ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma).

KBTBD4 Cancer Hotspot Mutations Drive Neomorphic Degradation of HDAC1/2 Corepressor Complexes.

Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) , the most common embryonal brain tumor in children, and pineoblastoma . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST .

Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins. However, the anatomical and cellular complexity of developing human tissues-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice.

Vorinostat and isotretinoin with chemotherapy in young children with embryonal brain tumors: A report from the Pediatric Brain Tumor Consortium (PBTC-026).

Background: Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone.

Methods: PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS.

Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma: A Randomized Clinical Trial From the Children's Oncology Group.

Importance: Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed.

Objective: To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma.

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma.

Managing Do Not Attempt Cardiopulmonary Resuscitation conversations in the community.

Clear, sensitive and timely communication with palliative and end-of-life (EoL) patients and their families is important. Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) conversations can help patients accept their impending death and achieve a more dignified death. This research explored the experiences and communication strategies of clinical nurse specialists (CNSs) in palliative care when managing DNACPR conversations in the community.

A Single-Cell Transcriptional Atlas of the Developing Murine Cerebellum.

The cerebellum develops from a restricted number of cell types that precisely organize to form the circuitry that controls sensory-motor coordination and some higher-order cognitive processes. To acquire an enhanced understanding of the molecular processes that mediate cerebellar development, we performed single-cell RNA-sequencing of 39,245 murine cerebellar cells at twelve critical developmental time points. Using recognized lineage markers, we confirmed that the single-cell data accurately recapitulate cerebellar development.

Change in brain network topology as a function of treatment response in schizophrenia: a longitudinal resting-state fMRI study using graph theory.

A number of neuroimaging studies have provided evidence in support of the hypothesis that faulty interactions between spatially disparate brain regions underlie the pathophysiology of schizophrenia, but it remains unclear to what degree antipsychotic medications affect these. We hypothesized that the balance between functional integration and segregation of brain networks is impaired in unmedicated patients with schizophrenia, but that it can be partially restored by antipsychotic medications. We included 32 unmedicated patients with schizophrenia (SZ) and 32 matched healthy controls (HC) in this study.

Aberrant Hippocampal Connectivity in Unmedicated Patients With Schizophrenia and Effects of Antipsychotic Medication: A Longitudinal Resting State Functional MRI Study.

To better characterize hippocampal pathophysiology in schizophrenia, we conducted a longitudinal study evaluating hippocampal functional connectivity during resting state, using seeds prescribed in its anterior and posterior regions. We enrolled 34 unmedicated patients with schizophrenia or schizoaffective disorder (SZ) and 34 matched healthy controls. SZ were scanned while off medication, then were treated with risperidone for 6 weeks and re-scanned (n = 22).

Abnormalities in large scale functional networks in unmedicated patients with schizophrenia and effects of risperidone.

Objective: To describe abnormalities in large scale functional networks in unmedicated patients with schizophrenia and to examine effects of risperidone on networks.

Material And Methods: 34 unmedicated patients with schizophrenia and 34 matched healthy controls were enrolled in this longitudinal study. We collected resting state functional MRI data with a 3T scanner at baseline and six weeks after they were started on risperidone.

Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication.

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto-temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ.

Hippocampal-parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia.

Abnormalities in resting state connectivity in schizophrenia (SZ) are now well established, but the biological substrates of these functional alterations remain to be elucidated. We performed a combined functional magnetic resonance imaging and magnetic resonance spectroscopy study in 22 unmedicated patients with SZ and 22 matched healthy controls (HCs) to evaluate resting state functional connectivity of the hippocampus and Glx/Cr (a combined glutamate + glutamine peak normalized to creatine) in the hippocampus and investigate functional and neurometabolic abnormalities and examine the relationship between these. Functional connectivity between the left hippocampus and bilateral precuneus was significantly decreased in unmedicated patients with SZ when compared to HCs [t(4.

Early life trauma and directional brain connectivity within major depression.

Objective: Early life trauma (ELT) is a significant risk factor for the onset of depression. Emerging findings indicate ELT is associated with enhanced amygdala reactivity to aversive stimuli in never-depressed healthy controls as well as those with acute depression but may be absent in non-ELT exposed depressed. The precise mechanism mediating these differences in amygdala reactivity remains unclear.

Ventral tegmental area/midbrain functional connectivity and response to antipsychotic medication in schizophrenia.

Medication management in schizophrenia is a lengthy process, as the lack of clinical response can only be confirmed after at least 4 weeks of antipsychotic treatment at a therapeutic dose. Thus, there is a clear need for the discovery of biomarkers that have the potential to accelerate the management of treatment. Using resting-state functional MRI, we examined the functional connectivity of the ventral tegmental area (VTA), the origin of the mesocorticolimbic dopamine projections, in 21 healthy controls and 21 unmedicated patients with schizophrenia at baseline (pre-treatment) and after 1 week of treatment with the antipsychotic drug risperidone (1-week post-treatment).

Antipsychotic Drugs Alter Functional Connectivity between the Medial Frontal Cortex, Hippocampus, and Nucleus Accumbens as Measured by H215O PET.

To evaluate changes in functional connectivity as a result of treatment with antipsychotic drugs (APDs) in subjects with schizophrenia (SZ), we identified a limited number of regions that have been implicated in the mechanism of action of APDs and that are part of a neuronal network known to be modulated by dopamine (DA). These regions consisted of the nucleus accumbens (NAcc), the hippocampus (Hip), and the medial frontal cortex (MFC). SZ participants were blindly randomized into a haloperidol treatment group (n = 12) and an olanzapine treatment group (n = 17).

Quantitative metrics of net proliferation and invasion link biological aggressiveness assessed by MRI with hypoxia assessed by FMISO-PET in newly diagnosed glioblastomas.

Glioblastoma multiforme (GBM) are aggressive and uniformly fatal primary brain tumors characterized by their diffuse invasion of the normal-appearing parenchyma peripheral to the clinical imaging abnormality. Hypoxia, a hallmark of aggressive tumor behavior often noted in GBMs, has been associated with resistance to therapy, poorer survival, and more malignant tumor phenotypes. Based on the existence of a set of novel imaging techniques and modeling tools, our objective was to assess a hypothesized quantitative link between tumor growth kinetics [assessed via mathematical models and routine magnetic resonance imaging (MRI)] and the hypoxic burden of the tumor [assessed via positron emission tomography (PET) imaging].

Panoramic imaging reveals basic mechanisms of induction and termination of ventricular tachycardia in rabbit heart with chronic infarction: implications for low-voltage cardioversion.

Background: Sudden cardiac death due to arrhythmia in the settings of chronic myocardial infarction (MI) is an important clinical problem. Arrhythmic risk post-MI continues indefinitely even if heart failure and acute ischemia are not present due to the anatomic substrate of the scar and border zone (BZ) tissue.

Objective: The purpose of this study was to determine mechanisms of arrhythmia initiation and termination in a rabbit model of chronic MI.

Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium.

KCNQ2 and KCNQ3 potassium-channel subunits can form both homomeric and heteromeric channels; the latter are thought to constitute native ganglionic M channels. We have tried to deduce the stoichiometric contributions of KCNQ2 and KCNQ3 subunits to currents generated by the coexpression of KCNQ2 and KCNQ3 cDNA plasmids in Chinese hamster ovary (CHO) cells, and to native M currents in dissociated rat superior cervical ganglion (SCG) neurons, by comparing the block of these currents produced by tetraethylammonium (TEA) with the block of currents generated by a tandem KCNQ3/2 construct. TEA concentration-inhibition curves against coexpressed KCNQ2 plus KCNQ3 currents, and against native M currents in SCG neurons from 6-week-old [postnatal day 45 (P45)] rats, were indistinguishable from those for the expressed tandem construct, and fully accorded with a 1:1 stoichiometry.