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ObjectiveTo investigate the clinical manifestations, molecular genetics and gonadal pathology characteristics of patients with disorders of sex development (DSD), and to summarize the clinical experience of identifying rare diseases from common symptoms.MethodsThe clinical data of 416 patients with DSD diagnosed and treated in the multidisciplinary center of DSD of Guangzhou Women and Children′s Medical Center from May 2018 to August 2023 were retrospectively analyzed, summarized and discussed.ResultsAccording to chromosome karyotype, 416 cases of DSD were classified into three types: 92 cases(22.1%) of abnormal sex chromosome karyotype, 285 cases(68.5%) of 46, XY karyotype and 39 cases(9.4%) of 46, XX karyotype. Among the 92 patients with abnormal sex chromosome karyotype, 59 cases were raised as males, 18 cases (30.5%) complained of short penis with hypospadias and cryptorchidism. The most common karyotype was 45, X/46, XY(58 cases, 63.0%).Among the 285 patients with 46, XY karyotype, 238 cases were raised as males, and 63 cases(26.5%)complained of short penis and hypospadias; 47 cases were raised as females, and 13 cases(27.7%) complained of inguinal mass. A total of 216 patients with 46, XY karyotype were subjected to whole exome gene detection, and 155 cases(71.8%) were found to have molecular pathogenesis with the clinical phenotype. Among the 39 patients with 46, XX karyotype, 19 cases were raised as males, and 8 cases(42.1%) complained of short penis and hypospadias. In the 18 cases of gonad biopsy, 17 cases showed testicular tissue in gonads. Whole exome sequencing was performed in 14 cases. NR5A1 gene heterozygous mutation, SRY gene mutation and SOX3 gene mutation were found in 2 cases, respectively(14.3%). Twenty cases were raised as females, and 14 cases(70.0%) complained of clitoral hypertrophy. Gonad biopsy was performed in 8 cases, with 7 cases of ovotestis(87.5%) and 1 case of NR5A1 gene heterozygous mutation(14.3%).ConclusionsThe etiologies of DSD are complex and diverse, and the clinical manifestations are various, which can be manifested as hypospadias, micropenis, cryptorchidism and other common symptoms of the urinary system. Different etiologies have different treatment options. Therefore, chromosome karyotype, molecular genetic testing and gonadal pathology can be used to clarify the cause of disease, especially for rare diseases, improve the detection rate, reduce the rate of missed diagnosis, and ensure reasonable treatment, especially sex selection.

[Objective] The Late Devonian Frasnian-Famennian (F-F) transition is a critical time interval in geological history. This period saw major simultaneous marine ecological system changes that led to one of the Big Five mass extinctions in the Phanerozoic. The F-F event (also referred to as the Kellwasser event) was characterized by severe losses of low-latitude shallow-water benthic faunas, notably reef-dwelling coral and stromatoporoids. High-latitude, deep-sea and terrestrial faunas were the least affected. Various separate or combined hypotheses have been proposed as the causes of this mass extinction (sea-level change, marine anoxia, climate change, volcanic/hydrothermal activities, and bolide impact) . Of these, climate change and marine anoxia have been the most intensively researched and discussed hypotheses based on the Web of Science in recent years. However, some controversies remain, and the interactions of certain factors are still unclear. [Methods] This study systematically reviews available reports on the paleoclimatic and paleo-oceanic changes during the F-F transition and discusses the anoxic model during this critical period, based on related case studies in southern China. [Results and Conclusions] Conodont oxygen and strontium isotopes, as well as the carbon isotope records for carbonates, collectively suggest a cold climate during the F-F transition interval, with several rapid warming-cooling fluctuations. Conodont oxygen isotopes suggest that the sea-sur face temperature (SST) dropped by 5 ° C-8 ° C. Strontium isotopes also imply that the temperature fluctuations were due to frequent, short-duration volcanism. Palynological data and carbonate platform exposure/karstification are also suggestive of coeval climate cooling. Additionally, marine anoxia has been extensively hypothesized as a possible killing mechanism in the F-F mass extinction, based initially on the presence of bituminous limestones (or black shales), named the lower and upper Kellwasser horizons. Studies of pyrite framboids, biomarker compounds, trace elements, isotopes of nitrogen, sulfur and uranium, and iron speciation have variously suggested the existence of the Kellwasser anoxic events. However, these generally occurred in geographically specific environments notably in the pericontinental basins/sub-basins proximal to source hinterlands. Moreover, the range and degree of anoxia in the F-F transition also reportedly differed between study sections around the world. With regard to the anoxic model, studies have suggested that the Kellwasser anoxic events were caused by the increased nutrient input related to enhanced continental weathering. Marine anoxic studies from three F-F sections comprising different depositional facies in southern China also support this "top down" anoxic model. Clearly, the F-F biotic crisis was not caused by any single factor. Frequent short-term volcanic activity may have enhanced continental weathering and associated greenhouse gas emission, leading to frequent warming-cooling climate fluctuations and also increased oceanic nutrient input. In the latter case, eutrophication and anoxia would have occurred in shallow water, and the mutual interaction of the various environmental factors may have exerted biological pressure in the low-latitude shallow sea, and eventually led to the F-F biotic crisis. [ABSTRACT FROM AUTHOR]

Objective To explore the prognostic value of chemoradiotherapy based on the depth of invasion (DOI) in patients with oral squamous cell carcinoma. Methods Patients with oral squamous cell carcinoma who received surgical treatment in a hospital from 2008 to 2016 were enrolled. The chi-square test was used to compare the effects of DOI on postoperative cervical lymph node metastasis and local recurrence. The effects of chemoradiotherapy on postoperative cervical lymph node metastasis, local recurrence, and survival were analyzed based on the DOI. Results A total of 111 patients with oral squamous cell carcinoma were included in this study. The postoperative local recurrence rate (P 10 mm were significantly higher than those with DOI ≤ 5 mm. The time of postoperative recurrence was concentrated within two years after the operation. The greater the DOI was, the shorter the time to postoperative recurrence (P 0.05). Conclusion DOI has important predictive value for postoperative recurrence, cervical lymph node metastasis and survival rate. However, DOI cannot be used as an independent index to guide whether chemoradiotherapy is needed after oral cancer surgery.

Objective: To explore the clinical phenotype and genetic variant in a Chinese pedigree affected with Hunter syndrome and create immortalized cell lines for the affected pedigree members., Methods: A pedigree of six members who had visited Xi'an Children's Hospital in July 2022 was selected as the study subject. Clinical data was collected. Whole exome sequencing was carried out for the pedigree members. Candidate variant was verified by Sanger sequencing. In addition, peripheral B lymphocytes were transfected with Epstein-Barr virus to create immortalized cell lines, which were then subjected to enzyme activity analysis., Results: The patient, a five-year-and-seven-month-old boy, had exhibited stiff limbs and enlarged joints. He had developed hernia, scaphocephaly, and barrel chest from 3 months of age. His uncle also had stiff limbs, poor hearing, blindness, and right oblique inguinal hernia. Above features had resembled those of Hunter syndrome. Genetic testing revealed that both the child and his uncle had harbored an IDS (NM_000202.8): c.823G>A (p.D275N) variant, which was unreported previously. Bioinformatic analysis indicated that the D275 to be a highly conserved site, and the D275N variant may affect the stability of the protein's spatial conformation, thereby decrease the catalytic activity of the enzyme. The successfully constructed immortalized lymphoblastoid cell lines for the child and his parents showed increased volume, irregular shape, burr structure and cluster growth. And the value of IDS activity of the patient's immortalized lymphoblastoid cells was below the limit of detection. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PS3+PM2_Supporting+PM5+PP1+PP3)., Conclusion: Above finding has enriched the phenotypic and mutational spectra of Hunter syndrome, and provided a basis for the genetic counseling for this pedigree. The creation of immortalized cell lines has offered a model for further investigation of the impact of variant on the function of IDS and development of targeted drugs.

Objective: To analyze the clinical characteristics and genetic variant of a child featuring X-linked mental retardation., Methods: Whole exome sequencing and Sanger sequencing were used for the detection of variant and pedigree validation, respectively. Clinical manifestation of patients with DDX3X gene variants were also reviewed., Results: The child was found to harbor a heterozygous NM_001193416.3: c.1332_1333delCT (p.Leu445Serfs*19) variant of the DDX3X gene. The same variant was not found in either of her parents., Conclusion: The child was diagnosed with X-linked mental retardation due to variant of the DDX3X gene. Above finding has enriched the spectrum of DDX3X gene variants and provided a basis for clinical diagnosis and prenatal diagnosis for this pedigrees.

Objective: To explore the genetic basis for two unrelated patients with global developmental delay and coarse facial features., Methods: Clinical data and family history of the two pedigrees were collected. Whole exome sequencing and Sanger sequencing were carried out to detect potential variants., Results: The two patients have presented with global developmental delay, coarse facies, muscular hypotonia, congenital heart disease, and pectus excavatum, and were found to harbor two de novo loss-of-function variants of the ARID1B gene, namely c.3586delC (p.Gln1196Serfs*15) and c.4954_4957delACGT (p.Thr1652Glyfs*31). Both variants were unreported previously., Conclusion: The nonsense variants of the ARID1B gene probably underlay the etiology in these patients. Above finding has enriched the genotypic and phenotypic spectrum of the disease and provided a basis for prenatal diagnosis.

Objective: To analyze the clinical features and genetic variants in two unrelated patients with psychomotor retardation and facial abnormalities, and to explore their genotype-phenotype correlation., Methods: Clinical data and family history of the two pedigrees were collected. Whole exome sequencing (WES) and Sanger sequencing were carried out to detect the potential variants., Results: Both patients had presented with mental and language retardation, along with growth delay and facial anomalies. They were both found to harbor de novo loss-of-function variants in exon 12 of the ASXL3 gene, namely c.3096dup (p.Pro1033Thrfs*2) and c.3253G>T (p.Gly1085*). Neither variant was reported previously. Combined with their clinical features and genetic finding, both patients were diagnosed with Bainbridge-Ropes syndrome due to pathogenic variants of the ASXL3 gene., Conclusion: Diagnosis of Bainbridge Ropes syndrome in the two pedigrees has enriched the genotypic and phenotypic spectrum of this disorder and enabled genetic counseling for them.

Objective: To analyze the clinical features and genetic variants of two patients from a pedigree affected with Smith-Lemli-Opitz syndrome and explore their genotype-phenotype correlation., Methods: Clinical data and family history of the pedigree were collected. Whole exome sequencing was carried out to identify the potential variants. Suspected variants were verified by Sanger sequencing of the family members., Results: The proband and her sister both presented with feeding difficulty, facial dysmorphism, seizures, and mental and speech retardation. The third child of this family presented with feeding difficulty, poor weight gain and severe malnutrition after birth. He had died of unknown cause at 6 months without genetic testing. The fourth child was a healthy boy. Genetic testing showed that both the proband and her sister have carried c.127G>T (p.Val43Phe) and c.820_825del (p.Asn274_Val275del) compound heterozygous variants of the DHCR7 gene (NM_001360.2), but the fourth child carried neither of the variants. The two variants were unreported in the literature and disease-related databases, and were not included in the 1000G and gnomAD databases. The c.820_825del variant may affect the sterol-sensitive region of the DHCR7 protein, which can lead to deletion of two amino acids at positions 247 and 275, causing truncation of the DHCR7 protein. It is speculated that this may affect the stability of protein's spatial conformation, thereby decrease the activity of the enzyme. The c.127G>T variant may affect the first transmembrane region of the protein, which is involved in the transmembrane transport of proteins. Multiple software predicted it to be harmful. Conservation analysis suggested that the three amino acids all locate in a highly conserved region of the protein. In consideration of the clinical phenotype, family history and result of genetic testing, we speculated that both patients had Smith-Lemli-Opitz syndrome due to variants of the DHCR7 gene., Conclusion: This pedigree has enriched the phenotypic and genotypic data of Smith-Lemli-Opitz syndrome, which clarified the genetic etiology of the patients and provided a basis for genetic counseling of this pedigree.

Objective: To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia., Methods: Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene., Results: The patient presented with poor weight gain, poor feeding, lethargy, and a "sweaty feet" odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5: 3. 044, reference range 0.04 - 0.4 μmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 - 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported., Conclusion: The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.

Objective: To explore the molecular basis for a pedigree affected with coagulation factor V (FV) deficiency., Methods: Clinical data of the patient and his family members was analyzed. Targeted capture and next-generation sequencing (NGS) and Sanger sequencing were carried out to detect potential variant of the FV gene., Results: The patient presented with jaundice and prolonged prothrombin time (PT) and activated partial thromboplastic time (APTT). V factor activity measured only 0.1% of the normal level, though the patient had no sign of bleeding. A paternal heterozygous variant c.653T>C (p.F218S) and a maternal heterozygous variant c.3642_3643del (p.P1215Rfs*175) were identified in the FV gene of the patient. His elder brother was a heterozygous carrier of the c.653T>C (p.F218S) variant. c.653T>C(p.F218S) was a known pathogenic variant, while the c.3642_3643del (p.P1215Rfs*175) variant was unreported previously., Conclusion: Mutations of the FV gene probably underlie the hereditary coagulation factor V deficiency in this patient. NGS combined with Sanger sequencing has detected potential variant with efficiency and provided a reliable basis for clinical and prenatal diagnosis for this family.

Objective: To explore the genetic basis for a pedigree affected with Chediak-Higashi syndrome (CHS)., Methods: Clinical data of two CHS patients from the pedigree was collected and analyzed. Targeted next generation sequencing and Sanger sequencing were conducted to detect potential mutation of the LYST gene., Results: Both patients presented immunodeficiency, oculocutaneous albinism, and acidophilic inclusion body on bone marrow and blood smears. A homozygous c.6077_6078insA (p.Tyr2026Terfs) mutation was detected in the LYST gene in both patients., Conclusion: Genetic testing can play an important role in the diagnosis of CHS.

Background: The aim of this study is to explore clinical efficacy of crizotinib in advanced anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer., Methods: patients with advanced non-small cell lung cancer habouring ALK positive were randomly divided into crizotinib group (n=14) and chemotherapy group (n=14). Patients in the crizotinib group were receive oral treatment with crizotinib (250 mg) twice daily. Patients in the chemotherapy group were administrated docetaxel injection (75 mg/m2) every three weeks and every patient was treated at least 3 period. Then clinical efficacy was observed after 12 mo followed-up., Results: Effective rate of patients in the crizotinib group was 64.29%. It was significantly higher than that of the chemotherapy group (21.43%)(P=0.026). The stable rate of patients in the crizotinib group was 85.71%. It was significantly higher than that of the chemotherapy group 40.86% (χ2=5.600, P=0.018). Median progression free survival (PFS) of the crizotinib group was 7.0 mo. It was longer than that of the chemotherapy group (4.0 mo)(P=0.002)., Conclusions: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced ALK positive non-small cell lung cancer. The median PFS of patients is shorter. It can improve the quality of life about patients.
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Background and Objective: Epidermal growth factor receptor (EGFR) the development of orally activesmall molecule inhibitors for non-small cell lung cancer (NSCLC) provides anew treatment plan. EGFR gene mutation in patients with activation EGFR tyrosine kinase inhibitor (EGFR-TKIs) therapy for the treatment of sensitive, so that a large number of clinical benefit. The first generation of reversible ATP-competitive EGFR-TKIs, gefitinib and erlotinib as first-line, second-line or has the effect of maintenance therapy. Although the initial effect of these drugs have, but most patients will produce drug resistance. Within a year, 50%-60% patients had T790M housekeeping gene mutation associated with. Irreversible EGFR-TKIs recent background: afatinib and dac-omitinib covalent binding and inhibition of multiple ErbB family receptors (EGFR, HER2 and HER4). People evaluate these drugs as first-line treatment of significance, and acquired drug resistance situation significance on the first generation EGFR-TKIs. Afatinib is the first ErbB family approved blocking agent, used to treat with EGFR activating mutations in patients with non small cell lung cancer; dacomitinib are in the later stages of clinical development. EGFR inhibitors specifically targeting T790M resistance mutations (AZD9291, CO-1686, HM61713) are in the early stages of development. As discussed in this paper, the scope of the EGFR-TKIs kinase to target different, EGFR receptor binding was reversible and drug interaction potential is also different. For clinicians, these differences of the multi drug treatment of patients with non-small cell lung cancer with meaning, from the innovative anticancer drug combination therapy strategy point of view, these differences are also of great significance.

Objective: We evaluated antioxidative effect of two antioxidative strains, isolated from the traditional fermented dairy products., Methods: Both intact cells and cell-free extract of Lactobacillus casei subsp. casei SY13 and Lactobacillus delbrueckii subsp. bulgaricus LJJ were used to study the inhibited effect of linoleic acid peroxidation, the ability of scavenging 1,1-diphenyl-2-picrylhydrazyl radical, hydroxyl radical, superoxide anion radical,the ability of tolerancing hydrogen peroxide and the chelating capacity of ferrous ion and reducting activity., Results: Lactobacillus casei subsp. casei SY13 and Lactobacillus delbrueckii subsp. bulgaricus LJJ demonstrated highest inhibition on linoleic acid peroxidation by 62.95% and 66.16%, respectively. The cell-free extract showed excellent scavenging superoxide anion and hydroxyl radicals activity. However, the intact cells of Lactobacillus delbrueckii subsp. bulgaricus LJJ scavenging superoxide and hydroxyl radicals capacity were not detected. The intact cells of Lactobacillus casei subsp. casei SY13 and Lactobacillus delbrueckii subsp. bulgaricus LJJ on 1,1-diphenyl-2-picrylhydrazyl radical scavenging ability and chelating ferrous ion capacity were superior to cell-free extract. The highest reduced activety was equivalent to 305 micromol/L and 294 micromol/L L-cysteine., Conclusion: Two latobacilli strains had good antioxidant capacity. As potential probiotics, it can be used in future.