Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers.

Introduction: Neuronal nuclei are normally smoothly surfaced. In Alzheimer's disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies.

Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers.

Introduction: Neuronal nuclei are normally smoothly surfaced. In Alzheimer's disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies.

Extracellular Tau Oligomers Damage the Axon Initial Segment.

Background: In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described.

Rhabdomyosarcomas are oncogene addicted to the activation of AVIL.

Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS.

Localization, induction, and cellular effects of tau phosphorylated at threonine 217.

Introduction: Tau phosphorylation at T217 is a promising Alzheimer's disease (AD) biomarker, but its functional consequences were unknown.

Methods: Human brain and cultured mouse neurons were analyzed by immunoblotting and immunofluorescence for total tau, tau , tau , tau , and tau . Direct stochastic optical reconstruction microscopy (dSTORM) super resolution microscopy was used to localize tau in cultured neurons.

Rosai-Dorfman Disease: A Less Common Cause of Leptomeningeal and Nerve Root Enhancement.

A 46-year-old male experienced progressive neurocognitive decline, weight loss, intermittent headaches, and weakness over 6 months. Magnetic resonance imaging of the brain revealed hydrocephalus and the spinal cord imaging showed diffuse leptomeningeal enhancement with prominent nerve root involvement. Intradural biopsy of lumbar arachnoid tissue found mixed inflammatory infiltrate consisting predominantly of histiocytes, S100 and CD68 positivity, and lymphocytophagocytosis (emperipolesis) consistent with extranodal Rosai-Dorfman disease.

A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma.

Glioblastoma is a deadly cancer, with no effective therapies. Better understanding and identification of selective targets are urgently needed. We found that advillin (AVIL) is overexpressed in all the glioblastomas we tested including glioblastoma stem/initiating cells, but hardly detectable in non-neoplastic astrocytes, neural stem cells or normal brain.

A Rare Case of Pancreatoblastoma with Intracranial Seeding.

Background: Pancreatoblastoma is an extremely rare neoplasm that accounts for 0.5% of all pancreatic exocrine tumors. These rare entities typically manifest in the pediatric population but can rarely occur in adults.

Focused Ultrasound Preconditioning for Augmented Nanoparticle Penetration and Efficacy in the Central Nervous System.

Microbubble activation with focused ultrasound (FUS) facilitates the noninvasive and spatially-targeted delivery of systemically administered therapeutics across the blood-brain barrier (BBB). FUS also augments the penetration of nanoscale therapeutics through brain tissue; however, this secondary effect has not been leveraged. Here, 1 MHz FUS sequences that increase the volume of transfected brain tissue after convection-enhanced delivery of gene-vector "brain-penetrating" nanoparticles were first identified.

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study).

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard.

Proteomic identification of synaptic caspase substrates.

The dismantling and elimination of excess neurons and their connections (pruning) is essential for brain development and may be aberrantly reactivated in some neurodegenerative diseases. Growing evidence implicates caspase-mediated apoptotic and nonapoptotic cascades in the dysfunction and death of neurons in neurodegenerative disorders such as Alzheimer's, Parkinson, and Huntington's diseases. It is the cleaved caspase substrates that are the effectors of synapse elimination.

Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model.

Therapies capable of decelerating, or perhaps even halting, neurodegeneration in Parkinson's disease (PD) remain elusive. Clinical trials of PD gene therapy testing the delivery of neurotrophic factors, such as the glial cell-line derived neurotrophic factor (GDNF), have been largely ineffective due to poor vector distribution throughout the diseased regions in the brain. In addition, current delivery strategies involve invasive procedures that obviate the inclusion of early stage patients who are most likely to benefit from GDNF-based gene therapy.

Quantitative Analysis of the Cellular Microenvironment of Glioblastoma to Develop Predictive Statistical Models of Overall Survival.

Glioblastomas, the most common primary malignant brain tumors, have a distinct tissue microenvironment. Although non-neoplastic cells contribute to glioblastoma progression, very few quantitative studies have shown the effect of tumor microenvironmental influences on patient survival. We examined relationships of the cellular microenvironment, including astrocytes, microglia, oligodendrocytes, and blood vessels, to survival in glioblastoma patients.

mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease.

A major obstacle to presymptomatic diagnosis and disease-modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid-β oligomers (AβOs) and tau, the precursors of plaques and tangles.

Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells.

Background: Cell culture plays a pivotal role in cancer research. However, culture-induced changes in biological properties of tumor cells profoundly affect research reproducibility and translational potential. Establishing culture conditions tailored to the cancer cell of origin could resolve this problem.

Redefining the Prevalence of Dural Involvement in Rosai-Dorfman Disease of the Central Nervous System.

Background: Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease, is a rare condition, classically characterized by painless, massive cervical lymphadenopathy. Histologically, the pathognomonic findings include a dense, mixed inflammatory infiltrate with areas of emperipolesis. Albeit infrequent, when Rosai-Dorfman disease affects the central nervous system, it typically manifests as an isolated dural lesion, often mimicking a meningioma.

Disseminated Balamuthia mandrillaris Infection.

Balamuthia mandrillaris is a rare cause of human infection, but when infections do occur, they result in high rates of morbidity and mortality. A case of disseminated Balamuthia infection is presented. Early diagnosis and initiation of recommended therapy are essential for increased chances of successful outcomes.

Structural and functional features of central nervous system lymphatic vessels.

One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses.

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis.

Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders.

Histiocytic sarcoma of the cavernous sinus: case report and literature review.

Histiocytic sarcoma is a rare malignant neoplasm of hematopoietic origin composed of cells showing morphologic and immunophenotypic evidence of histiocytic differentiation. We describe the 2nd case of primary histiocytic sarcoma of the cavernous sinus/Meckel's cave, and the 8th case involving the CNS. A 61-year-old Caucasian man presented with numbness on the entire left side of his face, shooting pain in the left frontal region, and headaches.