OBJECTIVES: Metastasis is the primary cause of death in osteosarcoma, and current clinical treatments remain limited. BRD4, a key epigenetic regulator, has shown therapeutic promise in various cancers through its inhibition. However, the mechanistic role of BRD4 in osteosarcoma remains poorly understood. This study aims to elucidate the molecular mechanisms by which BRD4 regulate osteosarcoma progression and to explore novel therapeutic strategies. METHODS: Immunofluorescence was used to assess BRD4 expression levels in a tissue microarray containing 80 osteosarcoma samples from different patients. The Gene Expression Omnibus (GEO) dataset (GSE42352, containing survival data from 88 osteosarcoma patients) was downloaded to perform Kaplan-Meier survival analysis based on BRD4 gene expression levels. In vivo, an orthotopic intramedullary osteosarcoma model was established using HOS cells in C57 mice, followed by treatment with varying doses of the BRD4 inhibitor (+)-JQ1. Micro-CT, 3D reconstruction of bone tissue, and HE staining were employed to evaluate pathological changes in bone and intestinal lymph nodes. In vitro, cell viability was measured using the methyl thiazolyl tetrazolium (MTT) assay, while colony formation and Transwell assays assessed proliferative and invasive capacities. Chromatin-bound BRD4 was analyzed via co-immunoprecipitation combined with mass spectrometry (Co-IP/MS), and O-GlcNAc glycosylation sites and glycan chains of BRD4 were identified using Co-IP with Nano-LC MS/MS. Real-time PCR and Western blotting were used to analyze the relative mRNA and protein expression levels of target genes, respectively. RESULTS: BRD4 was positively expressed in 61.25% (49/80) of osteosarcoma tissues. Patients with high BRD4 expression exhibited significantly shorter survival times (P<0.05). In the orthotopic mouse model, intervention with (+)-JQ1, a potent and commonly used BETi, significantly inhibited tumor growth in vivo and reduced bone destruction (P<0.05). (+)-JQ1 treatment significantly suppressed the proliferation (P<0.001), invasion (P<0.001), and migration (P<0.05) of HOS cells. In osteosarcoma cells, BRD4 exhibited O-GlcNAc modifications at both N- and C- C-termini, particularly at Thr73, which is essential for protein stability. This modification also contributed to the activation of the EGFR tyrosine kinase inhibitor resistance pathway (KEGG Pathway: hsa01521). (+)-JQ1 treatment displaced BRD4 from enhancers and downregulated the transcription of pathway-related genes, such as EGFR and PDGFC, thereby suppressing the malignant behavior of osteosarcoma cells. CONCLUSIONS BRD4 promotes osteosarcoma progression via O-GlcNAc modification at Thr73 and plays a crucial role in tumor growth and metastasis.
Osteosarcoma/drug therapy* ; Humans ; Transcription Factors/metabolism* ; Animals ; Cell Cycle Proteins ; Mice ; Bone Neoplasms/drug therapy* ; Azepines/pharmacology* ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; Triazoles/pharmacology* ; Mice, Inbred C57BL ; Nuclear Proteins/metabolism* ; Gene Expression Regulation, Neoplastic ; Male ; Bromodomain Containing Proteins

To report the first case of congenital ichthyosis with woolly hair in China, and to elucidate its genetic variant profile. A 28-year-old female patient presented with rashes on the trunk and limbs for 28 years. Dermatological examination revealed dry and rough skin over the entire body, with well-defined, polygonal, dark brown, adherent scales densely distributed over the trunk and extremities. No significant abnormalities were observed in the mucous membranes, teeth, or nails. The patient exhibited uniformly distributed, woolly and curly hair with a soft, dry texture and normal density; no significant hair breakage or brittleness was observed, while the eyebrows appeared sparse. Hair microscopy showed irregular axial twisting of hair strands at varying intervals; scanning electron microscopy (SEM) revealed irregular hair shafts with some segments appearing flat in a belt-like pattern, and magnified SEM images further demonstrated hair cuticle damage on the surface of hair shafts, manifesting as localized upward curling and longitudinal grooves, indicating structural damage to the hair shafts. Whole-exome sequencing identified a homozygous variant c.124dupC in exon 3 of the PRSS8 gene in the proband, resulting in a frameshift mutation (p.Gln42Profs*24) in the PRSS8 protein. According to the guidelines of the American College of Medical Genetics and Genomics as well as the patient's clinical manifestations, this variant could be preliminarily classified as pathogenic. A diagnosis of syndromic ichthyosis was made. This case represents the first report of syndromic ichthyosis caused by PRSS8 variants in China and the second report in the world, and this condition is proposed to be tentatively named as "ichthyosis-woolly hair syndrome".

Objective To discuss the application of ultrasound multimodal diagnostic mode combined with ultrasonic precision interventional technology in differentiating the benign from malignant solid breast masses.Methods A total of 396 patients who underwent breast surgery at the Wuwei Cancer Hospital of China from May 2021 to July 2023 were enrolled in this study.Within 2 weeks before surgery,multimodal ultrasound examination(including two-dimensional ultrasound,color Doppler ultrasound,elastic ultrasound,breast three-dimensional ultrasound,and contrast-enhanced ultrasound)and ultrasound-guided needle biopsy were performed in all patients.The consistency between the results of multimodal ultrasound examination,ultrasound-guided needle biopsy,combination diagnosis and the postoperative pathological diagnoses was analyzed.Results Of the 396 patients with solid breast mass,malignant lesion was seen in 237(59.85％)and benign lesion was seen in 159(40.15％).The sensitivity of multimodal ultrasound in diagnosing benign and malignant solid breast masses was 77.64％(184/237),the specificity was 90.57％(144/159),the positive predictive value was 92.46％(184/199),the negative predictive value was 73.10％(144/197),the accuracy was 82.83％(328/396),and the consistency with the postoperative pathological diagnosis was 0.656.The sensitivity of ultrasound-guided needle puncture in diagnosing benign and malignant solid breast masses was 94.51％(224/237),the specificity was 100.00％(159/159),the positive predictive value was 100.00％(224/224),the negative predictive value was 92.44％(159/172),the accuracy was 96.72％(383/396),and the consistency with the postoperative pathological diagnosis was 0.933.The sensitivity of multimodal ultrasound combined with ultrasound-guided needle puncture in diagnosing benign and malignant solid breast masses was 100.00％(228/228),the specificity was 94.64％(159/168),the positive predictive value was 96.20％(228/237),the negative predictive value was 100.00％(159/159),the accuracy was 97.73％(387/396),and the consistency with the postoperative pathological diagnosis was 0.937.Conclusion The ultrasound multimodal diagnostic mode and ultrasonic precision interventional technology can be used in differentiating the benign from malignant solid breast masses with high diagnostic accuracy.

To report the first case of congenital ichthyosis with woolly hair in China, and to elucidate its genetic variant profile. A 28-year-old female patient presented with rashes on the trunk and limbs for 28 years. Dermatological examination revealed dry and rough skin over the entire body, with well-defined, polygonal, dark brown, adherent scales densely distributed over the trunk and extremities. No significant abnormalities were observed in the mucous membranes, teeth, or nails. The patient exhibited uniformly distributed, woolly and curly hair with a soft, dry texture and normal density; no significant hair breakage or brittleness was observed, while the eyebrows appeared sparse. Hair microscopy showed irregular axial twisting of hair strands at varying intervals; scanning electron microscopy (SEM) revealed irregular hair shafts with some segments appearing flat in a belt-like pattern, and magnified SEM images further demonstrated hair cuticle damage on the surface of hair shafts, manifesting as localized upward curling and longitudinal grooves, indicating structural damage to the hair shafts. Whole-exome sequencing identified a homozygous variant c.124dupC in exon 3 of the PRSS8 gene in the proband, resulting in a frameshift mutation (p.Gln42Profs*24) in the PRSS8 protein. According to the guidelines of the American College of Medical Genetics and Genomics as well as the patient's clinical manifestations, this variant could be preliminarily classified as pathogenic. A diagnosis of syndromic ichthyosis was made. This case represents the first report of syndromic ichthyosis caused by PRSS8 variants in China and the second report in the world, and this condition is proposed to be tentatively named as "ichthyosis-woolly hair syndrome".

Objective:To investigate the clinical characteristics of psoriasis and status quo of medical care for patients in county areas of China.Methods:This study was a cross-sectional investigation. Based on the “Qianxian Wuyin” Project (a national project for upgrating ability for psoriasis care at county level), an online questionnaire survey was conducted in the dermatology departments of 459 county hospitals in 404 pilot administrative counties across China from February to June 2023. The questionnaire included demographic information of patients (gender, ethnicity, age, place of residence, education, marital status), and clinical characteristics of psoriasis (disease course, type, comorbidities, body surface area (BSA) and previous treatment. The Dermatology Life Quality Index (DLQI) and Psoriasis Area and Severity Index (PASI) were applied for assessing the quality of life and disease severity, and completed by patients or guardian and doctors, respectively.Results:A total of 16 935 patients completed the questionnaire. The age of patients was 1-102(44.17±11.58)years, and 71.0% (12 036/16 935) were 30-59 years old. The ratio of male to female was 2.21∶1; 24.3%(4 117/16 935) of patients had high school education; there were 9 940 patients(58.7%) with previous or current smoking and/or alcohol use; 42.8%(7 218/16 855) of patients had a disease course of 1-5 years. There were 15 630 patients(92.3%) with DLQI≥10, 8 346 patients(49.7%) with PASI≥10, 15 017 patients(89.2%) with BSA≥10%. The plaque type was the most common disease type ( n=14 965, 88.7%), and spotting type ranked the second ( n=1 141, 6.8%). The most common initial site was the trunk ( n=12 309, 72.9%). Among the comorbidities, hypertension was the most common one ( n=1 681, 10.0%). There were 7 650 reports of treatment response to conventional topical drug therapy and 3 112 reports of treatment response to systemic drug therapy, with 6 269 (81.9%) and 2 493 (80.1%) reporting poor or no response, respectively. Conclusions:The survey shows that in the county areas of China, the majority of psoriasis patients are severe patients with short course of disease, plaque type is the most common type, and hypertension is the most common comorbidity; and the conventional treatment is less effective for most patients.

ObjectiveTo evaluate the reliability and validity of the Dampness Syndrome Scale of Chinese Medicine （DSSCM） among patients with persistent asthma， and to explore the correlation between dampness syndrome and clinical characteristics of persistent asthma. MethodsA cross-sectional survey was conducted. Basic information， examination results， DSSCM， Asthma Control Test （ACT）， Generalized Anxiety Disorder-7 （GAD-7）， and Patient Health Questionnaire-9 （PHQ-9） scores were collected from 206 patients with persistent asthma to evaluate the reliability and validity of DSSCM and to explore the correlation between dampness syndrome and clinical characteristics. ResultsThe mean score of DSSCM among 206 patients was 14.59 ± 10.53. The overall Cronbach α coefficient and Spearman-Brown split-half reliability coefficient of the scale were both greater than 0.8， and the success rate of scale convergent and discriminant validity calibration were greater than 80%. The confirmatory factor analysis showed that the χ²/df was 2.309， and the root mean square error of approximation （RMSEA） was 0.08； the root mean square residual （RMR） was 0.049， whereas the comparative fit index （CFI）， the goodness of fit index （GFI）， the adjusted goodness of fit index （AGFI）， the normed fit index （NFI） and the incremental fit index （IFI） were less than 0.9. Correlation analysis showed that DSSCM scores were positively correlated with disease duration， GAD-7 scores， and PHQ-9 scores （P＜0.05）， and negatively correlated with ACT scores （P＜0.01）. The DSSCM scores were significantly different between patients with different disease severity （H = 10.92， P = 0.01）， and the DSSCM scores of allergic patients were higher than those of non-allergic patients （Z = -4.19， P＜0.001）. ConclusionDSSCM has acceptable reliability and validity for patients with persistent asthma. The scores of DSSCM correlated with the disease duration， ACT score， GAD-7 score， PHQ-9 score， disease severity and allergic status of persistent asthmatics.

Autosomal recessive congenital ichthyosis caused by CERS3 mutations is extremely rare in clinical practice. We recently identified a family of autosomal recessive congenital ichthyosis and performed multigene exome sequencing for hereditary skin diseases to identify causative genes. Mutation analysis revealed compound heterozygous mutations of c.746A>G(from the mother) and exon12 deletion(from the father)in CERS3 were detected in the proband, which were verified by Sanger sequencing and co-segregated with the ichthyosis phenotype in the proband and her parents. These mutations were both reported for the first time. For the treatment, the proband received an oral acitretin capsules of 20 mg once daily. After 3-month follow up, the patient's lesion improved significantly.

Objective:To detect causative gene mutations in 1 patient with ADULT syndrome mainly presenting with ectodermal dysplasia.Methods:Clinical data were collected from a proband with ADULT syndrome, and genomic DNA was extracted from peripheral blood samples obtained from the proband and his parents. Exome sequencing was performed in the proband by using targeted panels for hereditary skin diseases to determine mutation sites, and then the candidate mutation sites were verified by Sanger sequencing in the family members.Results:The 22-year-old male patient presented with sparse and thin hair, scattered facial freckles, missing permanent teeth, cloudy corneas, palmoplantar erythema and keratosis, nail/toenail dystrophy, and nipple dysplasia. Genetic testing of the peripheral blood genomic DNA of the proband revealed a heterozygous mutation (c.1040G>T) in exon 8 of the TP63 gene, resulting in an amino acid change at position 347 (p.C347F) . The mutation was not detected in his father or mother with normal phenotypes, suggesting the cosegregation of the gene mutation with the disease phenotype in the family.Conclusion:The de novo heterozygous missense mutation in the TP63 gene may be the causative mutation in the proband, and combined with clinical manifestations, the proband was diagnosed with ADULT syndrome without finger/toe deformities.

Objective:To detect gene mutations and make a diagnosis in a family with ichthyosis accompanied by liver injury.Methods:Clinical data were collected from the proband, and genomic DNA was extracted from peripheral blood samples from the proband and his parents. Exome sequencing was performed in the proband by using a gene panel targeting hereditary skin diseases to identify mutation sites, and then the candidate mutation site was verified by PCR and Sanger sequencing in the family members. Results of peripheral blood smear examination and other auxiliary examinations were collected from the proband and his parents and analyzed.Results:The proband presented with generalized dry skin and tiny white scales on the lower limbs, accompanied by elevated transaminase levels, mild sensorineural hearing loss in both ears and fatty liver. Exome sequencing revealed a homozygous mutation c.933dupA in exon 6 of the ABHD5 gene encoding CGI-58 protein in the peripheral blood genomic DNA of the proband, resulting in a frameshift mutation p.R312Tfs*45 in the amino acid sequence. Heterozygous mutations at this site were identified in his father and mother. The mutation cosegregated with the disease phenotype in the family. The peripheral blood smear examination of the proband showed lipid vacuoles in neutrophils, which were called Jordan anomaly. Conclusion:The diagnosis of Chanarin-Dorfman syndrome was made in the proband based on the presentation of ichthyosis-like skin lesions and abnormal liver function, as well as the homozygous mutation in the ABHD5 gene and Jordan anomaly in peripheral blood smears.

From 1987 to 2017, cardiovascular disease (CVD) had been ranking the first cause of death in Suzhou, and the mortality rate showed an upward trend annual percentage changes (APC=0.62%, P=0.001), while the standardized mortality rate showed a downward trend (APC=-2.65%, P<0.001). The probability of premature death of CVD declined consistently from 7.06% in 1987 to 2.00% in 2017 (APC=-4.45%, P<0.001). When the life expectancy was set at 70, the potential years of life lost rate (PYLLR) decreased from 6.35‰ in 1987 to 3.30‰ in 2017, and the standardized PYLLR decreased from 7.30‰ to 2.68‰. When the life expectancy was set at 75, the PYLLR decreased from 10.12‰ to 5.19‰, and the standardized PYLLR decreased from 11.44‰ to 3.88‰. With the increase of years, all PYLLR and standardized PYLLR showed a significantly downward trend (APC=-2.51%--3.89%, P<0.001).