Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen i... more Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer’s disease (AD) and Parkinson’s disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.
Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion... more Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 12, 2016
Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failu... more Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug respons...
Tremor and other hyperkinetic movements (New York, N.Y.), 2016
Deep brain stimulation (DBS) has been shown to be effective for Parkinson's disease, essentia... more Deep brain stimulation (DBS) has been shown to be effective for Parkinson's disease, essential tremor, and primary dystonia. However, mixed results have been reported in Huntington's disease (HD). A single case of HD DBS was identified from the University of Florida DBS Brain Tissue Network. The clinical presentation, evolution, surgical planning, DBS parameters, clinical outcomes, and brain pathological changes are summarized. This case of HD DBS revealed that chorea may improve and be sustained. Minimal histopathological changes were noted around the DBS leads. Severe atrophy due to HD likely changed the DBS lead position relative to the internal capsule.
To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy deve... more To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy development, a mouse model that recapitulates the molecular and phenotypic features of the disease is urgently needed. Two groups recently reported BAC mouse models that produce RNA foci and RAN proteins but, surprisingly, do not develop the neurodegenerative or behavioral features of ALS/FTD. We now report a BAC mouse model of C9orf72 ALS/FTD that shows decreased survival, paralysis, muscle denervation, motor neuron loss, anxiety-like behavior, and cortical and hippocampal neurodegeneration. These mice express C9orf72 sense transcripts and upregulated antisense transcripts. In contrast to sense RNA foci, antisense foci preferentially accumulate in ALS/FTD-vulnerable cell populations. RAN protein accumulation increases with age and disease, and TDP-43 inclusions are found in degenerating brain regions in end-stage animals. The ALS/FTD phenotypes in our mice provide a unique tool that will fa...
Acta neuropathologica communications, Jan 14, 2015
Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human... more Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer's Disease (FAD). Although transgenic mice have been produced that overexpress wild-type mouse APP, no mice have been generated that express mouse APP with FAD mutations. Here we describe two different versions of such mice that produce amyloid deposits consisting of entirely of mouse Aβ peptides. One line of mice co-expresses mouse APP-Swedish (moAPPswe) with a human presenilin exon-9 deleted variant (PS1dE9) and another line expresses mouse APP-Swedish/Indiana (APPsi) using tetracycline-regulated vectors (tet.moAPPsi). Both lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1dE9 micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts a...
Huntington disease (HD) is caused by a CAG⋅CTG expansion in the huntingtin (HTT) gene. While most... more Huntington disease (HD) is caused by a CAG⋅CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open read...
Abstract A case of recurrent Lhermitte-Duclos disease is presented. Lhermitte-Duclos disease (dys... more Abstract A case of recurrent Lhermitte-Duclos disease is presented. Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) is a rare disorder of localized brain overgrowth that most often presents in middle-aged adults as a tumor-like cerebellar cortical mass. Symptoms are typically due to posterior fossa compressive effects and fourth ventricular obstruction. Neuroimaging features can be distinctive, with an alternating isointense and hyperintense lamination pattern (“tiger striping”) of grossly enlarged cerebellar folia by magnetic resonance imaging. The lesion is characterized histologically by marked hypertrophy of the cell bodies and axons of granule neurons, which send axons into the molecular layer as “parallel fibers.” Secondary myelination of parallel fibers (normally unmyelinated) adds to the mass effect of the lesion. Lhermitte-Duclos disease is strongly associated with the familial hamartoma-neoplasia syndrome (Cowden disease), and both conditions are linked to alterations of the PTEN/AKT/mTOR pathway. Current therapy for this essentially benign process is gross total excision, although the lesion may recur. Patients with Lhermitte-Duclos disease should be evaluated for Cowden disease because of the increased risk of some systemic malignancies (breast, endometrium, thyroid, kidney). Targeting the PTEN/AKT/mTOR pathway may provide novel therapies in the future.
Cortical dysgenesis (CD) describes a wide spectrum of brain anomalies that involve abnormal devel... more Cortical dysgenesis (CD) describes a wide spectrum of brain anomalies that involve abnormal development of the cerebral cortex. There is a strong association between CD and epilepsy, and it comprises a significant proportion of children and adults whose epilepsy cannot be controlled with medications. There has been intense effort to define the relationship between CD and epilepsy so that more effective therapies can be devised. These efforts have ranged from detailed study of people with CD and epilepsy from a clinical standpoint to single-cell analysis of mRNA expression and postsynaptic receptor function. Animal models have also been developed to mimic certain aspects of CD in a situation when quantitative, controlled, and interventional experiments can be performed that would not be possible in a clinical setting. This review will give an overview of human CD syndromes and their causes, when possible, and describe some specific abnormalities in dysplastic cortex that may underlie...
Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor th... more Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the brain, whereas non-neural metastases, as well as select lower grade gliomas, develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies–invasion and noninvasion–is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident ...
The safety of magnetic resonance imaging (MRI) for deep brain stimulation (DBS) patients is of gr... more The safety of magnetic resonance imaging (MRI) for deep brain stimulation (DBS) patients is of great importance to both movement disorders clinicians and to radiologists. The present study utilized the Deep Brain Stimulation Brain Tissue Network's (DBS-BTN's) clinical and neuropathological database to search for evidence of adverse effects of MRI performed on implanted DBS patients. Performing a 1.5 T MRI with a head receive coil on patients with implanted DBS devices should not result in evidence of adverse clinical or pathological effects in the DBS-BTN cohort. Further, exposing post-mortem DBS-BTN brains with DBS leads to extended 3T MRI imaging should not result in pathological adverse effects. An electronic literature search was performed to establish clinical and neuropathological criteria for evidence of MRI-related adverse reactions in DBS patients. A retrospective chart review of the DBS-BTN patients was then performed to uncover potential adverse events resulting from MRI scanning. DBS patient characteristics and MRI parameters were recorded for each patient. In addition, 3T MRI scans were performed on 4 post-mortem brains with DBS leads but without batteries attached. Detailed neuropathological studies were undertaken to search for evidence of MRI-induced adverse tissue changes. No clinical signs or symptoms or MRI-induced adverse effects were discovered in the DBS-BTN database, and on detailed review of neuroimaging studies. Neuropathological examination did not reveal changes consistent with MRI-induced heating damage. The novel study of four brains with prolonged 3T post-mortem magnetic field exposure (DBS leads left in place) also did not reveal pathological changes consistent with heat related damage. The current study adds important information to the data on the safety of MRI in DBS patients. Novel post-mortem MRI studies provide additional information regarding the safety of 3T MRI in DBS patients, and could justify additional studies especially post-mortem scans with battery sources in place. The lack of pathological findings in the DBS-BTN database and the lack of tissue related changes following prolonged exposure to 3T MRI in the post-mortem brains suggest that MRI scanning in DBS patients may be relatively safe, especially under current guidelines requiring a head receive coil. Subsequent studies exploring the safety of 1.5 T versus 3T MRI in DBS patients should utilize more in depth post-mortem imaging to better simulate the human condition.
Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pha... more Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need. Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n = 21), common glioma lines (n = 5), and noncancer human control cells (n = 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo. Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, stro...
Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen i... more Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer’s disease (AD) and Parkinson’s disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.
Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion... more Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 12, 2016
Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failu... more Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug respons...
Tremor and other hyperkinetic movements (New York, N.Y.), 2016
Deep brain stimulation (DBS) has been shown to be effective for Parkinson's disease, essentia... more Deep brain stimulation (DBS) has been shown to be effective for Parkinson's disease, essential tremor, and primary dystonia. However, mixed results have been reported in Huntington's disease (HD). A single case of HD DBS was identified from the University of Florida DBS Brain Tissue Network. The clinical presentation, evolution, surgical planning, DBS parameters, clinical outcomes, and brain pathological changes are summarized. This case of HD DBS revealed that chorea may improve and be sustained. Minimal histopathological changes were noted around the DBS leads. Severe atrophy due to HD likely changed the DBS lead position relative to the internal capsule.
To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy deve... more To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy development, a mouse model that recapitulates the molecular and phenotypic features of the disease is urgently needed. Two groups recently reported BAC mouse models that produce RNA foci and RAN proteins but, surprisingly, do not develop the neurodegenerative or behavioral features of ALS/FTD. We now report a BAC mouse model of C9orf72 ALS/FTD that shows decreased survival, paralysis, muscle denervation, motor neuron loss, anxiety-like behavior, and cortical and hippocampal neurodegeneration. These mice express C9orf72 sense transcripts and upregulated antisense transcripts. In contrast to sense RNA foci, antisense foci preferentially accumulate in ALS/FTD-vulnerable cell populations. RAN protein accumulation increases with age and disease, and TDP-43 inclusions are found in degenerating brain regions in end-stage animals. The ALS/FTD phenotypes in our mice provide a unique tool that will fa...
Acta neuropathologica communications, Jan 14, 2015
Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human... more Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer's Disease (FAD). Although transgenic mice have been produced that overexpress wild-type mouse APP, no mice have been generated that express mouse APP with FAD mutations. Here we describe two different versions of such mice that produce amyloid deposits consisting of entirely of mouse Aβ peptides. One line of mice co-expresses mouse APP-Swedish (moAPPswe) with a human presenilin exon-9 deleted variant (PS1dE9) and another line expresses mouse APP-Swedish/Indiana (APPsi) using tetracycline-regulated vectors (tet.moAPPsi). Both lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1dE9 micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts a...
Huntington disease (HD) is caused by a CAG⋅CTG expansion in the huntingtin (HTT) gene. While most... more Huntington disease (HD) is caused by a CAG⋅CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open read...
Abstract A case of recurrent Lhermitte-Duclos disease is presented. Lhermitte-Duclos disease (dys... more Abstract A case of recurrent Lhermitte-Duclos disease is presented. Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) is a rare disorder of localized brain overgrowth that most often presents in middle-aged adults as a tumor-like cerebellar cortical mass. Symptoms are typically due to posterior fossa compressive effects and fourth ventricular obstruction. Neuroimaging features can be distinctive, with an alternating isointense and hyperintense lamination pattern (“tiger striping”) of grossly enlarged cerebellar folia by magnetic resonance imaging. The lesion is characterized histologically by marked hypertrophy of the cell bodies and axons of granule neurons, which send axons into the molecular layer as “parallel fibers.” Secondary myelination of parallel fibers (normally unmyelinated) adds to the mass effect of the lesion. Lhermitte-Duclos disease is strongly associated with the familial hamartoma-neoplasia syndrome (Cowden disease), and both conditions are linked to alterations of the PTEN/AKT/mTOR pathway. Current therapy for this essentially benign process is gross total excision, although the lesion may recur. Patients with Lhermitte-Duclos disease should be evaluated for Cowden disease because of the increased risk of some systemic malignancies (breast, endometrium, thyroid, kidney). Targeting the PTEN/AKT/mTOR pathway may provide novel therapies in the future.
Cortical dysgenesis (CD) describes a wide spectrum of brain anomalies that involve abnormal devel... more Cortical dysgenesis (CD) describes a wide spectrum of brain anomalies that involve abnormal development of the cerebral cortex. There is a strong association between CD and epilepsy, and it comprises a significant proportion of children and adults whose epilepsy cannot be controlled with medications. There has been intense effort to define the relationship between CD and epilepsy so that more effective therapies can be devised. These efforts have ranged from detailed study of people with CD and epilepsy from a clinical standpoint to single-cell analysis of mRNA expression and postsynaptic receptor function. Animal models have also been developed to mimic certain aspects of CD in a situation when quantitative, controlled, and interventional experiments can be performed that would not be possible in a clinical setting. This review will give an overview of human CD syndromes and their causes, when possible, and describe some specific abnormalities in dysplastic cortex that may underlie...
Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor th... more Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the brain, whereas non-neural metastases, as well as select lower grade gliomas, develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies–invasion and noninvasion–is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident ...
The safety of magnetic resonance imaging (MRI) for deep brain stimulation (DBS) patients is of gr... more The safety of magnetic resonance imaging (MRI) for deep brain stimulation (DBS) patients is of great importance to both movement disorders clinicians and to radiologists. The present study utilized the Deep Brain Stimulation Brain Tissue Network's (DBS-BTN's) clinical and neuropathological database to search for evidence of adverse effects of MRI performed on implanted DBS patients. Performing a 1.5 T MRI with a head receive coil on patients with implanted DBS devices should not result in evidence of adverse clinical or pathological effects in the DBS-BTN cohort. Further, exposing post-mortem DBS-BTN brains with DBS leads to extended 3T MRI imaging should not result in pathological adverse effects. An electronic literature search was performed to establish clinical and neuropathological criteria for evidence of MRI-related adverse reactions in DBS patients. A retrospective chart review of the DBS-BTN patients was then performed to uncover potential adverse events resulting from MRI scanning. DBS patient characteristics and MRI parameters were recorded for each patient. In addition, 3T MRI scans were performed on 4 post-mortem brains with DBS leads but without batteries attached. Detailed neuropathological studies were undertaken to search for evidence of MRI-induced adverse tissue changes. No clinical signs or symptoms or MRI-induced adverse effects were discovered in the DBS-BTN database, and on detailed review of neuroimaging studies. Neuropathological examination did not reveal changes consistent with MRI-induced heating damage. The novel study of four brains with prolonged 3T post-mortem magnetic field exposure (DBS leads left in place) also did not reveal pathological changes consistent with heat related damage. The current study adds important information to the data on the safety of MRI in DBS patients. Novel post-mortem MRI studies provide additional information regarding the safety of 3T MRI in DBS patients, and could justify additional studies especially post-mortem scans with battery sources in place. The lack of pathological findings in the DBS-BTN database and the lack of tissue related changes following prolonged exposure to 3T MRI in the post-mortem brains suggest that MRI scanning in DBS patients may be relatively safe, especially under current guidelines requiring a head receive coil. Subsequent studies exploring the safety of 1.5 T versus 3T MRI in DBS patients should utilize more in depth post-mortem imaging to better simulate the human condition.
Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pha... more Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need. Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n = 21), common glioma lines (n = 5), and noncancer human control cells (n = 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo. Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, stro...
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Papers by Anthony Yachnis