The efficacy of using a multiparametric magnetic resonance imaging-based radiomics model to distinguish glioma recurrence from pseudoprogression.

OBJECTIVE: The early differential diagnosis of the postoperative recurrence or pseudoprogression (psPD) of a glioma is of great guiding significance for individualized clinical treatment. This study aimed to evaluate the ability of a multiparametric magnetic resonance imaging (MRI)-based radiomics model to distinguish between the postoperative recurrence and psPD of a glioma early on and in a noninvasive manner. METHODS: A total of 52 patients with gliomas who attended the Hainan Provincial People's Hospital between 2000 and 2021 and met the inclusion criteria were selected for this study. 1137 and 1137 radiomic features were extracted from T1 enhanced and T2WI/FLAIR sequence images, respectively.After clearing some invalid information and LASSO screening, a total of 9 and 10 characteristic radiological features were extracted and randomly divided into the training set and the test set according to 7:3 ratio. Select-Kbest and minimum Absolute contraction and selection operator (LASSO) were used for feature selection. Support vector machine and logistic regression were used to form a multi-parameter model for training and prediction. The optimal sequence and classifier were selected according to the area under the curve (AUC) and accuracy. RESULTS: Radiomic models 1, 2 and 3 based on T1WI, T2FLAIR and T1WI + T2T2FLAIR sequences have better performance in the identification of postoperative recurrence and false progression of T1 glioma. The performance of model 2 is more stable, and the performance of support vector machine classifier is more stable. The multiparameter model based on CE-T1 + T2WI/FLAIR sequence showed the best performance (AUC:0.96, sensitivity: 0.87, specificity: 0.94, accuracy: 0.89,95% CI:0.93-1). CONCLUSION: The use of multiparametric MRI-based radiomics provides a noninvasive, stable, and accurate method for differentiating between the postoperative recurrence and psPD of a glioma, which allows for timely individualized clinical treatment.

Yak IGFBP3 promotes hepatocyte proliferation through PI3K-Akt signaling pathway.

IGFBP3 (Insulin-like growth factor binding protein 3) constitutes a crucial constituent of the insulin-like growth factor (IGF), which are intimately associated with the organism's growth and development processes. Despite its significance, the precise function of IGFBP3 in yak liver development remains largely unexplored. In the present study, we systematically examined the expression profile of IGFBP3 in the liver tissues of yaks across various growth stages, elucidated its influence on the activity of yak hepatocytes, and probed its effects on murine liver development. A comparative analysis revealed that the expression of IGFBP3 was significantly higher in the liver tissue of 5-year-old yaks compared to their 15-month-old and 1-day-old counterparts (P < 0.01). To further validate its biological function, pET-28a-BgIGFBP3 prokaryotic expression vector was constructed. Upon exposing yak hepatocytes to varying concentrations of Bos grunniens (Bg) IGFBP3 protein, we observed augmented cellular activities and elevated colony formation rates. Moreover, our investigation revealed the upregulation of key genes within the PI3K-Akt signaling pathway, including ERBB2, IRS1, PIK3R1, AKT1, RAF1, MAP2K2, and MAPK3, in both yak hepatocyte cultures and murine models. These findings collectively indicate that BgIGFBP3 promotes the proliferation of yak hepatocytes and enhances murine liver development by modulating the PI3K-Akt signaling pathway. The functional relevance of BgIGFBP3 was substantiated through in vivo and in vitro experiments, thereby underscoring its potential as a regulatory factor in liver development processes.

Single-cell RNA sequencing reveals cellular and molecular landscape of fetal cystic hygroma.

BACKGROUND: The molecular mechanism of fetal cystic hygroma (CH) is still unclear, and no study has previously reported the transcriptome changes of single cells in CH. In this study, single-cell transcriptome sequencing (scRNA-seq) was used to investigate the characteristics of cell subsets in the lesion tissues of CH patients. METHODS: Lymphoid tissue collected from CH patients and control donors for scRNA-seq analysis. Differentially expressed gene enrichment in major cell subpopulations as well as cell-cell communication were analyzed. At the same time, the expression and interactions of important VEGF signaling pathway molecules were analyzed, and potential transcription factors that could bind to KDR (VEGFR2) were predicted. RESULTS: The results of scRNA-seq showed that fibroblasts accounted for the largest proportion in the lymphatic lesions of CH patients. There was a significant increase in the proportion of lymphatic endothelial cell subsets between the cases and controls. The VEGF signaling pathway is enriched in lymphatic endothelial cells and participates in the regulation of cell-cell communication between lymphatic endothelial cells and other cells. The key regulatory gene KDR in the VEGF signaling pathway is highly expressed in CH patients and interacts with other differentially expressed EDN1, TAGLN, and CLDN5 Finally, we found that STAT1 could bind to the KDR promoter region, which may play an important role in promoting KDR up-regulation. CONCLUSION: Our comprehensive delineation of the cellular composition in tumor tissues of CH patients using single-cell RNA-sequencing identified the enrichment of lymphatic endothelial cells in CH and highlighted the activation of the VEGF signaling pathway in lymphoid endothelial cells as a potential modulator. The molecular and cellular pathogenesis of fetal cystic hygroma (CH) remains largely unknown. This study examined the distribution and gene expression signature of each cell subpopulation and the possible role of VEGF signaling in lymphatic endothelial cells in regulating the progression of CH by single-cell transcriptome sequencing. The enrichment of lymphatic endothelial cells in CH and the activation of the VEGF signaling pathway in lymphatic endothelial cells provide some clues to the pathogenesis of CH from the perspective of cell subpopulations.

Duodenal-jejunal bypass improves hypothalamic oxidative stress and inflammation in diabetic rats via glucagon-like peptide 1-mediated Nrf2/HO-1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is often accompanied by impaired glucose utilization in the brain, leading to oxidative stress, neuronal cell injury and infla-mmation. Previous studies have shown that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats, the role and the metabolism of DJB in improving brain oxidative stress and inflammation condition in T2DM rats remain unclear. AIM: To investigate the role and metabolism of DJB in improving hypothalamic oxidative stress and inflammation condition in T2DM rats. METHODS: A T2DM rat model was induced via a high-glucose and high-fat diet, combined with a low-dose streptozotocin injection. T2DM rats were divided into DJB operation and Sham operation groups. DJB surgical intervention was carried out on T2DM rats. The differential expression of hypothalamic proteins was analyzed using quantitative proteomics analysis. Proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of T2DM rats were analyzed by flow cytometry, quantitative real-time PCR, Western blotting, and immunofluorescence. RESULTS: Quantitative proteomics analysis showed significant differences in proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of rats with T2DM-DJB after DJB surgery, compared to the T2DM-Sham groups of rats. Oxidative stress-related proteins (glucagon-like peptide 1 receptor, Nrf2, and HO-1) were significantly increased (P < 0.05) in the hypothalamus of rats with T2DM after DJB surgery. DJB surgery significantly reduced (P < 0.05) hypothalamic inflammation in T2DM rats by inhibiting the activation of NF-κB and decreasing the expression of interleukin (IL)-1ß and IL-6. DJB surgery significantly reduced (P < 0.05) the expression of factors related to neuronal injury (glial fibrillary acidic protein and Caspase-3) in the hypothalamus of T2DM rats and upregulated (P < 0.05) the expression of neuroprotective factors (C-fos, Ki67, Bcl-2, and BDNF), thereby reducing hypothalamic injury in T2DM rats. CONCLUSION: DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the glucagon-like peptide 1 receptor-mediated Nrf2/HO-1 signaling pathway.

Journey to inpatient hospice care: A qualitative study on the decision-making process of Chinese family caregivers of persons with terminal cancer.

OBJECTIVE: To understand family caregivers' decision-making process to place their family members with terminal cancer in inpatient hospice care, especially in the social-cultural contexts whereby the caregivers have a dominant say about the care of their seriously ill family members. METHODS: A qualitative study with a phenomenological approach was undertaken to understand the lived experience of caregivers of persons with terminal cancer in the decision-making process. Semi-structured qualitative interviews were conducted with a purposive sample of 17 caregivers in Shanghai, China. Thematic analysis was used to analyze the data. RESULTS: The caregivers underwent a winding and socioculturally mediated four-stage process. The stages are (i) trigger for alternatives: lost hope for a cure, (ii) meandering the see-saw process, (iii) the last straws: physical limitations and witnessing unbearable suffering, and (iv) the aftermath: acceptance versus lingering hope. Caregivers' attitudes towards death and their family members with advanced cancer expressed care wishes influence the state of the aftermath. CONCLUSIONS: Chinese sociocultural values and beliefs about caregiving and death provide insightful explanations for the observed process. PRACTICAL IMPLICATIONS: Training healthcare professionals in cultural competence, developing an effective hospice referral system, and delivering socioculturally acceptable death education are critical interventions to facilitate better decision-making experiences.

Prenatal diagnosis of polycystic renal diseases: diagnostic yield, novel disease-causing variants, and genotype-phenotype correlations.

BACKGROUND: Polycystic renal disease is a frequent congenital anomaly of the kidneys, but research using chromosomal microarray analysis and exome sequencing in fetuses with polycystic renal disease remains sparse, with most studies focusing on the multisystem or genitourinary system. OBJECTIVE: This study aimed to assess the detection rate of detectable genetic causes of fetal polycystic renal disease at different levels, novel disease-causing variants, and genotype-phenotype correlations. STUDY DESIGN: This study included 220 fetal polycystic renal disease cases from January 2014 to June 2022. Cases were divided into the following 3 groups: isolated multicystic dysplastic kidneys, nonisolated multicystic dysplastic kidneys, and suspected polycystic kidney disease group. We reviewed data on maternal demographics, ultrasonographic results, chromosomal microarray analysis/exome sequencing results, and pregnancy outcomes. RESULTS: In our cohort, chromosomal microarray analysis identified 19 (8.6%) fetuses carrying chromosomal abnormalities, and the most common copy number variation was 17q12 microdeletion (7/220; 3.2%). Furthermore, 94 families chose to perform trio-exome sequencing testing, and 21 fetuses (22.3%) were found to harbor pathogenic/likely pathogenic variants. There was a significant difference in the live birth rate among the 3 groups (91/130 vs 46/80 vs 1/10; P<.001). Among 138 live birth cases, 106 (78.5%) underwent postnatal ultrasound review, of which 95 (89.6%) had a consistent prenatal-postnatal ultrasound diagnosis. CONCLUSION: For both isolated and nonisolated polycystic renal disease, our data showed high detection efficiency with both testing tools. The detection of novel pathogenic variants expands the known disease spectrum of polycystic renal disease-associated genes while enriching our understanding of the genotype-phenotype correlation. Therefore, we consider it feasible to perform chromosomal microarray analysis+exome sequencing testing in fetal polycystic renal disease. Moreover, prenatal-postnatal ultrasound concordance was greater, the live birth rate was higher, and prognosis was better when known genetic disorders were excluded, indicating that genetic testing results significantly influenced pregnancy decisions.

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis.

AIM: Sacubitril/valsartan is a new cardiovascular agent characterized by its dual inhibition on the reninangiotensin system (RAS) and the neprilysin. As neprilysin also involved itself in the degradation of amyloid-ß, there is an ongoing concern about the effect of sacubitril/valsartan on cognition, especially in case of long-term administration. METHODS: The FDA Adverse Event Reporting System (FAERS) was mined between 2015Q3 and 2022Q4 to analyze the association between sacubitril/valsartan and adverse events (AEs) involving dementia. Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) with "broad" and "narrow" preferred terms (PTs) relevant to dementia was applied to systematically search demented AE reports. The Empirical Bayes Geometric Mean (EBGM) from Multi-Item Gamma Poisson Shrinker (MGPS) and proportional reporting ratio with Chi-square (PRR, χ2 ) were used to calculate the disproportionality. RESULTS: We filtered the query for indication and identified 80,316 reports with heart failure indication in FAERS during the analytical period. Among all the reports, sacubitril/valsartan was listed as primary suspected or secondary suspected drug in 29,269 cases. No significantly elevated reporting rates of narrow dementia were evident with sacubitril/valsartan. The EBGM05 for narrow dementia-related AEs associated with sacubitril/valsartan was 0.88 and the PRR (χ2 ) was 1.22 (2.40). Similarly, broad demented complications were not over-reported in the heart failure patients administrated with sacubitril/valsartan (EBGM05 1.11; PRR 1.31, χ2 109.36). CONCLUSION: The number of dementia-related cases reported to FAERS generate no safety signal attributable to sacubitril/valsartan in patients with heart failure for now. Further follow-ups are still warranted to address this question.

Case report: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay: Three cases and a literature review.

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is a serious autosomal recessive syndrome caused by biallelic mutations in cytosine-cytosine-adenosine tRNA nucleotidyltransferase 1 (TRNT1). The main clinical features of SIFD are periodic fevers, developmental delay, sideroblastic or microcytic anemia, and immunodeficiency. Herein, we report three cases of SIFD with compound heterozygous variants of TRNT1. Patients 1 and 2 were siblings; they presented with periodic fevers, arthritis, low immunoglobulin A, bilateral cataracts, anemia, and neurodevelopmental and developmental delay. Patient 3 had severed clinical features with recurrent fever and infections. She was treated with infliximab and symptomatic treatments but without therapeutic effect. She received a stem cell transplantation of umbilical cord blood but died of posttransplant infection and posttransplant graft-vs.-host disease 17 days after transplantation. Finally, a literature review revealed that TRNT1 variants differed among SIFD patients. Our cases and literature review further expand existing knowledge on the phenotype and TRNT1 variations of SIFD and suggest that the early genomic diagnosis of TRNT1 is valuable to promptly assess bone marrow transplantation and tumor necrosis factor inhibitor treatments, which might be effective for the immunodeficiency and inflammation caused by SIFD.

Artificial intelligence-based computer-aided diagnosis system supports diagnosis of lymph node metastasis in esophageal squamous cell carcinoma: A multicenter study.

Background: This study aimed to develop an artificial intelligence-based computer-aided diagnosis system (AI-CAD) emulating the diagnostic logic of radiologists for lymph node metastasis (LNM) in esophageal squamous cell carcinoma (ESCC) patients, which contributed to clinical treatment decision-making. Methods: A total of 689 ESCC patients with PET/CT images were enrolled from three hospitals and divided into a training cohort and two external validation cohorts. 452 CT images from three publicly available datasets were also included for pretraining the model. Anatomic information from CT images was first obtained automatically using a U-Net-based multi-organ segmentation model, and metabolic information from PET images was subsequently extracted using a gradient-based approach. AI-CAD was developed in the training cohort and externally validated in two validation cohorts. Results: The AI-CAD achieved an accuracy of 0.744 for predicting pathological LNM in the external cohort and a good agreement with a human expert in two external validation cohorts (kappa = 0.674 and 0.587, p < 0.001). With the aid of AI-CAD, the human expert's diagnostic performance for LNM was significantly improved (accuracy [95% confidence interval]: 0.712 [0.669-0.758] vs. 0.833 [0.797-0.865], specificity [95% confidence interval]: 0.697 [0.636-0.753] vs. 0.891 [0.851-0.928]; p < 0.001) among patients underwent lymphadenectomy in the external validation cohorts. Conclusions: The AI-CAD could aid in preoperative diagnosis of LNM in ESCC patients and thereby support clinical treatment decision-making.

Clinical impacts of genome-wide noninvasive prenatal testing for rare autosomal trisomy.

BACKGROUND: Genome-wide noninvasive prenatal testing identifies several rare autosomal trisomies in the general obstetrical population, but its use is questioned by its low positive predictive value. Furthermore, the origin of rare autosomal trisomies and the clinical effect of reporting them has not been sufficiently investigated. In addition, professional societies express their need for data assessing the clinical use of genome-wide noninvasive prenatal testing for rare autosomal trisomies for years. OBJECTIVE: This study aimed to investigate the origin of rare autosomal trisomies and the clinical effect of disclosing rare autosomal trisomies in clinical settings. STUDY DESIGN: Women who received noninvasive prenatal testing between March 2021 and March 2022 were prospectively enrolled. Clinical follow-up and cytogenetic and molecular investigations were performed. Posthoc analysis was performed to investigate the association between placental mosaicism and clinical outcomes. RESULTS: Overall, 154 rare autosomal trisomies were identified in 89,242 pregnancies (0.17%) through noninvasive prenatal testing. In the 120 cases in which cytogenetic and molecular investigations were carried out, the rare autosomal trisomies were found to originate from true fetal mosaicism (n=5), uniparental disomy (n=5), maternal mosaic trisomy (n=3), maternal malignancy (n=1), and confined placental mosaicism (n=106). Clinical follow-up showed that 40% of all rare autosomal trisomy cases had adverse perinatal outcomes. In women with false-positive noninvasive prenatal testing results originating from confined placental mosaicism, the frequency of adverse perinatal outcomes was 26%. More importantly, the placental mosaicism ratio revealed by noninvasive prenatal testing was significantly higher in women who experienced adverse perinatal outcomes than those who did not (0.688 vs 0.332; P<.001). CONCLUSION: Women with noninvasive prenatal testing results indicative of rare autosomal trisomies are at risk of adverse perinatal outcomes, and that risk can be stratified using chromosomes and the mosaicism ratio revealed by noninvasive prenatal testing. Our data are valuable for obstetrical caregivers advising a patient with a noninvasive prenatal testing result indicative of a rare autosomal trisomy and a false-positive diagnosis and for managing risks during pregnancy.

Prenatal diagnosis of Williams-Beuren syndrome by ultrasound and chromosomal microarray analysis.

BACKGROUND: There are a few literature reports of prenatal ultrasound manifestations of Williams-Beuren syndrome. We aimed to explore the prenatal diagnosis of Williams-Beuren syndrome by ultrasound and chromosomal microarray analysis and describe the prenatal ultrasound performance of this syndrome. METHODS: In this retrospective study, we reported eight cases of Williams-Beuren syndrome diagnosed at our prenatal diagnostic center from 2016 to 2021. We systematically reviewed clinical data from these cases, including indications for invasive testing, sonographic findings, QF-PCR results, chromosomal microarray analysis results, and pregnancy outcomes. RESULTS: In this study, the common ultrasound features were ventricular septal defect (37.5%), intrauterine growth retardation (25%), and aortic coarctation (25%). Moreover, all patients were found to have a common deletion in the Williams-Beuren syndrome chromosome region at the 7q11.23 locus, which contained the elastin gene. Deletion sizes ranged from 1.42 to 2.07 Mb. Seven parents asked for termination of pregnancy, and one patient was lost to follow-up. CONCLUSIONS: This study is the most extensive prenatal study using chromosomal microarray analysis technology for detailed molecular analysis of Williams-Beuren syndrome cases. We reported three cases combined with first-reported ultrasound manifestations. Case 1 was concomitant with multicystic dysplastic kidney and duodenal atresia combined with case 3. Notably, case 4 was combined with multiple cardiovascular malformations: Tetralogy of Fallot, right aortic arch, and supravalvar aortic stenosis. These manifestations expand the intrauterine ultrasound phenotype of Williams-Beuren syndrome in previous literature reports.

Notch1/Hes1­PTEN/AKT/IL­17A feedback loop regulates Th17 cell differentiation in mouse psoriasis­like skin inflammation.

IL­17A, the effector cytokine of T helper (Th) 17 cells, plays a crucial role in the pathogenesis of psoriasis. The Notch1 and PI3K/AKT signaling pathways are implicated in Th17 cell differentiation and IL­17A production. The present study aimed to evaluate the regulatory effect of the Notch1/hairy and enhancer of split 1 (Hes1)­PTEN/AKT/IL­17A feedback loop on Th17 cell differentiation via the PI3K/AKT inhibitor LY294002 in a mouse model of psoriasis. Mice were randomly divided into 3 groups: a control group, a model group [5% imiquimod (IMQ)­induced group] and an intervention group (5% IMQ­induced plus LY294002­treated group). Skin structural characteristics were recorded and evaluated by hematoxylin and eosin staining. The weights of the spleens and inguinal lymph nodes were measured. Th17 cell percentage, as well as the mRNA and protein expression levels of Notch1, Notch1 intracellular domain (NICD1), Hes1, PTEN, AKT, phosphorylated (p)­AKT, mTOR complex 1 (mTORC1), p­mTORC1, S6 kinase (S6K)1, S6K2 and IL­17A were detected in skin samples of the three experimental groups. Additionally, splenic mononuclear cells from model mice were treated by 10 and 50 µM LY294002 to further evaluate its regulatory effect on Notch1/Hes1­PTEN/AKT/IL­17A feedback loop. Increased Th17 cell percentage, increased expression of Notch1, NICD1, Hes1, AKT, p­AKT, mTORC1, p­mTORC1, S6K1, S6K2 and IL­17A, and decreased PTEN levels were observed in model mice alongside marked psoriasis­like skin inflammation, splenomegaly and lymphadenopathy. LY294002 treatment significantly alleviated the severity of psoriasis­like skin inflammation in the intervention mice, attenuated the degree of epidermal hyperplasia and dermal inflammatory cell infiltration, and mitigated splenomegaly and lymphadenopathy. In addition, LY294002 treatment reversed the increased Th17 cell percentage, as well as the increased expression of Notch1, NICD1, Hes1, AKT, p­AKT, mTORC1, p­mTORC1, S6K1, S6K2 and IL­17A, and the decreased expression of PTEN. In vitro study from 5% IMQ­induced mouse splenic mononuclear cells presented that high dose of LY294002 exerted more obviously regulatory effect on Notch1/Hes1­PTEN/AKT/IL­17A feedback loop. The current findings suggested that the Notch1/Hes1­PTEN/AKT/IL­17A feedback loop regulates Th17 cell differentiation within the disease environment of psoriasis. Blocking the Notch1/Hes1­PTEN/AKT/IL­17A feedback loop may thus be a potential therapeutic method for management of psoriatic inflammation.

Identification of differential microRNAs and messenger RNAs resulting from ASXL transcriptional regulator 3 knockdown during during heart development.

Congenital heart disease (CHD) is the most common birth defect. Although ASXL transcriptional regulator 3 (ASXL3) has been reported to cause hereditary CHD, ASXL3-mediated mechanisms in heart development remain unclear. In this study, we used dimethyl sulfoxide (DMSO) to induce differentiation in P19 cells, observed cell morphology using light microscopy after ASXL3 knockdown, and determined the levels of associated myocardial cell markers using reverse transcription-quantitative polymerase chain reaction and western blotting. Subsequently, we used microRNA sequencing, messenger RNA (mRNA) sequencing, and bioinformatics to initially identify the possible mechanisms through which ASXL3-related microRNAs and mRNAs affect heart development. The results indicated that DMSO induced P19 cell differentiation, which could be inhibited by ASXL3 knockdown. We screened 1214 and 1652 differentially expressed microRNAs and mRNAs, respectively, through ASXL3 knockdown and sequencing; these differentially expressed miRNAs were largely enriched in PI3K-Akt, mitogen-activated protein kinase, and Rap1 signaling pathways. Additionally, 11 miRNAs associated with heart development were selected through a literature review. Our analysis indicated the involvement of mmu-miR-323-3p in P19 cell differentiation through the PI3K-Akt pathway. In conclusion, ASXL3 may be involved in the regulation of heart development. This comprehensive study of differentially expressed microRNAs and mRNAs through ASXL3 knockdown in P19 cells provides new insights that may aid the prevention and treatment of CHD.

Validation of the Eighth American Joint Committee on Cancer Anatomic and Prognostic Staging System for Breast Cancer.

BACKGROUND: The eighth edition of new staging systems for breast cancer incorporated four biological factors and the anatomic staging system. Validating analysis on Chinese patients has been limited. Our study performed analysis comparing the prognostic value of the staging system based on Chinese data. METHODS AND MATERIALS: All patients were classified according to the eighth edition and compared between anatomic and prognostic staging systems. The Kaplan-Meier test was used to calculate the overall survival (OS) and disease-free survival (DFS). We performed Harrell concordance index (C-index) analyses to quantify a models' predictive performance. Akaike information criterion (AIC) via Cox regression analysis was used to conduct bootstrap-based goodness-of-fit comparisons of the competing staging systems. RESULTS: A total of 1556 patients were enrolled in the cohort. The median follow-up time was 76 mo (range, 4-146 mo), the median age was 48 y old (range, 21-87 y). The ratio of movement between anatomic stage (AS) and prognostic stage (PS) was 50.9%. Of these, 691 (44.5%) AS patients were down staged and 100 (6.4%) patients were upstaged when reclassified based on PS. Significant differences between two stages were achieved for stage IIIC in 5-y OS rates and for IIIB in 5-y DFS rates (63.5% versus 50.0% and 58.0% versus44.0%). The value of the C-index for PS and AS were 0.711 and 0.687 (P = 0.04). The AIC reaches a value of 3452.9 for the PS and a value of 3476.4 for the AS. CONCLUSIONS: The PS might provide better accuracy than the AS in predicting the prognosis of Chinese female breast cancer patients. It also provides a strong basis for the utility of clinical biomarkers to evaluate the prognosis of patients.

Cathepsin C inhibitors as anti-inflammatory drug discovery: Challenges and opportunities.

Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.

Molecular characterization, expression and functional analysis of yak IFITM3 gene.

IFITM3 is interferon-induced transmembrane 3, which plays an extremely key role in anti-proliferation, anti-virus and anti-tumor diseases. In this study, the yak (Bos grunniens) IFITM3 (BgIFITM3) gene contained a 5'-untranslated region (UTR) (25 bp), a coding region (441 bp), and a 3'-UTR (115 bp). The expression of BgIFITM3 gene in liver was significantly higher than that in heart, spleen, lung and kidney (P < 0.01). BgIFITM3 protein was localized on the yak hepatocyte plasma membrane, and its expression was significantly different between 1 day and 15 months of age (P < 0.05). Moreover, the prokaryotic expression vector of BgIFITM3 protein was constructed and expressed successfully, with a molecular weight of 19.5 kDa. The activities of yak hepatocyte were significantly inhibited after treating with BgIFITM3 protein (10 and 20 µg/mL) (P < 0.01). The expression levels of ERBB-2, IRS-1, PI3KR-1, AKT-1 and MAPK-3 were significantly lower after treating with 20 µg/mL BgIFITM3 protein (P < 0.05). Besides, the activities of HepG2 cells were significantly inhibited after treating with BgIFITM3 protein (1, 10 and 20 µg/mL) (P < 0.05). While, the cloning ability and migration ability of HepG2 cells were significantly inhibited after treating with 10 µg/mL BgIFITM3 protein (P < 0.05). Finally, the mitochondria of HepG2 cells was concentrated, cristae widened, and the double film density of mitochondria was increased after treating with 10 µg/mL BgIFITM3 protein. After 10 µg/mL BgIFITM3 protein treating, the expression levels of VDAC-2, VDAC-3 and p53 genes were significantly increased, but the expression level of GPX-4 gene was significantly decreased (P < 0.01). Taken together, the BgIFITM3 protein could inhibit the proliferations of yak hepatocyte and HepG2 cells by regulating the PI3K/Akt pathway or ferroptosis-related genes, respectively. These results benefit for further study of the function of BgIFITM3 protein.

Microarray analysis in fetuses with duodenal obstruction: It is not just trisomy 21.

OBJECTIVE: To explore the copy number variants (CNVs) in case of fetal duodenal obstruction (DO) and assess the associated prenatal findings and postnatal outcomes. MATERIALS AND METHODS: This retrospective study reviewed 51 fetuses with DO and the findings of chromosomal microarray analysis (CMA) used as a first-tier test in our institution between January 2014 and May 2019. RESULTS: The frequency of pathogenic aberrations in fetuses with DO was 15.7% (8/51), including 9.8% (5/51) pathogenic CNVs. Three fetuses with isolated DO each had a deletion on chromosome 13q, one fetus had duplication at 1q43q44, and one had microduplication at 17q12. No significant differences in pathogenic CNVs were observed between isolated DO and DO plus additional anomalies (4/42, 9.5% vs 1/9, 11.1%, P = .89). Of the 51 fetuses with DO, 11 pregnancies were terminated, and eight fetuses had chromosomal abnormalities; one pregnancy ended with intrauterine death, and there were 39 live births. Neonatal outcomes were available for 31 fetuses, and no neonatal deaths occurred after surgery. CONCLUSIONS: Our cohort study demonstrated the value of CMA in fetuses with DO, suggesting that CNVs may underly genetic etiologies that should be considered in the diagnostic evaluation of DO. We think CMA should be recommended in case of DO.

Molecular cloning, characterization of JunB in Schizothorax prenanti and its roles in responding to Aeromonas hydrophila infection.

The transcription factor JunB can induce physiological or pathological responses to various stimuli, including immune stimulants and bacteria, and plays an important role in the immune response process. In this study, we identified a JunB family member in Schizothorax prenanti (S. prenanti), which was designated SpJunB. The complete coding sequence (CDS) of SpJunB was 930 bp in length, which was submitted to GenBank (ID: MN215886). SpJunB encodes a putative protein of 309 amino acids, which is highly homologous to JunB of common carp. The SpJunB protein contained a conserved JunB domain, and its 3D structure was also highly similar to (77.61%) the human SpJunB protein. SpJunB was found to be extensively expressed in various tissues, with the highest expression in the spleen. The expression of SpJunB was significantly upregulated after Aeromonas hydrophila (A. hydrophila) challenge. Prokaryotic expression indicated that a 51 kDa recombinant protein was obtained after induction with 1.5 mmol/L isopropyl-beta-D-thiogalactopyranoside (IPTG) for 6 h at 37 °C. The expression levels of IL-1ß, IL-6 and IL-8 were significantly upregulated (p < 0.01) after treatment of S. prenanti with the SpJunB protein. The activities of SOD, AKP and LZM were also significantly increased (p < 0.01) after the treatment of S. prenanti with the SpJunB protein. Simultaneously, the SpJunB protein reduced the infection rate of A. hydrophila in S. prenanti. In conclusion, SpJunB may improve the immune functions of S. prenanti. It will be beneficial to further study the immune mechanism of JunB in fish.

Whole-exome sequencing in the evaluation of fetal congenital anomalies of the kidney and urinary tract detected by ultrasonography.

OBJECTIVE: We aimed to investigate the value of whole-exome sequencing (WES) in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT) with or without other structural anomalies but with normal findings upon karyotyping and chromosome microarray analysis (CMA). METHODS: Cases with CAKUT with or without other structural anomalies were screened for eligibility. Fetuses with abnormal karyotyping or CMA results were excluded. We performed WES on DNA samples from eligible fetus-parental trios and identified diagnostic genetic variants based on ultrasonographic features. RESULTS: A total of 163 eligible fetus-parental trios were successfully analyzed by WES. We found 26 likely pathogenic or pathogenic variants in 18 genes from 20 fetuses, with a total proportion of diagnostic genetic variants of 12.3% (20/163). Genetic variants were significantly more frequently detected in fetuses with multisystem anomalies (27.0%, 10/37), enlarged kidney/echogenic kidney (20%, 4/20), and multicystic dysplastic kidney (11.1%, 4/36). Pregnancy outcome data showed that 88 (94.6%, 88/93) of the surviving cases with negative WES results had a good prognosis in early childhood. CONCLUSIONS: Our study is the largest to use WES prenatally for CAKUT and shows that WES can be used diagnostically to define the molecular defects that underlie unexplained CAKUT.