Colleen Forster - Academia.edu (original) (raw)
Papers by Colleen Forster
Journal of Alzheimer's Disease, Jan 24, 2017
There exist several dozen lines of transgenic mice that express human amyloid-β precursor protein... more There exist several dozen lines of transgenic mice that express human amyloid-β precursor protein (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ~4.5 times that of 21-month Tg2576 mice and ~15 times that of 21-24month rTg9191 mice. Plaque-size distributions changed across the lifespan in a line-and regiondependent manner. We also compared the dense-core plaque burdens in the mice to those *
Alzheimers & Dementia, Jul 1, 2015
Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 ... more Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 and inh3, left, and AFM images of each condition after 150h incubation, right (AFM: 6mm 3 6mm scans). The fluorescence level of Ab 40 (green) is decreased by a factor of 4 with SEN304 and castalagin (red and orange), and by a factor of 2 in the presence of inh3 (yellow). These results were confirmed by AFM imaging : sparse protofibres could be seen with inh3 but no networks of mature fibres were formed, while no more fibres were observed in the presence of SEN304 and castalagin. P1-040 QUANTITATIVE COMPARISON OF DENSE-CORE AMYLOID PLAQUE BURDENS IN ALZHEIMER’S DISEASE PATIENTS AND AMYLOID PRECURSOR PROTEIN TRANSGENIC MICE Kathleen R. Zahs, Peng Liu, Laura S. Hemmy, John H. Reichl, Eshaan Rao, Colleen L. Forster, Robert J. Vassar, David R. Borchelt, Karen H. Ashe, University of Minnesota, Minneapolis, MN, USA; University of Minnesota, Minneapolis, MN, USA; Northwestern University, Chicago, IL, USA; University of Florida, Gainesville, FL, USA; Veterans Administration Medical Center, Minneapolis, MN, USA. Contact e-mail: zahsx001@umn.edu
Neurobiology of Aging, Mar 1, 2016
Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain.... more Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain. Lowering brain beta-amyloid is a major target for treatment and prevention of AD. Enrolling subjects based on clinical criteria alone may result in misclassification, as evidenced by the relatively high percent of subjects having normal brain PET beta-amyloid scans in two recent Phase 3 studies. Consequently, novel study protocols were designed testing immunotherapy in subjects with proven beta-amyloid deposition in brain (by PET or CSF) and with early symptomatic AD including those at the prodromal stage, e.g. PET beta-amyloid positive subjects with mild cognitive impairment (MCI) due to AD. Selected drugs in development will be reviewed. The clinical study programs sponsored by the pharmaceutical industry were recently complemented by public-private partnerships on prevention studies such as the A4 study coordinated by the Alzheimer's Disease Cooperative Study (ADCS), or the Dominantly Inherited Alzheimer Network (DIAN) drug trials. Challenges of immunotherapy include targeting of the most relevant Ab species, managing side effects such as amyloid related imaging abnormalities (ARIA E/H), the timing and duration of the intervention, selecting the most suitable study population, and choosing the most suitable clinical and biomarker endpoints. Both active and passive immunization approaches against tau proteins are being developed and are moving towards clinical testing, along with breakthroughs in tau imaging by novel PET ligands. Such potential therapies offer the prospect of treatment of tau-driven neurodegenerative conditions as well as potential for use with beta amyloid targeting therapies as combination therapy against AD.
BMC Cancer, Apr 5, 2014
Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient man... more Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient management and provide a bridge for developing novel therapeutics and imaging methods. Our objective was to evaluate the association between expression of 33 candidate protein biomarkers and time to biochemical failure (BF) after prostatectomy. Methods: PCa tissue microarrays were constructed representing 160 patients for whom clinicopathologic features and follow-up data after surgery were available. Immunohistochemistry for each of 33 proteins was quantified using automated digital pathology techniques. Relationships between clinicopathologic features, staining intensity, and time to BF were assessed. Predictive modeling using multiple imputed datasets was performed to identify the top biomarker candidates. Results: In univariate analyses, lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy, and biomarkers CCND1, HMMR, IGF1, MKI67, SIAH2, and SMAD4 in malignant epithelium were significantly associated with time to BF. HMMR, IGF1, and SMAD4 remained significantly associated with BF after adjusting for clinicopathologic features while additional associations were observed for HOXC6 and MAP4K4 following adjustment. In multibiomarker predictive models, 3 proteins including HMMR, SIAH2, and SMAD4 were consistently represented among the top 2, 3, 4, and 5 most predictive biomarkers, and a signature comprised of these proteins best predicted BF at 3 and 5 years. Conclusions: This study provides rationale for investigation of HMMR, HOXC6, IGF1, MAP4K4, SIAH2, and SMAD4 as biomarkers of PCa aggressiveness in larger cohorts.
Development
Ubiquitin-like, containing PHD and RING finger domains 2 (UHRF2) regulates cell cycle and binds 5... more Ubiquitin-like, containing PHD and RING finger domains 2 (UHRF2) regulates cell cycle and binds 5-hydroxymethylcytosine (5hmC) to promote completion of DNA demethylation. Uhrf2−/− mice are without gross phenotypic defects; however, the cell cycle and epigenetic regulatory functions of Uhrf2 during retinal tissue development are unclear. Retinal progenitor cells (RPCs) produce all retinal neurons and Müller glia in a predictable sequence controlled by the complex interplay between extrinsic signaling, cell cycle, epigenetic changes and cell-specific transcription factor activation. In this study, we find that UHRF2 accumulates in RPCs, and its conditional deletion from mouse RPCs reduced 5hmC, altered gene expressions and disrupted retinal cell proliferation and differentiation. Retinal ganglion cells were overproduced in Uhrf2-deficient retinae at the expense of VSX2+ RPCs. Most other cell types were transiently delayed in differentiation. Expression of each member of the Tet3/Uhrf2...
Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzhei-mer’s di... more Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzhei-mer’s disease. We here report the generation and characterization of a novel transgenic mouse model of Aβ toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and Londonmuta-tions (APPNLI) linked to familial Alzheimer’s disease, under the control of a tetracycline-re-sponse element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase IIα. In these mice, APPNLI is express-ed at a level four-fold that of endogenous mouse APP and its expression is restricted to fore-brain regions. Transgene expression was suppressed by 87 % after two months of doxycycline administration. Histologically, we showed that (1) Aβ plaques emerged in cere-bral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition ...
bioRxiv, 2021
Hemangiosarcoma and angiosarcoma are soft tissue sarcomas of malignant blood vessel-forming cells... more Hemangiosarcoma and angiosarcoma are soft tissue sarcomas of malignant blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs that support the niche, enabling progression of canine hemangiosarcoma and human angiosarcoma. Here, we show that the transcriptional landscape of canine hemangiosarcoma and human angiosarcoma included comparable angiogenic and inflammatory programs. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells, a trait that was not observed in xenografts from canine osteosarcoma and lymphoma. In some cases, the xenografted hemangiosarcoma cells created exuberant myeloid hyperplasia and ...
![Research paper thumbnail of Receptor for Hyaluronan-Mediated Motility (RHAMM [CD168]) peptide vaccination for patients with haematological malignancies: a phaseI/II pilot study](https://attachments.academia-assets.com/116008501/thumbnails/1.jpg)
](http://isrctn.org/>, 2013
Neurobiology of Aging, 2016
Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain.... more Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain. Lowering brain beta-amyloid is a major target for treatment and prevention of AD. Enrolling subjects based on clinical criteria alone may result in misclassification, as evidenced by the relatively high percent of subjects having normal brain PET beta-amyloid scans in two recent Phase 3 studies. Consequently, novel study protocols were designed testing immunotherapy in subjects with proven beta-amyloid deposition in brain (by PET or CSF) and with early symptomatic AD including those at the prodromal stage, e.g. PET beta-amyloid positive subjects with mild cognitive impairment (MCI) due to AD. Selected drugs in development will be reviewed. The clinical study programs sponsored by the pharmaceutical industry were recently complemented by public-private partnerships on prevention studies such as the A4 study coordinated by the Alzheimer's Disease Cooperative Study (ADCS), or the Dominantly Inherited Alzheimer Network (DIAN) drug trials. Challenges of immunotherapy include targeting of the most relevant Ab species, managing side effects such as amyloid related imaging abnormalities (ARIA E/H), the timing and duration of the intervention, selecting the most suitable study population, and choosing the most suitable clinical and biomarker endpoints. Both active and passive immunization approaches against tau proteins are being developed and are moving towards clinical testing, along with breakthroughs in tau imaging by novel PET ligands. Such potential therapies offer the prospect of treatment of tau-driven neurodegenerative conditions as well as potential for use with beta amyloid targeting therapies as combination therapy against AD.
Alzheimer's & Dementia, 2015
Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 ... more Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 and inh3, left, and AFM images of each condition after 150h incubation, right (AFM: 6mm 3 6mm scans). The fluorescence level of Ab 40 (green) is decreased by a factor of 4 with SEN304 and castalagin (red and orange), and by a factor of 2 in the presence of inh3 (yellow). These results were confirmed by AFM imaging : sparse protofibres could be seen with inh3 but no networks of mature fibres were formed, while no more fibres were observed in the presence of SEN304 and castalagin. P1-040 QUANTITATIVE COMPARISON OF DENSE-CORE AMYLOID PLAQUE BURDENS IN ALZHEIMER’S DISEASE PATIENTS AND AMYLOID PRECURSOR PROTEIN TRANSGENIC MICE Kathleen R. Zahs, Peng Liu, Laura S. Hemmy, John H. Reichl, Eshaan Rao, Colleen L. Forster, Robert J. Vassar, David R. Borchelt, Karen H. Ashe, University of Minnesota, Minneapolis, MN, USA; University of Minnesota, Minneapolis, MN, USA; Northwestern University, Chicago, IL, USA; University of Florida, Gainesville, FL, USA; Veterans Administration Medical Center, Minneapolis, MN, USA. Contact e-mail: zahsx001@umn.edu
Langmuir : the ACS journal of surfaces and colloids, Jan 9, 2015
The design of scaffolds which mimic the stiffness, nanofiber structure, and biochemistry of the n... more The design of scaffolds which mimic the stiffness, nanofiber structure, and biochemistry of the native extracellular matrix (ECM) has been a major objective for the tissue engineering field. Furthermore, mimicking the innate three-dimensional (3D) environment of the ECM has been shown to significantly altered cellular response compared to that of traditional two-dimensional (2D) culture. We report the development of a self-assembling, fibronectin-mimetic, peptide-amphiphile nanofiber scaffold for 3D cell culture. To form such a scaffold, 5 mol % of a bioactive PR_g fibronectin-mimetic peptide-amphiphile was mixed with 95 mol % of a diluent peptide-amphiphile (E2) whose purpose was to neutralize electrostatic interactions, increase the gelation kinetics, and promote cell survival. Atomic force microscopy verified the fibrilar structure of the gels, and the mechanical properties were characterized for various weight percent (wt %) formulations of the 5 mol % PR_g-95 mol % E2 peptide-a...
Genetic changes required for the formation and progression of human Schwann cell tumors remain el... more Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with down-regulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, Rspondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties to
Science, 2005
Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patie... more Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.
Neuro-Oncology, 2011
Although devascularization caused by antiangiogenic therapy limits tumor growth, the benefits of ... more Although devascularization caused by antiangiogenic therapy limits tumor growth, the benefits of antiangiogenic therapy are often transient, with tumor growth typically resuming through adaptive responses that need further characterization. Recent reports indicate that hypoxia in tumor microenvironments induces autophagy, a lysosomal degradation pathway that may promote tumor cell survival. We investigated the hypothesis that antiangiogenic therapy leads to hypoxia, which induces tumor cell autophagy as a cytoprotective adaptive response promoting evasion to antiangiogenic therapy. We found that patient specimens from glioblastomas evasive to bevacizumab exhibited nearly 80% more hypoxia than did pretreatment specimens from the same patients. Hypoxia (1% oxygen) induced autophagy in several primary glioblastoma cells and cell lines. Selective autophagy occurred independent of HIF-1a/AMPK hypoxia-upregulated pathways, while nonselective autophagy depended on both. Autophagy inhibitors transitioned hypoxic glioblastoma cells from autophagy to nonapoptotic cell death. Patient specimens from glioblastomas evading antiangiogenic therapy expressed 55% more autophagy-related BNIP3 than did pretreatment specimens from the same patients, with BNIP3 expression localizing to the increased hypoxic areas seen in the glioblastomas that evaded antiangiogenic therapy. Human glioblastoma xenografts exhibited persistent growth inhibition when treated with autophagy inhibitor chloroquine plus antiangiogenic bevacizumab; chloroquine prevented the evasive hypoxia-associated growth seen with bevacizumab alone and reversed the more than 2-fold increased expression of autophagy mediator BNIP3 seen in xenografts growing during bevacizumab monotherapy. These findings suggest that hypoxia-mediated autophagy promotes tumor cell survival after antiangiogenic therapy, a novel adaptive response to antiangiogenic therapy that can be pharmacologically disrupted to allow antiangiogenic therapy to fulfill its therapeutic promise.
Neurobiology of Aging, 2014
substantially in the coming decades in countries undergoing rapid demographic and health transiti... more substantially in the coming decades in countries undergoing rapid demographic and health transitions. Discussion. These issues are the contentions that dementia represents a global public health priority, and that concerted actions encompassing primary, secondary and tertiarty prevention should be taken without delay. Investments in research in LAMIC, and international collaborations can support the evidence-base of these actions, and can provide important clues to improve our understanding of the disease and of modifiable risk and protective factors.
Cryobiology, 2010
Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is l... more Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is local recurrence of disease within the previously frozen tissue. We have recently demonstrated that tumor necrosis factor alpha (TNF-α), given 4 hours prior to cryosurgery can yield complete destruction of prostate cancer within a cryosurgical iceball. The present work continues the investigation of the cellular and molecular mechanisms and dynamics of TNF-α enhancement on cryosurgery. In vivo prostate tumor (LNCaP Pro 5) was grown in a dorsal skin fold chamber (DSFC) on a male nude mouse. Intravital imaging, thermography, and post-sacrifice histology and immunohistochemistry were used to assess iceball location and the ensuing biological effects after cryosurgery with and without TNF-α pre-treatment. Destruction was specifically measured by vascular stasis and by the size of histologic zones of injury (i.e. inflammatory infiltrate and necrosis). TNF-α induced vascular pre-conditioning events that peaked at 4 hours and diminished over several days. Early events (4-24 hours) include upregulation of inflammatory markers (nuclear factor-κB (NFκB) and vascular cell adhesion molecule-1 (VCAM)) and caspase activity in the tumor prior to cryosurgery. TNF-α pre-conditioning resulted in recruitment of an augmented inflammatory infiltrate at day 3 post treatment vs. cryosurgery alone. Finally, preconditioning yielded enhanced cryosurgical destruction up to the iceball edge at days 1 and 3 vs. cryosurgery alone. Thus, TNF-α pre-conditioning enhances cryosurgical lesions by vascular mechanisms that lead to tumor cell injury via promotion of inflammation and leukocyte (esp. neutrophil) recruitment.
Cancer, 2014
Background-The clinical course of prostate cancer (PCa) measured by biochemical failure (BF) afte... more Background-The clinical course of prostate cancer (PCa) measured by biochemical failure (BF) after prostatectomy remains unpredictable in many patients, particularly in intermediate Gleason score (GS) 7 tumors, suggesting that identification of molecular mechanisms associated with aggressive PCa biology may be exploited for improved prognostication or therapy. Hyaluronan (HA) is a high molecular weight polyanionic carbohydrate produced by synthases (HAS1-3) and fragmented by oxidative/nitrosative stress and hyaluronidases (HYAL1-4, SPAM1) common in PCa microenvironments. HA and HA fragments interact with receptors CD44 and HMMR resulting in increased tumor aggressiveness in experimental PCa models. We evaluated the association of HA-related molecules with BF after prostatectomy in GS7 tumors.
BMC Cancer, 2014
Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient man... more Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient management and provide a bridge for developing novel therapeutics and imaging methods. Our objective was to evaluate the association between expression of 33 candidate protein biomarkers and time to biochemical failure (BF) after prostatectomy. Methods: PCa tissue microarrays were constructed representing 160 patients for whom clinicopathologic features and follow-up data after surgery were available. Immunohistochemistry for each of 33 proteins was quantified using automated digital pathology techniques. Relationships between clinicopathologic features, staining intensity, and time to BF were assessed. Predictive modeling using multiple imputed datasets was performed to identify the top biomarker candidates. Results: In univariate analyses, lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy, and biomarkers CCND1, HMMR, IGF1, MKI67, SIAH2, and SMAD4 in malignant epithelium were significantly associated with time to BF. HMMR, IGF1, and SMAD4 remained significantly associated with BF after adjusting for clinicopathologic features while additional associations were observed for HOXC6 and MAP4K4 following adjustment. In multibiomarker predictive models, 3 proteins including HMMR, SIAH2, and SMAD4 were consistently represented among the top 2, 3, 4, and 5 most predictive biomarkers, and a signature comprised of these proteins best predicted BF at 3 and 5 years. Conclusions: This study provides rationale for investigation of HMMR, HOXC6, IGF1, MAP4K4, SIAH2, and SMAD4 as biomarkers of PCa aggressiveness in larger cohorts.
Supplementary Table 2 - PDF 69K, QPCR primer sequences
Supplementary Figure 3 - PDF file 85K, Knockdown of β-catenin or TNKS and overexpression of GSK3B... more Supplementary Figure 3 - PDF file 85K, Knockdown of β-catenin or TNKS and overexpression of GSK3B results in decreased Wnt signaling in MPNST cell lines
Journal of Alzheimer's Disease, Jan 24, 2017
There exist several dozen lines of transgenic mice that express human amyloid-β precursor protein... more There exist several dozen lines of transgenic mice that express human amyloid-β precursor protein (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ~4.5 times that of 21-month Tg2576 mice and ~15 times that of 21-24month rTg9191 mice. Plaque-size distributions changed across the lifespan in a line-and regiondependent manner. We also compared the dense-core plaque burdens in the mice to those *
Alzheimers & Dementia, Jul 1, 2015
Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 ... more Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 and inh3, left, and AFM images of each condition after 150h incubation, right (AFM: 6mm 3 6mm scans). The fluorescence level of Ab 40 (green) is decreased by a factor of 4 with SEN304 and castalagin (red and orange), and by a factor of 2 in the presence of inh3 (yellow). These results were confirmed by AFM imaging : sparse protofibres could be seen with inh3 but no networks of mature fibres were formed, while no more fibres were observed in the presence of SEN304 and castalagin. P1-040 QUANTITATIVE COMPARISON OF DENSE-CORE AMYLOID PLAQUE BURDENS IN ALZHEIMER’S DISEASE PATIENTS AND AMYLOID PRECURSOR PROTEIN TRANSGENIC MICE Kathleen R. Zahs, Peng Liu, Laura S. Hemmy, John H. Reichl, Eshaan Rao, Colleen L. Forster, Robert J. Vassar, David R. Borchelt, Karen H. Ashe, University of Minnesota, Minneapolis, MN, USA; University of Minnesota, Minneapolis, MN, USA; Northwestern University, Chicago, IL, USA; University of Florida, Gainesville, FL, USA; Veterans Administration Medical Center, Minneapolis, MN, USA. Contact e-mail: zahsx001@umn.edu
Neurobiology of Aging, Mar 1, 2016
Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain.... more Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain. Lowering brain beta-amyloid is a major target for treatment and prevention of AD. Enrolling subjects based on clinical criteria alone may result in misclassification, as evidenced by the relatively high percent of subjects having normal brain PET beta-amyloid scans in two recent Phase 3 studies. Consequently, novel study protocols were designed testing immunotherapy in subjects with proven beta-amyloid deposition in brain (by PET or CSF) and with early symptomatic AD including those at the prodromal stage, e.g. PET beta-amyloid positive subjects with mild cognitive impairment (MCI) due to AD. Selected drugs in development will be reviewed. The clinical study programs sponsored by the pharmaceutical industry were recently complemented by public-private partnerships on prevention studies such as the A4 study coordinated by the Alzheimer's Disease Cooperative Study (ADCS), or the Dominantly Inherited Alzheimer Network (DIAN) drug trials. Challenges of immunotherapy include targeting of the most relevant Ab species, managing side effects such as amyloid related imaging abnormalities (ARIA E/H), the timing and duration of the intervention, selecting the most suitable study population, and choosing the most suitable clinical and biomarker endpoints. Both active and passive immunization approaches against tau proteins are being developed and are moving towards clinical testing, along with breakthroughs in tau imaging by novel PET ligands. Such potential therapies offer the prospect of treatment of tau-driven neurodegenerative conditions as well as potential for use with beta amyloid targeting therapies as combination therapy against AD.
BMC Cancer, Apr 5, 2014
Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient man... more Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient management and provide a bridge for developing novel therapeutics and imaging methods. Our objective was to evaluate the association between expression of 33 candidate protein biomarkers and time to biochemical failure (BF) after prostatectomy. Methods: PCa tissue microarrays were constructed representing 160 patients for whom clinicopathologic features and follow-up data after surgery were available. Immunohistochemistry for each of 33 proteins was quantified using automated digital pathology techniques. Relationships between clinicopathologic features, staining intensity, and time to BF were assessed. Predictive modeling using multiple imputed datasets was performed to identify the top biomarker candidates. Results: In univariate analyses, lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy, and biomarkers CCND1, HMMR, IGF1, MKI67, SIAH2, and SMAD4 in malignant epithelium were significantly associated with time to BF. HMMR, IGF1, and SMAD4 remained significantly associated with BF after adjusting for clinicopathologic features while additional associations were observed for HOXC6 and MAP4K4 following adjustment. In multibiomarker predictive models, 3 proteins including HMMR, SIAH2, and SMAD4 were consistently represented among the top 2, 3, 4, and 5 most predictive biomarkers, and a signature comprised of these proteins best predicted BF at 3 and 5 years. Conclusions: This study provides rationale for investigation of HMMR, HOXC6, IGF1, MAP4K4, SIAH2, and SMAD4 as biomarkers of PCa aggressiveness in larger cohorts.
Development
Ubiquitin-like, containing PHD and RING finger domains 2 (UHRF2) regulates cell cycle and binds 5... more Ubiquitin-like, containing PHD and RING finger domains 2 (UHRF2) regulates cell cycle and binds 5-hydroxymethylcytosine (5hmC) to promote completion of DNA demethylation. Uhrf2−/− mice are without gross phenotypic defects; however, the cell cycle and epigenetic regulatory functions of Uhrf2 during retinal tissue development are unclear. Retinal progenitor cells (RPCs) produce all retinal neurons and Müller glia in a predictable sequence controlled by the complex interplay between extrinsic signaling, cell cycle, epigenetic changes and cell-specific transcription factor activation. In this study, we find that UHRF2 accumulates in RPCs, and its conditional deletion from mouse RPCs reduced 5hmC, altered gene expressions and disrupted retinal cell proliferation and differentiation. Retinal ganglion cells were overproduced in Uhrf2-deficient retinae at the expense of VSX2+ RPCs. Most other cell types were transiently delayed in differentiation. Expression of each member of the Tet3/Uhrf2...
Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzhei-mer’s di... more Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzhei-mer’s disease. We here report the generation and characterization of a novel transgenic mouse model of Aβ toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and Londonmuta-tions (APPNLI) linked to familial Alzheimer’s disease, under the control of a tetracycline-re-sponse element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase IIα. In these mice, APPNLI is express-ed at a level four-fold that of endogenous mouse APP and its expression is restricted to fore-brain regions. Transgene expression was suppressed by 87 % after two months of doxycycline administration. Histologically, we showed that (1) Aβ plaques emerged in cere-bral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition ...
bioRxiv, 2021
Hemangiosarcoma and angiosarcoma are soft tissue sarcomas of malignant blood vessel-forming cells... more Hemangiosarcoma and angiosarcoma are soft tissue sarcomas of malignant blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs that support the niche, enabling progression of canine hemangiosarcoma and human angiosarcoma. Here, we show that the transcriptional landscape of canine hemangiosarcoma and human angiosarcoma included comparable angiogenic and inflammatory programs. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells, a trait that was not observed in xenografts from canine osteosarcoma and lymphoma. In some cases, the xenografted hemangiosarcoma cells created exuberant myeloid hyperplasia and ...
http://isrctn.org/>, 2013
Neurobiology of Aging, 2016
Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain.... more Alzheimer's disease (AD) is characterized by deposition of toxic protein aggregates in the brain. Lowering brain beta-amyloid is a major target for treatment and prevention of AD. Enrolling subjects based on clinical criteria alone may result in misclassification, as evidenced by the relatively high percent of subjects having normal brain PET beta-amyloid scans in two recent Phase 3 studies. Consequently, novel study protocols were designed testing immunotherapy in subjects with proven beta-amyloid deposition in brain (by PET or CSF) and with early symptomatic AD including those at the prodromal stage, e.g. PET beta-amyloid positive subjects with mild cognitive impairment (MCI) due to AD. Selected drugs in development will be reviewed. The clinical study programs sponsored by the pharmaceutical industry were recently complemented by public-private partnerships on prevention studies such as the A4 study coordinated by the Alzheimer's Disease Cooperative Study (ADCS), or the Dominantly Inherited Alzheimer Network (DIAN) drug trials. Challenges of immunotherapy include targeting of the most relevant Ab species, managing side effects such as amyloid related imaging abnormalities (ARIA E/H), the timing and duration of the intervention, selecting the most suitable study population, and choosing the most suitable clinical and biomarker endpoints. Both active and passive immunization approaches against tau proteins are being developed and are moving towards clinical testing, along with breakthroughs in tau imaging by novel PET ligands. Such potential therapies offer the prospect of treatment of tau-driven neurodegenerative conditions as well as potential for use with beta amyloid targeting therapies as combination therapy against AD.
Alzheimer's & Dementia, 2015
Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 ... more Thioflavin T fluorescence time course of Ab 40 aggregation in the presence of castalagin, SEN304 and inh3, left, and AFM images of each condition after 150h incubation, right (AFM: 6mm 3 6mm scans). The fluorescence level of Ab 40 (green) is decreased by a factor of 4 with SEN304 and castalagin (red and orange), and by a factor of 2 in the presence of inh3 (yellow). These results were confirmed by AFM imaging : sparse protofibres could be seen with inh3 but no networks of mature fibres were formed, while no more fibres were observed in the presence of SEN304 and castalagin. P1-040 QUANTITATIVE COMPARISON OF DENSE-CORE AMYLOID PLAQUE BURDENS IN ALZHEIMER’S DISEASE PATIENTS AND AMYLOID PRECURSOR PROTEIN TRANSGENIC MICE Kathleen R. Zahs, Peng Liu, Laura S. Hemmy, John H. Reichl, Eshaan Rao, Colleen L. Forster, Robert J. Vassar, David R. Borchelt, Karen H. Ashe, University of Minnesota, Minneapolis, MN, USA; University of Minnesota, Minneapolis, MN, USA; Northwestern University, Chicago, IL, USA; University of Florida, Gainesville, FL, USA; Veterans Administration Medical Center, Minneapolis, MN, USA. Contact e-mail: zahsx001@umn.edu
Langmuir : the ACS journal of surfaces and colloids, Jan 9, 2015
The design of scaffolds which mimic the stiffness, nanofiber structure, and biochemistry of the n... more The design of scaffolds which mimic the stiffness, nanofiber structure, and biochemistry of the native extracellular matrix (ECM) has been a major objective for the tissue engineering field. Furthermore, mimicking the innate three-dimensional (3D) environment of the ECM has been shown to significantly altered cellular response compared to that of traditional two-dimensional (2D) culture. We report the development of a self-assembling, fibronectin-mimetic, peptide-amphiphile nanofiber scaffold for 3D cell culture. To form such a scaffold, 5 mol % of a bioactive PR_g fibronectin-mimetic peptide-amphiphile was mixed with 95 mol % of a diluent peptide-amphiphile (E2) whose purpose was to neutralize electrostatic interactions, increase the gelation kinetics, and promote cell survival. Atomic force microscopy verified the fibrilar structure of the gels, and the mechanical properties were characterized for various weight percent (wt %) formulations of the 5 mol % PR_g-95 mol % E2 peptide-a...
Genetic changes required for the formation and progression of human Schwann cell tumors remain el... more Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with down-regulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, Rspondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties to
Science, 2005
Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patie... more Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.
Neuro-Oncology, 2011
Although devascularization caused by antiangiogenic therapy limits tumor growth, the benefits of ... more Although devascularization caused by antiangiogenic therapy limits tumor growth, the benefits of antiangiogenic therapy are often transient, with tumor growth typically resuming through adaptive responses that need further characterization. Recent reports indicate that hypoxia in tumor microenvironments induces autophagy, a lysosomal degradation pathway that may promote tumor cell survival. We investigated the hypothesis that antiangiogenic therapy leads to hypoxia, which induces tumor cell autophagy as a cytoprotective adaptive response promoting evasion to antiangiogenic therapy. We found that patient specimens from glioblastomas evasive to bevacizumab exhibited nearly 80% more hypoxia than did pretreatment specimens from the same patients. Hypoxia (1% oxygen) induced autophagy in several primary glioblastoma cells and cell lines. Selective autophagy occurred independent of HIF-1a/AMPK hypoxia-upregulated pathways, while nonselective autophagy depended on both. Autophagy inhibitors transitioned hypoxic glioblastoma cells from autophagy to nonapoptotic cell death. Patient specimens from glioblastomas evading antiangiogenic therapy expressed 55% more autophagy-related BNIP3 than did pretreatment specimens from the same patients, with BNIP3 expression localizing to the increased hypoxic areas seen in the glioblastomas that evaded antiangiogenic therapy. Human glioblastoma xenografts exhibited persistent growth inhibition when treated with autophagy inhibitor chloroquine plus antiangiogenic bevacizumab; chloroquine prevented the evasive hypoxia-associated growth seen with bevacizumab alone and reversed the more than 2-fold increased expression of autophagy mediator BNIP3 seen in xenografts growing during bevacizumab monotherapy. These findings suggest that hypoxia-mediated autophagy promotes tumor cell survival after antiangiogenic therapy, a novel adaptive response to antiangiogenic therapy that can be pharmacologically disrupted to allow antiangiogenic therapy to fulfill its therapeutic promise.
Neurobiology of Aging, 2014
substantially in the coming decades in countries undergoing rapid demographic and health transiti... more substantially in the coming decades in countries undergoing rapid demographic and health transitions. Discussion. These issues are the contentions that dementia represents a global public health priority, and that concerted actions encompassing primary, secondary and tertiarty prevention should be taken without delay. Investments in research in LAMIC, and international collaborations can support the evidence-base of these actions, and can provide important clues to improve our understanding of the disease and of modifiable risk and protective factors.
Cryobiology, 2010
Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is l... more Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is local recurrence of disease within the previously frozen tissue. We have recently demonstrated that tumor necrosis factor alpha (TNF-α), given 4 hours prior to cryosurgery can yield complete destruction of prostate cancer within a cryosurgical iceball. The present work continues the investigation of the cellular and molecular mechanisms and dynamics of TNF-α enhancement on cryosurgery. In vivo prostate tumor (LNCaP Pro 5) was grown in a dorsal skin fold chamber (DSFC) on a male nude mouse. Intravital imaging, thermography, and post-sacrifice histology and immunohistochemistry were used to assess iceball location and the ensuing biological effects after cryosurgery with and without TNF-α pre-treatment. Destruction was specifically measured by vascular stasis and by the size of histologic zones of injury (i.e. inflammatory infiltrate and necrosis). TNF-α induced vascular pre-conditioning events that peaked at 4 hours and diminished over several days. Early events (4-24 hours) include upregulation of inflammatory markers (nuclear factor-κB (NFκB) and vascular cell adhesion molecule-1 (VCAM)) and caspase activity in the tumor prior to cryosurgery. TNF-α pre-conditioning resulted in recruitment of an augmented inflammatory infiltrate at day 3 post treatment vs. cryosurgery alone. Finally, preconditioning yielded enhanced cryosurgical destruction up to the iceball edge at days 1 and 3 vs. cryosurgery alone. Thus, TNF-α pre-conditioning enhances cryosurgical lesions by vascular mechanisms that lead to tumor cell injury via promotion of inflammation and leukocyte (esp. neutrophil) recruitment.
Cancer, 2014
Background-The clinical course of prostate cancer (PCa) measured by biochemical failure (BF) afte... more Background-The clinical course of prostate cancer (PCa) measured by biochemical failure (BF) after prostatectomy remains unpredictable in many patients, particularly in intermediate Gleason score (GS) 7 tumors, suggesting that identification of molecular mechanisms associated with aggressive PCa biology may be exploited for improved prognostication or therapy. Hyaluronan (HA) is a high molecular weight polyanionic carbohydrate produced by synthases (HAS1-3) and fragmented by oxidative/nitrosative stress and hyaluronidases (HYAL1-4, SPAM1) common in PCa microenvironments. HA and HA fragments interact with receptors CD44 and HMMR resulting in increased tumor aggressiveness in experimental PCa models. We evaluated the association of HA-related molecules with BF after prostatectomy in GS7 tumors.
BMC Cancer, 2014
Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient man... more Background: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient management and provide a bridge for developing novel therapeutics and imaging methods. Our objective was to evaluate the association between expression of 33 candidate protein biomarkers and time to biochemical failure (BF) after prostatectomy. Methods: PCa tissue microarrays were constructed representing 160 patients for whom clinicopathologic features and follow-up data after surgery were available. Immunohistochemistry for each of 33 proteins was quantified using automated digital pathology techniques. Relationships between clinicopathologic features, staining intensity, and time to BF were assessed. Predictive modeling using multiple imputed datasets was performed to identify the top biomarker candidates. Results: In univariate analyses, lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy, and biomarkers CCND1, HMMR, IGF1, MKI67, SIAH2, and SMAD4 in malignant epithelium were significantly associated with time to BF. HMMR, IGF1, and SMAD4 remained significantly associated with BF after adjusting for clinicopathologic features while additional associations were observed for HOXC6 and MAP4K4 following adjustment. In multibiomarker predictive models, 3 proteins including HMMR, SIAH2, and SMAD4 were consistently represented among the top 2, 3, 4, and 5 most predictive biomarkers, and a signature comprised of these proteins best predicted BF at 3 and 5 years. Conclusions: This study provides rationale for investigation of HMMR, HOXC6, IGF1, MAP4K4, SIAH2, and SMAD4 as biomarkers of PCa aggressiveness in larger cohorts.
Supplementary Table 2 - PDF 69K, QPCR primer sequences
Supplementary Figure 3 - PDF file 85K, Knockdown of β-catenin or TNKS and overexpression of GSK3B... more Supplementary Figure 3 - PDF file 85K, Knockdown of β-catenin or TNKS and overexpression of GSK3B results in decreased Wnt signaling in MPNST cell lines