T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Given the increasing concern regarding antibacterial resistance, the antimicrobial properties of naphthoquinones have recently attracted significant attention. While 1,4-naphthoquinone and its derivatives have been extensively studied, the antibacterial properties of 5,8-dihydroxy-1,4-naphthoquinone derivatives remain relatively unexplored. This study presents a comprehensive in vitro and in vivo analysis of the antibacterial activity of 35 naturally sourced and chemically synthesized derivatives of 5,8-dihydroxy-1,4-naphthoquinone. Kirby-Bauer antibiotic testing identified three compounds with activity against methicillin-resistant Staphylococcus aureus (MRSA), with one compound (PNP-02) demonstrating activity comparable to vancomycin in minimum inhibitory concentration, minimum bactericidal concentration (MBC), and time-kill assays. Microscopic and biochemical analyses revealed that PNP-02 adversely affects the cell wall and cell membrane of MRSA. Mechanistic investigations, including proteomic sequencing analyses, Western blotting, and RT-qPCR assays, indicated that PNP-02 compromises cell membrane integrity by inhibiting arginine biosynthesis and pyrimidine metabolism pathways, thereby increasing membrane permeability and inducing bacterial death. In an in vivo mouse model of skin wound healing, PNP-02 exhibited antibacterial efficacy similar to vancomycin. The compound demonstrated low toxicity to cultured human cells and in hemolysis assays and remained stable during serum incubation. These findings suggest that PNP-02 possesses promising bioactivity against MRSA and represents a potential novel antibacterial agent.
Methicillin-Resistant Staphylococcus aureus/genetics* ; Anti-Bacterial Agents/chemistry* ; Naphthoquinones/administration & dosage* ; Animals ; Microbial Sensitivity Tests ; Mice ; Humans ; Staphylococcal Infections/microbiology* ; Molecular Structure

Small for gestational age (SGA) infants are more likely to experience neurocognitive impairments compared to appropriate for gestational age (AGA) infants. This paper reviews recent research on the neurocognitive development of SGA children. SGA can lead to a "brain-sparing effect" due to growth restriction, which may affect cerebral blood flow and brain structure. However, this does not guarantee normal brain development. Restrictive blood flow can result in changes in brain structure, such as reduced total white matter and gray matter volume in various brain regions, including the cerebral cortex, hippocampus and cerebellum, ultimately leading to decreased head circumference. SGA children also exhibit lower scores in all neurocognitive domains, including intelligence, attention, memory, and executive function. This may result in poor academic performance and an increased risk of social, behavioral, and neurological problems, such as cerebral palsy, epilepsy, visual and hearing impairments, as well as comorbidities like attention deficit hyperactivity disorder(ADHD), autism spectrum disorder(ASD), anxiety, depression, and schizophrenia. Several risk factors for SGA-related neurocognitive impairments have been identified, including gestational hypertension, abnormal gestational weight, smoking, and catch-up growth. Studies have shown that the best interventions to improve cognitive dysplasia include nutrient supplementation, continued breastfeeding, high-quality education, and appropriate early intervention (responsive parenting) are effective in improving cognitive outcomes for SGA children.

Objective:To construct a traditional Chinese medicine syndrome differentiation model for tinnitus using automatic machine learning technology, and to explore the key factors that affect the results of tinnitus syndrome differentiation.Methods:The clinical characteristics of 594 patients with subjective tinnitus in seven medical units in Shanghai from January 2021 to January 2022 were retrospectively analyzed. The Auto-sklearn automatic machine learning method was used to compare 15 algorithms, and the model with the best classification effect was selected to analyze the key factors affecting tinnitus.Results:The results showed that the optimal algorithm for classification results was the random forest, its accuracy, precision, sensitivity, specificity, F1-score, AUC and kappa coefficient were 87.37%, 88.34%, 89.06%, 96.63%, 88.38%, 97.50%, and 83.37%, respectively. It is concluded that the key factors affecting the classification of the pattern of kidney yin deficiency and fire effulgence, the pattern of liver fire disturbing upward, the pattern of stagnation and binding of phlegm and fire, the pattern of spleen and stomach deficiency, the pattern of wind and heat attacking the external are smooth pulse, string pulse, smooth pulse, weak tongue, and floating pulse respectively.Conclusions:Random forest can provide a good classification prediction function for structured clinical data, suggesting that machine learning technology has clinical application value in assisting the diagnosis of subjective tinnitus.

This study was aimed to investigate the expression of miR-651-3p in breast cancer and its role in regulating the expression of immunosuppressive factors IL-10 and TGFβ1 as well as the apoptosis level of breast cancer cells.qRT-PCR was used to detect the expression level of miR-651-3p in MCF-7 cells.miR-651-3p-over-expressng/-silencing plasmids and SP2-silencing plasmid were used to transfect MCF-7 cells.The expression levels of SP2,IL-10 and TGFβ1 were detected by Western blot assays.The apoptosis level of MCF-7 cells was detected by flow cytometry.The binding between miR-651-3p and SP2 was verified by dual luciferase gene report,and the binding of SP2 to IL-10 and TGFβ1 promoter region was verified by ChIP assay.Our results showed that miR-651-3p was down-regulated in breast cancer cells(P<0.05).The over-expression of miR-651-3p and the knockdown of SP2 significantly down-regulated the expression levels of IL-10 and TGFβ1 and promoted the apoptosis of breast cancer cells,while silenced miR-651-3p had the opposite effect.miR-651-3p binds to the SP2-3'-UTR end and down-regulates its expression.Based on the silencing of miR-651-3p,the silencing of SP2 can significantly reduce the influence of silenced miR-651-3p on the expression of IL-10 and TGFβ1 and apoptosis level in breast cancer cells.SP2 promotes the expression levels of IL-10 and TGFβ1 by binding to their promoters,respectively.Taken together,down-regulated miR-651-3p in breast cancer inhibited the expression of SP2 by binding to its 3'-UTR region,reduced the up-regulation effect of SP2 on the expression of IL-10 and TGFβ1,thus inhibiting the expression of immunosuppressive factors IL-10 and TGFβ1 and promoting apoptosis in breast cancer cells.

Objective Toinvestigatethealteredspontaneouscerebralactivitypatternsinpatientswithtype2diabeticretinopathy (DR).Methods 21patientswithDRand17healthycontrolsubjectswereprospectivelystudied.Allindividualsunderwentlaboratoryand neuropsychologicaltests.Thedifferencesintheamplitudeoflow-frequencyfluctuation (ALFF)valuesbetweentwogroupswere comparedandanalyzedstatisticallyusingDPRASFV2.3andREST1.6software.TherelationshipsamongALFFvaluesofbrainregionswith statisticalsignificance,HbA1c,durationofdiseaseandneuropsychologicalscoreswereanalyzedusinga multiple-factoranalysis.Results Comparedtothecontrols,theDRgroupshowedsignificantlyincreasedALFFvaluesinthebilateraloccipitalgyrus,rightlingualgyrus,and precuneus(P<0.01),anddecreasedvaluesintherightposterior/anteriorcerebellarlobe,fusiform,superiortemporal,inferiorparietal,and angulargyrus(P<0.05).Furthermore,theMoCAscoreswerenegativelycorrelatedwithdecreasedALFFvaluesintherightoccipitallobe oftheDRgroup,whileincreasedALFFvaluesintherightprecuneusandlingualgyruswerefoundtobepositivelycorrelatedwithglycosylated hemoglobin(HbA1c)levels.Conclusion PatientswithDRshowspontaneouscerebralabnormalactivityin manycerebralregions.ALFF valuechangesinthevisualcortexareassociatedwithcognitiveimpairments.Itisofimportantvaluetoevaluatebraindysfunctionin patientswithDRusingALFF method.

Objective To investigate germline mutation of breast cancer susceptibility genes BRCA1/2,TP53 and PTEN in Chinese breast cancer patients. Methods All of128 female breast cancer patients in Peking University People′s Hospital from January 2016 to August 2018 were selected as objects. Among them,44 cases were sporadic breast cancer and 84 werebreast cancer patients with genetic high risks. Germline mutations of BRCA1,BRCA2,TP53 and PTENwere detected by NGS.χ2 test was used to analyze the difference of pathogenic mutation rates between sporadic breast cancer group and breast cancer with high genetic risks.Groups were divided according to the clinical features of the patients(family history, triple-negative breast cancer,age and bilateral breast cancer).Among them,there were 42 cases with family history of breast cancer,34 cases of triple-negative breast cancer,33 cases of early-onset breast cancer and 7 cases of bilateral breast cancer. Fisher′s exact probability test compared the relationship between pathogenic mutations of BRCA1/2 gene and clinical characteristics of breast cancer patients with hereditary risk factors. Results In 128 cases of breast cancer,30 germline mutations of BRCA1/2 were detected, including 13 pathogenic mutations and 3 newly discovered mutations(BRCA1:c. 4760C>G,BRCA2:c. 44134414del and BRCA2:c. 64826485del). The new mutations may be unique mutations of Chinese population. There were 3 cases of TP53 mutations,including 1 pathogenic mutation. All of the 3 mutations were found in early-onset breast cancer. Germline mutation of T53 has important detection significance for early-onset hereditary breast cancer. There were 5 cases of PTEN mutations,including 3 pathogenic mutations. Among 84 breast cancer patients with genetic high risks,the carry mutation rate was 40.5％(34/84)and the pathogenic mutation rate was 15.4(13/84). Among 44 sporadic cases,the carry mutation rate was 9％(4/44). The pathogenic mutation rate was 6.8％(3/44). Breast cancer susceptibility genes were carried at a higher rate in breast cancer patients with genetic high risks(P<0.001). BRCA1/2 mutations did not show statistical differences among groups of breast cancer patients with hereditary high risk factors . Conclusion Germline mutation detection of breast cancer susceptibility genes by next-generation sequencing is of great significance in breast cancer risk prediction and prognosis evaluation.

Objective: To delineate the clinical and genetic features of two pedigrees affected with aromatic L-amino acid decarboxylase (AADC) deficiency. Methods: The clinical features, family history and results of genetic testing of 2 patients with AADC deficiency were retrospectively analyzed. Results: Both patients featured hypotension, developmental delay and oculogyric crisis during infancy.Genetic testing confirmed that they have respectively carried c. 714+ 4 (IVS6) A>T/c.175(exon2)G>A compound heterozygous variants and c. 714+ 4(IVS6)A>T homozygous variant. Conclusion The clinical manifestation of children with AADC deficiency may include hypotonia, developmental delay and paroxysmal oculogyric crisis. The combination of 3-O-methyldopa testing and variant analysis is not only very useful for early diagnosis, but also important for the evaluation of treatment effect and prognosis of the disease. Discovery of the novel variants has enriched the variant spectrum of AADC deficiency.

Objective Articular cartilage injury is one of the most common orthopedic diseases with high morbidity and morbidity,especially in the elderly. Articular cartilage injury causes degenerative changes of articular cartilage, such as osteoarthritis, which can lead to disability, pain during joint movement and deformation of bone and joint. The prevalence of osteoarthritis accounts for 10% ～12% of the total population in the world. It is a common disease. The prevalence of osteoarthritis has increased to 49. 7% for the elderly aged over 65 years old ( Statistics of the World Health Organization ( who) in 2010 show that with the development of social aging and obesity and other adverse factors,these figures will continue to rise. It is known that osteoarthritis is related to aging,trauma,genetic susceptibility,obesity and inflammation,but the specific cause of osteoarthritis has not been fully identified, which leads to many obstacles in clinical treatment of osteoarthritis. At present,most of the clinical and research work in this field is focused on the restoration of cartilage trauma. In this review, we summarize and discuss the methods of cartilage defect repair,as well as the hot spots and directions of future research work.

Objective To investigate the altered spontaneous cerebral activity in patients with type 2 diabetic retinopathy (T2DR). Methods Twenty-one patients with T2DR and sixteen healthy control subject underwent rs-fMRI scans,and the data were analyzed statistically using regional homogeneity(ReHo)method to observe the change of ReHo value.Results Compared to the control group,the T2DR group showed significantly increased ReHo value in the right occipital gyrus,occipital gyrus,inferior occipital gyrus and lingual gyrus regions (t=5.30,P＜0.05,voxel＞30,AlphaSim corrected),and significantly decreased ReHo value in the left posterior cingulate,margin lobe,right inferior parietal lobule,superior temporal gyrus and hippocampus (t=-4.01,-4.86,P＜0.05,voxel＞30, AlphaSim corrected).Conclusion The patients with T2DR showed significantly increased ReHo values in the brain visual cortex and visual pathway that were associated with the injury of brain function regions.It is of important value to evaluate brain dysfunction in patients with T2DR using ReHo method of rs-fMRI.