Purpose To investigate the clinicopathological features,diagnosis,and molecular genetic characteris-tics of central nervous system(CNS)high-grade neuroepithelial tumors with BCOR alterations.Methods Five cases of CNS high-grade neuroepithelial tumors harboring BCOR alterations were collected.Using immunohistochemistry and molecular detection to analyze its clinical and histological characteristics,and review relevant literatures.Results A-mong the 5 patients,3 cases with EP300 ∷ BCOR tumor(male-to-female ratio 2∶1).These tumors were located in supratentorial regions(right temporal lobe,right frontotemporal lobe,and right frontal lobe).The 2 patients with BCOR-ITD tumors were younger,both with tumors located in the left cerebellum.Imaging studies revealed well-defined large mass lesions in all cases.Histologically,all 5 cases tumor exhibited ependymoma-like or oligodendroglioma-like morphology,featuring uniformly oval or round cells.Focal areas showed increased cellular density,nuclear enlarge-ment,and readily identifiable mitotic figures indicative of anaplastic features.A rich capillary network was frequently observed in the stroma.Palisading necrosis,microcystic changes,and microcalcifications were present in 3 cases.Im-munohistochemically,all 5 cases consistently expressed vimentin and CD56,focal Olig-2 positivity,variable S-100 ex-pression,and were uniformly negative for GFAP.BCOR immunostaining was weakly positive in 1 case with an EP300∷ BCOR fusion and strongly positive in 2 cases with BCOR-ITD.NGS identified an EP300 ∷ BCOR fusion in 3 cases,and Sanger sequencing confirmed the ITD in exon 15 of BCOR gene in 2 cases.During a follow-up period of 8 to 77 months,one pediatric patient with a BCOR-ITD tumor died,while the remaining four patients were alive with no evi-dence of recurrence or metastasis.Conclusion BCOR-ITD and EP300 ∷ BCOR fusion tumors are similar in morphology and immunophenotype,and the incidence rate of BCOR fusion tumors may be underestimated.NGS sequencing based on DNA and RNA and DNA methylation spectrum analysis are helpful for accurate diagnosis of this type of tumor.

Purpose To investigate the clinicopathological features,diagnosis,and molecular genetic characteris-tics of central nervous system(CNS)high-grade neuroepithelial tumors with BCOR alterations.Methods Five cases of CNS high-grade neuroepithelial tumors harboring BCOR alterations were collected.Using immunohistochemistry and molecular detection to analyze its clinical and histological characteristics,and review relevant literatures.Results A-mong the 5 patients,3 cases with EP300 ∷ BCOR tumor(male-to-female ratio 2∶1).These tumors were located in supratentorial regions(right temporal lobe,right frontotemporal lobe,and right frontal lobe).The 2 patients with BCOR-ITD tumors were younger,both with tumors located in the left cerebellum.Imaging studies revealed well-defined large mass lesions in all cases.Histologically,all 5 cases tumor exhibited ependymoma-like or oligodendroglioma-like morphology,featuring uniformly oval or round cells.Focal areas showed increased cellular density,nuclear enlarge-ment,and readily identifiable mitotic figures indicative of anaplastic features.A rich capillary network was frequently observed in the stroma.Palisading necrosis,microcystic changes,and microcalcifications were present in 3 cases.Im-munohistochemically,all 5 cases consistently expressed vimentin and CD56,focal Olig-2 positivity,variable S-100 ex-pression,and were uniformly negative for GFAP.BCOR immunostaining was weakly positive in 1 case with an EP300∷ BCOR fusion and strongly positive in 2 cases with BCOR-ITD.NGS identified an EP300 ∷ BCOR fusion in 3 cases,and Sanger sequencing confirmed the ITD in exon 15 of BCOR gene in 2 cases.During a follow-up period of 8 to 77 months,one pediatric patient with a BCOR-ITD tumor died,while the remaining four patients were alive with no evi-dence of recurrence or metastasis.Conclusion BCOR-ITD and EP300 ∷ BCOR fusion tumors are similar in morphology and immunophenotype,and the incidence rate of BCOR fusion tumors may be underestimated.NGS sequencing based on DNA and RNA and DNA methylation spectrum analysis are helpful for accurate diagnosis of this type of tumor.

Objective:To explore the clinical and molecular basis for a Chinese pedigree affected with Complete androgen insensitivity syndrome (CAIS).Methods:A CAIS pedigree presented at Tianjin Medical University General Hospital between 2019 and 2021 was selected as the study subject. Clinical data of the proband was collected, along with peripheral blood samples from the proband and her family members. Chromosomal karyotyping, sex-determining region of the Y chromosome ( SRY) testing, and next-generation sequencing (NGS) were carried out for the proband, and candidate variant was verified by Sanger sequencing of her family members. Prenatal diagnosis was provided for the sister of the proband. This study was approved by Medical Ethics Committee of the Tianjin Medical University General Hospital (Ethics No. IRB2023-WZ-070). Results:The 18-year-old proband, who has a social gender of female, underwent laparoscopic examination, which showed no presence of uterus and ovaries. The karyotype of peripheral blood sample was 46, XY, with SRY gene detected. NGS indicated that the proband has harbored a heterozygous c. 1988C>G (p.Ser663Ter) variant of the AR gene. Sanger sequencing confirmed that her mother and sister had both harbored the same variant, whilst her father and younger sister were of the wild-type. Prenatal diagnosis revealed that her sister′s first fetus had harbored carried the same variant, which had led to termination of pregnancy. Her second fetus did not carry the variant, and a healthy boy was born. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PM2_Supporting+ PM4+ PP3_Moderate+ PP4). Conclusion:The c. 1988C>G (p.Ser663Ter) variant of the AR gene probably underlay the CAIS in the proband. The accurate diagnosis of sex development disorders will rely on the physicians′ thorough understanding of the clinical symptoms and pathogenic genes. Genetic testing and counseling can enable precise diagnosis, prenatal diagnosis, and guidance for reproduction

BACKGROUND: Numerous researches indicated that electromagnetic pulses (EMP) possessed advantages such as strong targeting, minimal side-effects and low treatment cost in tumor therapy, but its optimum parameters for treatment and the relationship between EMP and tumor-derived exosomes remains unclear. This study aims to clarify the effects of EMP with different parameters on the quantity and miRNA (microRNA) of exosomes secreted by human non-small cell lung cancer A549 cells, providing beneficial reference for the clinical application of EMP and related research. METHODS: A549 cells were randomly divided into control group and different EMP radiation groups with respective intensity of 400, 600 and 800 kV/m. EMP was performed with 2000 pulses once, 20 Hz of repetition frequency and 120 ns of pulse width. A549 cells were radiated once per day for continuous 3 days. After radiation, exosomes were collected and identified; cell number was measured by trypan blue staining; the concentration of exosomes was measured by nanoparticle tracking analysis (NTA); the abundance of miRNAs was determined by miRNA sequencing. RESULTS: Compared with control group, the morphology and cell viability of A549 cells in radiation group was not different, but the quantity of exosomes in 400 or 800 kV/m radiation group was significantly decreased (P<0.05), in contrast with obvious increase in 600 kV/m radiation group (P<0.05). The abundance of exosomal miRNAs between control group and each EMP group was obviously different (P<0.05) and target genes of differentially abundant miRNAs enriched in different pathways. CONCLUSIONS Under the experimental condition, the quantity and miRNA abundance of exosomes could be changed by EMP radiation, which could further influence the function of tumor-derived exosomes.
Humans ; Exosomes/genetics* ; A549 Cells ; MicroRNAs/metabolism* ; Lung Neoplasms/pathology* ; Cell Survival/radiation effects* ; Electromagnetic Fields

Clinical application of doxorubicin (DOX) is heavily hindered by DOX cardiotoxicity. Several theories were postulated for DOX cardiotoxicity including DNA damage and DNA damage response (DDR), although the mechanism(s) involved remains to be elucidated. This study evaluated the potential role of TBC domain family member 15 (TBC1D15) in DOX cardiotoxicity. Tamoxifen-induced cardiac-specific Tbc1d15 knockout (Tbc1d15^CKO) or Tbc1d15 knockin (Tbc1d15^CKI) male mice were challenged with a single dose of DOX prior to cardiac assessment 1 week or 4 weeks following DOX challenge. Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbc1d15 were used for Tbc1d15 overexpression or knockdown in isolated primary mouse cardiomyocytes. Our results revealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality, the effects of which were ameliorated and accentuated by Tbc1d15 deletion and Tbc1d15 overexpression, respectively. DOX overtly evoked apoptotic cell death, the effect of which was alleviated and exacerbated by Tbc1d15 knockout and overexpression, respectively. Meanwhile, DOX provoked mitochondrial membrane potential collapse, oxidative stress and DNA damage, the effects of which were mitigated and exacerbated by Tbc1d15 knockdown and overexpression, respectively. Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Liquid chromatography-tandem mass spectrometry and co-immunoprecipitation denoted an interaction between TBC1D15 and DNA-PKcs at the segment 594-624 of TBC1D15. Moreover, overexpression of TBC1D15 mutant (∆594-624, deletion of segment 594-624) failed to elicit accentuation of DOX-induced cytosolic retention of DNA-PKcs, DNA damage and cardiomyocyte apoptosis by TBC1D15 wild type. However, Tbc1d15 deletion ameliorated DOX-induced cardiomyocyte contractile anomalies, apoptosis, mitochondrial anomalies, DNA damage and cytosolic DNA-PKcs accumulation, which were canceled off by DNA-PKcs inhibition or ATM activation. Taken together, our findings denoted a pivotal role for TBC1D15 in DOX-induced DNA damage, mitochondrial injury, and apoptosis possibly through binding with DNA-PKcs and thus gate-keeping its cytosolic retention, a route to accentuation of cardiac contractile dysfunction in DOX-induced cardiotoxicity.

The Chinese Society of Clinical Oncology (CSCO) issued the new version of the guidelines on diagnosis and treatment of NSCLC in April 2023.The new version updated the diagnostic and therapeutic strategy of rare oncogenic mutations, including ROS1 fusion, BRAF V600E mutation, NTRK fusion, MET exon 14 skipping mutation, RET fusion, and EGFR exon 20 insertion mutation, in NSCLC.This review will interpret the most important updates in the guidelines 2023 regarding the diagnosis as well as first-line and post-line therapies of these rare oncogenic mutations.

Objective:To explore the collaborative innovation development mechanism of hospitals and research institutes, fully integrate the institute personnel with hospitals, and conduct classified management and performance appraisal, promoting the integrated development of hospitals and research institutes.Methods:The idea of personnel classification, the establishment of an integrated research team, and technical team groupings and service directions were determined through key informant interviews, research ability and technical strength surveys, and other research methods; The performance appraisal scheme of research teams were established by using literature analysis and optimization and Delphi expert investigation; The platform team assessment programs were established by qualitative research methods.Results:Built a position setting framework for research institutes, formed hospital-institute integrated research teams around the hospital's clinical advantageous disciplines with researchers and clinical staff, set up platform teams based on existing equipment and technicians′ specialties, established a performance appraisal scheme for research teams based on Science and Technology Evaluation Metrics(STEM), determined a full-dimensional comprehensive performance evaluation scheme for the technology platforms based on service volume and quality.Conclusions:This study formulated a set of position setting and performance evaluation schemes that fit with the current situation of municipal research institutes, and explored a new scientific research cooperation mechanism of resource sharing, team co-construction, and technology sharing, which can provide a certain reference value for the reform of other medical research institutes.

Objective:To study the correlation between anti-gp210 antibody, anti-sp100 antibody with clinical features and prognosis of patients with PBC.Methods:A total of 992 patients with PBC from 9 medical centers in Yunnan Province from January 1, 2015 to December 31, 2021 were included retrospectively. The demographic data, medical history, UDCA treatment, laboratory and imaging data were collected, and telephone follow-up was conducted. The positive rates of anti-gp210 antibody and anti-sp100 antibody in PBC patients with different clinical characteristics were compared, and the differences of laboratory parameters and prognosis between the anti-gp210 and anti-sp100 antibodies positive and negative groups were compared. T test, rank sum test, variance analysis were used for statistical analysis.Results:The positive rate of anti-gp210 antibody in Han patients was significantly higher than that in minority patients (21.5% vs 9.9%, χ2=6.88, P=0.009), but there was no significant difference in the positive rate of anti-sp100 antibody between the two groups (10.9% vs 6.6%, χ2=1.62, P=0.204).There were no significant differences in the positive rates of anti-gp210 antibody and anti-sp100 antibody among different genders ( χ2=0.50, P=0.478)( Z=-0.41, P=0.682)and ages( χ2=0.01, P=0.951)( Z=-0.60, P=0.549). There was no significant difference in the positive rate of anti-gp210 antibody between AMA M2 antibody positive and negative patients ( χ2=3.45, P=0.063), PBC patients with Sj?gren′s syndrome compared with those without Sj?gren′s syndrome (21.3% vs 20.4%, χ2=0.05, P=0.828), and PBC patients with viral hepatitis compared with those without viral hepatitis(19.6% vs 20.5%, χ2=0.02, P=0.877). The positive rate of anti-gp210 antibody was significantly increased in patients with PBC confirmed by liver biopsy with unknown diagnosis (25.6% vs 18.4%, χ2=6.52, P=0.011), patients with AIH (26.6% vs 18.9%, χ2=5.82, P=0.016), cirrhosis (23.3% vs 11.3%, χ2=16.00, P<0.001), decompensation of cirrhosis (23.9% vs 18.2%, χ2=4.66, P=0.031), jaundice (29.7% vs 17.1%, χ2=18.59, P<0.001) and hyperlipidemia (24.9% vs 18.1%, χ2=6.30, P=0.012). The positive rate of anti-sp100 antibody was significantly increased in patients with negative AMA M2 antibody PBC patients (20.9% vs 7.2%, χ2=36.54, P<0.001)and patients with PBC confirmed by liver biopsy with unknown diagnosis (17.9% vs 7.5%, χ2=23.40, P<0.001), while in patients with AIH (11.1% vs 10.3%, χ2=0.09, P=0.769), Sj?gren′s syndrome (15.7% vs 10.0%, χ2=2.87, P=0.090), viral hepatitis (4.3% vs 10.8%, χ2=1.94, P=0.164), cirrhosis(10.5% vs 10.5%, χ2<0.01, P=0.991), decompensated symptoms of cirrhosis (10.3% vs 10.6%, χ2=0.03, P=0.868), jaundice (12.5% vs 9.7%, χ2=1.62, P=0.203)and hyperlipidemia (8.7% vs 11.5%, χ2=1.86, P=0.172), the positive rate was not significantly increased. The levels of ALT [71.00(48.00, 111.00)U/L vs 58.00 (31.00,112.75)U/L, Z=-2.63, P=0.009], AST [92.00 (54.00, 133.00)U/L vs 76.00(42.00, 128.00)U/L, Z=-2.73, P=0.006], ALP[306.00(176.00, 528.00)U/L vs 204.00(126.25, 350.75)U/L, Z=-4.78, P<0.001], GGT[284.00(131.00, 524.00)U/L vs 165.00(53.63, 389.00)U/L, Z=-4.36, P<0.001], TBIL[33.60(16.60, 82.10)mmol/L vs 23.45 (14.80, 61.13)mmol/L, Z=-3.00, P=0.003], DBIL [20.30 (6.60, 66.40)mmol/L vs 11.60 (5.90, 45.00)mmol/L, Z=-3.13, P=0.002], bile acid[53.40(19.50, 148.00)mmol/L vs 39.30(11.70, 118.58)mmol/L, Z=-2.26, P=0.024], IgM[3.61(2.03,5.26)g/L vs 2.39(1.37, 3.67)g/L, Z=-5.38, P<0.001] and APTT[37.40(33.10, 41.30)s vs 35.70 (31.30, 41.30)s, Z=-3.28, P=0.001])were significantly increased in patients with positive anti-gp210 antibody compared patients with negative anti-gp210 antibody, while the IgG level was significantly increased in patients with positive anti-sp100 antibody compared with patients with negative anti-gp210 antibody( Z=-2.25, P=0.025), but no other indexes were significantly increased. The Mayo risk score[3.48(2.46, 5.01) vs 3.18 (2.20, 4.64), Z=-2.052, P=0.04] and mortality at the end of follow-up (24.6% vs 16.7%, χ2=6.57, P=0.0.038)in patients with positive anti-gp210 antibody were much higher than those in patients with negative anti-gp210 antibody, but there were no significant differences in Mayo risk score [3.16 (2.21, 4.53) vs 3.28 (2.23,4.71), Z=-0.86, P=0.392] and mortality at the end of follow-up (13.5% vs 18.9%, χ2=2.12, P=0.346) between anti-sp100 antibody positive and negative patients. Conclusion:PBC patients with positive anti-gp210 antibody may have more serious liver pathologic damage and extra-hepatic complications, more serious liver function impairment, more obvious cholestasis, and worse prognosis. Anti-sp100 antibody has been shown to have no significant correlation with disease severity and prognosis.

Few studies have described the key features and prognostic roles of lung microbiota in patients with severe community-acquired pneumonia (SCAP). We prospectively enrolled consecutive SCAP patients admitted to ICU. Bronchoscopy was performed at bedside within 48 h of ICU admission, and 16S rRNA gene sequencing was applied to the collected bronchoalveolar lavage fluid. The primary outcome was clinical improvements defined as a decrease of 2 categories and above on a 7-category ordinal scale within 14 days following bronchoscopy. Sixty-seven patients were included. Multivariable permutational multivariate analysis of variance found that positive bacteria lab test results had the strongest independent association with lung microbiota (R² = 0.033; P = 0.018), followed by acute kidney injury (AKI; R² = 0.032; P = 0.011) and plasma MIP-1β level (R² = 0.027; P = 0.044). Random forest identified that the families Prevotellaceae, Moraxellaceae, and Staphylococcaceae were the biomarkers related to the positive bacteria lab test results. Multivariable Cox regression showed that the increase in α-diversity and the abundance of the families Prevotellaceae and Actinomycetaceae were associated with clinical improvements. The positive bacteria lab test results, AKI, and plasma MIP-1β level were associated with patients' lung microbiota composition on ICU admission. The families Prevotellaceae and Actinomycetaceae on admission predicted clinical improvements.
Acute Kidney Injury/complications* ; Bacteria/classification* ; Chemokine CCL4/blood* ; Community-Acquired Infections/microbiology* ; Humans ; Lung ; Microbiota/genetics* ; Pneumonia, Bacterial/diagnosis* ; Prognosis ; RNA, Ribosomal, 16S/genetics*

Primary biliary cholangitis (PBC) is an chronic progressive intrahepatic cholestasis autoimmune liver disease with unknown causes, and at present, the etiology and pathogenesis of PBC remain unclear. Nuclear receptor is a ligand-dependent transcription factor superfamily that regulates cell growth and differentiation by establishing a relationship between signal molecules and transcriptional responses. The human nuclear receptor family consists of 48 members, including peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, liver X receptors, farnesoid X receptor, vitamin D receptor, and glucocorticoid receptor, which have attracted wide attention. These nuclear receptors regulate the key enzymes and transporter genes of bile acid metabolism at the transcriptional level and thus regulate the level of bile acid in the body and participate in inflammatory response. Bile acid metabolism disorder and persistent inflammation may be the key factors for the development and progression of PBC. This article reviews the research advances in nuclear receptors in the development and progression of PBC, in order to provide a theoretical basis for exploring the pathogenesis of PBC and new therapeutic targets.