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Heterozygous missense mutations in TUBB3 have been implicated in various neurological disorders encompassing either isolated congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or complex cortical dysplasia with other brain malformations 1 (CDCBM1). The description of seizures in patients with TUBB3 mutations is rare. Here, we reported a patient who had febrile seizures before and focal seizure this time, which was diagnosed as epilepsy in combination with an abnormal EEG. MRI showed hypoplastic corpus callosum. Mutation analysis showed a novel de novo heterozygous variant of TUBB3 gene (NM_006086), c.763G>A (p.V255I). He had global developmental delay, photophobia and elliptic pupil, but lacking extraocular muscles involvement and malformations of cortical development, which might be a less severe phenotype of TUBB3 mutations. This was the first report of elliptic pupil in patients with TUBB3 mutations and expanded the spectrum of TUBB3 phenotypes. It indicated that the phenotypic range of TUBB3 mutations might be more continuous than discrete, with a severity ranging from mild to severe. Further studies are needed to elucidate the complete spectrum of TUBB3-related phenotypes.

Guillain-Barré syndrome (GBS) is an immune-mediated polyradiculoneuropathy with the classic presentation of acute onset neurological symptoms preceded by an infective illness, followed by progressive limb weakness. Unilateral facial paralysis is rarely seen in GBS.We reported a child presented with unilateral facial paralysis, limited outward movement of one eye and unilateral lower limb weakness, who was later diagnosed to have GBS. Through reviewing the patients with similar presentation reported previously, we found that the onset time of unilateral facial weakness in relation to other presentations of GBS seemed to be variable, which could be later or earlier than other symptoms, or concomitant. Most of the patients had a relatively good outcome within 2 weeks to 12 months of follow-up.Unilateral facial paralysis may be a feature of GBS, albeit a rare thing. Recognising the clinical patterns of such atypical variants of GBS allows for more timely and accurate diagnosis, and for treatment to be initiated without delay.

Ferredoxin reductase (FDXR), located in 17q25.1, encodes for a mitochondrial NADPH: adrenodoxin oxidoreductase or ferredoxin reductase, the sole human ferredoxin reductase involved in the biosynthesis of iron-sulfur (Fe-S) clusters and heme formation. Iron-sulfur (Fe-S) clusters are involved in enzymatic catalysis, gene expression, and DNA replication and repair. Variants in FDXR lead to sensorial neuropathies, damage optic, and auditory neurons. Here, we report a Chinese boy with hearing loss, visual impairment, and motor retardation, with two novel compound heterozygous variants in FDXR (NM_004110), namely, c.250C > T (p.P84S) and c.634G > C (p.D212H), identified by whole-exome sequencing. Compared with the reported cases, except hearing loss and visual impairment, the clinical manifestations of this boy were more serious, who also had motor retardation and died in infancy after infection. The present study expands our knowledge of FDXR variants and related phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis.

Background Selective activation of Delta-like 1 (DLL1)-Notch signaling is a new approach to activate CD8+ T cell and suppress tumor growth, while the efficacy remains modest. Lentinan (LNT) is a clinically used immunomodulation agent. Thus, we hypothesized that LNT could improve the efficacy of DLL1. Methods The effects of LNT combined with DLL1 on tumor growth were evaluated by growth curve and tumor weight in EO771 breast and LAP0297 lung tumor models. The impacts on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR. Neutrophil depletion was used to investigate the mechanism of the combination therapy on tumor growth. The data sets were compared using unpaired student’s t-test or ordinary one-way ANOVA. Results LNT treatments additively improved the antitumor effects of DLL1 in EO771 breast tumor growth. Remarkably, LNT treatments synergistically enhanced the suppression of DLL1 on LAP0297 lung tumor growth, resulting in tumor regression. Mechanically, the combination of LNT and DLL1 interventions not only promoted the accumulation and activation of CD8+ T cells, but also increased intratumoral CD45+CD11b+Ly6G+ neutrophils. Reduced neutrophils by anti-Gr1 antibody administrations reversed the improved antitumor effects by LNT treatments in LAP0297 lung tumor. These results suggest that LNT treatments improve the inhibition of DLL1 on tumor growth via neutrophils. Conclusions Our findings indicates that LNT and DLL1 may induce synergistical antitumor immunity via simultaneous modulating lymphoid and myeloid cell populations regardless of the type of tumor, providing a potential new strategy to potentiate cancer immunotherapy.

Background MED13L-related intellectual disability is a new syndrome that is characterized by intellectual disability (ID), motor developmental delay, speech impairment, hypotonia and facial dysmorphism. Both the MED13L haploinsufficiency mutation and missense mutation were reported to be causative. It has also been reported that patients carrying missense mutations have more frequent epilepsy and show a more severe phenotype. Case presentation We report a child with ID, speech impairment, severe motor developmental delay, facial deformity, hypotonia, muscular atrophy, scoliosis, odontoprisis, abnormal electroencephalogram (EEG), and congenital ureteropelvic junction obstruction (UPJO) combined with high ureter attachment. We used whole-exome sequencing (WES) to detect the genetic aberration of the child and found a de novo mutation, c.2605C > T (p.Pro869Ser), in the MED13L gene. Neither of her parents carried the mutation. Additionally, we review the literature and summarize the phenotypes and features of reported missense mutations. After reviewing the literature, approximately 17 missense mutations in 20 patients have been reported thus far. For 18 patients (including our case) whose clinical manifestations were provided, 100% of the patients had ID or developmental delay (DD). A total of 88.9, 83.3 and 66.7% of the patients had speech impairment, delayed milestones and hypotonia, respectively. A total of 83.3% of the patients exhibited craniofacial deformity or other dysmorphic features. Behavioral difficulties and autistic features were observed in 55.6% of the patients. Cardiac anomalies were seen in only 27.8% of the patients. Of these patients, 44.4% had epileptic seizures. Of the 17 mutations, 2 were located in the N-terminal domain, 8 were located in the C-terminal domain, and 1 was located in an α-helical sequence stretch. One of them was located in the MID domain of the MedPIWI module. Conclusions We report a new patient with a reported missense mutation, c.2605C > T (p.Pro869Ser), who exhibited some infrequent manifestations except common phenotypes, which may broaden the known clinical spectrum. Additionally, by reviewing the literature, we also found that patients with missense mutations have a higher incidence of seizures, MRI abnormalities, autistic features and cardiac anomalies. They also have more severe ID and hypotonia. Our case further demonstrates that Pro869Ser is a hotspot mutation of the MED13L gene.

With the rapid development of genetic detection technology, especially next-generation sequencing, identification of the aetiology of unexplained intellectual disabilities accompanied by seizures and other dysmorphic features has become possible. The purpose of our paper is to make a definitive diagnosis of a girl with neonatal hypotonia, severe global developmental delay, seizures and mild facial dysmorphism.The clinical data of the patient were retrospectively studied. Whole-exome sequencing was performed on a blood sample from the patient. Subsequently, Sanger sequencing was utilized for validation of variants and parental validation.The patient had hypotonia since the neonatal period. She showed a significant delay in physical and psychomotor development. She did not have any speech until the age of 2 years and 6 months. She had seizures that were easy to control with levetiracetam. The craniocerebral magnetic resonance imaging (MRI) then showed mild delayed myelination, enlarged bilateral ventricles and widened frontotemporal extracerebral space. Interictal video electroencephalogram (VEEG) was normal. She had esotropia and mild facial abnormalities with a flat nasal bridge and a short nose. She showed no abnormalities in the heart, genitourinary or skeletal systems. Whole-exome sequencing revealed a novel de novo variant c.5334_5335delAG (p. Arg1778Serfs*11) in the SON gene.Our paper reports a novel variant in the SON gene and provides a definitive diagnosis of a female with neonatal hypotonia, severe global developmental delay, seizures and mild facial abnormalities, which are symptoms consistent with Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome).

To characterize the clinical and genetic characteristics of a large cohort of patients with pyridoxine-dependent epilepsy (PDE).We retrospectively collected clinical and genetic information of 33 (15 males, 18 females; mean [SD] age 4y 11mo [2y 5mo]; 1y 3mo-10y 4mo) patients with PDE from 31 unrelated families at a single centre.There were many types of seizures, with focal seizures in 32 cases. Dravet syndrome was suspected clinically in two patients. Electroencephalogram (EEG) was normal in seven patients at the initial stage and then in 17 patients during pyridoxine maintenance therapy. Genetic studies revealed 26 kinds of variants in ALDH7A1 and four in PLPBP with 18 variants unreported previously, and 48 ALDH7A1 variants were located in exon 11, 12, 14, and 17 or intron 9 and 11. In addition, three patients carried different exons deletion. Among these, seizures could be controlled for several years in one patient by levetiracetam monotherapy. Another patient remained seizure free for up to 7 months without therapy. All patients received oral pyridoxine treatment, with only one case (with exon 8-13 deletion) showing poor control.This study illustrates the range of clinical presentations and genetic causes in PDE, as well as responsiveness to antiepileptic drugs. A relationship between EEG and pyridoxine therapy could be seen in many cases. Seizure control was seen in all with pyridoxine monotherapy except for one patient.There is a parallel relationship between electroencephalogram and pyridoxine therapy in many patients. Patients with pyridoxine-dependent epilepsy may respond well to low-dose pyridoxine.目的: 总结33例吡哆醇依赖性癫痫（pyridoxine-dependent epilepsy, PDE）患者的临床特征及遗传学特点。 方法: 回顾性收集33例PDE患者的临床资料（15位男性，18位女性；平均年龄[SD]：4岁11个月[2岁5个月]；1岁3个月~10岁4个月), 所有患者均进行遗传学检测。 结果: 癫痫发作类型多样，32例患者出现局灶性发作。2例患者在未经遗传学确诊前临床疑诊为Dravet综合征。7例患者初次脑电图正常，随后，在吡哆醇维持治疗期间，17的患者脑电图恢复正常。基因检测结果提示有26种不同的ALDH7A1突变，4种PLPBP突变。其中，18种突变国际上未见相关报道。48个ALDH7A1突变位于外显子11、12、14和17或内含子9和11。此外，3例患者携带不同的外显子缺失。33例患者中，1例经左乙拉西坦单药治疗可控制数年无发作，另1例在接受治疗前，可7个月无癫痫发作。所有患者均口服吡哆醇治疗，仅有1例携带8-13号外显子缺失的患者经吡哆醇单药治疗后，发作未控制。 结论: 本研究总结了33例PDE患者临床及遗传学特征，以及抗癫痫药的治疗效果。本研究揭示了脑电图与长期吡哆醇维持治疗之间的一种平行关系。另外，在本研究中，32例患者可被吡哆醇单药控制。.

Background Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of severe disorders that are characterized by early-onset, refractory seizures and developmental slowing or regression. Genetic variations are significant causes of these changes. De novo variants in an increasing number of candidate genes have been found to be causal. The YWHAG gene is one such gene that has been reported to cause developmental and epileptic encephalopathy 56 (DEE56). Here, we report a heterozygous missense variant, c.170G > A (p.R57H), in the YWHAG gene that caused early-onset epilepsy and developmental delay in a Chinese family. Methods We described the clinical manifestations of the proband and his mother in detail. Then, we use trio-based whole-exome sequencing to search the etiology of this family. Results Both the proband and his mother exhibited early-onset seizures, intellectual disability, and developmental delay. While the proband attained seizure control with sodium valproate, his mother's seizures were not well controlled. Trio-based whole-exome sequencing revealed a heterozygous missense variant, c.170G > A (p.R57H), in the YWHAG gene, which was considered as the cause of early-onset epilepsy and developmental delay in this family. Conclusions Our report further confirmed that YWHAG haploinsufficiency results in developmental and epileptic encephalopathy 56.

Variants in HNRNPU have been reported in patients with epileptic encephalopathy, early infantile 54 (OMIM 602869). We hereby describe two children from different families with autosomal dominance early-onset epileptic encephalopathy, and summarize the genotype and phenotype of reported individuals. Whole exome sequencing analysis was applied to the patients. De novo frameshift variants in the HNRNPU, c.143_149del7 (p.G48Afs*11) and c.1282delC(p.G429Afs*53) were identified respectively. This is the first time to report Chinese patients with early infantile epileptic encephalopathy causing by HNRNPU variants, and so far, these variants have not been reported in population gene database. The present study expands our knowledge of HNRNPU variants and emphasizes the importance of early gene diagnosis.

To explore the genetic basis for a child with mental and motor retardation, language impairment, facial dysmorphism and epilepsy.Whole exome sequencing was carried out to detect pathogenic variant in the proband, and candidate variant was selected based on his phenotype. Sanger sequencing was used to verify the variant in the proband, his parents and other family members.The proband was found to carry a frameshifting mutation of MBD5 gene, namely c.2217delT (p.F739Lfs*6), which was inherited from his mother and unreported previously. Sanger sequencing confirmed that his brother carried the same mutation with a similar phenotype. His mother also had poor language expression when she was young, in addition with poor academic performance, though she could do some housework and had no history of convulsion.A novel pathogenic variant of the MBD5 gene was discovered, which has enriched the mutational spectrum of the MBD5 gene. Above discovery has enabled genetic counseling and prenatal diagnosis for the family.

Background Hemiconvulsion–hemiplegia–epilepsy (HHE) syndrome is a rare syndrome characterized by childhood onset partial motor convulsions, hemiplegia, and epilepsy in sequence. Exact pathogenesis is not clear. Case presentation: We present a girl with global developmental delay with history and brain MRI consistent with the diagnosis of HHE syndrome. The cytogenetic microarray (CMA) showed 9.1 Mb deletion in 5q33.3q34 region. Along with HHE syndrome, the patient also had global developmental delay. Clinical phenotype of this microdeletion region has not been described in association with HHE syndrome in the literature. We compared the patient’s phenotype with other patients in 5 previously published papers of a common region of deletion spanning 157501989–164166203. GABRA1, GABRB2, GABRG2, CYFIP2, THG1 are the important genes in the present deleted region, which may be responsible for the fever sensitivity and global developmental delay. Conclusions This is the first case of HHE syndrome in which CMA showed a microdeletion of 5q33.3q34 region. This case report links HHE syndrome and global developmental delay to microdeletions of 5q33.3q34, which has never been reported in literature. Cause of HHE syndrome remains unexplained in present case and HHE may be a causal or chance co-occurrence.

Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.

In Vibrio parahaemolyticus, type III secretion system 1 (T3SS1) is a major virulence factor that delivers effectors into the host eukaryotic cytoplasm; however, studies on its infection mechanism are currently limited. To determine the function of the vscF gene, we constructed the vscF deletion mutant ΔvscF and complementation strain CΔvscF. Compared with those of wild-type POR-1 and CΔvscF, the cytotoxic, adherent, and apoptotic abilities of ΔvscF in HeLa cells were significantly reduced (P < 0.01). Furthermore, in infected HeLa cells, the mutant strain reduced the translocation rates of VP1683 and VP1686 effectors compared to the wild-type and complementation strains. A BLAST search showed that vscF is homologous to the MixH needle protein of Shigella flexneri, indicating that the vscF gene encodes the needle protein of T3SS1 in V. parahaemolyticus. Additional translocation assays showed that VPA0226 translocated into the HeLa eukaryotic cytoplasm via T3SS1, secretion assays showed that VPA0226 can be secreted to supernatant by T3SS1, indicating that VPA0226 belongs to the unpublished class of T3SS1 effectors. In conclusion, our data indicate an essential role of vscF in V. parahaemolyticus T3SS1 and revealed that VPA0226 can be secreted into the host cell cytoplasm via T3SS1. This study provides insights into a previously unexplored aspect of T3SS1, which is expected to contribute to the understanding of its infection mechanism.

Objective To summarize and extend the phenotypic characterization of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome, and to discuss genotype-phenotype correlations. Methods Collecting clinical information of 17 patients with pathogenic variants in PIGN, PIGA, and PIGT. Genetic studies were performed on all patients. Results There were 7 patients with 15 PIGN mutations (one patient carrying 3 mutations), 8 patients with 8 PIGA mutations, and 2 patients with 5 PIGT mutations (one patient carrying 3 mutations). All patients had epilepsy and developmental delay, with 71% of them showed hypotonia. And among these patients’ various seizure types, the focal seizure was the most common one. Eighty-two percent patients showed a significant relationship between seizures and fever. Serum ALP was elevated in one patient with PIGN mutations and in two patients with PIGA mutations. Brain MRI showed enlarged subarachnoid space in 56% of patients. Some other different characteristics had also been found in our patients: First, atypical absence seizures presented in three patients with PIGN mutations; Second, diffuse slow waves mixed with focal or multifocal discharges of interictal EEG in 88% cases with PIGA-deficient; Third, phenotypes of seven out of eight patients with PIGA mutations were difficult to be classified as severe or less severe group; Last, mild neurological symptoms and developmental status rather than severe conditions occurred in one patient with PIGT mutations. Conclusion With epilepsy, developmental delay, and/or hypotonia as common features, the knowledge of MCAHS in terms of phenotype and genotype has been expanded. In cases with PIGN-deficient, we expanded the types of atypical absence seizures, and described one patient with elevated serum ALP. Focal seizures with diffuse slow waves mixed with focal or multifocal discharges on EEG rather than infantile spasms with hypsarrhythmia, which as previously reported were often seen in our patients with PIGA mutations. The classifications of phenotypes caused by PIGA mutations should be more continuous than discrete. The mild phenotype of one patient with PIGT mutations expanded the clinical presentation of MCAHS3.

Objective To investigate high-frequency oscillations (HFOs) in epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) with different etiologies. Methods Twenty-one CSWS patients treated with methylprednisolone were divided into structural group and genetic/unknown group. Comparisons were made between the two etiological groups: selected clinical variables including gender, age parameters, seizure frequencies and antiepileptic drugs; distribution of HFOs in pre-methylprednisolone electroencephalography (EEG) and percentage changes of HFOs and spikes after methylprednisolone treatment. Results There were 7 patients (33%) in structural group and 14 patients (68%) in genetic/unknown group. No significant difference was found between the two groups regarding selected clinical variables. HFOs were found in 12 patients in pre-methylprednisolone EEG. The distribution of HFOs was focal and accordant with lesions in 5 of structural group, and it was also focal but in different brain regions in 7 of genetic/unknown group. The percentage reduction of total HFOs and spikes was 81% (158/195) and 19% (1956/10,037) in structural group, while 98% (315/323) and 55% (6658/12,258) in genetic/unknown group after methylprednisolone treatment. Conclusion The etiologies had no distinct correlation with some clinical characteristics in CSWS. HFOs recorded on scalp EEG might not only be used as makers of seizure-onset zone (SOZ), but also have association with functional disruption of brain networks. Both HFOs and spikes reduced more in genetic/unknown patients than that in structural patients after methylprednisolone treatment and HFOs were more sensitive to treatment than spikes.

Objective To investigate the general characteristics and the category of myoclonic epilepsy in infancy (MEI) with or without afebrile generalized tonic-clonic seizures (GTCS). Methods Thirty-three children were retrospectively recruited from approximately 42,814 video-electroencephalogram (VEEG) recordings monitored in our department over last nearly 10 years. Myoclonic seizures (MS) must be identified by VEEG in all patients. The clinical, EEG features and outcome were analyzed among these patients. Results The 33 patients (25 boys and 8 girls) were divided into three groups: 11 patients with typical MEI; 16 patients with MEI experienced afebrile GTCS before MS onset; and 6 patients with MEI presented afebrile GTCS occurring concurrently with MS. No significant differences were found among the three groups, including gender distribution, family history, personal history of febrile seizures, the age at seizure onset and control, the duration of MS, the interval between age at onset and seizure control, the age at EEG normalization, the interval between seizure onset age and EEG normalization age and normal psychomotor development at the end of follow-up. More patients in group two and group three were controlled by two or three kinds of antiepileptic drugs compared with those in group one. Conclusions In this study, three groups of patients had similar clinical, EEG features and outcome. Afebrile GTCS was associated with a stronger cortical hyperexcitability. It was worth considering whether MEI with preceding or concurrent afebrile GTCS should be recognized as subgroups or different epileptic syndromes independent of MEI.

Creating a favorable thermal environment in an outdoor space is essential for attracting more occupants to outdoor areas and vitalizing a city. It is possible to study occupants’ needs in an outdoor thermal environment by observing their attendance and behaviors, since people may exhibit certain adaptive measures, such as seeking shade, using parasols, etc., “vote with their feet”, or even leave the space, if they feel uncomfortable. In order to investigate the influence of thermal environment on attendance and adaptive behaviors in outdoor spaces, in this study we carried out field campaigns in a university campus in a cold-climate city. The thermal environment was monitored, while surveys of thermal perceptions and observations of attendance and adaptive behaviors were conducted. Through the data analyses, it was found that the thermal environment had a great impact on the attendance of optional activities, but necessary activities were not influenced. The greatest influence on attendance came from air temperature. The influences of wind and humidity on attendance were found to be coupled with that of air temperature. Adaptive behaviors, such as seeking shade, using parasols, changing clothes, and changing the lengths of stay, were also greatly influenced by air temperature.

Radiotherapy is emerging as an important modality for the local control of pancreatic cancer, but pancreatic cancer cell radioresistance remains a serious concern. Peroxisome proliferator-activated receptor α (PPARα) is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. The clinical relevance of PPARα and its biological function in pancreatic cancer radiosensitivity have not been previously described. In this study, we examined PPARα expression in tissue samples of pancreatic cancer patients. We found significantly higher expression of PPARα in pancreatic cancer tissues than in tumor-adjacent tissues and that the PPARα expression level is inversely associated with higher overall patient survival rate. We further observed that PPARα activation by its agonist clofibrate sensitizes pancreatic cancer cells to radiation by modulating cell cycle progression and apoptosis in several pancreatic cancer cell lines. Small interfering RNA-mediated PPARα silencing and PPARα blockade by the antagonist GW6471 abolish the effect of clofibrate on radiosensitization. An in vivo study showed that PANC1 xenografts treated with clofibrate are more sensitive to radiation than untreated xenografts. mRNA profiling by microarray analysis revealed that the expression of PTPRZ1 and Wnt8a, two core components of the β-catenin pathway, is downregulated by clofibrate. Chromatin immunoprecipitation analysis confirmed that clofibrate abrogates the binding of nuclear factor-κB to the PTPRZ1 and Wnt8a promoters, ultimately decreasing Wnt/β-catenin signaling activity, which is associated with radiosensitivity. Overall, we demonstrate that PPARα is overexpressed in pancreatic cancer tissues and clofibrate-mediated PPARα activation sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway.

Objective To elucidate the characteristics of the myoclonic seizures alone, or predominant myoclonus combined with generalized tonic-clonic seizures (GTCS) and/or absences, in early childhood, and discuss its classification. Methods Forty-two children were retrospectively recruited between January 2006 and June 2015. Results The mean age of seizure onset was 40.5 months. They were divided into 4 groups: myoclonic seizures alone; predominant myoclonus combined with GTCS; predominant myoclonus combined with absences; predominant myoclonus combined with both GTCS and absences. Interictal EEG showed generalized spike- or polyspike-wave discharges at 2–4 Hz. Seizures were controlled in 22 patients at a mean age of 60.5 months. The psychomotor development was normal (30/37) or mildly delayed (7/37). Conclusions We reported a cohort of patients with early childhood myoclonic epilepsy (ECME), with the following characteristics: Seizures started below 5 years old in otherwise normal children; Seizure types included myoclonic seizures alone or combined with GTCS and/or absences; Febrile or afebrile GTCS might appear firstly; Interictal EEG showed generalized spike- or polyspike-wave; Seizures usually were in remission before adolescence with normal development or mild cognitive or behavioral deficits in most. Significance ECME might be an independent epileptic syndrome not established by International League Against Epilepsy (ILAE) previously.

Epilepsia partialis continua (EPC) was one type of focal status epilepticus. The aim of this study was to analyze the clinical and electroencephalography (EEG) characteristics, and outcome of 57 child-onset patients with EPC according to different etiologies, and further explore the electro-clinical-etiological associations.We retrospectively reviewed 57 children diagnosed with EPC in our department over last ten years. Etiology, clinical and EEG data, and outcome were categorized and analyzed.For the 57 child-onset patients, EPC was caused by different etiologies, including immune-related disease (43.9%), focal lesions (17.5%), inborn errors of metabolism (24.6%), and unknown (14.0%). EEG background abnormalities showed generalized slowing in 45 patients (78.9%) and focal slowing in two patients (3.5%). Nineteen patients (33.3%) presented clear correlation of ictal EEG/EMG and the remaining 38 patients (66.7%) showed no clear correlation of ictal EEG/EMG. Both EEG background activity and ictal EEG/EMG correspondence among different etiologies had statistical significance (P0.05). The ictal patterns without clear EEG/EMG correspondence in immune-related disease and the ictal patterns with clear EEG/EMG correspondence in focal lesions were more prominent (P0.05).This is the first study of child-onset EPC with a large series in a pediatric epilepsy center in China. The most common cause for EPC was immune-related disease. The EEG background activity and the EEG/EMG correspondence might be influenced by the etiologies of EPC to some degree. These findings might guide the direction of EPC diagnosis in conjunction with other examinations.

Objective To study the atonic elements combined or uncombined with epileptic spasms in infantile spasms. Methods The demographic data, clinical characteristics, electroencephalogram (EEG), and polyelectromyography (PEMG) features were analyzed in 12 infantile spasm patients with atonic elements. Results A total of 29 EEGs were recorded. Hypsarrhythmia or hypsarrhythmia variants were identified during interictal EEG. Insular or clustered epileptic spasms occurred in all. Three subtypes of atonic elements combined or uncombined with epileptic spasms (spasm-atonic, pure atonic, and atonic-spasm seizures) were observed electroclinically, which could present insularly or in cluster or altered with epileptic spasms in the same cluster. The ictal EEG showed generalized high-amplitude slow waves presenting alone or combined with other patterns. The corresponding PEMG showed an obvious electrical silence alone or preceding or following a crescendo-decrescendo pattern generated from myoelectric burst. Conclusions Atonic elements combined or uncombined with epileptic spasms was a newly noticed phenomenon in infantile spasms, which was artificially divided into three subtypes here. It might be a variant of epileptic spasms or a unique seizure type. Significance Atonic elements combined or uncombined with epileptic spasms was a previously ignored phenomenon in infantile spasms, which should be seriously considered in clinical practice.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, is widely studied as a cancer chemopreventive agent with potential anti-cancer effects. The NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway is considered to mediate cellular resistance to EGCG. Metformin, a classical antidiabetic drug, has been shown to prevent cancer progression. Researchers have not reported whether metformin potentiates the anti-cancer efficacy of EGCG. In this study, metformin inhibited HO-1 expression and augmented the anti-tumor effect of EGCG. Metformin also enhanced ROS (reactive oxygen species) generation induced by EGCG (100 μM), subsequently resulting in apoptosis. Based on the results of the in vivo study, size of xenografts treated with the combination of metformin and EGCG was smaller than other groups. Mechanistically, metformin modulated the EGCG-activated Nrf2/HO-1 pathway through Sirtuin 1 (SIRT1)-dependent deacetylation of Nrf2. Moreover, metformin upregulated SIRT1 expression partially through the NF-kB pathway. Comparatively, the combination of EGCG and metformin showed little impact on normal lung epithelial BEAS-2B cells. Based on our findings, metformin sensitized NSCLC cells to the EGCG treatment by suppressing the Nrf2/HO-1 signaling pathway.

Background and purpose The aim was to determine the electroclinical findings in benign childhood focal epilepsy with vertex spikes (BEVS) with epileptic negative myoclonus (ENM) restricted to the lower limbs. Methods The electroencephalogram database of Peking University First Hospital and medical records of patients with BEVS and ENM restricted to the lower limbs were reviewed. Results Twenty-seven patients with BEVS had ENM restricted to the lower limbs. Twelve started as ENM restricted to the lower limbs. The age at seizure onset ranged from 1.5 to 4.8 years. During the course, half of the 12 patients developed focal sensorimotor seizures and then were diagnosed as benign childhood epilepsy with centrotemporal spikes (BECTS), with BEVS (four cases) and without BEVS (two cases). Five of them had electrical status epilepticus during sleep (ESES) and met the diagnostic criteria of atypical benign partial epilepsy (ABPE). Fifteen of the 27 patients had ENM restricted to the lower limbs during the course. The age at seizure onset ranged from 1.3 to 9.8 years. All had ESES and were diagnosed as ABPE, 11 as ABPE with BEVS and four as ABPE evolving into BEVS. Conclusions Benign childhood focal epilepsy with vertex spikes (BEVS) might represent a specific epileptic syndrome of the continuum of benign childhood focal epilepsy. ENM restricted to the lower limbs was a special phenomenon in BEVS. BEVS could overlap with BECTS or evolve into BECTS and further into ABPE and vice versa. Ignorance of vertex spikes with associated ENM restricted to the lower limbs might lead to a misunderstanding of BEVS, a specific type of benign childhood focal epilepsy.

Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as attractive therapeutic targets for obesity and hypercholesteremia, respectively. Obesity and hypercholesteremia usually co-exist, however no dual-inhibitors against PTL and NPC1L1 were reported for the treatment of obesity patients with hypercholesteremia so far. In this work, molecular hybridization-based one-step modification screening identified a potent dual-inhibitor against PTL and NPC1L1. Compound P1-11 has IC50 values of 2.1 μM against PTL through covalent binding, as well as significantly reduces cholesterol absorption in a non-competitive inhibitory manner. Molecule docking and molecular dynamics studies revealed the reason of its activity to both PTL and NPC1L1. Moreover, the gene and protein expression levels of PTL and NPC1L1 were also determined respectively after the treatment of P1-11. Development of dual-inhibitors against PTL and NPC1L1 could provide novel treatment options for obesity patients with hypercholesteremia. The results of current research would great support the development of dual-inhibitors against PTL and NPC1L1.

Purpose Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder caused by mutations of the ALDH7A1 gene. We aimed to analyze the relations between the clinical diagnosis and treatment of PDE and ALDH7A1 gene mutations in Chinese PDE patients. Methods The clinical manifestations, diagnosis and treatment were observed in a cohort of PDE patients with early onset of seizure. Video-electroencephalogram (VEEG) and magnetic resonance imaging (MRI) were performed. The mutation of ALDH7A1 gene was analyzed. Results Of eight patients, six were males and two were females. Age of seizure onset ranged from 1 to 100 days and 75% patients presented with seizures in the neonatal period. All patients showed different degrees of developmental delay. EEGs showed focal or multifocal discharges, or were normal. Molecular analysis revealed 10 ALDH7A1 mutations, including 2 splice site mutations. Five patients had mutation at IVS11+1G>A site, six patients had missense mutations, one with nonsense mutation and another patient had 9-bp genomic deletion mutation. Among them, two mutations were first time reported. Conclusions Seizure onset was in neonatal or early infantile period in our PDE patients. Early recognition and diagnosis of the disease is necessary for early intervention and improve cognitive development in the later life. In this study, on the molecular level, we also identified the splice site mutation IVS11+1G>A as a high prevalence mutation site with a frequency of 31.25% (5 of 16 alleles) in Chinese PDE patients.

Objective The aim of this study was to investigate the effects of epigallocatechin-3-gallate on the proliferation and apoptosis of odontogenic keratocyst (OKC) keratinocytes in vitro. Materials and methods Keratinocytes isolated from the epithelial lining of the OKC were cultured in keratinocyte serum-free medium and identified by CK10, CK14, pan-cytokeratin and vimentin immunofluorescence staining. The cells were exposed to EGCG at different concentrations, and proliferation inhibition was measured by cell counting kit 8 assay. Cell cycle and apoptosis were assessed by flow cytometry, and expression of the WNT signalling pathway-related proteins FZD3 and JNK3 was detected by quantitative real-time PCR and Western blotting. Human oral keratinocytes (HOKs) were used as the control. Results The OKC keratinocytes were successfully cultured. The primary cells were tile-like and expressed the epithelial biomarkers CK10, CK14 and pan-cytokeratin. Epigallocatechin-3-gallate inhibited cell proliferation in a dose- and time-dependent manner, arrested cell cycle in the G1 phase and induced apoptosis of OKC keratinocytes. FZD3 and JNK3 were overexpressed in OKC keratinocytes compared with HOKs and were downregulated by epigallocatechin-3-gallate treatment. Conclusion Epigallocatechin-3-gallate inhibited proliferation and induced apoptosis in OKC keratinocytes, possibly by suppressing the WNT/JNK signalling pathway. It may thus be potentially used for OKC treatment.

In the present study, two polysaccharides (HIOP1-S and HIOP2-S) were isolated and purified from Inonotus obliquus using DEAE-52 cellulose and Sephadex G-100 column chromatography. The structural characterization and in vitro and in vivo hypoglycaemic activities of these molecules were investigated. HPLC analysis HIOP1-S was a heterpolysaccharide with glucose and galactose as the main compontent monosaccharides (50.247%, molar percentages). However, HIOP2-S was a heterpolysaccharide with glucose as the main monosaccharide (49.881%, molar percentages). The average molecular weights of HIOP1-S and HIOP2-S were 13.6 KDa and 15.2 KDa, respectively. The β-type glycosidic bond in HIOP1-S and HIOP2-S was determined using infrared analysis. 1H-NMR spectra indicated that HIOP2-S contains the β-configuration glycosidic bond, and the glycoside bonds of HIOP1-S are both α-type and β-type. The ultraviolet scanning showed that both HIOP1-S and HIOP2-S contained a certain amount of binding protein. Congo red test showed that HIOP1-S and HIOP2-S could form a regular ordered triple helix structure in the neutral and weakly alkaline range. HIOP1-S and HIOP2-S showed strong α-glucosidase inhibitory activities and increased the glucose consumption of HepG2 cells. In addition, Streptozotocin (STZ)-induced hyperglycaemic mice were used to evaluate the antihyperglycaemic effects of HIOP1-S and HIOP2-S in vivo. The results showed that HIOP2-S had antihyperglycaemic effects. Taken together, these results suggest that HIOP1-S and HIOP2-S have potential anti-diabetic effects.

Clinically, some patients having genetic (idiopathic) epilepsy with photosensitive seizures were difficult to be diagnosed. We aimed to discuss whether the genetic (idiopathic) epilepsy with photosensitive seizures is a focal entity, a generalized entity or a continuum. Twenty-two patients with idiopathic epilepsies and photoconvulsive response (PCR) were retrospectively recruited. In the medical records, the seizure types included “generalized tonic-clonic seizures (GTCS)” in 15, “partial secondarily GTCS (PGTCS)” in 3, partial seizures (PS) in 3, myoclonic seizures in 2, eyelid myoclonus in one, and only febrile seizures in one. Seizure types of PCR included GTCS (1/22), PGTCS (6/22), PS (9/22), electrical seizures (ES) (3/22) and GTCS/PGTCS (3/22). Combined the medical history with PCR results, they were diagnosed as: idiopathic (photosensitive) occipital lobe epilepsy (I(P)OE) in 12, genetic (idiopathic) generalized epilepsy (GGE) in one, GGE/I(P)OE in 5, pure photosensitive seizure in one, and epilepsy with undetermined generalized or focal seizure in 3. So, the dichotomy between generalized and focal seizures might have been out of date regarding to pathophysiological advances in epileptology. To some extent, it would be better to recognize the idiopathic epilepsy with photosensitive seizures as a continuum between focal and generalized seizures.

Formyl peptide receptor 2 (FPR2), a classical chemoattractant receptor of G-protein-coupled receptors, is reported to be involved in invasion and metastasis of some cancers, but the role of FPR2 in gastric cancer (GC) has not yet been elucidated. In this study, we found that the levels of FPR2 expression in GC were positively correlated with invasion depth, lymph node metastasis and negatively correlated with the patients’ overall survival. Multivariate analysis indicated that FPR2 expression was an independent prognostic marker for GC patients. FPR2-knockdown significantly abrogated the migration and invasion stimulated by Hp(2–20) and Ac(2–26), two well-characterized ligands for FPR2 in GC cells. FPR2 deletion also reduced the tumorigenic and metastatic capabilities of GC cells in vivo. Mechanistically, stimulation with FPR2 ligands resulted in down-regulation of E-cadherin and up-regulation of vimentin, which were reversed by FPR2 knock-down, implying the involvement of epithelial–mesenchymal transition (EMT). Moreover, the activation of FPR2 was accompanied with ERK1/2 phosphorylation, which could be attenuated by FPR2 silencing or treatment with MEK inhibitor, PD98059. Altogether, our results demonstrate that FPR2 is functionally involved in invasion and metastasis, and potentially acts as a novel prognostic marker as well as a potential therapeutic target in human GC.

Radiation-induced skin injury is a common side effect of radiotherapy and can limit the duration and dose of radiotherapy. Most early work focused on elimination of reactive oxygen species (ROS) after radiation; however, less is known about the mechanisms underlying amplification of ROS and consequent skin injury by radiation. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for all nitric oxide synthases. Inadequate availability of BH4 leads to uncoupling of nitric oxide synthases and production of highly oxidative radicals. In this study, we demonstrated that radiation disrupted BH4, which resulted in nitric oxide synthases uncoupling and augmented radiation-induced ROS. Overexpression of GTP cyclohydrolase I (GCH1), the rate-limiting enzyme for BH4 synthesis, restored cellular BH4 levels and nitric oxide production and decreased radiation-induced ROS. GCH1 also protected skin cells and rat skins against radiation-induced damage. We found that GCH1 was regulated by NF-E2-related factor 2, a key mediator of the cellular antioxidant response. Importantly, we identified GCH1 as a key effector for NF-E2-related factor 2-mediated protection against radiation-induced skin injury by inhibiting ROS production. Taken together, the findings of this study illustrate the key role of the NF-E2-related factor 2/GCH1/BH4 axis during radiation-induced skin damage.

Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, is a potent antioxidant and free radical scavenger that may have therapeutic applications for the treatment of many disorders. Radiation therapy is widely used for the treatment of various types of cancers; however, radiation-induced skin injury remains a serious concern. EGCG has not yet been reported as protecting skin cells against ionizing radiation. In the present study, we investigated whether EGCG confers cytoprotection against ionizing radiation. We found that, compared with the control, pretreatment with EGCG significantly enhanced the viability of human skin cells that were irradiated with X-rays, and decreased apoptosis induced by X-ray irradiation. Mito-Tracker assay showed that EGCG suppressed the damage to mitochondria induced by ionizing radiation via upregulation of SOD2. Reactive oxygen species (ROS) in HaCaT cells were significantly reduced when pretreated with EGCG before irradiation. Radiation-induced γH2AX foci, which are representative of DNA double-strand breaks, were decreased by pretreatment with EGCG. Furthermore, EGCG induced the expression of the cytoprotective molecule heme oxygenase-1 (HO-1) in a dose-dependent manner via transcriptional activation. HO-1 knockdown or treatment with the HO-1 inhibitor tin protoporphyrin (SnPPIX) reversed the protective role of EGCG, indicating an important role for HO-1. These results suggest that EGCG offers a new strategy for protecting skin against ionizing radiation.

To analyze the clinical and genetic characteristics of Chinese patients with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency. The clinical presentations and the responses to treatments were analyzed in 4 patients. Blood and urinary metabolic screenings, electroencephalogram (EEG), brain magnetic resonance imaging (MRI) and epilepsy-related genes detection were performed in all patients. Patient 1 and 2 were identical twin brothers, who were born at 35+5 w gestation with a sign of encephalopathy. Their seizures started within the first day and could not be controlled by pyridoxine or pyridoxal-5'-phosphate (PLP) completely. Patient 3 presented seizures at 5 months, responding well to pyridoxine. Seizures in patient 4 began at 40 days after birth and were controlled by valproic acid and topiramate. EEG showed atypical hypsarrhythmia or multifocal epileptiform discharges in 3 patients, and showed normality in patient 4. MRI showed nonspecific abnormality or normality. Blood metabolic screening showed multiple amino acids level abnormalities in all cases. Urinary metabolic screening showed vanillactic acid prominently elevated in 3 patients. Genetic analysis revealed 5 mutations of PNPO, three of which were novel. The mutation c.445_448del was carried by the twins and patient 3. Assessment of psychomotor development indicated severe delay in 3 patients and borderline to mild delay in patient 3. This is the first time to report patients with PNPO deficiency diagnosed by gene analysis in China. The novel clinical characteristics and novel mutations found here expanded the phenotypes and genotypes of this disease. Further, the frameshift mutation c.445_448del might be high prevalence in PNPO deficiency in Chinese patients.

Infantile spasms (IS) was an epileptic disease with varied treatment widely among clinicians. Here, we aimed to compare and analyze the clinical characteristics of IS response to pyridoxine or topiramate monotherapy (TPM control IS). The clinical manifestations, treatment processes and outcomes were analyzed in 11 pyridoxine responsive IS and 17 TPM-control IS. Of the 11 patients with pyridoxine responsive IS, nine were cryptogenic/idiopathic. Age of seizure onset was 5.36 ± 1.48 months. Spasms were controlled within a week in most of the patients. At the last follow-up, EEG returned to normal in 8. Psychomotor development was normal in 6, mild delay in 3, severe delay in 2. Of the 17 patients with TPM-control IS, 10 were cryptogenic/idiopathic. The age of seizure onset was 5.58 ± 2.09 months. All patients were controlled within a month. At the last follow-up, EEG was normal in 10. Psychomotor development was normal in 8, mild delay in 5, severe delay in 4. Genetic analysis did not show any meaningful results. The clinical characteristics and disease courses of pyridoxine responsive IS and TPM-control IS were similar, which possibly clued for a same pathogenic mechanism. Pyridoxine should be tried first in all IS patients, even in symptomatic cases. If patients were not responsive to pyridoxine, TPM could be tried.

To predict the survival of appendiceal mucinous adenocarcinoma (AMA) by prognostic nomogram. A total of 3234 patients with AMA were collected from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2015. Univariate and multivariate Cox proportional hazards (PH) regression analyses were used to generate independent prognostic factors. These variables were included in the nomogram to predict overall survival (OS) and disease-specific survival (DSS) at 1-, 3-, and 5- years. These data are validated both internally and externally. The consistency index (C-index) and calibration chart were used to estimate the accuracy of the nomogram. The study cohort was randomly divided into the training (n = 2155) and validation group (n = 1799). According to univariate and multivariate analyses, age at diagnosis, marital status, sex, histological differentiation, SEER extent of disease, number of local lymph nodes examined, whether they were positive, and surgical methods were independent prognostic factors for OS and DSS. These factors were incorporated into the nomogram. Internal validation in the training cohort showed that the C-index values for nomogram predictions of OS and DSS were 0.73 (95% CI 0.70–0.76) and 0.77 (95% CI 0.73–0.81), respectively. Similarly, the corresponding C-index values in the external validation cohort were 0.76 (95% CI 0.70–0.81) and 0.75 (95% CI 0.71–0.80). The Calibration plots revealed that the actual survival and nomogram prediction had a good consistency. Build a nomogram in the SEER database to predict OS and DSS in patients with AMA. It can provide accurate and personalised survival prediction for clinicians and patients.

Polysaccharides from the fungus Inonotus obliquus have been found to be biologically active. In this study, we carried out a preliminary characterisation and assessment of the hypoglycaemic activities of the polysaccharides (IOEP) from Inonotus obliquus obtained by liquid fermentation. Two polysaccharides, IOEP1 and IOEP2, were isolated from IOEP. IOEP1, with a molecular weight of 20 KDa, was mainly composed of galatose and mannose, while IOEP2, with a molecular weight of 200 KDa, was mainly composed of arabinose. Fourier-transform infrared analysis showed that both IOEP1 and IOEP2 were pyran-type polysaccharides. 1H-NMR spectra showed that the glycosidic bonds of IOEP1 and IOEP2 were both &alpha, type and &beta, type. In addition, IOEP1 and IOEP2 strongly increased the glucose consumption of HepG2 cells and insulin-resistant HepG2 cells in vitro. These findings provide a theoretical basis that IOEP1 and IOEP2 might be suitable as anti-diabetes agents in functional foods and natural drugs.

Objective To investigate how high-frequency oscillations (HFOs) were affected by methylprednisolone treatment and the clinical significance of HFOs in patients with atypical benign partial epilepsy (ABPE). Methods In 14 ABPE patients with methylprednisolone treatment, we measured interictal HFOs and spikes during sleep in pre- and post-methylprednisolone scalp electroencephalography (EEG). Patients with benign childhood epilepsy with centrotemporal spikes (BECTS) were taken as control. Results Before methylprednisolone treatment, 10/14 ABPE patients had HFOs, with a mean value of 85.79 per 60s per patient, while 2/14 BECTS patients had HFOs with a mean value of 1.86 per 60s per patient ( p =0.006). The 10 ABPE patients with HFOs tended to have more frequent epileptic negative myoclonus/atypical absences than the other 4 ABPE patients without HFOs. Rates reduced by methylprednisolone treatment were statistically significant for both spikes ( p =0.027) and HFOs ( p =0.005). The percentage of reduction was 41.8% (4653/11,133) and 95% (1141/1202) for spikes and HFOs, respectively. Conclusion Proportion and rates of HFOs in ABPE were more prevalent than in BECTS. HFO rates reduced by methylprednisolone treatment might be more significant than spike rates. Significance Prevalence of HFOs reflected at least some aspect of epileptic severity of ABPE. HFOs were more sensitive to methylprednisolone treatment than spikes.

To investigate electroencephalographic (EEG) characteristics of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in children.Clinical data of 28 children diagnosed as anti-NMDAR encephalitis were retrospectively analyzed for EEG characteristics in different periods and severity of disease and outcome.Among the 28 patients with anti-NMDAR encephalitis, 15 were males and 13 were females. Their age at disease onset ranged from 1 year 3 months to 12 years 4 months. Patients were divided into mild group (5 cases) and severe group (23 cases). In the different stage of the disease, occipital background activity of the EEG was preserved in more than half of patients. Accompanied by the evolution of disease course, the occipital background activity and slow waves gradually recovered to normal. In the peak phase of disease, occipital background activity in the awake state was preserved in 4/5 patients of the mild group and 9/17 patients of the severe group. Alpha and theta band rhythms in non-rapid eye movement (NREM) sleep existed in 77% (17/22) patients. EEG monitoring showed delta brushes in 2 cases, and the delta brushes were mixed with background fast waves in one case; 71% (20/28) patients had epileptiform discharges in EEG during the course, and among them, 6 patients had secondary epilepsy.The background activity in the awake state and abnormal diffuse slow waves of EEG were evolved and gradually recovered during the course of the disease. Regardless milder or severe illness condition, occipital background activity was still preserved during different stages in most patients. Alpha and theta rhythms in NREM sleep might represent a relatively overt EEG characteristic. The presence of delta brush in EEG was rare, and sometimes they were difficult to be distinguished from fast wave activities caused by drugs. The presence of epileptiform discharges in EEG suggested the possibility of secondary epilepsy.

Objective Hyperphosphatasia mental retardation syndrome (Mabry syndrome) is an autosomal recessive disorder. We aim to analyze two Chinese patients diagnosed as Mabry syndrome. Methods The clinical manifestations, diagnosis and treatment were observed in two patients. Genetic analysis including PIGV and PIGO was examined. Results Two patients were diagnosed as Mabry syndrome clinically and genetically. Developmental delay, hyperphosphatasia and seizures were presented in both of them. Typical facial dysmorphism and hypoplastic terminal phalanges were only found in one. Some novel presentations including congenital laryngeal cartilage softening, inguinal hernia, broken palmprint, optic atrophy and skeleton dysplasia such as carpal age delay and metaphysis anomalies were observed in two patients. Molecular genetic analysis revealed compound heterozygous mutations of PIGV or PIGO in our patients, including c.615C>G (p.Asn205Lys) and c.854A>G (p.Tyr285Cys) of PIGV in patient 1, and c.458T>C (p.Phe153Ser) and c.1355_1356del (p.Ala452Glyfs*52) of PIGO in patient 2. Additionally, a heterozygous c.2926G>A (Asp976Asn) of PCDH19 was identified in patient with PIGV mutations, the causative gene of Epilepsy and mental retardation limited to females (EFMR). Conclusion To our best knowledge, this is the first time to report Chinese patients diagnosed as Mabry syndrome. For the PCDH19 mutation in our patient carrying PIGV mutations, due to lacking characteristics of EFMR and the ambiguity results in pathogenicity analysis, we were not sure how much pathogenic role PCDH19 mutation shared with PIGV mutations in this disease. The novel mutations of PIGV and PIGO, and novel clinical manifestations reported here might expand the genotype and phenotype spectrum of Mabry syndrome.

To analyze clinical characteristics, treatment and prognosis in a cohort of children with vitamin B6 responsive infantile spasms.Ten patients were diagnosed as vitamin B6 responsive infantile spasms in Peking University First Hospital between January 2012 and May 2015.The clinical manifestations, diagnosis and treatment process, video-electroencephalogram, magnetic resonance imaging (MRI), epilepsy related genes and prognosis were retrospectively analyzed.Of the 10 patients, 5 were male, and 5 were female. Eight of them were normal at birth, and the other 2 patients had intracranial hemorrhage or anoxia.The age of epilepsy onset was from 3.5 to 8.0 months.All patients presented spasms primarily.Interictal electroencephalogram (EEG) showed hypsarrhythmia at seizures onset. MRI showed normal in 8 patients, and subarachnoid hemorrhage or multiple encephalomalacia foci after hemorrhage respectively in the other 2 patients. The results of blood biochemical, cerebrospinal fluid examination and urinary metabolic screening were negative. Epilepsy related genes including ALDH7A1 gene analysis showed wild type in all patients. Two patients were classified as symptomatic and eight might be idiopathic or cryptogenic. The initial dose of vitamin B6 was 10.0 mg/(kg·d). The interval between seizures onset and taking vitamin B6 was 0 to 4.0 months. Seizures disappeared completely within a week after administration of vitamin B6 in 9 patients and in 1.5 months in one patient.Of the 8 patients whose seizures were controlled completely during the follow-up period, 7 patients' EEG recovered within 1.5 to 4.0 months and then continued to be normal. The EEG of the rest of a patient returned to normal, but showed abnormal discharges after stopping taking vitamin B6. Two patients' EEG continued abnormal and seizures recurred due to vitamin B6 withdrawal. At the last follow-up, seizures were controlled in all patients. Drug treatment in one case had stopped. Vitamin B6 was used in 9 patients at a dose of 0.4 to 10.0 mg/(kg·d). Among them, vitamin B6 monotherapy or coadministration with one low dose antiepileptic drug was applied in 6 or 3 patients respectively. The psychomotor development was normal in 5 patients, mild delay in 3 patients, and severe delay in 2 patients with autism behavior. Of the 2 symptomatic patients, one developed normally and the other showed severe delay.Vitamin B6 might have effects on both idiopathic or cryptogenic and symptomatic patients, especially for the former. High dose vitamin B6 should be first tried in all patients with infantile spasms. Patients who had response to vitamin B6 could be controlled within a short time and might have better outcomes. Seizures were not easy to relapse in those whose seizures were controlled and EEG recovered completely. Vitamin B6 could be gradually reduced during the course and might be withdrawn in the future. The recurrence of seizures was closely related to EEG abnormality.

Purpose To investigate the molecular changes underlying the pathogenesis of radiation-induced skin fibrosis. Methods and Materials Rat skin was irradiated to 30 or 45 Gy with an electron beam. Protein expression in fibrotic rat skin and adjacent normal tissues was quantified by label-free protein quantitation. Human skin cells HaCaT and WS-1 were treated by x-ray irradiation, and the proteasome activity was determined with a fluorescent probe. The effect of proteasome inhibitors on Transforming growth factor Beta (TGF-B) signaling was measured by Western blot and immunofluorescence. The efficacy of bortezomib in wound healing of rat skin was assessed by the skin injury scale. Results We found that irradiation induced epidermal and dermal hyperplasia in rat and human skin. One hundred ninety-six preferentially expressed and 80 unique proteins in the irradiated fibrotic skin were identified. Through bioinformatic analysis, the ubiquitin-proteasome pathway showed a significant fold change and was investigated in greater detail. In vitro experiments demonstrated that irradiation resulted in a decline in the activity of the proteasome in human skin cells. The proteasome inhibitor bortezomib suppressed profibrotic TGF-β downstream signaling but not TGF-β secretion stimulated by irradiation in HaCaT and WS-1 cells. Moreover, bortezomib ameliorated radiation-induced skin injury and attenuated epidermal hyperplasia. Conclusion Our findings illustrate the molecular changes during radiation-induced skin fibrosis and suggest that targeting the ubiquitin-proteasome system would be an effective countermeasure.

Unlike normal differentiated cells, cancer cells primarily rely on glycolysis to generate energy needed for cellular processes even in normoxia conditions. This phenomenon is called aerobic glycolysis or "the Warburg effect." Aerobic glycolysis is inefficient to generate ATP, but the advantages it confers to cancer cells remain to be fully explained. Several oncogenic signaling pathways, interplaying with enzymes and kinases involved in glucose metabolism, participate in the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Non-coding RNAs (ncRNAs) are a family of functional RNA molecules that are not further translated into proteins, which exert regulatatory roles in gene transcription and translation. ncRNAs, especially miRNAs and long non-coding RNAs (lncRNAs), may also have great effect on glucose metabolism by targeting not only glycolysis enzymes directly but also oncogenic signaling pathways indirectly. A better understanding of the Warburg effect and the regulatory role of ncRNAs in cancer glucose metabolism may contribute to the treatment of cancers.

To elucidate the effects of human keratinocyte-derived HaCaT cells (HIV-TAT) protein transduction domains (PTD) coupled heme oxygenase-1 (HO-1) fusion protein (TAT-HO-1) on radiation-induced human keratinocyte-derived HaCaT cells.This study was conducted between May 2010 and February 2013 in the School of Radiation Medicine and Protection, Soochow University, Suzhou, China. This experimental study was designed to explore the protective role of TAT-HO-1 in skin cells. The human HO-1 gene was fused with a gene fragment encoding TAT PTD to produce in-frame TAT-HO-1. The distribution of TAT-HO-1 was measured by immunostaining and Western blot. The radioprotection for TAT-HO-1 was determined using clonogenic assay. Alterations in apoptosis were analyzed by flow cytometry.The expressed and purified TAT-HO-1 recombinant protein could be incorporated into human HaCaT cells. We then evaluated the protective role of TAT-HO-1 against ionizing radiation. The TAT-HO-1 attenuated the generation of reactive oxygen species and decreased HaCaT cell radiosensitivity to irradiation. Moreover, HaCaT cells pretreated with TAT-HO-1 resulted in less apoptosis by radiation. In addition, TAT-HO-1 could penetrate rat skin.These results suggest that TAT-HO-1 can protect HaCaT cells from ionizing radiation.

Background Radiation-induced skin injury remains a serious concern during radiotherapy. Cu/Zn-superoxide dismutase (Cu/Zn-SOD, SOD1) is a conserved enzyme for scavenging superoxide radical in cells. Because of the integrity of cell membranes, exogenous molecule is not able to be incorporated into cells, which limited the application of natural SOD1. The aim of this study was to evaluate the protective role of HIV-TAT protein transduction domain mediated protein transduction of SOD1 (TAT-SOD1) against ionizing radiation. Methods The recombinant TAT-SOD1 and SOD1 were obtained by prokaryotic–based protein expression system. The transduction effect and biological activity of TAT-SOD1 was measured by immunofluorescence and antioxidant capability assays in human keratinocyte HaCaT cells. Mito-Tracker staining, reactive oxygen species (ROS) generation assay, cell apoptosis analysis and malondialdehyde (MDA) assay were used to access the protective effect of TAT- SOD1. Results Uptake of TAT-SOD1 by HaCaT cells retained its biological activity. Compared with natural SOD1, the application of TAT-SOD1 significantly enhanced the viability and decreased the apoptosis induced by X-ray irradiation. Moreover, TAT-SOD1 reduced ROS and preserved mitochondrial integrity after radiation exposure in HaCaT cells. Radiation-induced γH2AX foci, which are representative of DNA double strand breaks, were decreased by pretreatment with TAT-SOD1. Furthermore, subcutaneous application of TAT-SOD1 resulted in a significant decrease in 45 Gy electron beam-induced ROS and MDA concentration in the skins of rats. Conclusions This study provides evidences for the protective role of TAT-SOD1 in alleviating radiation-induced damage in HaCaT cells and rat skins, which suggests a new therapeutic strategy for radiation-induced skin injury.