Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia.

MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.

Relationship between syncopal symptoms and head-up tilt test modes.

OBJECTIVE: Head-up tilt test (HUTT) is an important tool in the diagnosis of pediatric vasovagal syncope. This research will explore the relationship between syncopal symptoms and HUTT modes in pediatric vasovagal syncope. METHODS: A retrospective analysis was performed on the clinical data of 2513 children aged 3-18 years, who were diagnosed with vasovagal syncope, from Jan. 2001 to Dec. 2021 due to unexplained syncope or pre-syncope. The average age was 11.76 ± 2.83 years, including 1124 males and 1389 females. The patients were divided into the basic head-up tilt test (BHUT) group (596 patients) and the sublingual nitroglycerine head-up tilt test (SNHUT) group (1917 patients) according to the mode of positive HUTT at the time of confirmed pediatric vasovagal syncope. RESULTS: (1) Baseline characteristics: Age, height, weight, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and composition ratio of syncope at baseline status were higher in the BHUT group than in the SNHUT group (all P < 0.05). (2) Univariate analysis: Age, height, weight, HR, SBP, DBP, and syncope were potential risk factors for BHUT positive (all P < 0.05). (3) Multivariate analysis: syncope was an independent risk factor for BHUT positive, with a probability increase of 121% compared to pre-syncope (P<0.001). CONCLUSION: The probability of BHUT positivity was significantly higher than SNHUT in pediatric vasovagal syncope with previous syncopal episodes.

Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms.

Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.

[Advances of structure and mechanisms of bromodomain-containing protein 4 and its related research in tumors].

The bromodomain and extraterminal domain (Bet) family are the regulators of the epigenome and also the pivotal driving factors for the expression of tumor related genes that tumor cells depend on for survival and proliferation. Bromodomain-containing protein 4 (Brd4) is a member of the Bet protein family. Generally, Brd4 identifies acetylated histones and binds to the promoter or enhancer region of target genes to initiate and maintain expression of tumor related genes. Brd4 is closely related to the regulation of multiple transcription factors and chromatin modification and is involved in DNA damage repair and maintenance of telomere function, thus maintaining the survival of tumor cells. This review summarizes the structure and function of Brd4 protein and the application of its inhibitors in tumor research.

Monocyte count is associated with the severity of human adenovirus pneumonia in hospitalized children aged less than 6 years.

BACKGROUND: Human Adenovirus (HAdV) pneumonia is common in young children and infants. Overall, 7-8% of all viral respiratory illnesses among children for less than 5 years are induced by HAdVs. Unfortunately little is known about the role of monocyte count in the disease severity. METHODS: Data were gathered from 595 children (age < 6 years) who were diagnosed with HAdV infection at the 1st People's Hospital (Changde City, China) between January 2019 and December 2019. There were 181 cases of severe adenovirus pneumonia. RESULTS: The correlation between the patients' monocyte count and the severity of HAdV pneumonia was estimated by performing a multiple linear regression analysis. The results showed a negative association (OR: 0.53, 95% CI 0.31 to 0.89, P < 0.05). We further built Generalized Additive Models (GAMs) and demonstrated that the monocyte count had a non-linear association with severe HAdV pneumonia. The inflection point of monocyte count detected in the two-stage linear regression model was 1.5. On the left side of this point, the monocyte count was negatively interrelated (OR: 0.26, 95% CI 0.13 to 0.52, P < 0.001), while on the opposite side, there was a positive association (OR: 7.48, 95% CI 1.30 to 43.08, P < 0.05). CONCLUSIONS: Based on the results of this investigation, we established a link between monocyte count and the severity of HAdV pneumonia. Monocyte count is negatively associated with severe HAdV pneumonia. The inflection point of monocyte count detected in the two-stage linear regression model was 1.5 × 109/L.

Sequential Organ Failure Assessment (SOFA) and 90-day mortality in patients with kidney transplant status at first ICU admission: a cohort study of 428 patients.

PURPOSE: We investigated the prognostic accuracy of scores of SOFA for 90-day mortality in patients with kidney transplant status identified from the public Medical Information Mart for Intensive Care III databank. METHODS: A total of 428 participants with kidney transplant status who were admitted for the first time to the ICU were included. The target-independent and target-dependent variables were the SOFA scores in the first 3 days of ICU admission and 90-day mortality, respectively. RESULTS: Fully adjusted binary logistic regression indicated that the day-2 and day-3 SOFA scores were positively associated with a risk of 90-day mortality after adjustment for confounders (odds ratio: 1.196, 95% confidence interval: 1.052-1.360; odds ratio: 1.233, 95% confidence interval: 1.062-1.432). The receiver operating characteristic curve showed areas under the curve for the prediction of 90-day mortality from SOFA scores on days 1, 2 and 3 were 0.524, 0.654, and 0.727, respectively. Further analysis using Kaplan-Meier survival curves and multivariate regression models of 90-day survival showed that patients with low SOFA scores survived longer than those with high scores. CONCLUSION: The SOFA scores in the early days of ICU admission were positively associated with 90-day outcomes although the first-day score showed no significant correlation.

Massive gastrointestinal hemorrhage caused by Henoch-Schoenlein purpura: A case report.

RATIONALE: Henoch-Schoenlein purpura (HSP) is a systemic small-vessel vasculitis that commonly occurs in children. Gastrointestinal HSP can rarely progress to gastrointestinal perforation, followed by massive gastrointestinal bleeding. PATIENT CONCERNS: An 8-year-old Chinese boy was transferred to the pediatric intensive care unit of our hospital with an emergency occurrence of purpura, severe hematemesis, large bloody stools, and sharp abdominal pain, and complained of abdominal pain and rash 2 weeks prior. DIAGNOSIS: The patient had purpura with lower limb predominance, abdominal pain, and gastrointestinal bleeding. Immunofluorescence microscopy of histological sections showed granular and lumpy IgA focal deposition in the blood vessel walls. He was diagnosed with HSP. INTERVENTIONS: Initially, he was treated with methylprednisolone, posterior pituitary injection, somatostatin, and hemocoagulase, together with the infusion of large blood products. Postoperatively, he was administered nasal continuous positive airway pressure -assisted ventilation, anti-infection treatment, albumin transfusion, platelet transfusion, abdominal drainage, methylprednisolone, fluconazole anti-fungal treatment, and wound dressing. OUTCOMES: There was no evidence of rebleeding, abdominal pain, or purpura at the 2-month follow-up assessment. LESSONS: Abdominal HSP should be alert to gastrointestinal perforation when using hormone therapy.

High levels of unbound bilirubin are associated with acute bilirubin encephalopathy in post-exchange transfusion neonates.

BACKGROUND: Although it is known that unbound bilirubin can enter the brain, there is little evidence of its association with the development of acute bilirubin encephalopathy. Here, we investigated this potential relationship in neonates who had undergone exchange transfusion. METHODS: Data from 46 newborns who underwent exchange transfusion between 2016 and 1-1 to 2018-12-31 at the First People's Hospital of Changde City in China were analyzed. The unbound bilirubin level was taken as the independent variable and the development of the acute bilirubin encephalopathy as the dependent variable. The covariates were age, birth weight, sex, red blood cell count, blood glucose, hemolytic disease, and whether the infant had received phototherapy. RESULTS: The mean age and gestational age of the neonates were 146.5 ± 86.9 h and 38.6 ± 1.3 weeks [38.7(34.6-41.1) weeks] old, respectively; 52.17% were male. Binary logistic regression analysis after adjustment for covariates showed a positive association between the levels of unbound bilirubin and the development of acute bilirubin encephalopathy (odds ratio = 1.41, 95% confidence intervals 1.05-1.91, P = < 0.05). CONCLUSION: There is a significant association between unbound bilirubin levels and the development of acute bilirubin encephalopathy in neonates. Further investigations are required to explore the mechanisms.

The Relationship Between Children's Birth Time and Short Stature.

BACKGROUND: There are few current reports on the relationship between time of birth and short stature in children. Therefore, we aimed to investigate whether there is an association between time of birth and short stature in children. MATERIALS AND METHODS: In this study, basic information was collected from 462 children aged 2-14 years old. We collected data on gender, height, height standard deviation score (SDS), weight, body mass index (BMI), serum 25(OH)D levels, date of birth, and whether the above children were short stature. Demographic description, univariate analysis, multivariate logistic regression analysis, smooth curve fitting, and threshold effects were used to explore possible linear or non-linear relationships between children's birth time and short stature. RESULTS: The mean age of the 462 children was 9.76 ± 3.10 years old, and 52.16% were male. A total of 129 (27.92%) children were defined as 25(OH)D insufficiency, including 107 (38.91%) in the short stature group and 22 (11.76%) in the normal stature group. Fully adjusted logistic regression showed that the risk of short stature was reduced by 56.5% in children born in summer compared with spring (P < 0.05) [odds ratio (OR): 0.435, 95% confidence interval (CI): 0.197-0.959]. A non-linear relationship was found between "sequential day of the year" and short stature from the 1st to the 250th day of the year, the risk of short stature in children is reduced by 0.6% for each day that passes (P = 0.002) (OR: 0.994, 95% CI: 0.990-0.998), and from the 250th to the 365th day of the year, the risk of short stature in children was increased by 0.8% for each day that passed (P = 0.008) (OR: 1.008, 95% CI: 1.001-1.025). CONCLUSIONS: Children born in summer have a lower risk of short stature than spring. For children born before the 250th day of the year, "sequential day of the year" was negatively associated with short stature, and for children born after the 250th day, "sequential day of the year" was positively associated with short stature.

[Efficiency of heart rate and heart rate difference at different time points during head-up tilt test in the diagnosis of postural tachycardia syndrome in children and adolescents].

OBJECTIVE: To study the efficiency of heart rate (HR) and heart rate difference (HRD) at different time points during head-up tilt test (HUTT) in the diagnosis of postural tachycardia syndrome (POTS) in children and adolescents. METHODS: A total of 217 children and adolescents, aged 6-16 years, who were diagnosed with POTS were enrolled as the POTS group, and 73 healthy children and adolescents, matched for sex and age, were enrolled as the control group. The POTS group was further divided into ≤12 years old group with 127 children/adolescents and >12 years old group with 90 children/adolescents. The two groups were compared in terms of HR at baseline and at 5 and 10 minutes of HUTT (HR0, HR5, and HR10 respectively), difference between HR5/HR10 and HR0 (HRD5 and HRD10 respectively). The efficiency of HR5, HR10, HRD5 and HRD10 in the diagnosis of POTS was assessed. RESULTS: Compared with the control group, the POTS group had significant increases in HR5, HR10, HRD5, and HRD10 (P<0.05). The coincidence rate of HR or HRD for the diagnosis of POTS in males was higher than that in females at 5 minutes of HUTT (P<0.05), while the coincidence rate of HR or HRD for the diagnosis of POTS in males was lower than that in females at 10 minutes of HUTT (P<0.05). The coincidence rate of HR for the diagnosis of POTS was higher in the >12 years old subgroup (P<0.05), while the coincidence rate of HRD for the diagnosis of POTS was higher in the ≤12 years old subgroup (P<0.05). The combination of HR5, HR10, HRD5, and HRD10 for the diagnosis of POTS had a greater area under the curve (0.974; 95%CI: 0.949-0.989) than HR5, HR10, HRD5, or HRD10 alone, with a sensitivity of 87.80% and a specificity of 95.83%. The diagnostic efficacy of HRD for POTS was higher than that of HR (P<0.05). CONCLUSIONS: HR and HRD at different time points during HUTT have a good value in the diagnosis of POTS in children and adolescents, and the accuracy of diagnosis varies with age and gender.

Heart Rate and Heart Rate Difference Predicted the Efficacy of Metoprolol on Postural Tachycardia Syndrome in Children and Adolescents.

OBJECTIVE: To evaluate the ability of heart rate (HR) and HR difference during head-up tilt test (HUTT) and to predict clinical improvement related to metoprolol treatment in children and adolescents with postural tachycardia syndrome (POTS). STUDY DESIGN: This was a retrospective cohort study. A total of 53 subjects (27 male, aged 6-12 years old, mean age 11.79 ± 1.50 years old) with POTS treated with metoprolol were involved from July 2012 to September 2019. In total, 52 subjects who underwent health examination during the same period were matched as the control group. Subjects in both groups underwent HUTT. The HR distance between 5 minutes and 0 minutes (HR difference 5) and between 10 minutes and 0 minutes (HR difference 10) during HUTT was calculated. RESULTS: The POTS group was significantly greater than the control group in HR 5, HR 10, HR difference 5, and HR difference 10 (P < .01). There was no statistical difference in HR 0 between the 2 groups (P > .05). In total, 53 subjects with POTS were followed up for 96.0 (IQR, 40.5, 134.5) days during treatment with metoprolol. HUTT results demonstrated that 58.49% of subjects with POTS had a response and symptom scores were reduced after intervention. HR and HR difference were useful in predicting the efficacy of metoprolol on POTS. When HR 5, HR 10, HR difference 5, and HR difference 10, respectively, were ≥110, 112, 34, and 37 beats/min, the sensitivity and specificity were 82.50% and 69.23%, 84.62% and 69.70%, 85.29% and 89.47%, and 97.56% and 64.86%, respectively. CONCLUSIONS: HR and HR difference are helpful to predict the efficacy of metoprolol on POTS in children and adolescents.

[Value of CD, MPO, Ki-67 and C-MYC Positive Rate in the Pathological Tissues and C-MYC Gene of Patients with T-LBL/ALL for Predicting Prognosis].

OBJECTIVE: To explore the value of of CD, MPO, Ki-67, C-MYC positive rates in the pathological tissues and C-MYC gene of patients with T-LBL/ALL for predicting Prognosis. METHODS: Ninty cases of T-LBL/ALL patients in our hospital were selected and included in the T-LBL/ALL group, and 30 cases of lymphnode reactive hyperplasia were selected as control group. Immunohistochemical staining was used to detect the changes of CD, MPO, Ki-67 and C-MYC positive rate in 2 groups, and the changes of C-MYC gene were detected by fluorescence in situ hybridization. RESULTS: In 90 patients with T-LBL/ALL, there were CD1a+ 34 cases (37.8%), CD3+ 67 cases (74.4%), epsilon CD3+ 47 cases (52.2%), CD7+ 85 cases (94.4%), CD10+ 33 cases (36.7%), CD34+ 22 cases (24.4%), CD43+ 48 cases (53.3%), CD45RO+ 46 cases (51.1%), CD99+ 88 cases (97.8%), TDT+ 85 cases (94.4%); and CD23, CD20, and MPO all were negative; Ki-67>80% 47 cases (52.2% cases), Ki-67≤80%, 43 cases (47.8%). In 90 T-LBL/ALL patients, the positive rate of C-MYC (66.7%) was significantly higher than the control group (positive rate 0.0%) (P< 0.05); the Ki-67 index, mediastinal widening of T-LBL/ALL patients and the positive rate of C-MYC positively were correlated (P< 0.05). The overall survival rate (44.0%) of C-MYC negative patients was significantly higher than that of C-MYC positive patients (0.0%). The overall survival rate of C-MYC negative patients was significantly higher than that of C-MYC positive patients (P< 0.05).Ann Arbor staging, LDH, bone marrow involvement, mediastinal widening, Ki-67 positive index, and C-MYC protein expression of patients with T-LBL/ALL did not correlated with increased C-MYC gene breakage and copy number (P> 0.05). CONCLUSION: The overall survival rate of C-MYC positive patients decreases, which positively correlates with Ki-67 positive index and mediastinal width, suggesting that the prognosis of the patients with C-MYC protein expression is poorer.

[Clinical characteristics in adults and children with vasovagal syncope].

OBJECTIVE: To analyze the clinical characteristics in adults and children with vasovagal syncope (VVS). METHODS: Clinical data including head-up tilt table (HUTT) results were analyzed and compared in 136 children (mean age 12.3 +/- 2.7 years, 50 boys, 86 girls) and 119 adults (mean age 36.4 +/- 14.0 years, 29 men, 90 women) with VVS. RESULTS: (1) There were more female VVS patients in adults group than that in children group (male and female ratio: children group 1:1.7 and adults group 1:3.1, P = 0.033) in this cohort. (2) The incidence of chest distress in adults group was significantly higher than that in children group [45.4 (54/119) vs. 27.2% (37/136), P = 0.003] while the incidence of headache [10.9% (13/119) vs. 20.6% (28/136), P = 0.036] and abdominal pain in children group was significantly higher than that in adults group [7.6% (9/119) vs. 19.1% (26/136), P = 0.008]. (3) Incidences of muggy environment [22.8% (26/114) vs. 12.5% (17/136), P = 0.032] and urination VVS [9.7% (11/114) vs. 1.5% (2/136), P = 0.004] were significantly higher in adults group than those in children group. (4) The mean time of mixed response vasogal episode in adults group was significantly longer than that in children group in sublingual nitroglycerin head-up tilt table test (SNHUT) stage (5.04 +/- 2.27 min vs. 3.50 +/- 1.24 min, P = 0.036). CONCLUSIONS: The incidences of chest distress, muggy environment and urination VVS were more often and the mean time of vasogal episode of mixed response in SNHUT stage was longer in adults VVS while the incidence of abdominal pain and headache was higher in children VVS patients compared to adults VVS patients.