Molecular Target Therapy against Neuroblastoma

Neuroblastoma, originated from neural crest cells, is the most common extracranial solid tumor in childhood. Treatment is of limited utility for high-risk neuroblastoma and prognosis is poor. The high incidence of resistance of advanced-stage neuroblastoma to conventional therapies has prompt investigators to search for novel therapeutic approaches. Activation of IGF-R/PI3K/Akt/mTOR signaling pathway correlates with oncogenesis, poor prognosis, and chemotherapy resistance in neuroblastoma. Therefore, we investigated the effect of IGF-R/PI3K/Akt/mTOR signaling inhibitors in neuroblastoma. Significantly, IGF-R/PI3K/Akt/mTOR signaling inhibitors effectively inhibited cell growth and induced cell cycle arrest, autophagy, and apoptosis in neuroblastoma cells. Moreover, IGF-R/PI3K/Akt/mTOR signaling inhibitors significantly reduced tumor growth in mice xenograft model without apparent toxicity. Therefore, these results highlight the potential of IGF-R/PI3K/Akt/mTOR signaling pathway as a promising target for neuroblastoma treatment. Therefore, IGF-1R/PI3K/Akt/mTOR signaling inhibitors should be further investigated for treatment in clinical trials for high-risk neuroblastoma

Case report: Thyroid storm in a three-year-old girl presenting with febrile status epilepticus and hypoglycemia

Thyroid storm, though extremely rare in toddlers, requires prompt diagnosis and treatment because it can be fatal if left untreated. However, thyroid storm is not often considered in the differential diagnosis of a febrile convulsion due to its rarity in children. Herein, we report the case of a 3-year-old girl with thyroid storm who presented with febrile status epilepticus. Although the seizure was stopped by diazepam administration, her tachycardia and widened pulse pressure persisted, and severe hypoglycemia was observed. Based on the findings of thyromegaly, a history of excessive sweating and hyperactivity, and a family history of Graves' disease, she was eventually diagnosed with a thyroid storm. The patient was successfully treated with thiamazole, landiolol, hydrocortisone, and potassium iodide. Propranolol, a non-selective β-blocker, has been used to manage tachycardia during thyroid storm. However, a cardio-selective β1-blockers, landiolol hydrochloride, was used in our case to avoid worsening hypoglycemia. Febrile status epilepticus is one of the most common medical emergencies in childhood; it is necessary to rule out treatable underlying critical diseases such as septic meningitis and encephalitis. Thyroid storm should be considered in children presenting with prolonged febrile convulsion accompanied by findings that are not usually observed with febrile convulsions

Impact of HBV Infection on Outcomes of Direct-Acting Antiviral Therapy of Chronic Hepatitis C

Background: Most clinical trials of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection have excluded hepatitis B virus (HBV) coinfection, and little is known about the effects of DAA on chronic hepatitis C patients with HBV coinfection. Recent studies have reported that DAA therapy for HCV can also cause HBV reactivation in patients with HBV and HCV coinfection. The aim of this study was to assess the effects of DAA on sustained virologic response (SVR) and HBV reactivation in patients with chronic hepatitis C. Methods: Participants comprised 199 chronic hepatitis C patients who received DAA therapy (96 men, 103 women; mean age, 66.7 ± 12.0 years). Results: Twelve patients were coinfected with HCV and HBV. Sixty patients were HBV surface antigen negative but positive for hepatitis B core antibody and/or hepatitis B surface antibody, and one hundred and twenty-seven patients had not been exposed to HBV. Rates of SVR in HBV and HCV coinfected patients, HBV prior infection, and no exposure to HBV were 100, 95, and 97%, respectively. Significant differences were seen between each group. No case showed HBV reactivation. Conclusions: DAA treatments were effective in patients with HBV coinfection or HBV prior infection, as well as HCV monoinfection. As the number of cases was small, we still suggest caution regarding HBV reactivation in HCV and HBV coinfected patients undergoing treatment with DAA

The first Japanese biobank of patient‐derived pediatric acute lymphoblastic leukemia xenograft models

A lack of practical resources in Japan has limited preclinical discovery and testing of therapies for pediatric relapsed and refractory acute lymphoblastic leukemia (ALL), which has poor outcomes. Here, we established 57 patient-derived xenografts (PDXs) in NOD.Cg-Prkdcscidll2rgtm1Sug/ShiJic (NOG) mice and created a biobank by preserving PDX cells including three extramedullary relapsed ALL PDXs. We demonstrated that our PDX mice and PDX cells mimicked the biological features of relapsed ALL and that PDX models reproduced treatment-mediated clonal selection. Our PDX biobank is a useful scientific resource for capturing drug sensitivity features of pediatric patients with ALL, providing an essential tool for the development of targeted therapies

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

ポリオウイルスを用いた神経芽腫の新しい治療法の研究

application/pdf我々は今まで、ポリオウイルス（PV）の神経細胞に対する親和性に着目し、PVを神経芽腫の治療に応用しようと試みてきました。我々は、マウスを用いた研究でPVは神経芽腫細胞に対して強い抗腫瘍活性を持ち、マウスに移植した腫瘍が消失する事を報告してきました。さらに驚いたことに神経芽腫をPVで治療することで抗腫瘍免疫が誘導されることが示唆されました。以上の結果をふまえ、三重大学医学部附属病院では2010年から、再発神経芽腫の患者さんに弱毒PVの腫瘍内投与により治療する、第１相の臨床試験を開始しました。In a previous study, we demonstrated that neuroblastoma subcutaneously implanted in immuno-competent mice is eliminated by intratumoral administration of neuroattenuated poliovirus (PV). Our results also suggested that the in vivo destruction of neuroblastoma cells by virotherapy lead to a robust antitumor immune response. In accordance with these findings, we started phase 1 clinical trial, novel treatment of neuroblastoma by live-attenuated poliovirus.平成21~23年度科学研究費補助金(基盤研究(C))研究成果報告書2159135