Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.

In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function.

The PM20D1-NADA pathway protects against Parkinson's disease.

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD.

Fit-for-Purpose Ki-67 Immunohistochemistry Assays for Breast Cancer.

New therapies are being developed for breast cancer, and in this process, some "old" biomarkers are reutilized and given a new purpose. It is not always recognized that by changing a biomarker's intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer.

Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma.

Introduction: Most patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation.

Cholestanol accelerates α-synuclein aggregation and spreading by activating asparagine endopeptidase.

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson's disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants.

Immunohistochemistry and immunofluorescence utilization audit by subspecialty in an academic setting: A step toward stewardship.

There are immunohistochemistry (IHC) and immunofluorescence (IF) panels described in the literature and established by personal and institutional experiences that are in common use by pathologists in their daily practice. Stewardship is a difficult discussion because IHC utilization is influenced by many factors including the pathologist's experience, background, practice setting, personal bias, and medicolegal culture. We developed the methodology to audit the IHC/IF utilization in our academic subspecialty practice.

27-Hydroxycholesterol Drives the Spread of α-Synuclein Pathology in Parkinson's Disease.

Background: The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD.

CXCR4 antagonists disrupt leukaemia-meningeal cell adhesion and attenuate chemoresistance.

The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge. Developing novel and more effective CNS-directed therapies has been hampered, in part, by our limited understanding of the leukaemia niche in the CNS relative to the bone marrow. Accordingly, defining the molecular and cellular components critical for the establishment and maintenance of the CNS leukaemia niche may lead to new therapeutic opportunities.

Galectin-9/Tim-3 pathway mediates dopaminergic neurodegeneration in MPTP-induced mouse model of Parkinson's disease.

Galectin-9 (Gal-9) is a crucial immunoregulatory mediator in the central nervous system. Microglial activation and neuroinflammation play a key role in the degeneration of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). However, it remains unknown whether Gal-9 is involved in the pathogenesis of PD.

Ubiquitin-positive astrogliopathy clinically mimicking Parkinson's disease.

Several neurodegenerative pathologies can clinically mimic Parkinson's disease, including neurodegenerative diseases with glial pathology. However, the glial aggregates are typically composed of known pathogenic proteins and are associated with prominent neuronal loss in the substantia nigra. Here we present an unusual case of a 91-year-old man with a clinical diagnosis of Parkinson's disease, but whose autopsy findings showed a ubiquitin-positive astrogliopathy without significant neuronal loss in the substantia nigra.

Initial Clinical Experience With ClearPoint SmartFrame Array-Aided Stereotactic Procedures.

Background: The ClearPoint SmartFrame Array (ClearPoint Neuro, Inc., Solana Beach, CA) system consists of a magnetic resonance imaging compatible frame supported by a customized neuro navigation software. This system received U.

GammaTile® brachytherapy in the treatment of recurrent glioblastomas.

Background: GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform.

Modeling the effect of cerebral capillary blood flow on neuronal firing.

Adequate cerebral blood flow has long been recognized as essential for the maintenance of the neuronal function while interruption of cerebral blood flow for durations as short as minutes can result in permanent brain damage. A primary goal of this work is to determine how a neuron's ability to respond to synaptic input depends on parameters that control cerebral blood flow. A complex mathematical model is constructed that integrates detailed biophysical models of neuronal action potentials, mitochondrial ATP production and cerebral capillary blood flow.

Molecular Profile of a Pituitary Rhabdomyosarcoma Arising From a Pituitary Macroadenoma: A Case Report.

Pituitary sarcoma arising in association with pituitary adenoma is an uncommon finding. Most cases of secondary sarcoma have been noted to arise with a median interval of 10.5 years post radiation.

Association of acute disseminated encephalomyelitis (ADEM) and COVID-19 in a pediatric patient.

Cases of acute disseminated encephalomyelitis (ADEM) and its hyperacute form, acute hemorrhagic leukoencephalitis (AHLE), have been reported in coronavirus disease 2019 (COVID-19) patients as rare, but most severe neurological complications. However, histopathologic evaluations of ADEM/AHLE pathology in COVID patients are extremely limited, so far having only been reported in a few adult autopsy cases. Here we compare the findings with an ADEM-like pathology in a pediatric patient taken through a biopsy procedure.

Mathematical modeling of cerebral capillary blood flow heterogeneity and its effect on brain tissue oxygen levels.

Maintaining cerebral blood flow is critical for adequate neuronal function. Previous computational models of brain capillary networks have predicted that heterogeneous cerebral capillary flow patterns result in lower brain tissue partial oxygen pressures PO2). However, these previous models have often considered simple capillary networks in terms of their geometric properties.

IDH1 and IDH2 Mutations in Colorectal Cancers.

Objectives: To elucidate clinicopathologic and molecular characteristics of IDH1 and IDH2 (IDH1/2) mutations in colorectal cancers (CRCs).

Methods: We evaluated IDH1/2 mutations in 1,623 CRCs using a next-generation sequencing assay.

Results: IDH1/2 mutations, predominantly IDH1 p.

Associations of Alzheimer's Disease Neuropathologic Changes with Clinical Presentations of Parkinson's Disease.

Background: Parkinson's disease (PD) and Alzheimer's disease (AD) are the two most prevalent neurodegenerative diseases associated with age. Pathological studies have shown that these two diseases share a certain degree of neuropathological overlap. AD neuropathologic change contributes to cognitive impairment in PD.

Cerebral Microbleeds and Intracranial Hemorrhages in Adult Patients on Extracorporeal Membrane Oxygenation-Autopsy Study.

Unlabelled: Current studies lack robust information on the prevalence and associated factors of cerebral microbleeds in patients who underwent extracorporeal membrane oxygenation.

Design: Retrospective analysis.

Setting: We reviewed patients who underwent (extracorporeal membrane oxygenation) and subsequent brain autopsy with gross and microscopic examinations from January 2009 to December 2018 from a single tertiary center.