OBJECTIVE: This study aimed to determine the expression levels and prognostic significance of MYCN in bone marrow of adult patients with newly diagnosed acute myeloid leukemia (AML). METHODS: A total of 62 newly diagnosed patients with non-M3 AML were enrolled as the study group, and 20 healthy donors as the control group. Real-time quantitative reverse transcription-polymerase chain reaction (PCR) was performed to detect the expression level of MYCN, and the relationship between MYCN expression and prognosis of AML patients was analyzed. RESULTS: MYCN was up-regulated in newly diagnosed AML patients compared with normal controls (P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed that MYCN could serve as a diagnostic biomarker for AML. Kaplan-Meier survival analysis showed that the patients with high MYCN expression had a shorter overall survival (OS) time than the patients with low MYCN expression (P =0.016). The expression level of MYCN was lower during the complete ressimion (CR) phase of AML compared to the initial diagnosis, but it returned to the initial diagnostic level or even higher during relapse phase. Multivariate Cox regression analysis showed that high expression of MYCN was an independent risk factor for OS of AML patients (P =0.021). CONCLUSION MYCN is highly expressed and associated with poor prognosis in de novo AML, which might be serve as a novel diagnostic and prognostic biomarker for adult AML.
Humans ; Leukemia, Myeloid, Acute/metabolism* ; Prognosis ; N-Myc Proto-Oncogene Protein ; Adult ; Female ; Male ; Middle Aged

Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective:To explore the risk factors affecting the survival and efficacy of patients with acute myeloid leukemia with myelodysplasia-related changes(AML-MRC)transformed from myelodysplastic syndrome(MDS).Methods:The clinical data of 60 patients with AML-MRC transformed from MDS who hospitalized in The Third Affiliated Hospital of Soochow University from January 2010 to December 2021 were retrospectively analyzed.The demographic data and laboratory parameters,cytogenetic karyotypes,target genes of AML detected by next generation sequence,risk stratification,treatment regimen,therapeutic efficacy and survival outcome were documented.Rank sum test and Chi-square test or Fisher exact test were used to compare the survival and efficacy.The effects of clinical parameters,risk stratification and treatment regimens on the survival and efficacy of the AML-MRC patients were analyzed by univariate and multivariate analysis.Results:The median overall survival(OS)of the AML-MRC patients was 4.5 months,the 1-year OS rate was 28.3％,and the complete remission(CR)rate after treatment was 33.3％.The univariate analysis showed that age≥60 years,leukocytosis,severe thrombocytopenia,poor-risk group and only accepted hypomethylating agents(HMAs)or supportive therapy were the risk factors affecting OS.COX multivariate analysis showed that thrombocytopenia(HR=4.46),HMAs therapy(compared to transplantation,HR=10.47),supportive therapy(compared to transplantation,HR=25.80)and poor-risk group(compared to medium-risk group,HR=13.86)were independent hazard factors for median OS of patients with AML-MRC.The univariate analysis showed that the risk factors affecting 1-year OS in patients with AML-MRC were age ≥ 60 years,thrombocytopenia,time of transformation from MDS to AML(TTA)≥3 months,fibrinogen-albumin ratio index(FARI)≥ 0.07,CONUT score≥5,poor-risk group and supportive therapy.Binary logistic regression analysis showed that the independent risk factors for 1-year OS in AML-MRC patients were age ≥ 60 years(HR=11.23),thrombocytopenia(HR=8.71),FARI ≥ 0.07(HR=5.19)and poor-risk group(HR=14.00).The risk factors affecting CR of AML-MRC patients in univariate analysis were age ≥ 60 years,thrombocytopenia,FARI ≥ 0.1,CONUT score ≥ 5,poor-risk group and supportive therapy,while binary logistic regression analysis showed that age ≥ 60 years(HR=7.35),CONUT score ≥ 5(HR=9.60),thrombocytopenia(HR=12.05)and poor-risk group(HR=32.5)were independent risk factors affecting CR of the patients.Conclusion:The OS of AML-MRC patients is poor,old age(≥ 60 years old),supportive therapy,HMA therapy,poor-risk,thrombocytopenia,FARI ≥ 0.07 and CONUT score ≥ 5 may be associated with poor prognosis.

Objective:To investigate the prognostic significance of DTA(DNMT3A,TET2,ASXL1)gene mutations in patients with non-M3 acute myeloid leukemia(AML).Methods:The clinical data of 180 newly diagnosed AML patients hospitalized in the First People's Hospital of Changzhou from January 2018 to April 2022 were retrospectively analyzed.Next-generation sequencing technology was used to detect 150 gene mutations in the patients,and log-rank tests and Cox regression models were used to analyze the prognostic factors.Results:DTA gene mutations were detected in 83(46.1％)of 180 AML patients.Compared to patients without DTA mutations,patients with DTA mutations were significantly older(P＜0.001).The median overall survival(OS)time and disease-free survival(DFS)time in the DTA mutation group were significantly shorter than those in the group without DTA mutation(both P＜0.05).Multivariate analysis showed that age ≥ 60 years(P＜0.001),with DTA mutation(P=0.018),and intermediate-risk(relative to favorable-risk)(P=0.005)were independent risk factors for OS in AML patients.Conclusion:AML patients with DTA mutations are relatively older,with shorter median OS time and DFS time,and poor prognosis.

Objective:To investigate which indicator is more advantageous when using arterial oxygen saturation(SaO2)and fingertip pulse oxygen saturation(SpO2)for blood oxygen detection in patients with hyperleukocytic acute leukemia(HAL).Methods:In this prospective research,the difference between SaO2 and SpO2 of 18 HAL patients(observation group)and 14 patients(control group),as well as the relationship between the difference and white blood cell(WBC)counts were analyzed.Results:SaO2 was lower than SpO2 in the observation group(P＜0.05),and SpO2-SaO2 difference was positively correlated with WBC counts(r=0.47).However,there was no statistical difference between SaO2 and SpO2 in the control group.SaO2 and PO2 showed a downward trend with the prolongation of detection time after arterial blood was collected in the observation group,but there was no statistical difference.There was no downward trend of SaO2 and PO2 in the control group.Conclusion:HAL patients have a phenomenon where SaO2 is lower than SpO2,that is pseudohypoxemia,and this phenomenon may be caused by excessive consumption of oxygen by the leukemia cells in vitro.SpO2 can be monitored bedside in real time and is non-invasive,it is a better way to detect the blood oxygen status of HAL patients.

Objective:To explore the association between triglyceride-glucose (TyG) index and carotid artery plaque in patients with type 2 diabetic kidney disease (DKD).Methods:Clinical data of 620 DKD patients admitted in the Department of Endocrinology, the Affiliated Huai′an First People′s Hospital of Nanjing Medical University from August 2018 to August 2022 were retrospectively analyzed, including 366 cases with carotid artery plaque and 254 cases without carotid plaque. According to TyG index quartile patients were divided into Q 1,Q 2, Q 3 and Q 4 groups with TyG index<8.94,≥8.94 and<9.44,≥9.44 and<9.96, and≥9.96, respectively. The prevalence of carotid plaque in DKD patients with different TyG index levels was analyzed. The relationship between TyG index and carotid plaque occurrence in DKD patients were analyzed with Logistic regression analysis and restricted cubic lines (RCS). Results:The age, course of disease, smoking rate, SBP, HbA1c, TG, BUN, eGFR and TyG indexes in carotid plaque group were significantly higher than those in non-carotid plaque group (all P<0.05). Binary logistic regression analysis showed that age, disease course, smoking rate, SBP, HbA1c, TG, BUN, low eGFR and TyG index were independent influencing factors for carotid plaque ( OR=1.05, 1.05, 1.88, 1.01, 1.09, 1.11, 1.09, 0.99 and 1.28, all P<0.05). The risk of carotid plaque in DKD patients in Q 3 and Q 4 groups was 2.20 and 2.50 times higher than that in Q 1 group. After adjusting for age, sex, course of disease, smoking, BMI, blood pressure (SBP and DBP), blood lipids (TC, HDL and LDL) and renal function, the risk of carotid plaque in DKD patients in Q 3 and Q 4 groups was higher than that in Q 1 group ( OR=1.95 and 2.24). RCS analysis showed that the correlation between TyG index and the risk of carotid plaque in DKD patients was linear(χ 2=0.40, P=0.527), and DKD patients with TyG index>9.95 had a higher risk of carotid plaque. Conclusions:TyG index is significantly elevated in DKD patients with carotid plaque, and TyG index is an independent risk factor for the occurrence of carotid plaques in DKD patients.

OBJECTIVE: To observe the protective effect and mechanism of hydroxyl safflower yellow A (HSYA) from myocardial ischemia-reperfusion injury on human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were treated with oxygen-glucose deprivation reperfusion (OGD/R) to simulate the ischemia reperfusion model, and cell counting kit-8 was used to detect the protective effect of different concentrations (1.25-160 µ mol/L) of HSYA on HUVECs after OGD/R. HSYA 80 µ mol/L was used for follow-up experiments. The contents of inflammatory cytokines interleukin (IL)-18, IL-1 β, monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor α (TNF-α) and IL-6 before and after administration were measured by enzyme-linked immunosorbent assay. The protein expressions of toll-like receptor, NOD-like receptor containing pyrin domain 3 (NLRP3), gasdermin D (GSDMD) and GSDMD-N-terminal domain (GSDMD-N) before and after administration were detected by Western blot. NLRP3 inflammasome inhibitor cytokine release inhibitory drug 3 sodium salt (CRID3 sodium salt, also known as MCC950) and agonist were added, and the changes of NLRP3, cysteine-aspartic acid protease 1 (Caspase-1), GSDMD and GSDMD-N protein expressions were detected by Western blot. RESULTS: HSYA inhibited OGD/R-induced inflammation and significantly decreased the contents of inflammatory cytokines IL-18, IL-1 β, MCP-1, TNF-α and IL-6 (P<0.01 or P<0.05). At the same time, by inhibiting NLRP3/Caspase-1/GSDMD pathway, HSYA can reduce the occurrence of pyroptosis after OGD/R and reduce the expression of NLRP3, Caspase-1, GSDMD and GSDMD-N proteins (P<0.01). CONCLUSIONS The protective effect of HSYA on HUVECs after OGD/R is related to down-regulating the expression of NLRP3 inflammasome and inhibiting pyroptosis.
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Human Umbilical Vein Endothelial Cells/metabolism* ; Humans ; Chalcone/analogs & derivatives* ; Quinones/pharmacology* ; Pyroptosis/drug effects* ; Caspase 1/metabolism* ; Glucose ; Phosphate-Binding Proteins/metabolism* ; Signal Transduction/drug effects* ; Intracellular Signaling Peptides and Proteins/metabolism* ; Oxygen/metabolism* ; Cytokines/metabolism* ; Gasdermins

Objective To study the effect of dexmedetomidine (DEX), an α2- adrenoceptor agonist, on the pain-related anxiety-like and depression-like behaviour induced by complete Freund' s adjuvant (CFA) injection and its possible regulatory mechanism. Methods Thirty-six ICR female mice were randomly divided into normal saline (NS) group, CFA group and DEX + CFA group, n = 12 for each group. Chronic inflammatory pain model was established by subcutaneous injection of 10 μl CFA into the right hind limb of mice. DEX + CFA group mice were injected intraperitoneally with 0.025 mg/kg DEX 30 minutes before nociceptive behavior test, and once a day for 7 days. Von-frey fiber was used to evaluate the threshold of mechanical pain in mice, n = 12 for each group. The anxiety-like behavior of mice were detected by open field test, n = 12 for each group. Sucrose preference, tail suspension test and forced swimming test were used to detected the depression-like behavior of mice, n = 12 for each group. The expression of adrenergic receptor β2 (ADRB2), Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), and glutamate receptors 1 (GluR1) and GluR2 were detected by Western blotting, n = 8 for each group. Immunohistochemical staining was used to detect the expression of recombinant doublecortin(DCX), which is a marker of newborn neurons in the hippocampus, n = 4 for each group. Results Compared with the NS group, the mechanical threshold of mice on the 1st, 3rd and 7th day after CFA injection decreased significantly (P < 0.05); But there was no significant difference between DEX + CFA group and CFA group (P>0.05). Compared with the NS group, the time spent in the inner ares (P<0.01), number of entering the central grid area (P<0.01) and distance travelled in the inner area (P<0.01) of CFA group mice reduced significantly, while the time (P<0.01), numbers (P < 0.05) and distance (P < 0.05) of DEX + CFA group mice entering the central grid area enhanced significantly. The result of depression-like behavior tests showed that the sucrose preference percentage (P < 0.05) reduced significantly in CFA group when compared with NS group, and the immobility time increased significantly in tail suspension test (P<0.01) and forced swimming test (P< 0.001) in CFA mice when compared with NS group, while DEX intervention could significantly increase the sucrose preference scores (P<0.05) and decreased the immobility time in tail suspension test (P<0.05) and forced swimming test (P<0.05). The result of Western blotting showed that compared with the NS group, the levels of ADRB2 (P<0.0010), BDNF (P < 0.001), TrkB (P < 0.01), GluR1 (P < 0.001) and GluR2 (P < 0.001) in the hippocampus of CFA group were significantly decreased, while DEX intervention could significantly increase the expression of ADRB2 (P<0.05), BDNF (P < 0.001), TrkB (P < 0.001), GluR1 (P < 0.001) and GluR2 (P < 0.001). Immunohistochemical result showed that compared with the NS group, the average absorbance (AA) of DCX decreased significantly in hippocampus of CFA group (P<0.05), but increased significantly in DEX+CFA group (P < 0.05). Conclusion Dexmedetomidine may promote hippocampal neurogenesis through upregulated the expression of BDNF-TrkB, thus improving CFA-induced anxiety-like and depression-like behaviors in mice.

Objective: To investigate the neuroprotective effect of mesenchymal stem cells (MSC) combined with low⁃intensity transcranial ultrasound (LITUS) treatment on traumatic brain injury (TBI) . Methods: Seventy⁃two SD rats were randomly divided into four groups , namely , control group , TBI group , MSC injection group , and combined treatment group , with 18 rats in each group. TBI model was established by applying a pneumatic controlled cortical impingement instrument. Within 24 h after surgery , MSC was injected into the injury site by microinjector and microinjector pump using in situ injection. After injection , the injury site was treated with LITUS for 28 consecutive days using an ultrasound stimulator. The modified neurological functioning score ( mNSS) was performed on rats in each group at 1 , 3 , 7 , 14 , 21 and 28 days postoperatively , and then the brains were extracted to detect pathological changes at the injury site and the mRNA and protein expression of brain⁃derived neurotrophic factor (BDNF) , growth associated protein⁃43 ( GAP⁃43) , postsynaptic density protein⁃95 ( PSD⁃95 ) and glial fibrillary acidic protein(GFAP) by HE staining , immunohistochemistry , Western blot and RT⁃PCR. Results: Compared with the control group , the mNSS score increased in the TBI group (P < 0. 05) , the expression of GAP⁃43 and PSD⁃95 decreased , and the expression of GFAP increased ( P < 0. 05 ) ; Compared with the TBI group , the mNSS score of MSC group was lower (P < 0. 05) , the expression of BDNF , GAP⁃43 , PSD⁃95 increased , and the expression of GFAP decreased (P < 0. 05) ; mNSS scores were lower in the combined treatment group than those in the MSC group (P < 0. 05) , the expression of BDNF , GAP⁃43 , PSD⁃95 increased , and the expression of GFAP decreased (P < 0. 05) . Conclusion The mechanism by which MSC combined with LITUS exerts neuroprotective effects in TBI may be related to the promotion of BDNF , GAP⁃43 , and PSD⁃95 expression and reduction of GFAP expression.

Objective: To report the clinical manifestations and laboratory features of five patients with congenital thrombotic thrombocytopenic purpura (cTTP) and explore its standardized clinical diagnosis and treatment along with a review of literature. Methods: Clinical data of patients, such as age of onset, disease manifestation, personal history, family history, and misdiagnosed disease, were collected. Treatment outcomes, therapeutic effects of plasma infusion, and organ function evaluation were observed. The relationship among the clinical manifestations, treatment outcomes, and ADAMTS13 gene mutation of patients with cTTP was analyzed. Additionally, detection of ADAMTS13 activity and analysis of ADAMTS13 gene mutation were explored. Results: The age of onset of cTTP was either in childhood or adulthood except in one case, which was at the age of 1. The primary manifestations were obvious thrombocytopenia, anemia, and different degrees of nervous system involvement. Most of the patients were initially suspected of having immune thrombocytopenia. Acute cTTP was induced by pregnancy and infection in two and one case, respectively. ADAMTS13 gene mutation was detected in all cases, and there was an inherent relationship between the mutation site, clinical manifestations, and degree of organ injury. Therapeutic or prophylactic plasma transfusion was effective for treating cTTP. Conclusions: The clinical manifestations of cTTP vary among individuals, resulting in frequent misdiagnosis that delays treatment. ADAMTS13 activity detection in plasma and ADAMTS13 gene mutation analysis are important bases to diagnose cTTP. Prophylactic plasma transfusion is vital to prevent the onset of the disease.
Female ; Pregnancy ; Humans ; Adult ; Blood Component Transfusion ; Plasma ; Purpura, Thrombotic Thrombocytopenic/therapy* ; Mutation ; Purpura, Thrombocytopenic, Idiopathic ; ADAMTS13 Protein/therapeutic use*