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Recently, the survival of the high-risk population of preterm infants has steadily improved, and the severity of prematurity is a growing threat of gestational-age-related fatal conditions. Posthemorrhagic hydrocephalus (PHH) is the most common but serious neurological complication in premature infants, which can have life-threatening consequences during the acute phase in the neonatal period and life-long psychomotor and cognitive sequelae in their later life. Although neonatologists, pediatric neurologists, and pediatric neurosurgeons have investigated a diversified strategy for several decades, a consensus on the best management of PHH in premature infants still must be reached. Several approaches have tried to reduce the incidence of intraventricular hemorrhage (IVH) and mitigate the effect of IVH-related hydrocephalus. This paper reviews and discusses the clinical feature of PHH in premature infants, general/nonsurgical management of prematurity for IVH prevention, and posthemorrhagic management, and how and when to intervene.

This is the first report of a carotid aneurysm that developed from a cavernous carotid artery contiguous with a prolactinoma during medical treatment of the prolactinoma, which gradually grew larger while the tumor regressed. A 78-year-old woman presented with headache and neurological symptoms indicating the involvement of cranial nerves in the cavernous sinus. Gadolinium-enhanced T1-weighted magnetic resonance imaging on admission revealed an abnormal right cavernous sinus, with an approximately 17 mm mass extending into the right cavernous portion of the internal carotid artery, and was contiguous with the intracavernous carotid artery. She was diagnosed with pituitary apoplexy due to a prolactinoma and started cabergoline treatment. After medical treatment, a carotid aneurysm emerged. The aneurysm continued to grow and reached a maximum diameter of 10.4 mm at 81 months after the initiation of treatment. The patient underwent endovascular coil embolization, following which the aneurysm regressed. Association between a prolactinoma and the development of a contiguous aneurysm remains undetermined. However, this is an odd phenomenon, and to the best of our knowledge, this is the first reported case of the development of an aneurysm that was associated with a pituitary tumor.

Background The long-term outcomes of CyberKnife-based hypofractionated stereotactic radiotherapy (SRT) for intra/ extracranial non-vestibular schwannomas (nVS) need to be accumulated. Method Patients who received SRT by CyberKnife for nVS from 2010 to 2019 were retrospectively reviewed. Results A total of 45 patients with nVS were identified. The mean age was 53 (± 18) years old, and 23 patients (51%) were female. Twenty-nine patients (64%) had previous procedures. As for the tumor extension, 22 (49%) nVS were classified as primary intracranial, five (11%) were classified as intra/ extracranial (dumbbell shape), and 18 (40%) were classified as primary extracranial. The median prescribed dose, covering 95% of the planning target volume, was 21 (IQR 21 – 25) Gy, and the median target volume was 7 (IQR 3.6-13.1) cm3. The local control rate of nVS for patients without neurofibromatosis type 2 (NF2) was 100%. Old age (OR 0.92, p-value 0.03) and previous surgery (OR 0.02, p-value 0.02) were significant risk factors for no symptomatic improvement. The progression-free survival was 74 (±33) months clinically and 69 (IQR 36 – 94) months radiologically. During follow-up, two cases (4%) with NF2 resulted in treatment failure, 13 cases (41%) resulted in transient tumor expansion (TTE), 10 (22%) suffered from transient adverse radiation effect (ARE), and two (4%) resulted in permanent ARE. Conclusions Hypofractionated SRT for head, neck, and spine nVS was an effective treatment regardless of tumor extension relative to the cranium. Although the risk of permanent ARE was low, some patients experienced transient clinical worsening due to TTE.

Background: Cerebellar hemorrhage is rare in children, and its cause is usually vascular disorders such as arteriovenous malformations or hematological disorders. Case Description: A previously healthy 10-year-old girl presented with a loss of consciousness following sudden headache and vomiting. A non-contrast brain computed tomography (CT) scan revealed a massive cerebellar hemorrhage with obstructive hydrocephalus; however, subsequent CT angiography (CTA) showed no vascular abnormalities. An emergency craniotomy was performed to evacuate the hematoma, and histological analysis of the specimen obtained from the tissue surrounding the hematoma revealed a pilocytic astrocytoma (PA). Six months after the ictus, her recovery was scored at 2 on the modified Rankin Scale. Conclusion: PA can be a cause of critical cerebellar hemorrhage. In this case of life-threatening massive hematoma, CTA was useful to exclude a major vascular pathology and to save time.

In a previous study, we showed that folate receptor‐α (FRα) translocates to the nucleus where it acts as a transcription factor and upregulates Hes1, Oct4, Sox2, and Klf4 genes responsible for pluripotency. Here, we show that acetylation and phosphorylation of FRα favor its nuclear translocation in the presence of folate and can cause a phenotypic switch from differentiated glial cells to dedifferentiated cells. shRNA‐FRα mediated knockdown of FRα was used to confirm the role of FRα in dedifferentiation. Ocimum sanctum hydrophilic fraction‐1 treatment not only blocks the folate mediated dedifferentiation of glial cells but also promotes redifferentiation of dedifferentiated glial cells, possibly by reducing the nuclear translocation of ~38 kDa FRα and subsequent interaction with chromatin assembly factor‐1. stem cells 2019;37:1441–1454, Possible mechanisms by which Ocimum sanctum hydrophilic fraction‐1 prevents the formation of folate receptor‐α complex are: (a) the caffeoylquinic acid component of O. sanctum hydrophilic fraction‐1 presumably decreases acetylation of folate receptor‐α by decreasing the acetyl transferase or increasing the deacetylases activity, and subsequent nuclear translocation, and (b) since nuclear folate receptor‐α binds to chromatin assembly factor‐1 in folate‐induced dedifferentiated cells and not in differentiated glial cells, the reduction of folate receptor‐α in the nucleus by O. sanctum hydrophilic fraction‐1 may reactivate chromatin assembly factor‐1 and favor differentiation.

Few reports exist demonstrating the effects of CyberKnife radiotherapy (CKRT) on the central skull base meningiomas (CSMs). Retrospective analysis of 113 patients were performed. The median age was 62 (IQR 50 – 72) years old, and 78 patients (69%) were female. Upfront CKRT was performed in 41 (36%), where 17 (15%) patients were asymptomatic. The other CKRT was for postoperative adjuvant therapy in 32 (28%), and for the recurrent or relapsed tumors in 40 (35%) patients. Previous operation was done in 74 patients (66%). Among the available pathology in 46 patients, 37 (80%) were WHO grade I, 8 (17%) were grade II, and 1 (2%) were grade III. The median prescribed dose covered 95% of the planning target volume was 2500 (IQR 2100 – 2500) cGy and the median target volume was 9.5 (IQR 3.9 – 16.9) cm3. The median PFS was 48 (IQR 23 – 73) months and 84% and 78% were free of tumor progression at five, and 10 years respectively. The median follow-up was 49 (IQR 28 – 83) months. PFS was better in grade I than grade II (p = 0.02). No other baseline factors including the history of previous operation was associated with PD or PFS. Adverse events of radiation therapy were radiation- induced optic neuropathy (0.9%), and cerebral edema (4.4%). Asymptomatic cavernous carotid stenosis was found in three (2.7%), five (4.4%) underwent ventriculoperitoneal shunt placement for normal pressure hydrocephalus, and five (4.4%) died. CKRT is useful for the management of CSMs with low rate of adverse events.

IntroductionTo analyze the long-term follow-up data of CyberKnife treatment (CKT) for head and neck paragangliomas (HNPGs). MethodsPatients who received CKT to HNPGs from 2010 to 2019 were retrospectively reviewed. ResultsA total of 34 HNPGs from 29 patients were identified. The mean age was 50 (± 16) years old, and 15 patients (52%) were female. Previous operation was done in 15 patients (55%). Four cases (14%) were functional in hormone production. According to Fisch classification, one case (3%) was B, 12 (42%) were C, 14 (48%) were D, and two cases (7%) were out of classification. The median prescribed dose covered 95% of the planning target volume was 2500 (IQR 2100 – 2600) cGy and the median target volume was 10 (IQR 5.8 – 21.3) cm3. The local control rate was 97%. The median progression-free survival was 66 (IQR 27.5 – 95.0) months and 93.8%, and 91.7% were free of tumor progression at five, and seven years respectively. During the follow-up, one case (3%) resulted in permanent facial nerve palsy (CTCAE 1, House-Brackmann grade II), and another case (3%) resulted in asymptomatic cerebellar radiation necrosis. Univariate and multivariate analysis showed no previous surgical history (OR 10.3, 95% CI 1.5 – 69.3, p = 0.02) was a positive predictor of symptom improvement. We devised a treatment flow-chart based on our finding. ConclusionsCKT for HNPGs was an effective treatment with little side effect over the long term and should be considered the first-line therapy for symptomatic nonfunctional HNPGs for better symptom control.

Background: A dissection beginning from a point distal to the endpoint of the carotid endarterectomy (CEA) is called distal carotid artery dissection (CAD), which is known as one of the significant surgical complications of CEA. Case Description: We present a case of distal CAD as a perioperative complication after CEA using indwelling shunt. We estimated this pathophysiology to be caused by the mechanical conflict of the inflated balloon with the elongated styloid process. Conclusion: Since a distal CAD can cause severe, irreversible neurological deficits, preoperative assessment of the styloid process should be routinely performed in CEA.

Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have been associated with steroid-responsive cortical encephalitis and comorbid generalized epilepsy. A 44-year-old woman developed repeated epilepsia partialis continua (EPC) without generalized seizures and was anti-MOG antibody-positive. Radiological abnormalities were detected in the bilateral medial frontoparietal cortices, but there were no cerebrospinal fluid abnormalities. She achieved remission with anti-epileptic drugs alone. However, encephalitis recurred four months later when pleocytosis appeared, and steroid therapy was effective. Altogether, EPC without typical cerebrospinal fluid features can be an early sign of anti-MOG antibody-positive encephalitis. Thus, patients with EPC of unknown etiology need to be screened for anti-MOG antibodies.

The vital role of folic acid is to reduce the risk of having a neonate afflicted with neural tube defects. The prevalence of neural tube defects (myelomeningocele and anencephaly) has been reported in an incomplete form over the last 40 years in Japan. We aimed to evaluate the total number of neural tube defects including those delivered or terminated, to clarify the proportion of those terminated, and to internationally compare their prevalence. Through information on >311 000 deliveries obtained from 262 hospitals/clinics for 2 years of 2014 and 2015, we identified that the rate of total neural tube defects (termination of pregnancy, live births and stillbirths) was 8.29 per 10 000 deliveries for the year 2014 and was 8.72 for 2015, which were 1.5 and 1.6 times higher than the respective values (live births and stillbirths) reported. It is also observed that the ratio of the total number of myelomeningocele (termination of pregnancy, live births, and stillbirths) to that of anencephaly was approximately 1:1.2, that a half of pregnancies afflicted with neural tube defects were terminated, and that the proportion of termination of pregnancy due to myelomeningocele and due to anencephaly was 20% and 80%, respectively. Internationally, the real prevalence of neural tube defects in Japan was comparatively high, ranking fifth among the seven developed countries. In conclusion, the real prevalence of total neural tube defects was approximately 1.5 times higher than that currently reported by the Japan Association of Obstetricians and Gynecologists.

INTRODUCTION In recent years, hypofractionated radiotherapy (HRT) 40Gy in 15 fractions with concomitant temozolomide(TMZ) has come to be used as standard treatment for elderly glioblastoma. However, the treatment duration of 3–4 weeks for radiation is not enough short, and there is also a problem of radiation sickness. We performed hypofractionated stereotactic radiotherapy with CyberKnife (CK) for less than 2weeks. We retrospectively analyzed eight newly diagnosed elderly patients with glioblastoma treated by CK. METHODS Surgical cavity, contrast enhanced lesion, FLAIR high signal intensity area were set as gross tumor volume (GTV). To planned target volume (PTV) as GTV + 2 mm, Marginal dose (D95) 35 Gy in 5 fractions (Fr) was prescribed. The dose prescription and number of fractions were adjusted taking into consideration dose distribution, dose-limiting for important organs such as optic chiasm and brainstem. RESULTS The eight patients consisted of 3 men and 5 women. The median age was 78 (range 68–84) years old. All patients were pathologically diagnosed as glioblastoma. Two of 8 cases had undergone gross total removal of contrast area. Median postoperative KPS was 70 (40–80). Thirty three (28–33.5) Gy was administered in 5 (3–10) Fr to PTV 117 (44–243) ml. TMZ was used in 7 patients. Bevacizumab (BEV) was used together from 4 weeks after surgery in 5 patients. Progression-free survival was 6.5 (2.9–10.6) months and overall survival was 17.5 (7.1–28.5) months. 7 patients had experienced controllable hypertension with antihypertensive agents, Two patients had suffered from deep vein thrombosis, and anticoagulation therapy was used. One patient had nausea and malaise due to TMZ and had continue BEV alone. Asymptomatic cerebral infarction in the radiation field was observed in a patient. CONCLUSION CK treated in less than half duration of conventional HRT is expected as less invasive treatment.

BACKGROUND The prognosis for patients with recurrent glioblastoma after Bevacizumab (Bev) treatment is extremely poor. No effective treatment has been established. PURPOSE We retrospectively investigated the efficacy and safety of hypofractionated stereotactic radiotherapy with Cyberknife (CK-HSRT) for recurrent glioblastoma after Bev treatment in our institution. METHODS GTV (Gross tumor volume) was set in the FLAIR abnormal high signal area that resulted in the contrast lesion and invasive recurrence, and PTV (Planning target volume) = GTV + 2 mm. As aimed CK dose,30 Gray(Gy) in 5 fraction was performed on PTV. Bev(10mg/kg biweekly) was continued after CK. The case background, treatment effect, survival and adverse events were investigated for 21 cases from January 2013 to the end of May 2018. RESULTS The median age was 69 (range;31–85) years, and The D95% marginal dose was 27.5 (23–35) Gy in 5 (3–8) divisions. Median PTV was 112 (2–305) ml. The median time to progression after CK was 3.9 months, and the median overall survival after CK was 10.9 months. Early treatment-related adverse events included hair loss in the irradiated area, seizures, headache, nausea and vomiting. As late treatment-related adverse events, symptomatic cerebral radiation necrosis was not observed, but 2 cases of symptomatic cerebral infarction and a case of cerebral hemorrhage were observed. All cases were treated conservatively. CONCLUSION CK-HSRT may be well tolerated and effective as a salvage treatment for the patients with recurrent glioblastoma after Bev.

Neurofibromatosis type 1 (NF1) is common, occurring in 1/3000 live births, and results in skin pigmentation and the growth of tumors along nerves in the skin, brain, and other parts of the body. Loss of polycomb repressive complex 2 (PRC2) has been implicated in the tumorigenesis of Schwann cells (SCs) in malignant peripheral nerve sheath tumors (MPNSTs). In the absence of PRC2, the H3K27me repressive marks are absent and thus the SCs can re-enter the cell cycle and form tumors. In the absence of PRC2, nucleosome remodeling deacetylase (NuRD) chromatin silencing complex, by itself cannot takes over its function. To compensate for the loss of PRC2 complex, there must be a decrease in activating histone marks, H3K27Ac and H3K4me3, by a reciprocal increase in HDAC2 expression and the decrease in H3K4 methylation. Using a systems biology approach as a part of the combination therapy, we have identified a novel naturally occurring multi-target cocktail in the methanolic extracts from the hydrophilic fraction of Ocimum Sanctum leaves (OSHP-1) as potential treatment option for MPNSTs. Here we show that OSHP-1 (i) increased the expression of HDAC2 (a component of NuRD), and decreased the expression of lysine acetyl transferase 7 (KAT7); (ii) altered FRα signaling and disrupted the DNA replication complex comprising of FRα-NuRD-PCNA-CAF-1; (iii) reversed the expression of certain actively transcribed genes PAX2, FOXN4, IGF2 and TLX1 in NF1-MPNST cells; (iv) increased the expression of a Schwann cell differentiation marker NCAM-140 KD. Thus, NuRD and KAT7 in NF1-MPNST can be potential therapeutic targets.

Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF)-κB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-κB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-κB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma.

Background Although brain arteriovenous malformations (AVM) usually remain asymptomatic during pregnancy, they can cause intracranial hemorrhage and lead to serious neurological deficits. Nowadays, it is accepted that treatment of a ruptured brain AVM during pregnancy should be based on neurologic, not obstetric, indications. Recently, endovascular treatment has been recognized as a treatment option associated in pregnant patients with brain AVMs. Case presentation A 34-year-old woman presented at 25 weeks of gestation with a history of severe headache followed by severe consciousness disturbance. Brain CT showed a subcortical hematoma in the right occipital lobe along with bilateral intraventricular hematomas. A cerebral angiogram was performed to confirm the diagnosis, which revealed right occipital AVM. At 27 weeks of gestation, endovascular embolization of the AVM was attempted under general anesthesia. The feeding artery and the nidus were simultaneously obliterated by injection of 50 % n-butyl-cyanoacrylate. As a result, the blood flow into the nidus was drastically decreased and the risk of re-bleeding was substantially reduced. At 38 weeks of gestation, elective cesarean section was performed to deliver the baby under combined spinal-epidural anesthesia (CSEA). An infant weighing 3665 g was delivered, with Apgar scores of 8 and 9 at 1 and 5 min, respectively. Postoperative analgesia was provided by a continuous infusion of ropivacaine via the epidural catheter. The infant was confirmed as not having any congenital anomalies. On POD 5, both of the patient and the infant were discharged home without any medical problems. The mother has shown no evidence of re-bleeding from the intracranial lesion since, and the infant is thriving well. Conclusions Endovascular treatment in pregnant women is associated with various unique concerns. However, it can be carried out safely and effectively and is useful not only for saving the mother’s life but also for allowing the pregnancy to continue to term.

Prenatal folic acid (FA) supplementation prevents neural tube defects. Folate receptor alpha (FRα) is critical for embryonic development, including neural crest (NC) development. Previously we showed that FRα translocates to the nucleus in response to FA, where it acts as a transcription factor. In this study, we examined if FA through interaction with FRα regulates stem cell characteristics of cranial neural crest cells (CNCCs)-critical for normal development. We hypothesized that FRα upregulates coding genes and simultaneously downregulates non-coding miRNA which targets coding genes in CNCCs. Quantitative RT-PCR and chromatin immunoprecipitation showed that FRα upregulates Oct4, Sox2, and Klf4 by binding to their cis-regulator elements-5′ enhancer/promoters defined by H3K27Ac and p300 occupancy. FA via FRα downregulates miRNAs, miR-138 and miR-let-7, which target Oct4 and Trim71 (an Oct4 downstream effector), respectively. Co-immunoprecipitation data suggests that FRα interacts with the Drosha-DGCR8 complex to affect pre-miRNA processing. Transfecting anti-miR-138 or anti-miR-let-7 into non-proliferating neural crest cells (NCCs) derived from Splotch (Sp−/−), restored their proliferation potential. In summary, these results suggest a novel pleiotropic role of FRα: (a) direct activation of Oct4, Sox2, and Klf4 genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules.

The epigenetic mechanism of folic acid (FA) action on dorsal root ganglion (DRG) cell proliferation and sensory neuron differentiation is not well understood. In this study, the ND7 cell line, derived from DRG cells, was used to elucidate this mechanism. In ND7 cells differentiated with dbcAMP and NGF, Hes1 and Pax3 levels decreased, whereas Neurog2 levels showed a modest increase. Chromatin immunoprecipitation (ChIP) assays examining epigenetic marks at the Hes1 promoter showed that FA favored increased H3K9 and H3K19 acetylation and decreased H3K27 methylation. Hence, FA plays a positive role in cell proliferation. In differentiated ND7 cells, H3K27 methylation decreased, whereas H3K9 and H3K18 acetylation increased at the Neurog2 promoter. FA did not favor this phenotypic outcome. Additionally, in differentiated ND7 Neurog2 associated with the NeuroD1 promoter, FA decreased this association. The results suggest that the switch from proliferation to sensory neuron differentiation in DRG cells is regulated by alterations in epigenetic marks, H3K9/18 acetylation and H3K27 methylation, at Hes1 and Neurog2 promoters, as well as by Neurog2 association with NeuroD1 promoter. FA although positive for proliferation, does not appear to play a role in differentiation.

The mechanism(s) behind folate rescue of neural tube closure are not well understood. In this study we show that maternal intake of folate prior to conception reverses the proliferation potential of neural crest stem cells in homozygous Splotch embryos (Sp(-/-)) via epigenetic mechanisms. It is also shown that the pattern of differentiation seen in these cells is similar to wild-type (WT). Cells from open caudal neural tubes of Sp(-/-) embryos exhibit increased H3K27 methylation and decreased expression of KDM6B possibly due to up-regulation of KDM6B targeting micro-RNAs such as miR-138, miR-148a, miR-185, and miR-339-5p. In our model, folate reversed these epigenetic marks in folate-rescued Sp(-/-) embryos. Using tissue from caudal neural tubes of murine embryos we also examined H3K27me2 and KDM6B association with Hes1 and Neurog2 promoters at embryonic day E10.5, the proliferative stage, and E12.5, when neural differentiation begins. In Sp(-/-) embryos compared with WT, levels of H3K27me2 associated with the Hes1 promoter were increased at E10.5, and levels associated with the Neurog2 promoter were increased at E12.5. KDM6B association with Hes1 and Neurog2 promoters was inversely related to H3K27me2 levels. These epigenetic changes were reversed in folate-rescued Sp(-/-) embryos. Thus, one of the mechanisms by which folate may rescue the Sp(-/-) phenotype is by increasing the expression of KDM6B, which in turn decreases H3K27 methylation marks on Hes1 and Neurog2 promoters thereby affecting gene transcription.

Neurofibromatosis type 1 (NF1) is common, occurring in 1 in 3000 live births, and results in skin pigmentation and the growth of tumors along nerves in the skin, brain, and other parts of the body. It arises from a mutated and non-functional tumor suppressor gene NF1. Tumors of the peripheral nerves, called neurofibromas and of the main eye nerve, called optic glioma, are debilitating and deadly. Epigenetic mechanisms have been shown to play an important role in the progression of neurofibromas to malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs with polycomb repressive complex 2 (PRC2) loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3). We hypothesized that owing to the loss of this repressive complex PRC2, there is an overexpression of genes related to tumorigenesis in MPNSTs because of reciprocal gain of the activation marks such as trimethylation at lysine 4 of histone H3 (H3K4me3) and acetylation of lysine 27 of histone H3 (H3K27Ac) at their promoters. Using RT-PCR, we observed an increase in the expression of candidate oncogenes genes PAX2, FOXN4, IGF2 and TLX1 in NF1 associated MPNST cell line ST88-14 versus the normal Schwann cells and normal human fibroblasts. Western blots using purified histones revealed that there was an increase in the expression of H3K4me3, H3K9me2, H3K18Ac and H3K27Ac. Recently, aqueous extracts of Ocimum Sanctum has been used as investigational cancer preventive drug. We wanted to know the effects of extracts of O. Sanctum on MPNST cell line ST88-14. Treatment of ST88-14 cells with the hydrophilic fraction of methanolic extract of Ocimum Sanctum (OSHP-1) not only showed a dose dependent decrease in the above histone marks but also showed an increase in the expression of N-CAM 140KD, characteristic of mature Schwann cells, in addition to a significant decline in proliferation. Further evaluation of the nuclear extracts showed that OSHP-1 treatment increased the expression of HDAC2, a component of NuRD complex and decreased that of lysine acetyl transferase 7 (KAT7) in a dose dependent manner suggesting that both HDAC2 and KAT7 may be responsible for the decrease in the acetylation of H3K27Ac and therefore reversal of the tumorigenic MPNSTs to a differentiated Schwann cell phenotype. Chromatin immunoprecipitation (ChIP) data revealed H3K27Ac occupancy on candidate genes (PAX2, FOXN4, IGF2 and TLX1) promoters was reduced by OSHP-1 treatment. In conclusion, OSHP-1 reprograms the epigenome and may be an effective treatment option for NF1 associated MPNSTs. Citation Format: Chandra S. Mayanil, Mariam M. Khan, Vineet Mohanty, Raj Kumar, Guifa Xi, Shunsuke Ichi, Bal Ram Singh, Barbara Mania-Farnell, Tadanori Tomita. Reprogramming the epigenome as an effective treatment option for neurofibromatosis1 associated malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2084.

Pax3 regulates neural crest cell migration and is critical during neural crest development. TGFbs modify neural crest cell migration and differentiation. TGFbeta2 nullizygous embryos (TGFbeta2(-/-)Pax3(+/+)) display open neural tube and bifid spine, whereas in wild type embryos, the neural tube is closed. In previous work, we have demonstrated that Pax3 regulates TGFbeta2 by directly binding to cis-regulatory elements on its promoter. In this study, we found that the TGFbeta2 nullizygous phenotype can be reversed to the wild type phenotype by down-regulating one allele of Pax3, as in TGFbeta2(-/-)Pax3(+/-) embryos obtained through breeding TGFb2(+/-)Pax3(+/-) mice. The data in this paper suggest that Pax3 and TGFbeta2 interact in a coordinated gene regulatory network, linked by common downstream effector genes, to bring about this phenotypic reversal. Downstream effectors may include Hes1, Ngn2 and Sox9, as well as other genes involved in neuronal differentiation.

Pax3 is expressed early during embryonic development in spatially restricted domains including limb muscle, neural crest, and neural tube. Pax3 functions at the nodal point in melanocyte stem cell differentiation, cardiogenesis and neurogenesis. Additionally Pax3 has been implicated in migration and differentiation of precursor cell populations. Currently there are questions about how Pax3 regulates these diverse functions. In this study we found that in the absence of functional Pax3, as in Splotch embryos, the neural crest cells undergo premature neurogenesis, as evidenced by increased Brn3a positive staining in neural tube explants, in comparison with wild-type. Premature neurogenesis in the absence of functional Pax3 may be due to a change in the regulation of basic helix–loop–helix transcription factors implicated in proliferation and differentiation. Using promoter-luciferase activity measurements in transient co-transfection experiments and electro-mobility shift assays, we show that Pax3 regulates Hairy and enhancer of split homolog-1 (Hes1) and Neurogenin2 (Ngn2) by directly binding to their promoters. Chromatin immunoprecipitation assays confirmed that Pax3 bound to cis-regulatory elements within Hes1 and Ngn2 promoters. These observations suggest that Pax3 regulates Hes1 and Ngn2 and imply that it may couple migration with neural stem cell maintenance and neurogenesis.

Folic acid (FA) has traditionally been associated with prevention of neural tube defects; more recent work suggests that it may also be involved in in the prevention of adult onset diseases. As the role of FA in human health and disease expands, it also becomes more critical to understand the mechanisms behind FA action. In this work we examined the hypothesis that folate receptor alpha (FRα) acts as a transcription factor. FRα is a GPI-anchored protein and a component of the caveolae fraction. The work described here shows that FRα translocates to the nucleus, where it binds to cis-regulatory elements at promoter regions of Fgfr4 and Hes1, and regulates their expression. The FRα recognition domain mapped to AT rich regions on the promoters. Until this time FRα has only been considered as a folate transporter, these studies describe a novel role for FRα as a transcription factor.

The authors wish to retract this paper owing to the use of misidentified cell lines in the study. According to the description on the ATCC official website and reanalysis of the STR for cell line authentication, two misidentified glioblastoma cell lines, U251MG and U373MG, were used in this work.

A 57-year-old man presented with a posterior fossa hemangioblastoma associated with primary hyperparathyroidism. The hemangioblastoma was completely removed. Further imaging found parathyroid and thyroid tumors which were resected. Hyperparathyroidism might be a manifestation of von Hippel-Lindau (VHL) disease, but sequencing of the VHL gene of the constitutional deoxyribonucleic acid of the hemangioblastoma was negative. The present association is rare, but the hemangioblastoma and the parathyroid adenoma may have some germ-line mutation in common.

Here we address how Pax3 regulates stem cell maintenance and neurogenesis during caudal neural tube development. Pax3 acetylation at lysine residues K437 and K475 results in down-regulation of Hes1 and up-regulation of Neurog2 expression., Pax3 plays a role in regulating Hes1 and Neurog2 activity and thereby stem cell maintenance and neurogenesis. A mechanism for Pax3 regulation of these two opposing events, during caudal neural tube development, is examined in this study. Pax3 acetylation on C-terminal lysine residues K437 and K475 may be critical for proper regulation of Hes1 and Neurog2. Removal of these lysine residues increased Hes1 but decreased Neurog2 promoter activity. SIRT1 deacetylase may be a key component in regulating Pax3 acetylation. Chromatin immunoprecipitation assays showed that SIRT1 is associated with Hes1 and Neurog2 promoters during murine embryonic caudal neural tube development at E9.5, but not at E12.5. Overexpression of SIRT1 decreased Pax3 acetylation, Neurog2 and Brn3a positive staining. Conversely, siRNA-mediated silencing of SIRT1 increased these factors. These studies suggest that Pax3 acetylation results in decreased Hes1 and increased Neurog2 activity, thereby promoting sensory neuron differentiation.

A 57-year-old man presented with a posterior fossa hemangioblastoma associated with primary hyperparathyroidism. The hemangioblastoma was completely removed. Further imaging found parathyroid and thyroid tumors which were resected. Hyperparathyroidism might be a manifestation of von Hippel-Lindau (VHL) disease, but sequencing of the VHL gene of the constitutional deoxyribonucleic acid of the hemangioblastoma was negative. The present association is rare, but the hemangioblastoma and the parathyroid adenoma may have some germ-line mutation in common.

Corrigendum Corrigendum to “Key basic helix–loop–helix transcription factor genes Hes1 and Ngn2 are regulated by Pax3 during mouse embryonic development” [Dev. Biol. 316 (2008) 510–523] Hiromichi Nakazaki, Anvesh C. Reddy, Barbara L. Mania-Farnell, Yueh-Wei Shen, Shunsuke Ichi, Christopher McCabe, David George, David G. McLone, Tadanori Tomita, C.S.K. Mayanil ⁎ Laboratory for Neural Tube Research, Developmental Biology Program, ChildrenTs Memorial Research Center; Department of Pediatric Neurosurgery, ChildrenTs Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA