se consideran como el factor de riesgo genético más importante para su desarrollo

Parkinson's and Alzheimer's are the most frequent neurodegenerative diseases worldwide. They have a multifactorial etiology, including genetics, and are of interest in current scientific research. A narrative review was carried out with the aim of determining the genetic alterations associated with these pathologies, as well as their influence on their evolution and response to treatment. Original articles, literature reviews, systematic reviews, meta-analyses in English and Spanish, with publication date between January 1, 2018 and May 20, 2023, were consulted in databases such as PubMed and Medline. MeSH terms "Alzheimer Disease", "Parkinson Disease", "Drug Therapy" and "Mutation" were used. Hereditary risk for Parkinson's disease is usually polygenetic, however, there are genes related to monogenic mutations. Alterations in α-synuclein, glucocerebrosidase and leucine-rich kinase 2 genes have been identified that are related to an increased risk of developing Parkinson's disease, in addition to variations in the clinical picture and age of symptom onset. As for Alzheimer's disease, alterations in the genes of the amyloid precursor protein, presenilin 1 and 2 are related to the familial form of the disease; on the other hand, those of apolipoprotein E4 have been identified in the sporadic form, and are therefore considered to be the most important genetic risk factor for its development

Analysis of the Results of Deafness Gene Screening in 301 Severe and Very Severe Non-syndrome Deafness Children / 医学研究杂志

Objective To study the results of the deafness gene in 301 children with severe and very severe non-syndrome deafness in Xinjiang,to provide a reference for rehabilitation and genetic counseling after cochlear implantation.Methods A total of 301 patients with severe and very severe non-syndrome deafness who were admitted to the People's Hospital of Xinjiang Uygur Autonomous Region from 2017 to 2019 were collected.After informed consent,the patients were screened for deafness genes,including 25 loci in GJB2,SLC26A4,mt12SrRNA,OTOF,and SLC17A8 genes(c.35delG,c.167delT,c.176_191del16,c.235delC,c.299_300delAT,c.281C＞T,c.589G＞A,c.IVS7-2A＞G,c.1174A＞T,c.1226G＞A,c.1229C＞T,c.IVS15+5G＞A,c.1975G＞C,c.2027T＞A,c.2162C＞T,c.2168A＞G,c.1494C＞T,c.1555A＞G,c.1585A＞G,c.1047A＞G,c.1095T＞C,c.960_961 insC/961delT,c.4023G＞A,c.4819C＞T,c.824C＞A),and the detection results were analyzed.Results Among 301 cases of severe and very severe non-syndrome deaf-ness,80 cases of positive mutation were screened,and the total detection rate was 26.58％(80/301).The mutation rates of GJB2,SLC26A4,and mt12SrRNA genes were 10.96％(37/301),12.62％(38/301),and 4.32％(13/301),respectively.The main forms of GJB2 mutations were c.235delC and c.35delG,accounting for 37.50％(30/80)and 8.75％(7/80)of the mutations,respectively.The main forms of SLC26A4 mutations were c.IVS7-2A and c.1174 A＞T,accounting for 26.25％(21/80)and 11.25％(9/80)of the mutations,respectively.The main mutation forms of mt12SrRNA were c.960_961 insC/961delT and c.1555A＞G,accounting for 7.50％(6/80)and 5.00％(4/80)of the mutations,respectively.The c.4023G＞A and c.4819C＞T mutations in OTOF and c.824C＞A mutations in SLC17A8 were not detected.The total detection rate of mutation sites in the Han nationality was significantly higher than that in the Uygur nationality(x2=19.064,P＜0.001).Conclusion GJB2 and SLC26A4 are common pathogenic genes in children with severe and very severe non-syndrome deafness in Xinjiang.There may be other hot spot mutation sites in the Uygur nationality.

NUDT2 gene induced intellectual disability with or without peripheral neuropathy: a case report and literature review / 中国综合临床

Objective:To summarize the clinical characteristics and pathogenic mutation of gene NUDT2 in the child with intellectual disability with or without peripheral neuropathy (IDDPN). Methods:The clinical characteristics and development of one child attending the Department of Rehabilitation of Tianjin Children's Hospital were evaluated retrospectively,and the relationship between the clinical phenotype and gene mutation profile of NUDT2 was analyzed. Results:The child had global developmental delay, special appearance, low muscle tone of the limbs, accompanied by peripheral nerve damage in the limbs, and whole exome sequencing found that the child carried a homozygous mutation of NUDT2 gene, c.34C>T (p.R12X), which was a nonsense mutation. Sanger verified that both parents were carriers of c.34C>T heterozygous mutations. In the inclusion of 10 registered IDDPN patients, it was found that all of them were homozygous mutations, and the clinical phenotypes all had different degrees of cognitive impairment and movement disorders, among which only 3 cases were complicated by peripheral nerve damage. Conclusions:The child in this case had low birth weight/length, weak sucking ability in infancy, cognitive impairment, peripheral nerve damage, and genetic testing showed homozygous nonsense mutation of NUDT2 gene, which provided evidence support for the clinical understanding of the disease.

Study on the correlation between bone marrow adipocytokines and myelodysplastic syndromes / 中国肿瘤临床

Objective:To explore the relationship between adipocytokine levels in bone marrow and the onset,progression,and prognosis of myelodysplastic syndromes(MDS).Methods:Retrospective analysis of adipocytokine levels in the bone marrow of 72 patients with MDS and 16 patients with MDS-related secondary acute myeloid leukemia(sAML),including adiponectin(ADP),leptin(LEP),visfatin/nicotinamide phosphoribosyltransferase(NAMPT),adipsin/complement factor D(CFD),and C1q/TNF-related protein 1(CTRP1),detected by enzyme-linked immunosorbent assay(ELISA)at The Affiliated Cancer Hospital of Zhengzhou University from February 2020 to February 2022.High-throughput sequencing was used to detect MDS-related genes in 70 patients and the relationship between adipocytokines and the clinical characteristics,disease subtypes,mutant genes,and prognosis of patients were analyzed.Seventy-eight MDS-related genes were identified.Results:Clinical characteristics showed that ADP(P=0.027)and LEP(P=0.019)levels were significantly lower in men than inwomen;ADP(P=0.020),CFD(P<0.001),and NAMPT(P=0.021)levels were significantly lower in patients aged<65 years than in patients aged≥65,where-as LEP levels were significantly higher(P=0.043).Adiponectin levels were significantly higher in patients with BMI<24 than in patients with BMI≥24(P=0.025),whereas LEP levels were significantly lower(P=0.020);NAMPT levels were significantly higher in the group with in-creased blasts than in the group with no blasts(P=0.037).The CTRP1 levels were significantly higher in the MDS group than in the sAML group(P=0.010).Abnormal gene correlation analysis showed that elevated CTRP1 levels were positively correlated with the occurrence of epigenetically related abnormal genes(P=0.001)and were positively correlated with the occurrence of TET2 and U2AF1(P<0.001 and P=0.036,respectively);ADP and CFD levels were positively correlated with the occurrence of NPM1(P=0.048 and P=0.026,respectively).Multifactorial Cox proportional hazards regression model analysis showed that LEP<0.2 ng/mL was an independent risk factor for progres-sion-free survival(PFS)and overall survival in patients with MDS(P=0.002 and P<0.001,respectively),whereas NAMPT<2.1 ng/mL was a protective factor for PFS in patients with MDS(P=0.043).Conclusions:Adipocytokines in the bone marrow microenvironment are closely as-sociated with the clinical characteristics,gene mutations,and prognosis of patients with MDS,with LEP<0.2 ng/mL being an independent prognostic risk factor and NAMPT<2.1 ng/mL being a prognostic protective factor.

Prediction of EGFR mutation status in lung adenocarcinoma based on standardized enhanced CT radiomics nomogram / 中华放射医学与防护杂志

Objective:To investigate the value of radiomics nomogram based on standardized pre-treatment chest enhanced CT in predicting the mutation status of epidermal growth factor receptor (EGFR) for patients with lung adenocarcinoma.Methods:A retrospective analysis was conducted on pre-treatment chest enhanced CT images and clinical data of 262 patients from the affiliated hospital of Jining Medical University with pathologically proven primary lung adenocarcinoma who received EGFR gene testing, including EGFR wild type ( n=122) and mutant type ( n=140). The patients were divided into training group ( n=183) and testing group ( n=79) according to a ratio of 7∶3 by stratified sampling method. Standardized pre-processed the images, delineated the ROI and extracted the radiomics features. Least absolute shrinkage and selection operator (LASSO) algorithm was used to reduce the dimension and select key features. The standardized radiomics model, clinical model and the combined model were established by Logistic Regression (LR) machine learning method. Calculated the Rad-score and drew the nomogram. ROC curve and Delong were used to evaluate and compare the predictive performance of different models. Results:23 standardized enhanced CT radiomics features and 4 clinical features were selected. The predictive performance of standardized radiomics model was better than that of non-standardized radiomics model [area under curve (AUC): 0.863 vs. 0.805, t=2.19, P<0.05]. The AUCs of the combined model and standardized radiomics model were higher than that of the clinical model (training group: 0.885, 0.863 vs. 0.774, t=3.57, 2.17, P<0.05; testing group: 0.873, 0.829 vs. 0.763, t=2.19, 2.02, P<0.05). The radiomics nomogram was built based on Rad-score, age, sex, smoking history and BMI. Conclusions:The combined model and standardized radiomics model could effectively predict the mutation status of EGFR gene in lung adenocarcinoma patients before treatment, providing valuable clinical insights.

Value of early radiotherapy for EGFR mutation-positive non-small cell lung cancer with brain metastasis in the era of third-generation targeted drugs: a single center retrospective study of 85 cases / 中华放射肿瘤学杂志

Objective:To explore the reasonable timing of radiotherapy for epidermal growth factor receptor ( EGFR) mutation-positive non-small cell lung cancer patients with brain metastasis in the era of third-generation targeted drugs. Methods:Clinical data of EGFR mutation-positive non-small cell lung cancer patients with brain metastasis who received first-line treatment with third-generation targeted drugs and stereotactic radiotherapy at Shanghai Armed Police Corps Hospital from September 2019 to May 2022 were retrospectively analyzed. According to the timing of radiotherapy before / after targeted drug resistance, all patients were divided into the early and salvage radiotherapy groups. The proportion of brain metastasis, physical fitness, complete response rate, objective response rate, delaying the progression of brain metastasis and overall survival (OS) were compared between two groups. Kaplan-Meier method was used for survival analysis, log-rank test was used for univariate prognostic analysis, and factors with P <0.1 were included in Cox multivariate analysis. Results:A total of 85 patients were included, including 51 (60%) cases receiving early radiotherapy. Patients who participated in early radiotherapy had a higher proportion of symptomatic brain metastasis (82% vs. 56%, P=0.013) and poorer physical fitness (Kanofsky performance score <70: 61% vs. 26%, P=0.002) compared to patients who underwent salvage radiotherapy. Early radiotherapy significantly improved the complete response rate of intracranial lesions (35% vs. 12%, P=0.015) and objective response rate (88% vs. 71%, P=0.041), delayed the progression of brain metastasis (median intracranial progression free survival: 23.0 months vs. 16.0 months, P=0.005; median intracranial secondary progression free survival: 31.0 months vs. 22.0 months, P=0.021), and improved OS (median OS: 44.0 months vs. 35.0 months, P=0.046). In multivariate analysis, diagnosis-specific graded prognostic assessment score <2.5, mutation of EGFR exon 21, and salvage brain radiotherapy were adverse prognostic factors for OS. Conclusion:In the era of third-generation targeted drugs therapy, early involvement of stereotactic radiotherapy in non-small cell lung cancer patients with brain metastasis can bring greater clinical benefits.

Predictive value of intratumoral heterogeneity measured by 18F-FDG PET/CT for EGFR mutation of adenocarcinoma / 中华核医学与分子影像杂志

Objective:To investigate the value of traditional metabolic parameters, CT features and intratumoral heterogeneity parameters measured by 18F-FDG PET/CT in predicting the mutation status of the epidermal growth factor receptor (EGFR) gene in patients with adenocarcinoma. Methods:A total of 147 patients (73 males, 74 females, age (59.8±10.2) years) with pathological confirmed adenocarcinoma between January 2016 and June 2020 in the Affiliated Hospital of Jining Medical University were retrospectively included. The differences of clinical data (smoking history, tumor location and clinical stage), CT features (maximum diameter, ground-glass opacity content, lobulation, speculation, cavitation, air-bronchogram, pleural retraction and bronchial cut-off sign), 18F-FDG PET/CT traditional metabolic parameters (SUV max, SUV mean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG)) and intratumoral heterogeneity parameters ( CV, heterogeneity index (HI)) were analyzed between patients with EGFR mutation and patients with EGFR wild-type. Independent-sample t test, Mann-Whitney U test and χ2 test were used to analyze the data. Multivariate logistic regression was used to analyze the predictors of EGFR mutation. ROC curve analysis was used to evaluate the predictive value of clinical and PET/CT information. Results:Among 147 patients, 87 were with EGFR mutation and 60 were with EGFR wild-type. There were significant differences in gender (male/female), smoking history (with/without), location (peripheral lesion/central lesion), pleural retraction (with/without), SUV max, SUV mean, TLG, CV and HI ( χ2 values: 4.72-23.89, z values: from -2.31 to 5.74, all P<0.05). Multivariate logistic regression analysis showed that smoking history (odds ratio ( OR)=0.167, 95% CI: 0.076-0.366; P<0.001), pleural retraction ( OR=1.404, 95% CI: 1.115-3.745; P=0.012), SUV max ( OR=0.922, 95% CI: 0.855-0.995; P=0.003), TLG ( OR=0.991, 95% CI: 0.986-0.996; P=0.001) and HI ( OR=0.796, 95% CI: 0.700-0.859; P<0.001) were predictors of EGFR mutation. ROC curve analysis showed the AUC of HI was 0.779, with the sensitivity of 76.67%(46/60) and the specificity of 79.31%(69/87). The predictive model was constructed by combining smoking history, pleural retraction, TLG, SUV max and HI, and the AUC was 0.908, with the sensitivity of 88.33%(53/60) and the specificity of 68.97%(60/87). The difference of AUCs between HI and the predictive model was statistically significant ( z=3.71, P<0.001). Conclusion:HI can predict EGFR mutations better, and the predictive value for EGFR mutations can be enhanced when combining HI with smoking history, pleural retraction, TLG and SUV max.

Genetic and clinical features of two cases with familial hyperaldosteronism type Ⅲ / 中华内分泌代谢杂志

Familial hyperaldosteronism type Ⅲ(FH-Ⅲ) is extremely rare, and there are no reported cases in China. Herein, we reported two cases with FH Ⅲ, both of which presented with severe hypertension and hypokalemia in their early childhood. One patient had significantly enlarged adrenal glands and developed clinical manifestations of Cushing′s syndrome at the age of 20. Complete relief of symptoms was achieved after bilateral adrenalectomy. The other case had normal adrenal imaging, and with spironolactone treatment, blood pressure and potassium levels were well-controlled. Both cases had germline mutation of KCNJ5 gene which were c. 433G>C(p.Glu145Gln) and c. 452G>A(p.Gly151Glu), respectively.

Clinical and genetic analysis of children with developmental and epileptic encephalopathy 18 caused by SZT2 gene variants / 中华神经科杂志

Objective:To investigate the clinical phenotype and genetic characteristics of developmental epileptic encephalopathy 18 (DEE18) caused by SZT2 gene variants. Methods:Clinical data of 2 children with SZT2 related DEE18 who visited the Department of Pediatric Neurology, Linyi People′s Hospital in March 2020 and July 2023 were collected. The whole exome sequencing (WES) and Sanger sequencing were applied to verify the child and their parents. SWISS-MODEL software was used to perform protein 3D modeling for the selected SZT2 gene variants. Results:Both of the 2 cases showed severe global developmental delay, epileptic seizures, autism, megacephaly, facial deformity, hypotonia, corpus callosum malformation, persistent cavum septum pellucidum, and slow background activity and focal discharge in video electroencephalography. Case 1 was easy to startle and thin in stature; case 2 had immune deficiency and clustered seizures. WES results showed that case 1 carried a compound heterozygous variant of c.5811G>A (p.W1937X) (paternal) and c.9269delG (p.S3090Ifs *94) (maternal), while case 2 carried a compound heterozygous variant of c.6302A>C(p.H2101P) (paternal) and c.7584dupA (p.E2529Rfs *20) (maternal), the parents of both patients with normal clinical phenotypes. The 4 mutations mentioned above were novel variations that had not yet been reported domestically or internationally. According to the American College of Medical Genetics and Genomics variant classification criteria and guidelines, the p.S3090Ifs *94 variant was interpreted as pathogenic; p.W1937X variant was interpreted as pathogenic; p.E2529Rfs *20 variant was interpreted as likely pathogenic; p.H2101P variant was interpreted as uncertain significance. 3D modeling showed that the variant of p.H2101P resulted in a significant change in the hydrogen bond around the 2 101st amino acid encoded, leading to a decrease in protein stability. The other 3 variants led to early truncation of peptide chain and obvious changes in protein structure. Conclusions:DEE18 caused by SZT2 gene mutation is mainly an autosome recessive genetic disease, and its clinical manifestations include global developmental delay, epileptic seizures, autism, craniofacial malformation, hypotonia, epileptic discharge, corpus callosum malformation, persistent cavum septum pellucidum, shock, small and thin stature, and immune deficiency. Four novel variants related to the SZT2 gene may be the genetic etiology of DEE18 patients in this study.

Clinical phenotype and genetic analysis of BRWD3 gene variation related infantile epileptic spasm syndrome / 中华神经科杂志

Objective:To investigate the clinical phenotype and genetic characteristics of infantile epileptic spasm syndrome caused by BRWD3 gene mutation. Methods:Clinical data of a child with BRWD3 related infantile epileptic spasm syndrome who was admitted to Department of Pediatric Neurology of Linyi People′s Hospital on August 2, 2019 were collected and followed up, whole exome sequencing technology and Sanger sequencing were applied to verify the child and his parents, and the pathogenicity of mutation site was analyzed. The studies till June 2023 were searched with keywords of " BRWD3" in both English and Chinese databases of China National Knowledge Infrastructure, Wanfang, Online Mendelian Inheritance in Man, and PubMed. The clinical phenotype and genetic characteristics of patients with BRWD3 related epilepsy were summarized. Results:The patient was a 4 years and 4 months old boy, with a clinical phenotype including severe global development delay, focal seizures (the onset age was 4 months), epileptic spasm (the onset age was 6 months), autism, megacephaly, high forehead as well as hypsarrhythmia. The whole exome sequencing results showed a de novo and frameshift variation c.4318_4319del(p.Q1441Efs*20)(NM_153252) in the BRWD3 gene, and the variation was interpreted as pathogenic (PVS1+PS2+PM2) according to the American College of Medical Genetics and Genomics variant classification criteria and guidelines. A total of 7 English literature articles were retrieved reporting 16 cases of BRWD3 gene related epilepsy in children (including 1 case of infantile epileptic spasm syndrome), and there has been no report in China yet. Totally there were 17 cases of BRWD3 gene related epilepsy including this case. All the cases showed X chromosome dominant inheritance, of whom 15 cases showed minor variations, including 7 missense variations, 3 frameshift variations, 3 splicing variations, 2 nonsense variations, and the remaining 2 cases showed large segment deletions. A total of 15 different variants were found. The phenotypes of the 17 patients mainly included epileptic seizures (17/17), intellectual disability (10/17), motor development disorder (7/17), speech impairment (9/17), megacephaly (8/17), facial malformation (8/17), autism (4/17) and hypotonia (4/17). The common seizure types were found to be focal seizures, occasionally epileptic spasm seizures and tonic seizures. Conclusions:BRWD3 gene variation related epilepsy is an X chromosome dominant genetic disease with a wide clinical phenotype spectrum. BRWD3 gene mutation c.4318_4319del(p.Q1441Efs *20) could cause infantile epileptic spasm syndrome, manifested as severe global developmental delay, epileptic spasm, focal seizures, autism, craniofacial malformation and hypsarrhythmia. This research enriches BRWD3 gene mutation spectrum.

Clinical phenotype and genotype characteristics of tuberous sclerosis complex in 52 children / 中华神经科杂志

Objective:To analyze the clinical phenotypes and TSC1/TSC2 gene variations in 52 children with tuberous sclerosis complex. Methods:The clinical data of 59 children with tuberous sclerosis complex hospitalized in Linyi People′s Hospital between January 2017 and October 2022 were collected. The analysis of TSC1 and TSC2 gene variations on main family members was performed, and then bioinformatics analysis followed. The positive children were divided into TSC1 gene group and TSC2 gene group, and the difference of clinical characteristics between the two groups was analyzed. Results:Among 59 children, 52 cases were detected TSC1/ TSC2 gene variations (17 cases in the TSC1 gene group and 35 cases in the TSC2 gene group). Of the 52 children, 28 (53.8%) were male, 24 were female (46.2%); 17 (32.7%) were familial cases (10 with TSC1 gene variations and 7 with TSC2 gene variations), 35 (67.3%) were sporadic cases; 46 (88.5%) had hypomelanotic macules, 13 (25.0%) had facial angiofibromas, 5 (9.6%) had shagreen patches, 49 (94.2%) had subependymal nodules/calcifications, 47 (90.4%) had cortical nodules, 2 (3.8%) had subependymal giant cell astrocytomas, 39 (75.0%) had intellectual/developmental disabilities, 49 (94.2%) had epileptic seizures, 8 (15.4%) had cardiac rhabdomyomas, 9 (17.3%) had renal angiomyolipomas, and 4 (7.7%) had retinal hamartomas. Of the 52 children, 49 variations were detected, including 4 large fragment deletion/duplication variations, and 45 point variations; 41 pathogenic variations, 7 likely pathogenic variations, and 1 variation of uncertain significance. In this study, 16 point mutations and 1 large fragment duplication mutation which had not been reported at home and abroad, and 3 high-frequency mutation sites (p.Arg692 *, p.Arg228 *, and p.Arg1200Try) were found. There was a statistically significant difference in the proportion of familial cases [10/17 vs 7/35(20%), χ2=7.838, P=0.005], median onset age of epilepsy [38.0(0.5-134.0) months vs 8.0(0.1-63.0) months, Z=3.506 , P<0.001] and the incidence of developmental retardation/intellectual impairment [8/17 vs 31/35(88.6%), χadj2=8.423, P=0.004] between the TSC1 gene and TSC2 gene groups. Conclusions:Tuberous sclerosis compiex has widespread phenotypes, can affect every body system, especially the skin and nervous system. The pathogenic gene is TSC1/ TSC2. The TSC1 gene group has more familial cases. The TSC2 gene group has an earlier onset age of epilepsy and a higher incidence of developmental retardation/intellectual impairment. In this study, 16 novel point mutations, 1 novel large fragment duplication mutation, and 3 hotspot mutations were identified, expanding the gene variation spectrum of tuberous sclerosis complex.

Analysis of clinical phenotype and genotype of PAX2 mutation in Chinese children / 中华肾脏病杂志

Objective:To analyze and summarize the clinical, genotypic and pathological characteristics of children with PAX2 gene mutation in China, and to provide information for the monitoring, treatment and prognosis of the disease. Methods:It was a case series analysis study. The clinical data of children with PAX2 gene mutation in Pediatric Nephrology Department, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology from January 2014 to December 2022 were collected, and peripheral blood gene DNA was extracted and sequenced for whole exome sequencing. The clinical, pathological and genotypic characteristics of PAX2 gene variation of children in China were summarized by searching PubMed, Medline, China National Knowledge Infrastructure and Wanfang database and compared with the cases in this single center. Results:Among the 13 children with PAX2 gene mutation, there were 9 males and 4 females, 12 patients with abnormal urine tests, 7 patients with small kidney volume by imaging examination, and 5 patients with renal cysts. The clinical phenotypes were congenital renal and urinary tract malformations in 8 cases, renal coloboma syndrome in 1 case, and hematuria or proteinuria in 3 cases. Five patients underwent renal biopsies, showing focal segmental glomerulosclerosis and C3 glomerulopathy in 1 case, focal segmental glomerulosclerosis in 1 case, thin basement membrane lesion in 1 case, and IgA nephropathy in 2 cases. The genetic testing in 13 children showed 9 de novo mutations and 4 new mutations of c.321G>A, c.213-8C>G, c.63C>A and c.449C>T. There were 2 cases of 76dupG (p.V26Gfs*28) mutant. A total of 51 Chinese children with PAX2 gene mutation were found in the literature search. There were 32 males and 19 females, 8 cases with small kidney volume and 12 cases with renal cysts. The clinical phenotypes were congenital anomalies of kidney and urinary tract in 28 cases, renal coloboma syndrome in 17 cases, and hematuria or proteinuria in 6 cases. Seven patients underwent renal biopsies, including 2 cases with focal segmental glomerulosclerosis, 1 case with minimal lesion, 1 case with mesangial proliferative glomerulonephritis, 1 case with IgA nephropathy, 1 case with membranous nephropathy and a case with focal proliferative sclerosing purpura nephritis combined with glomerular hypertrophy. Thirty-four cases were de novo mutations, and 12 mutations were from the father or mother. The father or mother of 5 children had no clinical manifestations, with normal renal function. There were 11 cases of 76dupG (p.V26Gfs*28) mutant. Conclusions:The clinical phenotypes and genotypes of PAX2 gene variation in Chinese children are diverse. The most common clinical phenotype of PAX2 gene variation is congenital anomalies of kidney and urinary tract. c.76dupG (p.V26Gfs*28) is the most common of PAX2 gene variant.

Establishment of a method for rapid detection of the minimum inhibitory concentration of imipenem in KPC-producing Klebsiella pneumoniae based on ompK36 mutation / 中华检验医学杂志

Objective:To establish a rapid method to detect the minimum inhibitory concentration (MIC) of imipenem in Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) based on ompK36 gene′s GD mutation. Methods:This was a methodological evaluation study. A total of 258 isolates of Klebsiella pneumoniae were collected from Lishui Municipal Central Hospital from March 2011 to December 2019. Porin gene ompK36 and carbapenemase genes blaKPC, blaNDM, blaIMP and blaOXA-48 were amplified by PCR and confirmed by sequencing. The MIC was detected and confirmed by microbroth dilution susceptibility test, and the corresponding patterns of genotype and MIC were constructed. Based on the patterns, a method for rapid detection of imipenem MIC by real-time fluorescence PCR (RT-PCR) was designed and established. The 159 isolates of non-repetitive Klebsiella pneumoniae collected by Lishui Disease Prevention and Control Center (CDC) from 2017 to 2019 were used for further verification. The sensitivity and specificity were calculated by fourfold table. Kappa test was used to compare the consistency between RT-PCR and microbroth dilution susceptibility test. Results:Among 258 isolates, 109 isolates did not carry carbapenemase gene, 65 isolates carried ompK36 gene GD mutation, 127 isolates carried blaKPC, 15 isolates carried blaNDM, 9 isolates carried blaIMP, and blaOXA-48 was not detected. With mircobroth dilution susceptibility test as the standard, there were 3 corresponding patterns between the drug resistance gene and the imipenem MIC of Kp: when all the 4 carbapenemase genes were negative, MIC≤1 mg/L, the sensitivity was 100% (107/107) and the specificity was 98.4% (125/127); when blaKPC was positive and ompK36 gene GD mutation was negative, 4 mg/L≤MIC≤16 mg/L, the sensitivity was 88.2% (60/68) and the specificity was 98.8% (164/166); when blaKPC and ompK36 gene GD mutation were both positive, MIC≥32 mg/L, the sensitivity was 96.6% (57/59) and the specificity was 96.6% (169/175). RT-PCR detected blaKPC, blaNDM, blaIMP, blaOXA-48 genes accurately.The RT-PCR results of ompK36 gene GD mutation in the KPC-producing isolates were 100% consistent with the sequencing results. In the 159 isolates from Lishui CDC, the sensitivity and specificity of imipenem MIC detected by RT-PCR were higher than 95% in all 3 patterns with mircobroth dilution susceptibility test as the standard, and Kappa value was 0.971. Conclusion:The RT-PCR based on ompK36 gene GD mutation was helpful to quickly determine the MIC range of imipenem in KPC-Kp.

Efficacy and prognosis comparison of first-line treatment with EGFR-TKI versus chemotherapy for non-small cell lung cancer patients harboring EGFR rare mutation / 肿瘤研究与临床

Objective:To investigate the therapeutic effect difference between first-line treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) and chemotherapy in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) rare mutation.Methods:A retrospective case-control study was performed. Data of NSCLC patients with rare EGFR mutation who were treated in Shanxi Province Cancer Hospital from January 2013 to October 2019 were retrospectively analyzed. EGFR mutations in living tissues or blood were detected by using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) before first-line treatment. According to first-line treatment methods,they were divided into EGFR-TKI treatment group and chemotherapy group. Objective remission rate (ORR) and disease control rate (DCR) of both groups were compared. Kaplan-Meier method was used to draw progression-free survival (PFS) and the overall survival (OS) curves. Log-rank test was used for comparison among groups. Single-factor and multi-factor Cox proportional risk models were used to analyze the influencing factors of PFS and OS.Results:A total of 169 patients with EGFR rare mutations were included, and the age [ M (IQR)] was 63 years (12 years); there were 96 cases (56.8%) < 65 years and 73 cases (43.2%) ≥65 years; 70 (41.4%)males and 99 (58.6%) females; 55 cases (32.5%) had EGFR G719X mutation,45 cases (26.6%) had L861Q mutation, 17 cases (10.1%) had S768I mutation, and 52 cases (30.8%) had complex mutation; 55 cases (32.5%) received the first-line chemotherapy and 114 cases (67.5%) received the first-line EGFR-TKI treatment. In the chemotherapy group, ORR was 36.4% (20/55) and DCR was 85.5% (47/55); in EGFR-TKI treatment group, ORR was 72.8% (83/114) and DCR was 90.4% (103/114). The ORR of EGFR-TKI treatment group was higher than that of chemotherapy group ( χ2 = 20.70, P = 0.001), and there was no statistically significant difference in DCR between two groups ( χ2 = 1.76, P = 0.184). Subgroup analysis showed that ORR in EGFR-TKI treatment group with G719X, L861Q and complex mutations was higher than that of the corresponding mutations in chemotherapy group, and the differences were statistically significant (all P < 0.05), while there were no significant differences in DCR among subgroups (all P > 0.05). The median PFS time was 9.7 months (95% CI: 6.0-13.4 months) and 3.8 months (95% CI: 3.1-7.1 months), respectively in EGFR-TKI treatment group and chemotherapy group, and there was a statistically significant difference in PFS between the two groups ( P < 0.001). The median OS time was 25.6 months (95% CI: 18.0-37.9 months) and 31.7 months (95% CI: 18.0-42.8 months), respectively in EGFR-TKI treatment group and chemotherapy group, and there was no statistically significant difference in OS between the two groups ( P = 0.231). Multivariate Cox regression analysis showed that brain metastasis [with vs. without: HR = 2.306, 95% CI: 1.452-3.661, P < 0.001] and the first-line treatment methods (EGFR-TKI vs. chemotherapy: HR = 0.457, 95% CI:0.317-0.658, P < 0.001) were independent influencing factors for PFS of NSCLC patients with EGFR rare mutation; brain metastasis (with vs. without: HR = 2.087, 95% CI: 1.102-3.953, P = 0.024; unknown vs. without: HR = 2.118,95% CI: 1.274-3.520, P = 0.004) were independent influencing factors for OS of NSCLC patients with EGFR rare mutation. Conclusions:Compared with the first-line chemotherapy, EGFR-TKI first-line treatment could improve objective remission and PFS of NSCLC patients with EGFR rare mutation, while no OS benefit is observed.

Genotoxicity evaluation of HMS-01 / 药学实践与服务

Objective To provide a toxicological basis for HMS-01 in future clinical trials, through genotoxicity testing of safety evaluation. Methods The genotoxicity of HMS-01 was evaluated by Bacterial Reverse Mutation Assay （Ames test） with Salmonella typhimurium. Results HMS-01 was non-mutagenic against Salmonella typhimurium at six doses of 20.6, 61.7, 185.2, 555.6, 1666.7, and 5000 μg/dish with （or without） a metabolic activation system. Conclusion HMS-01 was not found to be mutagenic in the dose range of this experiment.

Advances in genetic characterization and genes of juvenile open angle glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

Juvenile open angle glaucoma(JOAG)is a subtype of primary open angle glaucoma(POAG)that severely affects the quality of life of young patients and has a high disability rate. While JOAG is commonly considered an autosomal dominant disease, it has been found to have a diverse mode of inheritance, including autosomal recessive inheritance in specific populations. The variable genetic predisposition of JOAG may be attributed to the co-regulation of several key disease-causing genes, such as MYOC, CYP1B1, and CPAMD8. Mutations in these genes are closely associated with various biological processes in ocular tissues, including cellular metabolic regulation, oxidative stress response, and abnormal induction of programmed death. Therefore, a comprehensive study of the causative genes associated with JOAG is crucial to understanding the specific genetic background of disease onset, progression, and clinical phenotype. This knowledge will provide a strong foundation for early identification and screening of high-risk populations. The objective of this review is to focus on the genetic characterization and genetic studies of JOAG. Through a systematic review of the relevant literature, we summarize the causative genes and their mutations associated with JOAG and explore their potential applications and value in advancing research in the field, aiming to provide valuable insights for the diagnosis and treatment of JOAG.

Shikonin Inhibits APC-mutant Colon Cancer via Wnt/β-catenin Signaling / 肿瘤防治研究

Objective To identify small molecule inhibitors of APC-mutant colon cancer and provide lead compounds for targeted therapy of colon cancer. Methods APC-mutant colon cancer cell lines that stably express 7*Tcf-GFP/SV40-Cherry (7TGC) dual fluorescence reporter system was constructed for small-molecule inhibitor screening. Cell viability, colony formation, EdU incorporation, and xenograft tumor assay were used to evaluate the inhibitory effect of these inhibitors on APC-mutant colon cancer in vitro and in vivo. Western blot and co-immunoprecipitation assays were used to explore the molecular mechanism. Results Four small molecules that inhibited Wnt activity in APC-mutant colon cancer cells were discovered. Shikonin exhibited significant inhibition of cell viability and proliferation while inducing apoptosis of APC-mutant colon cancer cells. Xenograft tumor assay demonstrated that shikonin significantly reduced tumor growth in vivo. Furthermore, Western blot and co-immunoprecipitation assays revealed that shikonin markedly decreased β-catenin levels. Conclusion Shikonin effectively inhibits Wnt activity and suppresses tumor growth in APC-mutant colon cancer.