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Shuping Zhang,1,* Yamei Ma,1,* Xiu Zang,2 Hao Heng,2 Xuekui Liu,2 Gangshan Peng,3 Ran Liu,3 Jun Liang,1,2,* Houfa Geng1,2,* 1Graduate School, Bengbu Medical University, Bengbu, Anhui, People’s Republic of China; 2Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu, People’s Republic of China; 3The Affiliated Xuzhou Clinical College, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Houfa Geng; Jun Liang, Email genghoufa@xzhmu.edu.cn; liangjun@xzhmu.edu.cnAbstract: Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant inherited disorder prevalent among adolescents. Typically, it manifests with hyperglycemia before the age of 25. MODY5 is attributed to a mutation in the Hepatocyte Nuclear Factor-1β (HNF-1β) gene. A complete absence of HNF-1β is observed in 50% of those with MODY5. The 17q12 microdeletion syndrome closely linked with MODY5. Its incidence in the general population is around 1 in 14,500 and is linked with facial deformities, diabetes, polycystic kidneys, pancreatic hypertrophy, liver anomalies, and neuropsychological impairments. The most primary clinical signs are predominantly associated with the HNF-1β gene deletion. We chronicle the case of a male of 19 years of age diagnosed with diabetes, who, alongside persistent liver damage and polycystic kidneys, was referred from a community hospital to the Xuzhou Central Hospital. His clinical presentation included diabetes, liver dysfunction, polycystic kidneys, lipid irregularities, insulin resistance, and fatty atrophy. Subsequent genetic screening unveiled a 17q12 chromosomal deletion and an absence of the Hepatocyte Nuclear Factor-1β (HNF-1β) gene. Hence, for adolescent patients lacking a familial diabetes history but exhibiting symptoms like polycystic kidneys, liver damage, lipid irregularities, and fatty atrophy, a thorough assessment for the 17q12 microdeletion syndrome becomes imperative.Keywords: 17q12 microdeletion syndrome, HNF-1β gene, special-type diabetes, MODY5, polycystic kidneys, liver damage

Xingyue He,1 Tianjiao Hao,1 Hongxu Geng,2 Shengzhou Li,1 Chuanjiang Ran,1 Meirong Huo,1 Yan Shen1 1State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 2School of Pharmacy, Yantai University, Yantai, 264005, People’s Republic of ChinaCorrespondence: Yan Shen; Meirong Huo, Email shenyan@cpu.edu.cn; meironghuo@cpu.edu.cnAbstract: Gold nanomaterials have become very attractive nanomaterials for biomedical research due to their unique physical and chemical properties, including size dependent optical, magnetic and catalytic properties, surface plasmon resonance (SPR), biological affinity and structural suitability. The performance of biosensing and biodiagnosis can be significantly improved in sensitivity, specificity, speed, contrast, resolution and so on by utilizing multiple optical properties of different gold nanostructures. Lateral flow immunochromatographic assay (LFIA) based on gold nanoparticles (GNPs) has the advantages of simple, fast operation, stable technology, and low cost, making it one of the most widely used in vitro diagnostics (IVDs). However, the traditional colloidal gold (CG)-based LFIA can only achieve qualitative or semi-quantitative detection, and its low detection sensitivity cannot meet the current detection needs. Due to the strong dependence of the optical properties of gold nanomaterials on their shape and surface properties, gold-based nanomaterial modification has brought new possibilities to the IVDs: people have attempted to change the morphology and size of gold nanomaterials themselves or hybrid with other elements for application in LFIA. In this paper, many well-designed plasmonic gold nanostructures for further improving the sensitivity and signal output stability of LFIA have been summarized. In addition, some opportunities and challenges that gold-based LFIA may encounter at present or in the future are also mentioned in this paper. In summary, this paper will demonstrate some feasible strategies for the manufacture of potential gold-based nanobiosensors of post of care testing (POCT) for faster detection and more accurate disease diagnosis.Keywords: gold nanomaterials, LFIA, sensitivity, POCT

Haili Geng, Yong Wu, Yuanzhong Chen Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, People’s Republic of ChinaCorrespondence: Yuanzhong Chen, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86-13306908368, Email chenyz@mail.fjmu.edu.cn; TP123123gtt@163.comBackground: Fibronectin (FN) can improve organ function and slow the progression of sepsis, but full-length FN is hard to be exacted as a therapeutic.Objective: This study aimed to investigate the beneficial effects of C-terminal heparin-binding domain polypeptide of FN (rhFNHC-36) in a cecal ligation and puncture (CLP)-mediated murine septic model and explore its regulatory effects on macrophages.Methods: Mice were randomly assigned to four groups: unoperated control (Normal), sham operation control (Sham), CLP-operation with intravenous injection of phosphate-buffered saline (CLP+PBS), and CLP-operation with rhFNHC-36 treatment (CLP+rhFNHC-36). Blood and abdominal fluid samples were subjected to bacterial colony formation assays. Organs (liver, spleen, and lung) were undergone histopathological analyses and/or weighed to obtain organ indices. Serum interleukin-6 (IL-6) levels, nitric oxide (NO) release from isolated abdominal macrophages, and chemotactic effect of macrophages were measured with commercial kits. Surface programmed death ligand 1 (PD-L1) expression on macrophages was measured by flow cytometry.Results: Mice in the CLP+PBS group showed a lower survival rate than that in the CLP+rhFNHC-36 group. Improved survival was associated with better clearance of bacterial pathogens, as evidenced by colony formation assays. The CLP-induced decrease in thymus and spleen indices was attenuated by rhFNHC-36 treatments. rhFNHC-36 alleviated sepsis-associated tissue damage in liver, spleen, and lung. CLP-mediated increases in plasma IL-6 levels were reversed by rhFNHC-36 treatment. NO levels in peritoneal macrophages after lipopolysaccharides (LPS)-stimulation in the CLP+rhFNHC-36 group were lower than that in the CLP+PBS group. Notably, macrophages from the CLP+rhFNHC-36 group retained better chemotaxis ability. After LPS challenge, these macrophages had a reduced percentage of PD-L1-positive cells compared to those in the CLP+PBS group.Conclusion: rhFNHC-36 improved survival of mice with CLP-induced sepsis by reducing tissue damage and modulating macrophage function. Our work provides critical insight for developing FN-based and macrophages-targeted therapeutics for treating sepsis.Keywords: fibronectin, heparin-binding domain polypeptide, sepsis, macrophage, cecal ligation and puncture

Xiting Wang, Hao Wang, Qin Zheng, Hui Geng, Jing Zhang, Yan Fan, Xueru Feng, Xiahuan Chen, Meilin Liu Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of ChinaCorrespondence: Meilin Liu, Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China, Email liumeilin@hotmail.comPurpose: Although aspirin can effectively reduce the occurrence of atherothrombosis, it is significantly associated with increased bleeding, with elderly individuals being at increased risk of cardiovascular diseases (CVD) and hemorrhage. This study aims to evaluate the efficacy and safety of aspirin 50 mg/d and 100 mg/d for the prevention and management of CVD in Chinese elderly.Patients and Methods: The Low-dose Aspirin for Primary and Secondary Prevention of Cardiovascular Disease in the Elderly Study (LAPIS) is a multicenter, prospective, observational cohort study, this study was a single-center interim analysis of LAPIS. Patients aged ≥ 60 and required long-term aspirin for primary and secondary prevention of CVD were eligible. From Apr 1, 2019 to Feb 28, 2022, 165 patients who received 50 mg/d aspirin and 261 patients who received 100 mg/d aspirin were included in the study. The incidence of major cardiovascular events (MACEs), bleeding events, and gastrointestinal adverse events were compared between two groups.Results: After adjusting for patient characteristics using propensity score matching, aspirin 100 mg/d was associated with increased incidence rates of total bleeding events (28.34 vs.17.25 events/100 patient-years, HR 1.671, 95% CI 1.024– 2.712, P = 0.040) and minor bleeding events (27.63 vs.15.92 events/100 patient-years, HR 1.738, 95% CI 1.056– 2.861, P = 0.031), whereas the incidence of MACE (6.35 vs 6.65 events/100 patient-years, HR 0.921, 95% CI 0.399– 2.127, P = 0.848) and gastrointestinal adverse events (12.73 vs.10.42 events/100 patient-years, HR 1.206, 95% CI 0.623– 2.337, P = 0.578) were similar between the two groups. Multivariate Cox analysis identified that aspirin dose (100 mg/d vs. 50 mg/d, HR 1.918, 95% CI 1.137– 3.235, P = 0.015), concomitant use of other antiplatelets (HR 1.748, 95% CI 1.009– 3.028, P = 0.046) and anticoagulants (HR 2.501, 95% CI 1.287– 4.862, P = 0.007) were independently associated with bleeding events.Conclusion: 50 mg/d aspirin may be preferred to balance the safety and effectiveness in Chinese individuals over 60 years of age who need long-term aspirin for the prevention and management of CVD.Trial Registration: ChiCTR1900021980 (chictr.org.cn). Registered on 19 March 2019.Keywords: low-dose aspirin, effectiveness outcome, safety outcome, Chinese elderly

Jinhui Hu,1,2,* Zhixin Wu,1,* Huawei Wang,1 Haifeng Geng,1 Jie Huo,1,3 Xueping Zhu,1 Xiaoli Zhu4 1Department of Neonatology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China; 2Neonatal Medical Center, Huai’an Maternity and Child Health Care Hospital, Xuzhou Medical University, Huai’an, People’s Republic of China; 3Department of Neonatology, Yangzhou Maternity and Child Health Care Hospital, Yangzhou, People’s Republic of China; 4Department of Intervention, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueping Zhu, Department of Neonatology, Children’s Hospital of Soochow University, No. 92 Zhongnan Street, Industrial Park, Suzhou, Jiangsu, 215025, People’s Republic of China, Tel +86-13073304816, Fax +86-512-80693599, Email zhuxueping4637@hotmail.com Xiaoli Zhu, Department of Intervention, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Gusu District, Suzhou, Jiangsu, 215006, People’s Republic of China, Tel +86-13013805898, Fax +86-512-65233905, Email zhuxiaoli90@hotmail.comPurpose: Bronchopulmonary dysplasia (BPD) is a common and severe complication in preterm infants. Vitamin D (VitD) has been reported to protect against BPD; however, its role in the mitochondria-mediated and MEK1/2-ERK1/2 pathways has not yet been reported.Methods: We first performed in vivo studies using neonatal C57BL/6 mice in which we induced BPD by exposing them to a hyperoxic environment (85% O2). The mice were divided into room air (RA; 21% O2), RA+VitD, BPD, and BPD+VitD groups. Hematoxylin and eosin and Masson’s trichrome staining were used to evaluate lung injury. Inflammation and apoptosis were measured using ELISA, RT-qPCR, and TUNEL assays. We then analyzed BEAS-2B cells divided into the same groups along with an additional BPD+VitD+inhibitor group. Mitochondrial apoptosis was evaluated by transmission electron microscopy, mitochondrial membrane potential, and Western blotting. We then used VDR-shRNA to silence the Vitamin D Receptor (VDR) in the BEAS-2B cells. The inflammation, apoptotic rate, and the phosphorylated forms of MEK1/2 and ERK1/2 in cells were detected by RT-qPCR, flow cytometry, and Western blotting.Results: The mean linear intercept, septal thickness, and abnormal fibrosis increased, while radial alveolar count decreased in BPD lungs compared to RA lungs. VitD administration was able to ameliorate the phenotype in BPD lungs. IL-6, IFN-γ, and TNF-α expression and the apoptotic rate decreased in the BPD+VitD lung group. VitD pretreatment restored abnormal mitochondrial morphology, reduced mitochondrial membrane loss, and reduced the expression of cleaved caspase-3, Bax, and Bcl-2 in BEAS-2B cells. VitD administration also reduced IL-6, IFN-γ, and TNF-α mRNA, as well as pMEK1/2 and pERK1/2 expression and apoptosis rate in cells exposed to hyperoxia.Conclusion: We concluded that VitD treatment ameliorated apoptosis and inflammation by targeting the mitochondrial pathway and via the MEK1/2-ERK1/2 signaling pathway in BPD, thus supporting its potential therapeutic use in this condition.Keywords: bronchopulmonary dysplasia, vitamin D, hyperoxia, apoptosis, inflammation, mitochondria, MEK1/2-ERK1/2

Tingting Zhao,1,* Jing Guo,1,* Yafang Song,2 Hao Chen,2 Mengzhu Sun,1 Lu Chen,3 Hao Geng,3 Lixia Pei,3 Jianhua Sun3 1Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 2Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 3Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua Sun; Lixia PeiDepartment of Acupuncture Rehabilitation, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, People’s Republic of ChinaEmail 377201634@qq.com; 11801758@qq.comBackground: Migraine is the second-leading cause of disability worldwide. It is often characterized by attacks of severe, mostly unilateral, pulsating headache associated with symptoms such as photophobia, phonophobia, nausea, vomiting, and cutaneous allodynia. Acupuncture therapy has been used worldwide for the treatment of migraine. However, no visual bibliometric analysis has been conducted on the effects of acupuncture on migraine over the past 20 years. Therefore, this study aimed to explore the current status and trends on the use of acupuncture in the treatment of migraine from 2000 to 2020.Purpose: The objective of this study is to identify the current status and emerging trends of the global use of acupuncture on migraine from 2000 to 2020 using CiteSpace and VOSviewer.Methods: Web of Science databases were searched for publications related to acupuncture therapy for treating migraine between 2000 and 2020. CiteSpace and VOSviewer were used to analyze the number of publications per year, countries, institutions, authors, journals, references, and keywords.Results: A total of 572 publications were included in the final analysis. The total number of publications has continued to increase with some fluctuations over the past 20 years. The most productive country and institution in this field were the USA, and Chengdu University of Traditional Chinese Medicine, respectively. The most active and cited authors were Liang FR and Linde K, respectively. Cephalalgia was the most productive, cited, and co-cited journal. The Linde K (2005) had the highest co-citation, citation number and centrality. The keywords “migraine” ranked first in frequency. The common type of migraine (tension-type headache), research method (randomized controlled trial, multicenter, double-blind), acupuncture’s role (prophylactic, quality of life, pain), and evaluation (meta-analysis, systematic review) were the hotspots and frontier trends of acupuncture therapy on migraine between 2000 and 2020.Conclusion: The present study examined the research-related trend in acupuncture therapy on migraine using bibliometric methods and identified the statement and research frontiers over the past two decades. This may help researchers to identify potential hotspots and new directions for future research in this field.Keywords: acupuncture, migraine, bibliometric analysis, CiteSpace, VOSviewer, network

Zhuo Zhang,1 Lu Ma,2 Hui Geng,3 Ying Bian1 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, People’s Republic of China; 2Xi’an Shiyou University, Xi’an, Shaanxi, People’s Republic of China; 3Physical Examination Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Ying BianInstitute of Chinese Medical Sciences, University of Macau, Avenida Da Universidade, Room 2055, N22 Building, Taipa, Macau SAR, People’s Republic of ChinaTel + 86853-66548926Email bianyingum@163.comPurpose: Although drinking and smoking have been associated with gamma-glutamyl transferase (GGT) levels, studies on the effects of smoking and drinking on GGT levels are scarce. The objective of this study was to assess the individual and combined effects of smoking, drinking on GGT levels in the Shaanxi province of Northwest China.Participants and Methods: A questionnaire survey was conducted in a population that underwent health examination at the First Affiliated Hospital of Xi’an Jiaotong University and included employees of enterprises or public institutions. The survey was used to collect the baseline characteristics, smoking status, and drinking status of the participants. This information was collected from January 2019 to December 2019. Data related to the physical examinations were exported using the hospital information system (HIS). A linear regression model was employed to explore the effects of smoking and drinking on GGT levels. The restricted cubic spline model was applied to assess the dose–response relationship between amount of smoking, alcohol consumption and GGT levels.Results: A total of 10,177 participants were included in the study. Linear regression indicated that smoking (β=3.37, 95% CI: 2.57– 4.17) and drinking (β=5.55 L, 95% CI: 4.40– 6.71) individually, and collectively (β=9.30, 95% CI: 7.83– 10.76) had a positive effect on GGT levels. The restricted cubic spline presented a linear dose–response relationship between the amount of daily smoking and GGT levels (P for non-linearity=0.148, P for overall association < 0.001, OR=2.49, 95% CI: 1.27– 4.90), and that between weekly alcohol consumption and GGT levels (P for non-linearity=0.231, P for overall association < 0.001, OR=4.79, 95% CI: 1.72– 13.32). In case of females, stratified analysis showed that in comparison to the reference group, only current drinkers had a significant effect on GGT levels (OR=3.37, 95% CI: 0.19– 6.55).Conclusion: Smoking and drinking have a dose-dependent and a synergistic effect on GGT levels. They should be controlled concurrently, especially among males.Keywords: gamma-glutamyl transferase, smoking, drinking, restricted cubic spline

Jingjing Zhang,1,* Huayun Geng,2,* Ling Liu,1 Hao Zhang1 1Department of Hematology, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong Province, China; 2Department of Hematology, Dongchangfu People’s Hospital of Liaocheng, Liaocheng 252000, Shandong Province, China *These authors contributed equally to this work Background/Aims: Cytotoxicity induced by reactive oxygen species (ROS) is critical for the effectiveness of chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). This study aimed to investigate whether ROS contributes to cytotoxicity in AML cells when treated with homoharringtonine (HHT) and etoposide (ETP) in combination.Methods: AML cell lines THP1 and HL60 and primary AML cells from patients were treated with HHT and ETP alone or in combination, and cell viability was determined by trypan blue exclusion test, and apoptosis was analyzed by annexin-V/propidium iodide double staining as well as Western blot for measuring expression of cleaved caspase-9 and cleaved caspase-3. Intracellular ROS level was detected by DCFH-DA fluorescence assay, and N-Acetyl-L-cysteine (NAC) was used to scavenge intracellular ROS. Retroviral infection was applied to mediate stable overexpression in AML cells.Results: We show that HHT and ETP exhibit synergistic cytotoxicity in AML cell lines and primary AML cells in vitro, and meanwhile, HHT causes elevated ROS generation in ETP-treated AML cells. We next reveal that the elevated ROS is a critical factor for the synergistic cytotoxicity, since ROS scavenge by NAC remarkably diminishes this effect. Mechanistically, we demonstrate that HHT causes elevated ROS generation by disabling thioredoxin-mediated antioxidant defense. Finally, similar to HHT treatment, depletion of thioredoxin sensitizes AML to ETP treatment.Conclusion: These results provide the foundation for augmenting the efficacy of ETP in treating AML with HHT, and also highlight the importance of targeting ROS in improving treatment outcome in AML. Keywords: homoharringtonine, etoposide, synergistic cytotoxicity, acute myeloid leukemia, antioxidant defense, reactive oxygen species, thioredoxin

Xi Zhang,1 Hongjuan Geng,1 Lei Gong,2 Qian Zhang,1 Hongjie Li,1 Xu Zhang,1 Yonglan Wang,1 Ping Gao1 1School and Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, China; 2Department of Esophageal Cancer, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300070, China Background: Prevention of bacterial colonization remains a major challenge in the field of oral implant devices. Chimeric peptides with binding, antimicrobial, and osteogenesis motifs may provide a promising alternative for the inhibition of biofilm formation on titanium (Ti) surfaces. Methods: In this study, chimeric peptides were designed by connecting an antimicrobial sequence from human β-defensin-3 with a Ti-binding sequence and arginine-glycine-aspartic acid using a glycine-glycine-glycine linker. Binding to the Ti substrate and antimicrobial properties against streptococci were evaluated. Significant improvement in reduction of bacterial colonization onto the Ti surface was observed, with or without the presence of saliva or serum. The MC3T3-E1 cells grew well on the modified Ti surfaces compared with the control group. Results: The data showed that the three peptide functional motifs maintained their respective functions, and that the antibiofilm mechanism of the chimeric peptide was via suppression of sspA and sspB gene expression. Conclusion: These results indicated that the endogenous peptide fragments engineered on the Ti surface could provide an environmentally friendly approach for improving the biocompatibility of oral implants. Keywords: multifunctional chimeric peptide, modification of titanium surface, human β-defensin-3, Ti-binding peptide-1, arginine-glycine-aspartic acid-containing peptides

Jiayu Zhang,1 Shiqing Ma,1 Zihao Liu,1 Hongjuan Geng,1 Xin Lu,1 Xi Zhang,1 Hongjie Li,1 Chenyuan Gao,2 Xu Zhang,1 Ping Gao1 1School of Dentistry, Hospital of Stomatology, Tianjin Medical University, Tianjin, 2Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, People’s Republic of China Introduction: Membranes allowing the sustained release of drugs that can achieve cell adhesion are very promising for guided bone regeneration. Previous studies have suggested that aspirin has the potential to promote bone regeneration. The purpose of this study was to prepare a local drug delivery system with aspirin-loaded chitosan nanoparticles (ACS) contained in an asymmetric collagen-chitosan membrane (CCM). Methods: In this study, the ACS were fabricated using different concentrations of aspirin (5 mg, 25 mg, 50 mg, and 75 mg). The drug release behavior of ACS was studied. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were used to examine the micromorphology of ACS and aspirin-loaded chitosan nanoparticles contained in chitosan-collagen membranes (ACS-CCM). In vitro bone mesenchymal stem cells (BMSCs) were cultured and critical-sized cranial defects on Sprague-Dawley rats were made to evaluate the effect of the ACS-CCM on bone regeneration.Results: Drug release behavior results of ACS showed that the nanoparticles fabricated in this study could successfully sustain the release of the drug. TEM showed the morphology of the nanoparticles. SEM images indicated that the asymmetric membrane comprised a loose collagen layer and a dense chitosan layer. In vitro studies showed that ACS-CCM could promote the proliferation of BMSCs, and that the degree of differentiated BMSCs seeded on CCMs containing 50 mg of ACS was higher than that of other membranes. Micro-computed tomography showed that 50 mg of ACS-CCM resulted in enhanced bone regeneration compared with the control group.Conclusion: This study shows that the ACS-CCM would allow the sustained release of aspirin and have further osteogenic potential. This membrane is a promising therapeutic approach to guiding bone regeneration. Keywords: aspirin, nanoparticle, drug release, membrane, guided bone regeneration

Hua Geng, Chengzhong Wang Department of Pediatrics, Maternal and Child Health Hospital of Yancheng, Yancheng City, People’s Republic of China Background: To assess the efficacy and safety of oxcarbazepine (OXC) in the treatment of children with epilepsy.Methods: Randomized controlled trials (RCTs) published in PubMed, Embase, Web of Science, Cochrane Library, Scopus, SinoMed (Chinese BioMedical Literature Service System, China), and Chinese National Knowledge Infrastructure (China) database were systematically reviewed. Eligible studies were those that compared the efficacy and safety of OXC with other antiepileptic drugs in epilepsy. Risk ratio (RR) with 95% confidence intervals (95% CIs) was calculated using fixed-effects or random-effects model.Results: Eleven RCTs with a total of 1,241 patients met the inclusion criteria and were included in this meta-analysis. Compared with other antiepileptic drugs (sodium valproate, levetiracetam, phenytoin, and placebo), OXC was associated with similar seizure-free rate (RR =1.06, 95% CI: 0.94, 1.20; P=0.366) and percentage reduction from baseline in seizure frequency (for ≥75% reduction: RR =1.15, 95% CI: 0.88, 1.49; P=0.310; for 50%–75% reduction: RR =1.12, 95% CI: 0.90, 1.39; P=0.301; for

We formulate a version of the information paradox in de Sitter spacetime and show that it is solved by the emergence of entanglement islands in the context of the De Sitter/de Sitter correspondence; in particular, the entanglement entropy of a subregion obeys a time-dependent Page curve. Our construction works in general spacetime dimensions and keeps the graviton massless. We interpret the resulting behavior of the entanglement entropy using double holography. It suggests that the spatial distribution of microscopic degrees of freedom depends on descriptions, as in the case of a black hole. In the static (distant) description of de Sitter (black hole) spacetime, these degrees of freedom represent microstates associated with the Gibbons-Hawking (Bekenstein-Hawking) entropy and are localized toward the horizon. On the other hand, in a global (effective two-sided) description, which is obtained by the quantum analog of analytic extension and is intrinsically semiclassical, they are distributed uniformly and in a unique semiclassical de Sitter (black hole) vacuum state.

Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood.

Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation ofoncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation ofErk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels,we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse modelsfor pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. Shojaee etal. show that successful transformation of pre-B cells to pre-B acute lymphoblastic leukemia (ALL) requires negative feedback regulation of Erk signaling and inhibiting this feedback selectively kills pre-B ALL cells, suggesting negative feedback regulation of oncogenes as a vulnerability in human ALL.

© 2015 Macmillan Publishers Limited.Despite recent advances in the cure rate of acute lymphoblastic leukaemia (ALL), the prognosis for patients with relapsed ALL remains poor. Here we identify FOXM1 as a candidate responsible for an aggressive clinical cou