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1.
Cancers (Basel) ; 16(2)2024 Jan 05.
Article in English | MEDLINE | ID: mdl-38254737

ABSTRACT

BACKGROUND: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase (IDH) mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. Defining IDH status (wild type (WT) and mutant) and the associated transcriptome may prove useful in determining other therapeutic options in these neoplasms. METHODS: Formalin-fixed paraffin-embedded material from 69 primary and recurrent grade 2, 3 and dedifferentiated CS was obtained. DNA sequencing for IDH1 and IDH2 mutations (n = 47) and RNA sequencing via Nextseq 2000 (n = 14) were performed. Differentially expressed genes (DEGs) were identified and used to predict aberrant biological pathways with Ingenuity Pathway Analysis (IPA) software (Qiagen). Gene Set Enrichment Analyses (GSEA) using subsets C3, C5 and C7 were performed. Differentially expressed genes were validated by immunohistochemistry. Outcome analysis was performed using the Wilcoxon test. RESULTS: A set of 69 CS (28 females, 41 males), average age 65, distributed among femur, pelvis, humerus, and chest wall were identified from available clinical material. After further selection based on available IDH status, we evaluated 15 IDH WT and 32 IDH mutant tumors as part of this dataset. Out of 15 IDH WT tumors, 7 involved the chest wall/scapula, while 1 of 32 mutants arose in the scapula. There were far more genes overexpressed in IDH WT tumors compared to IDH mutant tumors. Furthermore, IDH WT and IDH mutant tumors were transcriptomically distinct in the IPA and GSEA, with IDH mutant tumors showing increased activity in methylation pathways and endochondral ossification, while IDH WT tumors showed more activity in normal matrix development pathways. Validation immunohistochemistry demonstrated expression of WT1 and AR in IDH WT tumors, but not in IDH mutants. SATB2 was expressed in IDH mutant tumors and not in WT tumors. Outcome analysis revealed differences in overall survival between mutant and WT tumors (p = 0.04), dedifferentiated mutant and higher-grade (2, 3) mutant tumors (p = 0.03), and dedifferentiated mutant and higher-grade (2, 3) WT tumors (p = 0.03). The longest survival times were observed in patients with higher-grade WT tumors, while patients with dedifferentiated mutant tumors showed the lowest survival. Generally, patients with IDH WT tumors displayed longer survival in both the higher-grade and dedifferentiated groups. CONCLUSIONS: Grade 2, 3 and dedifferentiated chondrosarcomas are further characterized by IDH status, which in turn informs transcriptomic phenotype and overall survival. The transcriptome is distinct depending on IDH status, and implies different treatment targets.

2.
Radiol Case Rep ; 18(10): 3632-3635, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37593330

ABSTRACT

Papillary glioneuronal tumors are a rare and typically benign entity with pathological and radiographic complexity. Presentation can mimic other neoplasms, making diagnosis more challenging. The literature to date describes the clinical understanding, diagnostic, therapeutic, and prognostic characteristics of this limited number of patients. In this article, we report an unusual case of a glioneuronal tumor with multifocal presentation, normal pressure hydrocephalus-like symptoms, and large peritumoral parenchymal cysts, which guided the surgical approach. This unusual presentation has not previously been reported and adds valuable information to the clinical recognition and management literature.

3.
Genes (Basel) ; 14(3)2023 03 06.
Article in English | MEDLINE | ID: mdl-36980931

ABSTRACT

Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the MYBPC3 and SMYD1 genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous MYBPC3 variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the SMYD1 gene. The second patient, the proband's sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous MYBPC3 variant. While this specific MYBPC3 variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel SMYD1 variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology.


Subject(s)
Cardiomyopathy, Hypertrophic , Heart Failure , Adult , Female , Humans , Infant , Male , Cardiomyopathy, Hypertrophic/genetics , Carrier Proteins/genetics , Cytoskeletal Proteins/genetics , DNA-Binding Proteins/genetics , Muscle Proteins/genetics , Mutation , Transcription Factors/genetics
5.
Histopathology ; 82(6): 946-952, 2023 May.
Article in English | MEDLINE | ID: mdl-36648026

ABSTRACT

AIMS: Ossifying fibromyxoid tumor (OFMT) is a rare enigmatic tumor of uncertain differentiation that can be classified as typical, atypical, and malignant subtypes based on cellularity, nuclear grade, and mitotic activity. The majority of OFMTs, regardless of the risk of malignancy, harbor genetic translocations. We report two malignant OFMTs, including one with evidence of dedifferentiation, with novel genefusions. METHODS AND RESULTS: Case 1 was a 63-year-old male with a dedifferentiated OFMT arising in the right wrist, while case 2 was a 41-year-old male with a malignant OFMT presenting as a posterior mediastinal mass. Case 2 showed multifocal expression with EMA and synaptophysin, while desmin and S100 were absent in both tumors. NGS sequencing studies detected PHF1::FOXR1 and PHF1::FOXR2 gene fusions in cases 1 and 2, respectively. Despite aggressive regimens, both progressed with wide spread metastases resulting in death within six years of diagnosis. CONCLUSIONS: We expand the genetic spectrum of OFMTs with two novel gene fusions, PHF1::FOXR1 and PHF1::FOXR2. These cases confirm the previously reported tendencies for OFMTs with rare variant fusions to demonstrate malignant behavior, unusual morphology, and non-specific immunophenotype.


Subject(s)
Fibroma, Ossifying , Fibroma , Soft Tissue Neoplasms , Male , Humans , Middle Aged , Adult , Fibroma, Ossifying/pathology , Soft Tissue Neoplasms/pathology , Fibroma/pathology , Gene Fusion , DNA-Binding Proteins/genetics , Polycomb-Group Proteins/genetics , Polycomb-Group Proteins/metabolism , Forkhead Transcription Factors/genetics
6.
Semin Diagn Pathol ; 40(1): 47-51, 2023 Jan.
Article in English | MEDLINE | ID: mdl-35843756

ABSTRACT

Germ cell tumors of the central nervous system (GCT-CNS) arise predominantly in midline locations of the CNS and affect young patients in their first to third decades of life. Involvement of the CNS is thought to be a sequelae of residual primordial germ cells with incomplete embryologic migration. Clinically, GCT-CNS present with symptoms of ventricular obstruction or compression of affected brain structures. Histologically, these tumors are analogous to their gonadal and extra-gonadal counterparts. Diagnosis relies heavily on morphology and immunohistochemical findings, and can be complicated by limited tumor sampling. There is currently only a limited role for molecular studies. Treatment of these lesions is made difficult by their involvement of deep and vital brain structures and accurate pathologic diagnosis is essential for appropriate therapy. Diagnosis should involve review of the clinical history, imaging studies, and assessment of serum and cerebrospinal fluid tumor markers. Current therapeutic strategies involving radiation therapy with or without chemotherapy are quite effective, in spite of the locational difficulties that often prevent gross total resection.


Subject(s)
Brain Neoplasms , Central Nervous System Neoplasms , Neoplasms, Germ Cell and Embryonal , Humans , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/therapy , Central Nervous System Neoplasms/pathology , Neoplasms, Germ Cell and Embryonal/diagnosis , Neoplasms, Germ Cell and Embryonal/therapy , Biomarkers, Tumor , Brain Neoplasms/therapy
8.
Case Rep Pathol ; 2022: 1087918, 2022.
Article in English | MEDLINE | ID: mdl-35573840

ABSTRACT

Concomitant schwannomas and benign meningothelial proliferations, including meningothelial hyperplasia or meningioma, rarely occur at the same location outside the setting of neurofibromatosis. Herein, we present a rare case of concurrent schwannoma and benign meningothelial hyperplasia concomitantly occurring in the cervical spine of a 69-year-old male patient with no history of any genetic disorder.

9.
Neurooncol Adv ; 4(1): vdab182, 2022.
Article in English | MEDLINE | ID: mdl-35047821

ABSTRACT

BACKGROUND: Infiltrative astrocytic tumors with and without isocitrate dehydrogenase (IDH) mutation frequently contain mutations in the TP53 tumor suppressor gene. Disruption of normal p53 protein activity confers neoplastic cells with a number of oncogenic properties and is a common feature of aggressive malignancies. However, the high prevalence of TP53 mutation and its pathogenic role in IDH-mutant (IDHmut) astrocytoma is not well understood. METHODS: We performed a retrospective analysis of molecular and clinical data from patients with IDHmut astrocytoma at the University of Pittsburgh Medical Center between 2015 and 2019 as our initial cohort. We validated and expanded our findings using molecular and clinical data from The Cancer Genome Atlas. RESULTS: We show that the TP53 mutational spectrum in IDHmut astrocytomas is dominated by a single hotspot mutation that codes for the R273C amino acid change. This mutation is not enriched in IDH-wildtype astrocytomas. The high prevalence of TP53 R273C mutation is not readily explained by known mutagenic mechanisms, and TP53 R273C mutant tumors have lower transcriptional levels of proliferation-related genes compared to IDHmut astrocytomas harboring other forms of mutant p53. Despite lower proliferation, TP53 R273C mutant tumors tend to progress more quickly and have a shorter overall survival than those with other TP53 mutations, particularly in male patients. CONCLUSIONS: Our findings suggest that compared to other TP53 mutations, IDHmut astrocytomas may select for TP53 R273C mutations during tumorigenesis. The genotype, sex, and mutation-specific findings are clinically relevant and should prompt further investigation of TP53 R273C.

10.
J Neurosurg Case Lessons ; 1(19): CASE2118, 2021 May 10.
Article in English | MEDLINE | ID: mdl-35854832

ABSTRACT

BACKGROUND: "Langerhans cell histiocytosis" (LCH) is a term that encompasses single-system or multisystem disorders traditionally characterized by a proliferation of clonal CD1a+/CD207+ myeloid-derived histiocytes. In most cases of LCH, mitogen-activated protein kinase (MAPK) pathway somatic mutations lead to near universal upregulation of phosphorylated extracellular signal-regulated kinase expression. The clinical manifestations of LCH are numerous, but bone involvement is common. Intracranial lesions, especially as isolated manifestations, are rare. OBSERVATIONS: The authors presented the case of a long-term survivor of exclusive intracranial LCH that manifested with isolated craniofacial bone and intraparenchymal central nervous system recurrences, which were managed with 3 decades of multimodal therapy. The patient was initially diagnosed with LCH at age 2 years, and the authors documented the manifestations of disease and treatment for 36 years. Most of the patient's treatment course occurred before the discovery of BRAF V600E. Treatments initially consisted of chemotherapy, radiosurgery, and open resections for granulomatous LCH lesions. Into young adulthood, the patient had a minimal disease burden but still required additional radiosurgical procedures and open resections. LESSONS: Surgical treatments alleviated the patient's immediate symptoms and allowed for tumor burden control. However, surgical interventions did not cure the underlying, aggressive disease. In the current era, access to systemic MAPK inhibitor therapy for histiocytic lesions may offer improved outcomes.

11.
Acta Neuropathol Commun ; 8(1): 169, 2020 10 20.
Article in English | MEDLINE | ID: mdl-33081848

ABSTRACT

IDH-mutant astrocytomas have a more indolent natural history and better prognosis than their IDH-wild type counterparts, but are still graded according to schemes developed prior to the recognition of this type of neoplasm as a distinct entity. Homozygous deletion of CDKN2A has been proposed as a molecular correlate of aggressive behavior in these tumors, and may be incorporated into future grading systems in an effort to improve prognostic stratification. Fluorescence in situ hybridization (FISH) is a common ancillary testing modality used to assess CDKN2A status, but the specifics of how to best interpret FISH results for prognostication of gliomas have not been clearly defined in the literature. To address this issue, we performed a retrospective analysis of prospectively collected CDKN2A FISH data from 108 primary and 43 recurrent IDH-mutant astrocytomas diagnosed between 2007-2020 at the University of Pittsburgh Medical Center. High level CDKN2A homozygous deletion was rare in primary tumors and was identified more frequently in recurrent tumors. Multivariate Cox Proportional-Hazards analysis demonstrated that histologic grade and CDKN2A status are independent predictors of survival, and the prognostic value of CDKN2A is maximized by applying a threshold of ≥ 30% of tumor cells with homozygous deletion by FISH to define a positive result. At this threshold, CDKN2A deletion significantly stratified survival of histologic grade 4 tumors, but grade 2 and 3 tumors rarely exceeded this cutoff value and did not show worse survival. Lower thresholds identified additional lower grade tumors, but were not prognostically useful. Compared to prior studies, the lack of prognostic significance of CDKN2A homozygous deletion by FISH in grade 2-3 IDH-mutant astrocytomas may reflect differences in cohort populations or technical differences between testing modalities. Definitive criteria for determining CDKN2A homozygous deletion by various methodologies will be critical if this is to be included in future grading schemes.


Subject(s)
Astrocytoma/genetics , Brain Neoplasms/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Gene Deletion , Adult , Aged , Astrocytoma/pathology , Brain Neoplasms/pathology , Female , Homozygote , Humans , In Situ Hybridization, Fluorescence , Isocitrate Dehydrogenase/genetics , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Neoplasm Grading , Prognosis , Proportional Hazards Models , Young Adult
12.
J Neuropathol Exp Neurol ; 79(10): 1115-1121, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32954433

ABSTRACT

Neurotoxic side effects of traditional systemic chemotherapy are abundantly described. The introduction of newly developed biologic therapeutics and cellular immune effector therapies has expanded the spectrum of neurotoxicity. Multifocal necrotizing leukoencephalopathy (MNL) is a pathologic condition of unknown etiology that has been observed in patients after prolonged critical illness. We observed a case of MNL in a patient treated with extensive multimodal therapy including chimeric antigen receptor T cells. A month before death, MRI demonstrated signs of inflammation and developing edema in brainstem structures. At autopsy the abnormal MRI regions showed a wave-like loss of microglia with hemorrhagic MNL in regions closest to the brain surface. These findings reiterate the susceptibility of white matter to antineoplastic therapy and suggest new mechanisms of neurotoxicity when traditional chemotherapy is combined with biologic or cellular effector therapy.


Subject(s)
Combined Modality Therapy/adverse effects , Immunotherapy, Adoptive/adverse effects , Leukoencephalopathy, Progressive Multifocal/etiology , Leukoencephalopathy, Progressive Multifocal/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Combined Modality Therapy/methods , Cyclophosphamide/adverse effects , Dexamethasone/adverse effects , Doxorubicin/adverse effects , Female , Humans , Inotuzumab Ozogamicin/administration & dosage , Inotuzumab Ozogamicin/adverse effects , Microglia/pathology , Middle Aged , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/pathology , Receptors, Chimeric Antigen , Vincristine/adverse effects
13.
Surg Neurol Int ; 11: 176, 2020.
Article in English | MEDLINE | ID: mdl-32754351

ABSTRACT

BACKGROUND: Spinal cavernous malformations are rare, accounting for approximately 5-12% of all spinal cord vascular lesions. Fortunately, improvements in imaging technologies have made it easier to establish the diagnosis of intramedullary spinal cavernomas (ISCs). CASE DESCRIPTION: Here, we report the case of a 63-year-old male with an >11-year history of left-sided radiculopathy, ataxia, and quadriparesis. Initially, radiographic findings were interpreted as consistent with spondylotic myelopathy with cord signal changes from the C3-C7 levels. The patient underwent a C3-C7 laminectomy/foraminotomy with instrumentation. It was only after several symptomatic recurrences and repeated magnetic resonance images (MRI) that the diagnosis of a ventrally-located intramedullary lesion, concerning for a cavernoma, at the level C6 was established. CONCLUSION: Early and repeated enhanced MR studies may be required to correctly establish the diagnosis and determine the optimal surgical management of ISCs.

14.
J Neuroimmune Pharmacol ; 14(1): 44-51, 2019 03.
Article in English | MEDLINE | ID: mdl-30617749

ABSTRACT

Mixed lineage kinases (MLKs) are a group of serine-threonine kinases that evolved in part to respond to endogenous and exogenous insults that result in oxidative stress and pro-inflammatory responses from innate immune cells. Human immunodeficiency virus type 1 (HIV-1) thrives in these conditions and is associated with the development of associated neurocognitive disorders (HAND). As part of a drug discovery program to identify new therapeutic strategies for HAND, we created a library of broad spectrum MLK inhibitors with drug-like properties. Serendipitously, the lead compound, URMC-099 has proved useful not only in reversing damage to synaptic architecture in models of HAND, but also serves to restore autophagy as a protective response when given in concert with nanoformulated antiretroviral therapy (nanoART) in persistently infected macrophages. These findings are reviewed in the context of MLK3 biology and cellular signaling pathways relevant to new HIV-1 therapies. Graphical abstract.


Subject(s)
AIDS Dementia Complex/virology , HIV-1/drug effects , MAP Kinase Kinase Kinases/antagonists & inhibitors , Macrophages/drug effects , Macrophages/virology , Animals , HIV-1/physiology , Humans , Macrophages/enzymology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrroles/pharmacology , Virus Latency/drug effects , Virus Latency/physiology , Mitogen-Activated Protein Kinase Kinase Kinase 11
15.
Glia ; 66(12): 2563-2574, 2018 12.
Article in English | MEDLINE | ID: mdl-30325063

ABSTRACT

Microglial activation, increased proinflammatory cytokine production, and a reduction in synaptic density are key pathological features associated with HIV-associated neurocognitive disorders (HAND). Even with combination antiretroviral therapy (cART), more than 50% of HIV-positive individuals experience some type of cognitive impairment. Although viral replication is inhibited by cART, HIV proteins such as Tat are still produced within the nervous system that are neurotoxic, involved in synapse elimination, and provoke enduring neuroinflammation. As complement deposition on synapses followed by microglial engulfment has been shown during normal development and disease to be a mechanism for pruning synapses, we have tested whether complement is required for the loss of synapses that occurs after a cortical Tat injection mouse model of HAND. In Tat-injected animals evaluated 7 or 28 days after injection, levels of early complement pathway components, C1q and C3, are significantly elevated and associated with microgliosis and a loss of synapses. However, C1qa knockout mice have the same level of Tat-induced synapse loss as wild-type (WT) mice, showing that the C1q-initiated classical complement cascade is not driving synapse removal during HIV1 Tat-induced neuroinflammation.


Subject(s)
Cognitive Dysfunction/pathology , Complement C1q/metabolism , HIV Infections/complications , Synapses/drug effects , tat Gene Products, Human Immunodeficiency Virus/pharmacology , Animals , Bone Marrow/metabolism , Bone Marrow Transplantation , Calcium-Binding Proteins/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/virology , Complement C1q/genetics , Complement C3/pharmacology , Disease Models, Animal , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Gliosis/chemically induced , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microfilament Proteins/metabolism , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Nerve Tissue Proteins/metabolism , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8A/metabolism , Synapses/metabolism , Synapses/pathology
16.
eNeuro ; 5(6)2018.
Article in English | MEDLINE | ID: mdl-30627663

ABSTRACT

Treatments to stop gray matter degeneration are needed to prevent progressive disability in multiple sclerosis (MS). We tested whether inhibiting mixed-lineage kinases (MLKs), which can drive inflammatory microglial activation and neuronal degeneration, could protect hippocampal synapses in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates the excitatory synaptic injury that occurs widely within the gray matter in MS. URMC-099, a broad spectrum MLK inhibitor with additional activity against leucine-rich repeat kinase 2 (LRRK2) and other kinases, prevented loss of PSD95-positive postsynaptic structures, shifted activated microglia toward a less inflammatory phenotype, and reversed deficits in hippocampal-dependent contextual fear conditioning in EAE mice when administered after the onset of motor symptoms. A narrow spectrum inhibitor designed to be highly selective for MLK3 failed to protect synapses in EAE hippocampi, and could not rescue cultured neurons from trophic deprivation in an in vitro model of MLK-driven neuronal degeneration. These results suggest that URMC-099 may have potential as a neuroprotective treatment in MS and demonstrate that a broad spectrum of inhibition against a combination of MLK and other kinases is more effective in neuroinflammatory disease than selectively targeting a single kinase.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/pathology , Hippocampus/pathology , Neuroprotective Agents/therapeutic use , Pyridines/therapeutic use , Pyrroles/therapeutic use , Synapses/drug effects , Animals , Apoptosis/drug effects , Apoptosis/genetics , Calcium-Binding Proteins/metabolism , Cells, Cultured , Conditioning, Psychological/drug effects , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Enzyme Inhibitors/therapeutic use , Fear/drug effects , Fear/psychology , Female , Male , Mice , Mice, Inbred C57BL , Microfilament Proteins/metabolism , Myelin-Oligodendrocyte Glycoprotein/toxicity , Neurons/drug effects , Peptide Fragments/toxicity , Superior Cervical Ganglion/cytology
17.
J Neuropathol Exp Neurol ; 76(5): 347-357, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28340257

ABSTRACT

We describe a novel disease entity with the clinical and radiologic presentation of neuromyelitis optica (NMO) and widespread CD8-positive T-cell leukoencephalitis and astrocytopathy. The 59-year-old female patient had a complex 2-year neurological history that included early changes in cognition and memory, progressive lower extremity motor dysfunction, and multimodal sensory involvement. MRI of the spinal cord showed increased T2 signal in the central cord extending from C2 through T4. MRI of the brain showed symmetric radial enhancement in periventricular deep white matter without evidence of demyelinating lesions. The constellation of findings met clinical criteria for NMO. Steroid treatment was initiated with subjective improvement but she developed urosepsis and died at age 61 years. At autopsy, the spinal cord showed typical NMO findings but no evidence of complement deposition or neutrophil infiltration. There was diffuse CD8-positive T-cell infiltration and CD68-positive macrophage activation throughout subcortical white matter, optic chiasm, brainstem, and spinal cord. This was accompanied by marked astrocytopathy in all areas. Serum was negative for aquaporin-4 autoantibodies suggesting a nonhumoral basis of astrocyte damage. This first example of CD8-positive T-cell leukoencephalitis in a patient with a clinical presentation of NMO may explain the recalcitrance of some patients to therapies targeting humoral immunity.


Subject(s)
Astrocytes/pathology , CD8-Positive T-Lymphocytes , Demyelinating Diseases/pathology , Encephalitis/pathology , Neuromyelitis Optica/pathology , Anti-Inflammatory Agents/therapeutic use , Antigens, CD/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Autopsy , Demyelinating Diseases/diagnostic imaging , Encephalitis/complications , Encephalitis/diagnostic imaging , Fatal Outcome , Female , Humans , Magnetic Resonance Imaging , Methylprednisolone/therapeutic use , Middle Aged , Neuromyelitis Optica/diagnostic imaging , Spinal Cord/pathology , White Matter/pathology
18.
J Neurosci ; 35(13): 5271-83, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25834052

ABSTRACT

Leucine-rich repeat kinase 2 (LRRK2) is the single most common genetic cause of both familial and sporadic Parkinson's disease (PD), both of which share pathogenetic and neurologic similarities with human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND). Pathologic LRRK2 activity may also contribute to neuroinflammation, because microglia lacking LRRK2 exposed to proinflammatory stimuli have attenuated responses. Because microglial activation is a hallmark of HIV-1 neuropathology, we have investigated the role of LRRK2 activation using in vitro and in vivo models of HAND. We hypothesize that LRRK2 is a key modulator of microglial inflammatory responses, which play a pathogenic role in both HAND and PD, and that these responses may cause or exacerbate neuronal damage in these diseases. The HIV-1 Tat protein is a potent neurotoxin produced during HAND that induces activation of primary microglia in culture and long-lasting neuroinflammation and neurotoxicity when injected into the CNS of mice. We found that LRRK2 inhibition attenuates Tat-induced pS935-LRRK2 expression, proinflammatory cytokine and chemokine expression, and phosphorylated p38 and Jun N-terminal kinase signaling in primary microglia. In our murine model, cortical Tat injection in LRRK2 knock-out (KO) mice results in significantly diminished neuronal damage, as assessed by microtubule-associated protein 2 (MAP2), class III ß-tubulin TUJ1, synapsin-1, VGluT, and cleaved caspase-3 immunostaining. Furthermore, Tat-injected LRRK2 KO animals have decreased infiltration of peripheral neutrophils, and the morphology of microglia from these mice were similar to that of vehicle-injected controls. We conclude that pathologic activation of LRRK2 regulates a significant component of the neuroinflammation associated with HAND.


Subject(s)
Cognition Disorders/metabolism , HIV Infections/metabolism , Inflammation/metabolism , Nerve Degeneration/metabolism , Protein Serine-Threonine Kinases/physiology , AIDS Dementia Complex/complications , AIDS Dementia Complex/metabolism , Animals , Biomarkers/metabolism , Cerebral Cortex/drug effects , Cognition Disorders/complications , Gene Expression/drug effects , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Gene Products, tat/administration & dosage , Gene Products, tat/toxicity , HIV Infections/complications , Inflammation/chemically induced , Inflammation Mediators/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Mice , Mice, Knockout , Microglia/drug effects , Microglia/metabolism , Microinjections , Neuroprotective Agents/metabolism , Primary Cell Culture , Protein Serine-Threonine Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
19.
J Med Chem ; 56(20): 8032-48, 2013 Oct 24.
Article in English | MEDLINE | ID: mdl-24044867

ABSTRACT

Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.


Subject(s)
Drug Discovery/methods , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrroles/pharmacology , Administration, Oral , Animals , Area Under Curve , Biological Availability , Blood-Brain Barrier/metabolism , Brain/metabolism , Carbazoles/chemical synthesis , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Cells, Cultured , Cognition Disorders/complications , Cognition Disorders/prevention & control , HIV Infections/complications , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Kinase Kinases/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Chemical , Molecular Structure , Monocytes/drug effects , Monocytes/metabolism , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Tumor Necrosis Factor-alpha/metabolism , tat Gene Products, Human Immunodeficiency Virus/pharmacology , Mitogen-Activated Protein Kinase Kinase Kinase 11
20.
J Neurosci ; 33(24): 9998-10010, 2013 Jun 12.
Article in English | MEDLINE | ID: mdl-23761895

ABSTRACT

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) is a significant source of disability in the HIV-infected population. Even with stringent adherence to anti-retroviral therapy, >50% of patients living with HIV-1 will develop HAND (Heaton et al., 2010). Because suppression of viral replication alone is not enough to stop HAND progression, there is a need for an adjunctive neuroprotective therapy in this population. To this end, we have developed a small-molecule brain-penetrant inhibitor with activity against mixed-lineage kinase 3 (MLK3), named URMC-099. MLK3 activation is associated with many of the pathologic hallmarks of HAND (Bodner et al., 2002, 2004; Sui et al., 2006) and therefore represents a prime target for adjunctive therapy based on small-molecule kinase inhibition. Here we demonstrate the anti-inflammatory and neuroprotective effects of URMC-099 in multiple murine and rodent models of HAND. In vitro, URMC-099 treatment reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells. In vivo, URMC-099 treatment reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure. In conclusion, these data provide compelling in vitro and in vivo evidence to investigate the utility of URMC-099 in other models of HAND with the goal of advancement to an adjunctive therapeutic agent.


Subject(s)
HIV Infections/complications , HIV Infections/drug therapy , Inflammation/prevention & control , MAP Kinase Kinase Kinases/antagonists & inhibitors , Neuroprotective Agents/therapeutic use , Animals , Bone Marrow Transplantation , CX3C Chemokine Receptor 1 , Cell Line, Transformed/drug effects , Cell Line, Transformed/virology , Cells, Cultured , Cytokines , Disease Models, Animal , Embryo, Mammalian , Gene Products, tat/immunology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , HIV Infections/virology , HIV-1/physiology , Hippocampus/pathology , Humans , Inflammation/genetics , Inflammation/pathology , Inflammation/virology , Mice , Mice, Transgenic , Microscopy, Immunoelectron , Phagocytosis/drug effects , Phagocytosis/genetics , Phosphorylation/drug effects , Pyridines/pharmacology , Pyridines/therapeutic use , Pyrroles/pharmacology , Pyrroles/therapeutic use , Rats , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Statistics, Nonparametric , Time Factors , Transfection , tat Gene Products, Human Immunodeficiency Virus , Mitogen-Activated Protein Kinase Kinase Kinase 11
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