Objective To report two cases of dyskeratosis congenita(DC)and provide a comprehensive literature review to improve the understanding of the disease.Methods Clinical characteristics of two DC cases were retrospectively collected and analyzed in Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology.Gene mutations were assessed by high-throughput sequencing analysis and telomere length was assessed by Terminal Restriction Fragment(TRF)analysis.A literature search was carried out using the National Knowledge Infrastructure(CNKI),Wanfang database,PubMed,and Web of Science,updated to June 2024,with"Dyskeratosis congenita"and"telomere biology disorders"as the keywords.Results Case 1 was a boy admitted with"nail dystrophy of fingers and toes for more than 8 years and pancytopenia for 1 week".Physical examination revealed fingernails and toenails dysplasia,reticular skin pigmentation over the neck,and restricted mouth opening.Genetic testing identified a mutation in the DKC1 gene and shorter telomeres.Case 2 was a girl admitted with"confirmed aplastic anemia over 3 years".Physical examination showed no specific abnormalities.A blood routine test showed pancytopenia,with missense mutations found in the RTEL1 and TERT genes.Case 1 received blood transfusion support,while Case 2 was treated with subcutaneous injections of PEGylated recombinant human granulocytes,cyclosporine,and eltrombopag olamine,but the outcomes were not satisfactory.Both cases developed bone marrow failure,prompting hematopoietic stem cell transplantation.However,both cases were lost to follow-up after discharge.Conclusions Dyskeratosis congenita is a rare disease with various clinical manifestations.It may present with skin manifestations or hematological abnormalities.A precise diagnosis is made through a genetic testing.Currently,efficacious medical treatment for DC is lacking,and hematopoietic stem cell transplantation is necessary for patients with bone marrow failure.

Objective:To analyze the clinical characteristics and risk factors of asparaginase-associated pancreatitis(AAP)in children with acute lymphoblastic leukemia(ALL),and to investigate the impact of AAP on their prognosis following re-exposure to asparaginase(ASP).Methods:Clinical children data with ALL at Tongji Hospital,Tongji Medical College of Huazhong University of Science and Technology between January 2015 and June 2020 were collected to analyze the clinical features of AAP.Logistic regression was used to identify risk factors for AAP.Prognostic analysis was performed using the Log-rank test and Kaplan-Meier survival curves.Results:Overall,252 children with ALL were included,among whom 23(9.1%)developed AAP.Most AAP cases(82.6%)occurred during remission induction,with a medi-an time from the last ASP to AAP of 12 d.Elevated total cholesterol(≥3.5 mmol/L)at initial diagnosis was identified as an independent risk factor.Six children(26.1%)were re-exposed to ASP,leading to recurrent pancreatitis in 3 cases.The 5-year overall survival(OS)was signific-antly lower in the AAP group(78.3%±8.6%)compared to the non-AAP group(90.3%±2.2%)(P<0.05).Similarly,children who discontinued ASP due to AAP had a 5-year OS of 77.8%±9.8%,significantly lower than the control group(90.1%±2.1%).Conclusions:AAP typically oc-curred within 12 d of the last ASP administration and was associated with poorer 5-year OS.Re-exposure to ASP posed a risk of recurrent AAP;however,completing the ASP chemotherapy regimen may be crucial for improving prognosis.

Objective: To investigate the clinical characteristics and maternal and fetal prognosis of pregnant women with acute fatty liver of pregnancy (AFLP). Methods: The clinical data of 86 AFLP pregnant women admitted to the Third Affiliated Hospital of Guangzhou Medical University from September 2017 to August 2022 were collected, and their general data, clinical characteristics, laboratory tests and maternal and fetal outcomes were retrospectively analyzed. Results: (1) General information: the age of the 86 pregnant women with AFLP was (30.8±5.4) years, and the body mass index was (21.0±2.5) kg/m². There were 50 primiparas (58.1%, 50/86) and 36 multiparas (41.9%, 36/86). There were 64 singleton pregnancies (74.4%, 64/86) and 22 twin pregnancies (25.6%, 22/86). (2) Clinical characteristics: the main complaints of AFLP pregnant women were gastrointestinal symptoms, including epigastric pain (68.6%, 59/86), nausea (47.7%, 41/86), anorexia (46.5%, 40/86), vomiting (39.5%, 34/86). The main non-gastrointestinal symptoms were jaundice of skin and/or scleral (54.7%, 47/86), edema (38.4%, 33/86), fatigue (19.8%, 17/86), bleeding tendency (16.3%, 14/86), polydipsia or polyuria (14.0%, 12/86), skin itching (8.1%, 7/86), and 17.4% (15/86) AFLP pregnant women had no obvious symptoms. (3) Laboratory tests: the incidence of liver and kidney dysfunction and abnormal coagulation function in AFLP pregnant women was high, and the levels of blood ammonia, lactate dehydrogenase and lactic acid were increased, and the levels of hemoglobin, platelet and albumin decreased. However, only 24 cases (27.9%, 24/86) of AFLP pregnant women showed fatty liver by imageology examination. (4) Pregnancy outcomes: ① AFLP pregnant women had a high incidence of pregnancy complications, mainly including renal insufficiency (95.3%, 82/86), preterm birth (46.5%, 40/86), hypertensive disorders in pregnancy (30.2%, 26/86), gestational diabetes mellitus (36.0%, 31/86), fetal distress (24.4%, 21/86), pulmonary infection (23.3%, 20/86), disseminated intravascular coagulation (16.3%, 14/86), multiple organ dysfunction syndrome (16.3%, 14/86), hepatic encephalopathy (9.3%, 8/86), and intrauterine fetal death (2.3%, 2/86). ② Treatment and outcome of AFLP pregnant women: the intensive care unit transfer rate of AFLP pregnant women was 66.3% (57/86). 82 cases were improved and discharged after treatment, 2 cases were transferred to other hospitals for follow-up treatment, and 2 cases (2.3%, 2/86) died. ③ Neonatal outcomes: except for 2 cases of intrauterine death, a total of 106 neonates were delivered, including 39 cases (36.8%, 39/106) of neonatal asphyxia, 63 cases (59.4%, 63/106) of neonatal intensive care unit admission, and 3 cases (2.8%, 3/106) of neonatal death. Conclusions: AFLP is a severe obstetric complication, which is harmful to mother and fetus. In the process of clinical diagnosis and treatment, attention should be paid to the clinical manifestations and laboratory tests of pregnant women, early diagnosis and active treatment, so as to improve maternal and fetal outcomes.
Pregnancy ; Infant, Newborn ; Female ; Humans ; Adult ; Retrospective Studies ; Premature Birth/epidemiology* ; Pregnancy Complications/diagnosis* ; Fatty Liver/diagnosis* ; Fetal Death ; Stillbirth

OBJECTIVES: Glioma is the most common primary intracranial tumor and there is still no ideal treatment at present. Gene therapy, as one of the new methods for treating glioma, has attracted attention in recent years. But its application in treating glioma is very limited due to lack of effective delivery vectors. This study aims to investigate the feasibility of biomimetic nanomaterials made from glioma cells-derived extracellular vesicles (EV) for targeted delivery of signal transducers and activators of transcription 3 (STAT3)-small interfering RNA (siRNA) in treating glioma. METHODS: First, U251 glioma cells-derived extracellular vessel (EVU251) was extracted by ultra-centrifugal method. Nanoparticle tracking analysis was used to characterize the particle size distribution, the transmission electron microscope was used to analyze the morphology, and Western blotting was used to verify the expression of srface characteristic protein. The homing ability was verified by cell uptake assay after labeling EVU251 with membrane dye kit PKH67; the EVU251 contents were removed by a low permeability method and then EVMU251 was prepared through a microporous membrane. Finally, the biomimetic nanomaterials EVMU251@STAT3-siRNA were prepared by loading STAT3-SiRNA with electro-dyeing method. The real-time quantitative PCR was used to quantify the successful encapsulation of siRNA, and the encapsulation and drug loading rate was calculated; then Cy5-labeled siRNA was used to evaluate the ability of biomimetic nanomaterials (EVMU251@CY5-siRNA) to target U251 cells. Lysosomal escape ability of the biomimetic nanomaterial was evaluated by lysosomal dye lyso-tracker green. At last, the ability of EVMU251@STAT3-siRNA to knock down STAT3 gene and selective killing of U251 cells was detected by cell experiments in vitro. RESULTS: The size of EVU251 ranged from 50 nm to 200 nm with a natural disc shape. The expression of extracellular vesicle marker proteins could be detected on the membrane of EVU251. The cell uptake assay demonstrated that it had homing ability to target U251 cells. After EVU251 was prepared as EVMU251@STAT3-siRNA, the particle size was (177.9±5.0) nm, the siRNA loading rate was (33.5±2.2)% and the drug loading rate was (3.24±0.21)%. The biomimetic nanomaterial EVMU251@STAT3-siRNA still had the ability to target U251 cells and successfully deliver siRNA to the cytoplasm without lysosomal degradation. The EVMU251@STAT3-siRNA can effectively knock down the expression of STAT3 gene and produce selective killing ability in U251 cells. CONCLUSIONS The biomimetic nanomaterials EVMU251@STAT3-siRNA made from glioma U251 cells-derived extracellular vesicles can knock down STAT3 gene of U251 cells and produce selective killing effect, which can provide a new idea for the treatment of glioma.
Humans ; RNA, Small Interfering/genetics* ; Biomimetics ; Cell Line, Tumor ; Glioma/therapy* ; Nanostructures ; Cell Proliferation ; STAT3 Transcription Factor/metabolism*

Objective:To investigate the clinical features of acute megakaryocytic leukemia (AMKL) in children.Methods:The clinical data of 14 children with AMKL in Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2012 to July 2021 were retrospectively analyzed, and the related literature was reviewed.Results:Among 14 children with AMKL, there were 5 males and 9 females, and the median age of onset was 19 months (0.1-109 months); 1 case was Down syndrome-related AMKL, and 13 cases were non-Down syndrome-related AMKL. Most of the children presented with fever, anemia or bleeding symptoms, and a few patients presented with joint pain as the primary symptom. Some children were accompanied by extramedullary infiltration such as hepatomegaly, splenomegaly or lymphadenovarix. Initial investigations of 14 children showed that the median white blood count, hemoglobin concentration and platelet count were 10.67×10 9/L [(6.56-83.62)×10 9/L], 84 g/L (55-121 g/L), 37×10 9/L [(8-1443) ×10 9/L], respectively, and the median proportion of naive cells in peripheral blood was 0.09 (0.00-0.79). Bone marrow smear showed that the primitive megakaryocytes were characterized by various size and irregular form, a few of which had cytoplasmic vacuoles, and the median proportion of bone marrow primitive megakaryocytes was 0.636 (0.332-0.976); the nuclei were round or irregular, with multiple nucleoli or hidden nucleoli. RAS staining was partially positive, and immunohistochemical assay showed that POX, AS-DNCE and α-NBE were negative. Detection of megakaryocyte-associated antigens by flow cytometry showed 12 children expressed CD41a or CD61, and 10 children expressed CD42b. Among 3 children who completed chemotherapy, 1 case of Down syndrome-related AMKL and 1 case of non-Down syndrome-related AMKL were event-free survival, and 1 case of non-Down syndrome-related AMKL died after bone marrow relapse. Conclusions:The clinical manifestations and biological characteristics of children with AMKL are complicated and the prognosis is poor. Some children can achieve disease-free survival through chemotherapy alone.

Objective: To explore the association between chronic hepatitis B virus infection and diabetes among adults. Methods: The baseline data of China Kadoorie Biobank ( CKB ) study from Tongxiang of Zhejiang Province was used for analysis. Community residents were investigated in the study from August 2004 to May 2008, including questionnaire survey, physical measurement and biological sample test. Univariate and multivariate logistic regression models were used to estimate the association of chronic hepatitis B virus infection with diabetes. Results: Totally 52 888 participants were included in the final analysis. The overall prevalence of HBsAg-positive was 3.55% ( N=1 877 ). The overall prevalence of diabetes was 5.17% ( N=2 733 ). The prevalence of HBsAg-positive in diabetic patients was 3.51% ( N=96 ). Both univariate and multivariate logistic regression models indicated that there was no association between chronic hepatitis B virus infection and diabetes（ P>0.05 ）. Conclusion No significant association has been found between chronic hepatitis B virus infection and diabetes among adults.

In this study, the effect of benzo[α]pyrene (BaP) on chaperone-mediated autophagy (CMA) in a simulated hypoxia environment was observed and the relationship to heat shock protein 90 (HSP90) was clarified. With HSP90 inhibitor geldanamycin (GA) and HSP90α silenced, the mRNA and protein expression of hypoxia-inducible factor-1α (HIF-1α), HSP90, heat shock cognate protein 70 (HSC70), and lysosomal associated protein 2A (LAMP-2A) of A549 cells on hypoxic environment by BaP were tested. Alkaline comet experiment, immunofluorescence γ-H2AX focus experiment, quantitative real-time PCR (qPCR), and Western blot analyses were used to clarify the relationship between the DNA damage of different concentrations of BaP in A549 cells and the mRNA and protein expression of CMA-related factors. The results show that hypoxia can promote the expression of mRNA and protein of CMA-related factors in A549 cells. This study found that BaP has an inhibitory effect on CMA under the hypoxic environment. The inhibition or silencing of HSP90 will enhance the inhibitory effect of BaP on CMA. In a normoxic environment, BaP causes DNA damage and promotes CMA.

Objective:To explore the association between snoring and prevalent hypertension among adults in Zhejiang with a cross-sectional study.Methods:After excluding participants with self-reported, physician-diagnosed heart diseases, stroke and cancer at baseline study, 56 728 participants aged 30-79 in the China Kadoorie Biobank study from Tongxiang, Zhejiang were included for the final analysis. Three multivariable logistic regression models were used to estimate the ORs for the associations of snoring with prevalent hypertension. Results:The proportion of participants who snored frequently, snored sometimes, and never snored were 24.55%, 23.94%, and 51.51%, respectively. The corresponding figures of males were 32.40%, 26.55%, and 41.05%, respectively. The corresponding figures of females were 19.00%, 22.08%, and 58.92%, respectively ( P<0.001). After adjusted socio-demographic factors, behavioral lifestyle, BMI, waist circumference, and sleep duration etc., in comparison with participants who never snored, the odds ratios (95% CI) of hypertension for those who snored frequently and snored sometimes were 1.17 (1.12-1.23) and 1.12 (1.07-1.18), respectively. The effects of snoring on hypertension were statistically significantly different between women and men, participants who were central obese and those who were not, and between premenopausal and post-menopausal women. Conclusion:Snoring was associated positively with hypertension among adults. The effect of snoring on prevalent hypertension were obvious, especially among people, being female, being central obese, and being premenopausal.

Objective: To investigate the efficacy and safety of rapamycin in children with tuberous sclerosis complex (TSC) associated renal disease. Methods: A prospective self-control study was conducted. The clinical data of 92 children diagnosed with tuberous sclerosis complex associated kidney disease at the People′s Liberation Army General Hospital from January 2011 to January 2019 were collected. The long-term rapamycin treatment for all patients initiated at 1 mg/(m²·d), which was gradually adjusted to reach a blood concentration of 5-10 μg/L. The changes of the maximum diameter of renal lesions in children after rapamycin treatment were observed and analyzed with Wilcoxon test. Results: Ninety-two children, including 52 males and 40 females, who met the criteria were analyzed. Sixty patients had only renal angiomyolipoma(RAML), while 24 patients had only multiple renal cysts(MRC), and 8 patients had both lesions. The age of TSC diagnosis was 16.0 (7.0, 42.0) months, and the age of initial treatment with rapamycin was 63.5 (21.0, 103.0) months. The follow-up lasted for 12.0 (4.0, 23.0) months. Sequencing of TSC1 and TSC2 genes was performed in 54 children with TSC, including 3 patients (6%) with mutations in TSC1 gene and 51 patients (94%) with mutations in TSC2 gene. The maximum RAML diameter before treatment was 7.0 (4.0, 9.0) mm. The best effect reached at 3 months of treatment, with the diameter of 4.0 (0,7.0) mm. The maximum diameters at 6 months, 1 year and 1-2 years were 5.0 (0,9.8) mm, 5.0 (1.5, 8.5) mm, 5.5 (3.0, 9.0) mm, respectively, and were significantly different from the baseline (Z=-2.404,-2.350,-2.750,P=0.016,0.019,0.006, respectively). The maximum diameter after 2-3 years, and ≥3 years were 5.0 (3.9,7.0) mm and 6.0 (1.0, 11.0) mm, without significant difference from the baseline (Z=-0.856,-0.102,P=0.393,0.919, respectively).The maximum diameters of MRC after 3 months, 6 months, 1 year,1-2 years, 2-3 years, and ≥3 years were 11.0 (5.0, 14.0) mm,3.0 (0.0,11.0) mm,5.0 (0,21.0) mm,0 (0,14.0) mm,0 (0,10.0) mm, and 0 (0,18.3) mm, respectively, but were not significantly different rom the baseline (7.0 (5.0, 15.7) mm)(Z=-0.944,-1.214,-1.035,-1.896,-1.603,-1.214,P=0.345,0.225,0.301,0.058,0.109,0.225, respectively).Twenty-nine patients (32%) had oral ulcers during the entire treatment period, and no serious adverse reactions were observed. Conclusions Rapamycin could decrease the diameter of TSC-related RAML, but could not inhibit the growth of cysts. It is well tolerated in the treatment of renal diseases associated with tuberous sclerosis complex.

To investigate the efficacy and safety of rapamycin in children with tuberous sclerosis complex (TSC) associated renal disease. Methods A prospective self?control study was conducted. The clinical data of 92 children diagnosed with tuberous sclerosis complex associated kidney disease at the People's Liberation Army General Hospital from January 2011 to January 2019 were collected. The long?term rapamycin treatment for all patients initiated at 1 mg/(m2·d), which was gradually adjusted to reach a blood concentration of 5-10 μg/L. The changes of the maximum diameter of renal lesions in children after rapamycin treatment were observed and analyzed with Wilcoxon test. Results Ninety?two children, including 52 males and 40 females, who met the criteria were analyzed. Sixty patients had only renal angiomyolipoma(RAML), while 24 patients had only multiple renal cysts(MRC), and 8 patients had both lesions. The age of TSC diagnosis was 16.0 (7.0, 42.0) months, and the age of initial treatment with rapamycin was 63.5 (21.0, 103.0) months. The follow?up lasted for 12.0 (4.0, 23.0) months. Sequencing of TSC1 and TSC2 genes was performed in 54 children with TSC, including 3 patients (6%) with mutations in TSC1 gene and 51 patients (94%) with mutations in TSC2 gene. The maximum RAML diameter before treatment was 7.0 (4.0, 9.0) mm. The best effect reached at 3 months of treatment, with the diameter of 4.0 (0, 7.0) mm. The maximum diameters at 6 months, 1 year and 1-2 years were 5.0 (0,9.8) mm, 5.0 (1.5, 8.5) mm, 5.5 (3.0, 9.0) mm, respectively, and were significantly different from the baseline (Z=-2.404,-2.350,-2.750, P=0.016,0.019,0.006, respectively). The maximum diameter after 2-3 years, and≥3 years were 5.0 (3.9,7.0) mm and 6.0 (1.0, 11.0) mm, without significant difference from the baseline (Z=-0.856,-0.102, P=0.393, 0.919, respectively).The maximum diameters of MRC after 3 months, 6 months, 1 year,1-2 years, 2-3 years, and≥3 years were 11.0 (5.0, 14.0) mm,3.0 (0.0,11.0) mm,5.0 (0,21.0) mm,0 (0,14.0) mm,0 (0,10.0) mm, and 0 (0, 18.3) mm, respectively, but were not significantly different rom the baseline (7.0 (5.0, 15.7) mm) (Z=-0.944,-1.214,-1.035,-1.896,-1.603,-1.214, P=0.345, 0.225, 0.301, 0.058, 0.109, 0.225, respectively). Twenty?nine patients (32%) had oral ulcers during the entire treatment period, and no serious adverse reactions were observed. Conclusions Rapamycin could decrease the diameter of TSC?related RAML, but could not inhibit the growth of cysts. It is well tolerated in the treatment of renal diseases associated with tuberous sclerosis complex.