Isocitrate dehydrogenase 1 (IDH1) R132H is the most common mutated gene in grade II-III gliomas and oligodendrogliomas. Instead of activating telomerase (a reverse transcriptase which using RNA as a template to extend telomere length), the majority of IDH1^R132H mutant glioma maintain telomere length through an alternative mechanism that relies on homologous recombination (HR), which is known as alterative lengthening of telomere (ALT).The phenotype of ALT mechanism include: ALT associated promyelocytic leukemia protein (PML) bodies (APBs); extrachromosomal telomeric DNA repeats such as C- and T-loops; telomeric sister chromatid exchange (T-SCE), etc. The mechanism of ALT activation is not fully understood. Recent studies have shown that mutation IDH1 contributes to ALT phenotype in glioma cells in at least three key ways. Firstly, the IDH1^R132H mutation mediates RAP1 down-regulation leading to telomere dysfunction, thus ensuring persistent endogenous telomeric DNA damage, which is important for ALT activation. Spontaneous DNA damage at telomeres may provide a substrate for mutation break-induced replication (BIR)‑mediated ALT telomere lengthening, and it has been demonstrated that RAP1 inhibits telomeric repeat-containing RNA, transcribed from telomeric DNA repeat sequences (TERRA) transcription to down-regulate ALT telomere DNA replication stress and telomeric DNA damage, thereby inhibiting ALT telomere synthesis. Similarly, in ALT cells, knockdown of telomere-specific RNaseH1 nuclease triggers TERRA accumulation, which leads to increased replication pressure. Overexpression of RNaseH1, on the other hand, attenuates the recombination capacity of ALT telomeres, leading to telomere depletion, suggesting that RAP1 can regulate the level of replication pressure and thus ALT activity by controlling TERRA expression. Secondly, the IDH1^R132H also alters the preference of the telomere damage repair pathway by down-regulating XRCC1, which inhibits the alternative non-homologous end joining (A-NHEJ) pathway at telomeres and alters cellular preference for the HR pathway to promote ALT. Finally, the IDH1^R132H has a decreased affinity for isocitric acid and NADP+ and an increased affinity for α ketoglutarate (α‑KG) and NADPH, so that the mutant IDH1^R132H catalyzes the hydrogenation of α‑KG to produce 2-hydroxyglutarate (2-HG)in a NADPH-dependent manner. Because 2-HG is structurally similar to α‑KG, which maintains the trimethylation level of H3k9me3 by competitively inhibiting the activity of the α‑KG-dependent histone demethylase KDM4B, and recruits heterochromatin protein HP1α to heterochromatinize telomeres, and promote ALT phenotypes in cooperation with the inactivating of ATRX. In addition, it has been shown that APBs contain telomeric chromatin, which is essentially heterochromatin, and HP1α is directly involved in the formation of APBs. Based on these studies, this article reviews the mechanism of IDH1^R132H mediated telomere dysfunction and the preference of DNA repair pathway at telomeres in cooperate with ATRX loss to promote ALT, which may provide references for clinical targeted therapy of IDH1^R132H mutant glioma.

Objective To investigate changes in the urinary metabolite profiles of children exposed to polycyclic aromatic hydrocarbons(PAHs)during critical brain development and explore their potential link with the intestinal microbiota. Methods Liquid chromatography-tandem mass spectrometry was used to determine ten hydroxyl metabolites of PAHs(OH-PAHs)in 36-month-old children.Subsequently,37 children were categorized into low-and high-exposure groups based on the sum of the ten OH-PAHs.Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to identify non-targeted metabolites in the urine samples.Furthermore,fecal flora abundance was assessed by 16S rRNA gene sequencing using Illumina MiSeq. Results The concentrations of 21 metabolites were significantly higher in the high exposure group than in the low exposure group(variable importance for projection>1,P<0.05).Most of these metabolites were positively correlated with the hydroxyl metabolites of naphthalene,fluorine,and phenanthrene(r=0.336-0.531).The identified differential metabolites primarily belonged to pathways associated with inflammation or proinflammatory states,including amino acid,lipid,and nucleotide metabolism.Additionally,these distinct metabolites were significantly associated with specific intestinal flora abundances(r=0.34-0.55),which were mainly involved in neurodevelopment. Conclusion Higher PAH exposure in young children affected metabolic homeostasis,particularly that of certain gut microbiota-derived metabolites.Further investigation is needed to explore the potential influence of PAHs on the gut microbiota and their possible association with neurodevelopmental outcomes.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective To observe the clinical efficacy of adjuvant PD-1 inhibitor in the treatment of patients with hepatocellular carcinoma after microwave ablation and the changes of lymphocyte subsets before and after treatment.Methods A total of 56 patients with hepatocellular carcinoma who underwent microwave ablation in our hospital were randomly divided into two groups according to different treatments,with 28 cases in each group.Patients in the group A received adjuvant treatment with PD-1 inhibitors after microwave ablation,while patients in the group B received microwave ablation alone.The local efficacy of microwave ablation,the survival of patients after adjuvant treatment of PD-1 inhibitor and the occurrence of related adverse reactions were observed.Peripheral venous blood was collected to detect the number of T lymphocyte subsets before microwave ablation in the two groups,after microwave ablation in the group B,and after six cycles of immunotherapy in the group A.Results There was no significant difference in the complete ablation rate of cases between group A and group B(89.3% vs.85.7%,P=0.69),and there was no significant difference in the complete ablation rate of lesions between group A and group B(91.7% vs.85.3%,P=0.40).The median progression-free survival(mPFS)of the group A was not yet reached,the mPFS of group B was 12.6 months,and there was a statistically significant difference in the mPFS between the two groups(P=0.03).The median overall survival(mOS)of the two group were not yet reached.The proportion of CD4+T lymphocytes after treatment in the group A significantly increased compared with that in the group B[(37.05±2.22)% vs.(29.23±2.88)%,P=0.03],while the proportion of CD8+T lymphocytes[(21.08±2.23)% vs.(27.18±1.75)%,P=0.04)]and the proportion of Treg cells[(4.26±0.31)% vs.(5.22±0.34)%,P=0.04]significantly decreased.There was no serious adverse reactions in all patients after microwave ablation,and 28 patients in the group A had no adverse reactions above grade 3 after PD-1 inhibitor treatment.Conclusion Adjuvant PD-1 inhibitor therapy after microwave ablation can prolong the progression-free survival of patients,enhance the function of T lymphocytes,and weaken the role of immunosuppressive cells,which may be an effective strategy to delay the recurrence of liver cancer after microwave ablation.

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

Objective: To evaluate the efficacy of the Hodgkin lymphoma (HL)-2013 regimen in the treatment of children with HL, and to investigate the prognostic factors of childhood HL. Methods: Clinical data of 145 children (aged ≤18 years) with newly diagnosed HL, treated with HL-2013 regimen in 8 tertiary referral centers for childhood cancer from August 2011 to April 2021 were analyzed retrospectively. All the diagnosis were confirmed by histopathological morphology and immunohistochemical examination. The clinical characteristics and treatment outcomes were summarized, and the patients were divided into different groups according to clinical characteristics. Kaplan-Meier method was used for survival analysis, and the comparison of survival rates between groups was performed with Log-rank test. Results: Of the 145 cases, there were 115 males and 30 females, the age at diagnosis was 7.9 (5.8, 10.6) years. Cervical lymph node enlargement (114 cases, 78.6%) was the common symptom of the disease, and 57 patients (39.3%) were accompanied by large masses. The most common pathological classification was mixed cell type (93 cases, 64.1%). According to the Ann Arbor staging system, there were 9 cases of stage Ⅰ, 62 cases of stage Ⅱ, 45 cases of stage Ⅲ, 29 cases of stage Ⅳ. According to the risk stratification: there were 14 cases of low-risk group, 76 cases of medium-risk group and 55 cases of high-risk group. Of all patients, 68 cases (46.9%) achieved an early complete remission (CR) after 2 courses of chemotherapy, and the CR rate was 93.8% (136/145) after first-line treatment. Disease recurrence or progression occurred in 22 cases (15.2%). Of all patients, 125 cases survived, 6 cases died and 14 cases were lost to follow-up. Among the survived cases, 123 cases were continuously at CR state,and the follow-up time was 55 (40, 76) months. The 5-year overall survival (OS) and event free survival (EFS) rates were (95.3±1.9)% and (84.2±3.0)% for the entire group, respectively. 5-year OS and EFS rates for patients with stage Ⅲ-Ⅳ were both lower than those for patients with stage Ⅰ-Ⅱ (χ²=6.28 and 7.58, both P<0.05), the 5-year OS and EFS rates for patients in high-risk group were both lower than those for patients in low-risk and medium-risk group (χ²=10.93, 7.79, both P<0.05). The 5-year OS rates for the patient with early CR and without early CR were 100.0% and (90.9±3.6)% (χ²=5.77, P=0.016). EFS rates for the patient with early CR (68 cases) and without early CR (77 cases) were (93.8±3.0)% and (75.8±5.0)% (χ²=8.78, P=0.003). Conclusions: HL-2013 regimen is significantly effective in the treatment of pediatric HL. However, the patients in high-risk group and those without early CR are prone to disease recurrence or progression. Stage Ⅲ-Ⅳ and without early CR were associated with worse prognosis.
Child ; Female ; Male ; Humans ; Hodgkin Disease ; Retrospective Studies ; Neoplasm Recurrence, Local ; China ; Antineoplastic Combined Chemotherapy Protocols ; Prognosis ; Disease-Free Survival

MicroRNA-494 (miR-494) is a small non-coding RNA located in chromosome 14q32.31 and regulates post-transcriptional gene expression by promoting the degradation of its target mRNAs via binding to the 3' untranslated regions (3'UTR). It has been reported that miR-494 plays an important role in the occurrence, development and prognosis of various diseases. Several signaling pathways modulated by miR-494 including the PTEN/PI3K/AKT, nuclear factor κ-B (NF-κB), mitogen-activated protein kinase (MAPK), transforming growth factor-β (TGF-β)/SMAD, and Wnt/β-catenin are associated with physiological regulation and pathological process in many diseases. The stably expression of miR-494 in the blood stream suggests its potential as a biological marker for disease diagnosis, treatment, and prognosis. Based on recent research, we summarize the role and molecular mechanism of miR-494 in disease development and progression. We also discuss its potential as a marker for clinical diagnosis and prognosis of various diseases.
MicroRNAs/metabolism* ; NF-kappa B/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Signal Transduction ; Transforming Growth Factor beta/metabolism*

Objective: To analyze the migration of the HIV/AIDS cases and related factors in Liangshan Yi autonomous prefecture (Liangshan). Methods: According to HIV/AIDS Comprehensive Response Information Management System of China Information System for Disease Control and Prevention, a total of 28 772 HIV/AIDS cases who had follow-up records in Liangshan in 2020 were included in the survey. The migration of the HIV/AIDS cases was described and the related factors were analyzed using multiple logistic regression models, and the migration destinations of the HIV/AIDS cases were mapped. Results: Among the 28 772 HIV/AIDS cases, 20.89% (6 010/28 772) had migration in 2020. Multivariate logistic regression analysis showed that among the HIV/AIDS cases, the migration related factors included being aged 15-24 years (compared with being aged 0-14 years, OR=2.74, 95%CI:2.04-3.69) and ethnic group (compared with Han ethnic group, OR=2.44, 95%CI:2.19-2.72), having education level of junior high school (compared with having education level of primary school or below, OR=1.25, 95%CI:1.14-1.38), being unmarried (compared with being married, OR=1.29, 95%CI:1.20-1.39), being engaged in business services (compared with being engaged in farming, OR=1.96, 95%CI:1.31-2.92), receiving antiviral treatment <1 year (compared with receiving antiviral treatment >3 years, OR=1.42, 95%CI:1.26-1.61), having recent CD4⁺T lymphocytes (CD4) counts >500 cells/μl (compared with having recent CD4 counts <200 cells/μl, OR=1.15, 95%CI:1.03-1.29). The geographical distribution maps showed that among all cities in Sichuan, Xichang (13.26%, 797/6 010) and Chengdu (10.12%,608/6 010) were the main migration destinations of the HIV/AIDS cases, and the provinces outside Sichuan where the HIV/AIDS cases would like to migrate to were mainly Guangdong (18.19%, 1 093/6 010) and Zhejiang provinces (7.67%, 461/6 010) in 2020. The HIV/AIDS cases who migrated where Liangshan, within Sichuan province, and to other provinces accounted for 27.67% (1 663/6 010), 15.34% (922/6 010) and 56.99% (3 425/6 010), respectively. Conclusions: More attention should be paid to the mobility characteristics and the classification management of HIV/AIDS cases according to their characteristics in Liangshan. Timely access to information on changes in the place of work and residence of HIV/AIDS cases should be warranted when they have migration. Good referrals and management for mobility of HIV/AIDS cases in different places should be made to reduce loss to follow-up and improving interventions.
Acquired Immunodeficiency Syndrome/epidemiology* ; Adolescent ; Adult ; Child ; Child, Preschool ; China/epidemiology* ; Ethnicity ; HIV Infections/epidemiology* ; Humans ; Infant ; Infant, Newborn ; Logistic Models ; Marriage ; Young Adult

Cranial Nerves ; Humans ; Lymphoma ; Nervous System Malformations

To investigate the toxicity and related mechanism of miltirone to human acute myeloid leukemia THP-1 cells. To be specific, the active components and targets of miltirone were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and the target proteins were converted into standard gene names with UniProt. Acute leukemia-rela-ted target genes were screened from GeneCards and DisGeNET. Venn diagram was constructed with Venny 2.1 to yield the common targets of the disease and the drug. The protein-protein interaction(PPI) network was constructed by STRING and Cytoscape 3.8.2. THP-1 cells in the logarithmic growth phase were treated with dimethyl sulfoxide(DMSO), and 2.5, 5, 10, 15, and 20 μmol·L~(-1) miltirone for 24 h, respectively. The proliferation rate of cells was analyzed by carboxyfluorescein diacetate succinimidyl ester(CFSE), apoptosis rate by flow cytometry with Annexin V-PE/7 AAD staining, and cell morphology by acridine orange staining. Real-time quantitative PCR(qPCR) was employed to detect the mRNA levels of nuclear receptor coactivator 2(NCOA2), poly(ADP-ribose) polymerase-1(PARP1), B-cell lymphoma-2(Bcl-2)-associated X protein(Bax), Bcl-2, and cysteine aspartyl protease-3(caspase-3). The effect of miltirone on apoptosis was detected in presence of caspase inhibitor Z-VAD-FMK. A total of 26 targets of miltirone, 1 046 genes related to acute leukemia, and 6 common targets of the two were screened out. Flow cytometry result showed miltirone at 10 μmol·L~(-1) can inhibit proliferation and promote apoptosis of THP-1 cells. The typical manifestations of apoptosis, such as cell shrinkage, nuclear rupture, and chromatin agglomerate were displayed by acridine orange staining. The decreased mRNA levels of NCOA2 and PARP1 and increased Bax/Bcl-2 ratio and the activity of pro-apoptotic protein caspase-3 were observed. Z-VAD-FMK can attenuate the apoptosis-inducing effect of miltirone. This study indicates that miltirone can inhibit the proliferation and promote the apoptosis of THP-1 cells, by down-regulating NCOA2 and PARP1, raising Bax/Bcl-2 ratio, and activating caspase-3.
Apoptosis ; Caspase 3/metabolism* ; Cell Proliferation ; Humans ; Leukemia/metabolism* ; Phenanthrenes/pharmacology* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; RNA, Messenger ; THP-1 Cells ; bcl-2-Associated X Protein/metabolism*