36 results on '"Jeff R. Gehlhausen"'
Search Results
2. A rapidly fluctuating rash in a stuporous patient
- Author
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Nelson Ugwu, BS, Jeff R. Gehlhausen, MD, PhD, Irwin M. Braverman, MD, and Jean L. Bolognia, MD
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benzodiazepine withdrawal ,blotchy rash ,catatonia ,neurologic deterioration ,rapidly fluctuating rash ,Dermatology ,RL1-803 - Published
- 2021
- Full Text
- View/download PDF
3. Psoriasis and COVID-19: a multifactorial consideration
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Jeffrey M. Cohen, Lourdes M. Perez-Chada, Dimitri De Kouchkovsky, and Jeff R. Gehlhausen
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Dermatology ,RL1-803 - Published
- 2022
- Full Text
- View/download PDF
4. Not all well-differentiated cutaneous squamous cell carcinomas are equal: Tumors with disparate biologic behavior have differences in protein expression via digital spatial profiling
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Matthew Vesely, Sandra Martinez-Morilla, Jeff R. Gehlhausen, Jennifer M. McNiff, Peter G. Whang, David Rimm, and Christine J. Ko
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Biological Products ,Keratoacanthoma ,Skin Neoplasms ,Carcinoma, Squamous Cell ,Humans ,Dermatology ,Immunohistochemistry - Published
- 2022
5. Distinguishing features of Long COVID identified through immune profiling
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Jon Klein, Jamie Wood, Jillian Jaycox, Peiwen Lu, Rahul M. Dhodapkar, Jeff R. Gehlhausen, Alexandra Tabachnikova, Laura Tabacof, Amyn A. Malik, Kathy Kamath, Kerrie Greene, Valter Silva Monteiro, Mario Peña-Hernandez, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Julio Silva, Dayna Mccarthy, Erica Breyman, Jenna Tosto-Mancuso, Yile Dai, Emily Perotti, Koray Akduman, Tiffany J. Tzeng, Lan Xu, Inci Yildirim, Harlan M. Krumholz, John Shon, Ruslan Medzhitov, Saad B. Omer, David van Dijk, Aaron M. Ring, David Putrino, and Akiko Iwasaki
- Subjects
Article - Abstract
SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID1–3. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions1–3; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.
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- 2022
6. Vascular-Targeted Therapy for Systemic Lupus Erythematosus–Associated Vasculitis
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Suzanne Xu, Robert J. Patrignelli, Sarika Ramachandran, Fotios Koumpouras, Deborah Desir, Christine J. Ko, and Jeff R. Gehlhausen
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Dermatology - Abstract
This case report describes a woman in her 40s with a medical history of systemic lupus erythematosus with 1 year of tender papules, plaques, and progressive ulcers on her hands and feet.
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- 2023
7. Leukocytoclastic Vasculitis and Microvascular Occlusion
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Christine J. Ko, Jennifer M. McNiff, and Jeff R. Gehlhausen
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0301 basic medicine ,Systemic disease ,Pathology ,medicine.medical_specialty ,Calciphylaxis ,business.industry ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Clinical diagnosis ,Leukocytoclastic vasculitis ,Occlusion ,cardiovascular system ,medicine ,Surgery ,Differential diagnosis ,business ,Vasculitis ,Microvascular occlusion - Abstract
Although clinicians often put vasculitis and microvascular occlusion in the same differential diagnosis, biopsy findings often are either vasculitis or occlusion. However, both vasculitis and occlusion are present in some cases of levamisole-associated vasculopathy and certain infections. Depth of dermal involvement and vessel size should be reported, because superficial and deep small vessel leukocytoclastic vasculitis and/or involvement of medium-sized vessels may be associated with systemic disease. Microvascular occlusion of vessels in the fat should prompt consideration of calciphylaxis. Clues to ultimate clinical diagnosis can be garnered from depth of involvement, size of vessels affected, and presence of both vasculitis and occlusion.
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- 2021
8. New bullous lesions in a 72-year-old woman
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Jennifer M. McNiff, Hadrian Mendoza, Justin Goodwin, Karthik Gnanapandithan, Jeff R. Gehlhausen, and Ian D. Odell
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Bullous lesions ,medicine.medical_specialty ,Blister ,business.industry ,Humans ,Medicine ,Female ,General Medicine ,business ,Dermatology ,Aged - Published
- 2021
9. PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2)
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Andrea R. Masters, Hoi-Yee Chow, Xiaohong Li, Maria Radu, Daniela Araiza-Olivera, Jonathan Chernoff, D. Wade Clapp, Charles W. Yates, Callie Burgin, Waylan K. Bessler, David R. Jones, Eric T. Hawley, Abbi Smith, Ciersten Burks, Li Jiang, Su Jung Park, Sofiia Karchugina, Jeff R. Gehlhausen, and Donna Edwards
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Neurofibromatosis 2 ,Indoles ,Cell Survival ,Longevity ,Biology ,Germline ,Mice ,03 medical and health sciences ,0302 clinical medicine ,PAK1 ,Piperidines ,otorhinolaryngologic diseases ,Genetics ,medicine ,Animals ,Genes, Tumor Suppressor ,Phosphorylation ,Neurofibromatosis type 2 ,Neurofibromatosis ,Molecular Biology ,Genetics (clinical) ,Cell Proliferation ,030304 developmental biology ,Neurofibromin 2 ,0303 health sciences ,Neural crest ,General Medicine ,medicine.disease ,Merlin (protein) ,Disease Models, Animal ,Pyrimidines ,p21-Activated Kinases ,030220 oncology & carcinogenesis ,Genetically Engineered Mouse ,Cancer research ,General Article ,Schwann Cells ,Haploinsufficiency ,Neurilemmoma - Abstract
Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.
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- 2021
10. A detailed analysis of the distribution, morphology, and histopathology of complex purpura in hospitalized patients: A case series of 68 patients
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Jennifer M. McNiff, David A. Wetter, Christine J. Ko, Caroline A. Nelson, Jeff R. Gehlhausen, and Sarika Ramachandran
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Vasculitis ,Systemic disease ,medicine.medical_specialty ,Biopsy ,Arterial Occlusive Diseases ,Dermatology ,Skin Diseases, Vascular ,Diagnosis, Differential ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Cutaneous small-vessel vasculitis ,Purpura ,Retrospective Studies ,Palpable purpura ,Microvascular occlusion ,Calciphylaxis ,business.industry ,Microcirculation ,medicine.disease ,Immunoglobulin A ,IgA vasculitis ,030220 oncology & carcinogenesis ,Vasculitis, Leukocytoclastic, Cutaneous ,medicine.symptom ,Differential diagnosis ,business ,Algorithms - Abstract
Background Purpura in inpatients commonly leads to dermatologic consultation. The differential diagnosis is broad and algorithms are intricate. Objective We evaluated inpatient consultations for complex purpura to document the most common diagnoses and to validate the true diagnostic utility of histopathology, clinical morphology, and distribution. Methods We reviewed a case series of 68 inpatients during a 4-year period with a dermatologic consultation for purpura and biopsy findings of vasculitis or microvascular occlusion. Results Key features of complex purpura are nonbranching (round) versus branching (retiform) morphology, dependent versus acral or generalized distribution, and leukocytoclastic vasculitis versus microvascular occlusion (with emphasis on depth of involvement). Dependent nonbranching purpura with only superficial vessels involved by leukocytoclastic vasculitis was most often due to IgA vasculitis or cutaneous single-organ small-vessel vasculitis. In contrast, deeper involvement by leukocytoclastic vasculitis was suggestive of systemic disease (eg, antineutrophil cytoplasmic antibody–associated vasculitis). Branching purpura was concerning, with greater than 90% sensitivity and specificity for microvascular occlusion and associated high mortality (≈50%). The majority of patients who died had acral branching lesions. Limitations Small sample size, inpatients at a tertiary care center, and retrospective nature are some limitations. Conclusion Nonbranching dependent purpura corresponded to leukocytoclastic vasculitis, with the most common diagnoses being IgA vasculitis or skin-limited small-vessel vasculitis; patients with deep involvement often had systemic diseases. In this series, branching purpura was due to microvascular occlusion rather than medium-vessel vasculitis, and had associated high mortality.
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- 2021
11. A novel NFkB1 mutation linking pyoderma gangrenosum and common variable immunodeficiency
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Sarika Ramachandran, Jeff R. Gehlhausen, Marianna Freudzon, Allen E. Bale, Ian D. Odell, Qisi Sun, Keith A. Choate, Mary M. Tomayko, and Nour Kibbi
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Myeloid ,PG, pyoderma gangrenosum ,Case Report ,neutrophilic ,inflammatory ,Dermatology ,Inflammatory bowel disease ,medicine ,genetics ,ulcers ,Immunodeficiency ,dermatoses ,business.industry ,Common variable immunodeficiency ,NF-κB, Nuclear-factor kappa B ,medicine.disease ,NFKB1 ,medicine.anatomical_structure ,Rheumatoid arthritis ,RL1-803 ,Mutation (genetic algorithm) ,Immunology ,business ,CVID, common variable immunodeficiency ,immunodeficiency ,Pyoderma gangrenosum ,pyoderma gangrenosum - Abstract
Pyoderma gangrenosum (PG) is a sterile neutrophilic dermatosis manifesting as painful inflammatory plaques and ulcers, frequently associated with inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome, and acute myeloid leukemia.1 We present a case of a young woman with a novel mutation in NFkB1 who experienced common variable immunodeficiency (CVID) and severe recurrent PG episodes.
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- 2021
12. Random skin biopsies for diagnosis of intravascular large B cell lymphoma: retrospective analysis of 31 biopsies from a US dermatology inpatient consultative service with literature review
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Sa Rang Kim, Christine J. Ko, Caroline A. Nelson, Sarika Ramachandran, and Jeff R. Gehlhausen
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Dermatology - Published
- 2022
13. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain
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Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Belgin Yalçın, Kathryn R. Taylor, Selena Dutton, Lehi Acosta-Alvarez, Lijun Ni, Daniel Contreras-Esquivel, Jeff R. Gehlhausen, Jon Klein, Carolina Lucas, Tianyang Mao, Julio Silva, Mario A. Peña-Hernández, Alexandra Tabachnikova, Takehiro Takahashi, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Marco Hefti, Daniel Perl, Rebecca Folkerth, David Putrino, Avi Nath, Akiko Iwasaki, and Michelle Monje
- Subjects
myelin ,COVID-19 ,long-COVID ,microglia ,oligodendrocytes ,hippocampal neurogenesis ,Article ,cognitive impairment ,neuroinflammation - Abstract
Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.
- Published
- 2022
14. Lack of association between pandemic chilblains and SARS-CoV-2 infection
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Jeff R, Gehlhausen, Alicia J, Little, Christine J, Ko, Marc, Emmenegger, Carolina, Lucas, Patrick, Wong, Jon, Klein, Peiwen, Lu, Tianyang, Mao, Jillian, Jaycox, Eric, Wang, Nelson, Ugwu, Cate, Muenker, Dilgash, Mekael, Rhonda Q, Klein, Robert, Patrignelli, Richard, Antaya, Jennifer, McNiff, William, Damsky, Kathy, Kamath, John, Shon, Aaron M, Ring, Inci, Yildirim, Saad, Omer, Albert I, Ko, Adriano, Aguzzi, and Yvette, Strong
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Adult ,Chilblains ,Male ,Connecticut ,Young Adult ,Multidisciplinary ,SARS-CoV-2 ,viruses ,COVID-19 ,Humans ,Female ,Middle Aged ,Retrospective Studies - Abstract
An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.
- Published
- 2022
15. Perniosis during the <scp>COVID</scp> ‐19 pandemic: Negative <scp>anti‐SARS‐CoV</scp> ‐2 immunohistochemistry in six patients and comparison to perniosis before the emergence of <scp>SARS‐CoV</scp> ‐2
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Jennifer M. McNiff, William Damsky, Jeff R. Gehlhausen, Christine J. Ko, Malini Harigopal, Marcus Bosenberg, and Robert Patrignelli
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medicine.medical_specialty ,Pathology ,Histology ,Coronavirus disease 2019 (COVID-19) ,biology ,business.industry ,Dermatology ,medicine.disease_cause ,medicine.disease ,Virus ,Pathology and Forensic Medicine ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pandemic ,medicine ,biology.protein ,Immunohistochemistry ,Histopathology ,Antibody ,business ,Chilblains ,Coronavirus - Abstract
BACKGROUND: Acral inflammatory lesions that have some resemblance to idiopathic or autoimmune-associated perniosis (chilblains) have been described in multiple countries during the COVID-19 pandemic. METHODS: We examined histopathologic findings in six consecutive such cases from five patients received in mid-May to mid-June of 2020, evaluating immunohistochemical staining for the SARS-CoV-2 nucleocapsid protein. We compared these six cases to eight cases diagnosed as perniosis between January and June of 2019. RESULTS: Five of six lesions with perniosis-like histopathology during the COVID-19 pandemic had distinctive tight cuffing of lymphocytes; intravascular material was present in one case. SARS-CoV-2 immunohistochemical staining using an antibody directed at the nucleocapsid protein was negative in all six cases. Only one of eight specimens with microscopic findings of perniosis received prior to the COVID-19 pandemic had tightly cuffed perivascular lymphocytes, and none had obvious intravascular occlusion. CONCLUSIONS: A tightly cuffed pattern of perivascular lymphocytes is a feature of perniosis during the COVID-19 pandemic. The absence of SARS-CoV-2 nucleocapsid protein in these cases suggests against the virus being directly present in these lesions. This article is protected by copyright. All rights reserved.
- Published
- 2020
16. A rare case of lupoid leishmaniasis defying diagnosis for a decade
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Matthew Grant, Amanda Zubek, Jeff R. Gehlhausen, Cosmas Sibindi, and Christine J. Ko
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Pathology ,medicine.medical_specialty ,Histology ,Granulomatous Rosacea ,biology ,business.industry ,Leishmaniasis ,Lupoid leishmaniasis ,Dermatology ,medicine.disease ,biology.organism_classification ,Leishmania braziliensis ,Pathology and Forensic Medicine ,Lesion ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Cutaneous leishmaniasis ,030220 oncology & carcinogenesis ,Rare case ,medicine ,Sarcoidosis ,medicine.symptom ,business - Abstract
Cutaneous leishmaniasis (CL) is a common disease affecting millions in endemic areas worldwide. We present a case of lupoid leishmaniasis, a rare variant of CL, which clinically mimicked sarcoidosis and/or granulomatous rosacea for 10 years until ultimate diagnosis. An 82-year-old U.S. citizen with an extensive travel history presented with a 10-year history of facial plaques on the cheeks and was previously diagnosed and treated as sarcoidosis. Multiple biopsies (previously and at presentation) revealed tuberculoid granulomas with negative special stains for microorganisms and negative sterile tissue cultures for acid-fast bacilli, bacteria, and fungal organisms. A diagnosis of granulomatous rosacea was rendered and multiple medical therapies were attempted, none with sustained improvement. Repeat biopsy of a new lesion revealed intracellular organisms consistent with leishmaniasis, which was confirmed by polymerase chain reaction (PCR). Lupoid leishmaniasis is a rare presentation of CL including facial plaques that can mimic granulomatous diseases affecting the face including sarcoidosis and granulomatous rosacea. CL can sometimes be challenging to diagnose through standard histopathologic examination; immunohistochemistry for CD1a can be used to augment tissue-based examination and PCR should be sent early in cases with sufficient concern.
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- 2020
17. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
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Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Michael R. O’Dea, Selena Dutton, Kiarash Shamardani, Kamsi Nwangwu, Rebecca Mancusi, Belgin Yalçın, Kathryn R. Taylor, Lehi Acosta-Alvarez, Karen Malacon, Michael B. Keough, Lijun Ni, Pamelyn J. Woo, Daniel Contreras-Esquivel, Angus Martin Shaw Toland, Jeff R. Gehlhausen, Jon Klein, Takehiro Takahashi, Julio Silva, Benjamin Israelow, Carolina Lucas, Tianyang Mao, Mario A. Peña-Hernández, Alexandra Tabachnikova, Robert J. Homer, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Hannes Vogel, Marco M. Hefti, Daniel P. Perl, Shane Liddelow, Rebecca Folkerth, David Putrino, Avindra Nath, Akiko Iwasaki, and Michelle Monje
- Subjects
Mice ,SARS-CoV-2 ,Neoplasms ,Influenza, Human ,Animals ,COVID-19 ,Humans ,Microglia ,Myelin Sheath ,General Biochemistry, Genetics and Molecular Biology - Abstract
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
- Published
- 2022
18. B cells join T cell clusters in the host response to recurrent herpes simplex virus 2 infection
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Jeff R. Gehlhausen and Akiko Iwasaki
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,T cell ,Naive B cell ,General Medicine ,medicine.disease_cause ,Immunoglobulin D ,Virus ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Herpes simplex virus ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Skin biopsy ,biology.protein ,medicine ,Antibody ,B cell - Abstract
Recurrent genital herpes lesions are infiltrated by various leukocytes, yet the role of B cell subsets in this process is unknown. In this issue of the JCI, Ford et al. describe the presence and antibody-secreting role of local B cell populations in herpes simplex virus 2 (HSV-2) recurrent lesions. The authors analyzed a comprehensive array of sequential skin biopsy specimens from HSV-2-infected patients over time and at various stages of infection. Using immunofluorescence and in situ hybridization, the authors show the presence of rare IgD+ naive B cells and IgG-expressing antibody-secreting cells (ASCs) in recurrent HSV-2 lesions embedded in CD4+ T cell-rich dermal immune infiltrates, levels of which transiently increase during lesion reactivation and healing. Notably, local increases in HSV-2-specific antibodies in recurrent lesions were detected, whereas serum HSV-2 antibody levels remained stable. Future research is needed to understand the precise role of these tissue-visiting B cells in disease resolution.
- Published
- 2021
19. Discordant anti-SARS-CoV-2 spike protein and RNA staining in cutaneous perniotic lesions suggests endothelial deposition of cleaved spike protein
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Jennifer M. McNiff, William Damsky, Jeff R. Gehlhausen, Christine J. Ko, Malini Harigopal, and Marcus Bosenberg
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Histology ,In situ hybridization ,Dermatology ,Biology ,Eccrine Glands ,law.invention ,Pathology and Forensic Medicine ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,law ,medicine ,Humans ,skin and connective tissue diseases ,Polymerase chain reaction ,Endotheliitis ,In Situ Hybridization ,Aged ,Aged, 80 and over ,SARS-CoV-2 ,RNA ,COVID-19 ,Endothelial Cells ,Middle Aged ,Toes ,medicine.disease ,Immunohistochemistry ,Epithelium ,Staining ,body regions ,Chilblains ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Spike Glycoprotein, Coronavirus ,biology.protein ,RNA, Viral ,Female ,Antibody - Abstract
Background Prior studies have shown the presence of immunohistochemical staining for the SARS-CoV-2 spike protein (SP) in endothelial cells and eccrine epithelium of acral perniosis classified as "COVID toes." Yet, other studies have been unable to detect SARS-CoV-2 RNA in skin biopsies of "COVID toes" by reverse-transcriptase polymerase chain reaction testing. Objective In order to address these apparently conflicting findings, we compared detection of SARS-CoV-2 SP, through RNA in situ hybridization (ISH) vs immunohistochemistry (IHC), in skin biopsies of acral perniotic lesions presenting during the COVID-19 pandemic. Results Three of six cases showed positive immunohistochemical labeling of endothelial cells, with one of three cases with sufficient depth also having labeling of eccrine glands, using an anti-SP SARS-CoV-2 antibody. These three cases positive with IHC were negative for SP by RNA ISH. Conclusion While the gold standard for detection of SARS-CoV-2 in tissue sections has yet to be determined, the detection of SARS-CoV-2 SP alone without spike RNA suggests that cleaved SP may be present in cutaneous endothelial cells and eccrine epithelium, providing a potential pathogenetic mechanism of COVID-19 endotheliitis.
- Published
- 2020
20. Development or worsening of sarcoidosis associated with IL‐17 blockade for psoriasis
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L. Milstone, I. Lim, J. Wang, J. Siegel, Brett King, Amanda Zubek, Jeff R. Gehlhausen, Young H. Lim, William Damsky, Noah I. Hornick, Alice Wang, Anjela Galan, and F. Foss
- Subjects
medicine.medical_specialty ,Sarcoidosis ,business.industry ,Interleukin-17 ,Brodalumab ,Dermatology ,medicine.disease ,Blockade ,Ixekizumab ,Infectious Diseases ,Psoriasis ,medicine ,Humans ,Secukinumab ,Interleukin 17 ,business - Published
- 2020
21. Diffuse Dermal Angiomatosis of the Breast With an Apparent Etiology of Underlying Calcified Thrombosed Artery With Adjacent Fat Necrosis
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Jeff R. Gehlhausen, Matthew B. Strausburg, Simon J.P. Warren, and Kandice Ludwig
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Angiomatosis ,Pathology ,medicine.medical_specialty ,Biopsy ,medicine.medical_treatment ,Arterial Occlusive Diseases ,Dermatology ,Skin Diseases, Vascular ,Revascularization ,Pathology and Forensic Medicine ,Diagnosis, Differential ,Breast Diseases ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,medicine ,Humans ,Fat necrosis ,Fat Necrosis ,Vascular Calcification ,Aged ,Skin ,medicine.diagnostic_test ,business.industry ,Thrombosis ,General Medicine ,medicine.disease ,Immunohistochemistry ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Differential diagnosis ,business ,Reticular Dermis ,Artery - Abstract
In this report, the authors present a case of diffuse dermal angiomatosis (DDA) with an underlying mass lesion of the breast, which proved to be a large calcified, thrombosed artery with adjacent fat necrosis. Histologically, DDA consists of hyperplastic vessels, which diffusely infiltrate the papillary and reticular dermis forming small vascular lumina. The condition is associated with various underlying conditions, many of which result in local tissue ischemia. In the past, DDA was most commonly reported on the lower extremities; however, it seems that this entity is more common on the breast than previously recognized. Various treatments have proven beneficial, including revascularization, oral corticosteroids, smoking cessation, and isotretinoin. In this case, our patient benefited from primary excision of the affected area.
- Published
- 2016
22. Early botryomycosis‐like plaques in the setting of Corynebacterium striatum septicemia
- Author
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Kathleen E. Gilbert, Matthew B. Strausburg, Jeff R. Gehlhausen, and Ahmed K. Alomari
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Male ,Pathology ,medicine.medical_specialty ,Fatal outcome ,Biopsy ,MEDLINE ,Dermatology ,Corynebacterium ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Fatal Outcome ,0302 clinical medicine ,Sepsis ,medicine ,Humans ,Skin pathology ,Aged ,Skin ,Corynebacterium Infections ,medicine.diagnostic_test ,business.industry ,Skin Diseases, Bacterial ,medicine.disease ,Corynebacterium striatum ,Botryomycosis ,Bacterial etiology ,030220 oncology & carcinogenesis ,business - Published
- 2018
23. Ketotifen Modulates Mast Cell Chemotaxis to Kit-Ligand, but Does Not Impact Mast Cell Numbers, Degranulation, or Tumor Behavior in Neurofibromas of Nf1- Deficient Mice
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Xiaohong Li, Shi Chen, George E. Sandusky, Ciersten A. Burks, Max Jacobsen, Eric T. Hawley, Jaishri O. Blakeley, Jin Yuan, Steven D. Rhodes, Jeff R. Gehlhausen, Abbi Smith, Qingbo Lu, Waylan K. Bessler, Li Jiang, D. Wade Clapp, and David R. Jones
- Subjects
0301 basic medicine ,Ketotifen ,Cancer Research ,Chemokine ,Mast cell chemotaxis ,Stem cell factor ,medicine.disease_cause ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Mast Cells ,Stem Cell Factor ,Neurofibroma ,Neurofibromin 1 ,biology ,business.industry ,Chemotaxis ,Degranulation ,Mast cell ,medicine.disease ,Allergic conjunctivitis ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Histamine H1 Antagonists ,business ,Carcinogenesis ,medicine.drug - Abstract
Neurofibromatosis Type 1 (NF1) is one of the most common genetic tumor predisposition syndromes in humans. Mutant NF1 results in dysregulated RAS allowing neoplasms throughout the neuroaxis. Plexiform neurofibromas (pNF) afflict up to 50% of patients with NF1. They are complex tumors of the peripheral nerve that cause major morbidity via nerve dysregulation and mortality via conversion to malignant sarcoma. Genetically engineered mouse models (GEMM) of NF1 provide valuable insights for the identification of therapies that have utility in people with pNF. Preclinical studies in GEMMs implicate mast cells and the c-Kit/Kit ligand pathway in pNF tumorigenesis. Kit ligand is a potent chemokine secreted by tumorigenic, Nf1-deficient Schwann cells. Ketotifen is an FDA-approved drug for the treatment of allergic conjunctivitis and asthma that promotes mast cell stabilization and has been used in prior case studies to treat or prevent pNFs. This study investigated the effect of ketotifen on mast cell infiltration and degranulation in the presence and absence of Kit ligand provocation and the effect of ketotifen on shrinking or preventing pNF formation in the Nf1flox/flox;PostnCre+ GEMM. Ketotifen decreased mast cell infiltration in response to exogenous Kit ligand administration, but did not affect mast cell degranulation. Importantly, ketotifen did not reduce mast cells numbers or activity in pNF and did not prevent pNF formation or decrease the volume of established pNF despite administration of pharmacologically active doses. These findings suggest that ketotifen has limited use as monotherapy to prevent or reduce pNF burden in the setting of Nf1 mutations.
- Published
- 2019
24. Toxoplasmosis: The Heart of the Diagnosis
- Author
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Jeff R. Gehlhausen, Donald H. Rubin, James England, and Samuel S Bailin
- Subjects
0301 basic medicine ,medicine.medical_specialty ,030106 microbiology ,Toxoplasma gondii ,Odocoileus ,Medical care ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,Medicine ,Ingestion ,030212 general & internal medicine ,ID Cases ,Foodborne pathogen ,biology ,business.industry ,Transmission (medicine) ,Public health ,medicine.disease ,biology.organism_classification ,Virology ,Toxoplasmosis ,white-tailed deer ,Infectious Diseases ,Oncology ,venison ,acute toxoplasmosis ,business - Abstract
Toxoplasma gondii is a common parasite that infects warm-blooded animals, including humans, and is a foodborne pathogen. We report a case of acute toxoplasmosis in a 76-year-old man after ingestion of the undercooked heart of a white-tailed deer (Odocoileus virginianus) in Tennessee. The patient’s adult grandson, who also consumed part of the heart, became ill with nearly identical symptoms, though he did not seek medical care. This case highlights important public health concerns about deer-to-human transmission of Toxoplasma.
- Published
- 2018
25. Correction for Sierra Potchanant et al., 'INPP5E Preserves Genomic Stability through Regulation of Mitosis'
- Author
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Donna Cerabona, Stéphane Schurmans, Stéphanie Gayral, Ying He, Elizabeth A. Sierra Potchanant, Jeff R. Gehlhausen, Grzegorz Nalepa, Zejin Sun, and Zahi Abdul Sater
- Subjects
Phosphatidylinositol 4,5-Diphosphate ,Mitosis ,Biology ,Models, Biological ,Genomic Instability ,Substrate Specificity ,Genomic Stability ,Combinatorics ,Mice ,Animals ,Homeostasis ,Humans ,Author Correction ,Interphase ,Molecular Biology ,Cell Nucleus ,Published Erratum ,Cell Cycle ,Cell Biology ,Fibroblasts ,Phosphoric Monoester Hydrolases ,Protein Transport ,Gene Knockdown Techniques ,M Phase Cell Cycle Checkpoints ,Line (text file) ,HeLa Cells ,Subcellular Fractions - Abstract
The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout of
- Published
- 2017
26. Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2
- Author
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Eric T. Hawley, Jin Yuan, Jeff R. Gehlhausen, Benjamin Mark Wahle, Simon J. Conway, Su Jung Park, Abbi Smith, Yongzheng He, Charles W. Yates, D. Wade Clapp, Andi R. Masters, and David R. Jones
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,neurofibromatosis type 2 ,Tumor suppressor gene ,Schwannoma ,transgenic mice ,03 medical and health sciences ,vestibular schwannoma ,Internal medicine ,medicine ,otorhinolaryngologic diseases ,Neurofibromatosis type 2 ,cyclooxygenase 2 ,neoplasms ,business.industry ,Cancer ,medicine.disease ,Penetrance ,Surgery ,030104 developmental biology ,Otorhinolaryngology ,Celecoxib ,non-steroidal anti-inflammatory agents ,Sensorineural hearing loss ,business ,medicine.drug ,Research Paper - Abstract
// Benjamin M. Wahle 1, 2 , Eric T. Hawley 1 , Yongzheng He 1 , Abbi E. Smith 1 , Jin Yuan 1 , Andi R. Masters 3 , David R. Jones 3 , Jeffrey R. Gehlhausen 1 , Su-Jung Park 1 , Simon J. Conway 1 , D. Wade Clapp 1 and Charles W. Yates 1, 2 1 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA 2 Department of Otolaryngology/Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA 3 Clinical Pharmacology Analytical Core, Indiana University Simon Cancer Center, Indianapolis, Indiana, USA Correspondence to: D. Wade Clapp, email: dclapp@iu.edu Charles W. Yates, email: cwyates@iupui.edu Keywords: neurofibromatosis type 2; vestibular schwannoma; cyclooxygenase 2; non-steroidal anti-inflammatory agents; transgenic mice Abbreviations: COX-2 (cyclooxygenase-2), NSAID (nonsteroidal antiinflamatory drug) Received: March 31, 2017 Accepted: October 02, 2017 Published: October 24, 2017 ABSTRACT Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo , despite elevated expression levels of COX-2 in Nf2 -deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms.
- Published
- 2017
27. INPP5E Preserves Genomic Stability through Regulation of Mitosis
- Author
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Zahi Abdul Sater, Grzegorz Nalepa, Zejin Sun, Elizabeth A. Sierra Potchanant, Ying He, Donna Cerabona, and Jeff R. Gehlhausen
- Subjects
mitosis ,0301 basic medicine ,Kinetochore ,INPP5E ,Cellular homeostasis ,Cell Biology ,Cell cycle ,Biology ,spindle assembly checkpoint ,Cell biology ,03 medical and health sciences ,Spindle checkpoint ,030104 developmental biology ,Mitotic exit ,Centrosome ,cell cycle ,aneuploidy ,centrosomes ,Molecular Biology ,Mitosis ,Research Article - Abstract
The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout of INPP5E in human and murine cells impairs the spindle assembly checkpoint, centrosome and spindle function, and maintenance of chromosomal integrity. Consistent with a cell cycle regulatory role, we found that INPP5E expression is cell cycle dependent, peaking at mitotic entry. INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. Our findings identify the previously unknown, essential role of INPP5E in mitosis and prevention of aneuploidy, providing a new perspective on the function of this phosphoinositide phosphatase in health and development.
- Published
- 2017
28. Capecitabine-induced lichenoid drug eruption: a case report
- Author
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Jeff R, Gehlhausen, Matthew B, Strausburg, Mouhammad, Aouthmany, Terrence M, Katona, and Matthew J, Turner
- Subjects
Antimetabolites, Antineoplastic ,Forearm ,Lichenoid Eruptions ,Humans ,Breast Neoplasms ,Female ,Drug Eruptions ,Middle Aged ,Capecitabine - Abstract
Capecitabine is a 5-fluorouracil basedchemotherapeutic drug widely used in the treatmentof solid tumors, especially colorectal and breast. Someof the most common side effects of capecitabine arecutaneous in nature, including hand-foot syndrome(palmar-plantar erythrodysesthesia). Several reports inthe literature link capecitabine use with photosensitivelichenoid eruptions. Herein, we present a case ofcapecitabine-induced lichenoid eruption in an elderlyfemale with metastatic breast cancer and discuss ourfindings in relationship to previously reported cases ofthis and other capecitabine-induced skin pathologies.
- Published
- 2017
29. Capecitabine-induced lichenoid drug eruption: a case report
- Author
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Matthew J. Turner, Mouhammad Aouthmany, Jeff R. Gehlhausen, Matthew B. Strausburg, and Terrence Katona
- Subjects
Drug ,Lichenoid drug eruption ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Dermatology ,General Medicine ,medicine.disease ,Metastatic breast cancer ,Capecitabine ,Lichenoid eruption ,Medicine ,business ,capecitabine, lichenoid, drug eruption, photosensitive, 5-fluorouracil ,media_common ,medicine.drug - Abstract
Capecitabine is a 5-fluorouracil basedchemotherapeutic drug widely used in the treatmentof solid tumors, especially colorectal and breast. Someof the most common side effects of capecitabine arecutaneous in nature, including hand-foot syndrome(palmar-plantar erythrodysesthesia). Several reports inthe literature link capecitabine use with photosensitivelichenoid eruptions. Herein, we present a case ofcapecitabine-induced lichenoid eruption in an elderlyfemale with metastatic breast cancer and discuss ourfindings in relationship to previously reported cases ofthis and other capecitabine-induced skin pathologies.
- Published
- 2017
30. Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk
- Author
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Jin Yuan, Grzegorz Nalepa, Steven D. Rhodes, Feng Chun Yang, Yong Zheng He, Donna Cerabona, Shi Chen, Karl Staser, Jeff R. Gehlhausen, D. Wade Clapp, Su Jung Park, Zejin Sun, Matthew Shew, Yi Zeng, Keshav Menon, and David A. Ingram
- Subjects
Mice, Knockout ,Myelopoiesis ,MAPK/ERK pathway ,Mitogen-Activated Protein Kinase 3 ,Neurofibromatosis 1 ,Neurofibromin 1 ,Juvenile myelomonocytic leukemia ,Tumor suppressor gene ,MAP Kinase Signaling System ,Brief Report ,General Medicine ,Biology ,medicine.disease ,Mice ,Leukemia ,Haematopoiesis ,Leukemia, Myelomonocytic, Juvenile ,Immunology ,medicine ,biology.protein ,Cancer research ,Animals ,Progenitor cell - Abstract
Neurofibromatosis type 1 (NF1) predisposes individuals to the development of juvenile myelomonocytic leukemia (JMML), a fatal myeloproliferative disease (MPD). In genetically engineered murine models, nullizygosity of Nf1, a tumor suppressor gene that encodes a Ras-GTPase-activating protein, results in hyperactivity of Raf/Mek/Erk in hematopoietic stem and progenitor cells (HSPCs). Activated Erk1/2 phosphorylate kinases and transcription factors with myriad mitogenic roles in diverse cell types. However, genetic studies examining Erk1/2's differential and/or combined control of normal and Nf1-deficient myelopoiesis are lacking. Moreover, prior studies relying on chemical Mek/Erk inhibitors have reached conflicting conclusions in normal and Nf1-deficient mice. Here, we show that while single Erk1 or Erk2 disruption did not grossly compromise myelopoiesis, dual Erk1/2 disruption rapidly ablated granulocyte and monocyte production in vivo, diminished progenitor cell number, and prevented HSPC proliferation in vitro. Genetic disruption of Erk1/2 in the context of Nf1 nullizygosity (Mx1Cre(+)Nf1(flox/flox)Erk1(-/-)Erk2(flox/flox)) fully protects against the development of MPD. Collectively, we identified a fundamental requirement for Erk1/2 signaling in normal and Nf1-deficient hematopoiesis, elucidating a critical hematopoietic function for Erk1/2 while genetically validating highly selective Mek/Erk inhibitors in a leukemia that is otherwise resistant to traditional therapy.
- Published
- 2012
31. The importance of nerve microenvironment for schwannoma development
- Author
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Robert Büttner, Thomas Mindos, Helen Morrison, Alexander Schulz, Lan Kluwe, David Parkinson, Victor-Felix Mautner, Johannes Salamon, Christian Hagel, D. Wade Clapp, Stephan L. Baader, and Jeff R. Gehlhausen
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Neurofibromatosis 2 ,Microenvironment ,Schwannoma ,Clinical Neurology ,Schwann cell ,Mice, Transgenic ,Sciatic nerve ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Tumor Microenvironment ,otorhinolaryngologic diseases ,Macrophage ,Animals ,Neurofibromatosis type 2 ,Myelin Sheath ,Tumor microenvironment ,Original Paper ,Crush injury, tissue inflammation ,business.industry ,medicine.disease ,Axons ,030104 developmental biology ,medicine.anatomical_structure ,Tumor induction ,nervous system ,tissue inflammation ,Crush injury ,NF2M ,NF2 ,Neurology (clinical) ,Schwann Cells ,business ,030217 neurology & neurosurgery ,Nerve sheath neoplasm ,Neurilemmoma - Abstract
Schwannomas are predominantly benign nerve sheath neoplasms caused by Nf2 gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of Nf2 gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with injury signals contribute to a persistent regenerative Schwann cell response promoting schwannoma development. Specifically in genetically engineered mice following crush injuries on sciatic nerves, we found macroscopic nerve swellings in mice with homozygous nf2 gene deletion in Schwann cells and in animals with heterozygous nf2 knockout in both Schwann cells and axons. However, patient-mimicking schwannomas could only be provoked in animals with combined heterozygous nf2 knockout in Schwann cells and axons. We identified a severe re-myelination defect and sustained macrophage presence in the tumor tissue as major abnormalities. Strikingly, treatment of tumor-developing mice after nerve crush injury with medium-dose aspirin significantly decreased schwannoma progression in this disease model. Our results suggest a multifactorial concept for schwannoma formation—emphasizing axonal factors and mechanical nerve irritation as predilection site for schwannoma development. Furthermore, we provide evidence supporting the potential efficacy of anti-inflammatory drugs in the treatment of schwannomas. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1583-8) contains supplementary material, which is available to authorized users.
- Published
- 2016
32. A murine model of neurofibromatosis type 2 that accurately phenocopies human schwannoma formation
- Author
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Su Jung Park, Jacquelyn D. Lajiness, Karl Staser, Matthew Shew, D. Wade Clapp, Ann E. Hickox, Xianlin Yang, Simon J. Conway, Keshav Menon, Paul R. Territo, Charles W. Yates, Gary D. Hutchins, Muithi Mwanthi, Grzegorz Nalepa, Michael G. Heinz, Jin Yuan, Jeff R. Gehlhausen, Steven D. Rhodes, Feng Chun Yang, and Anat Stemmer-Rachamimov
- Subjects
Pathology ,medicine.medical_specialty ,Neurofibromatosis 2 ,Acoustic neuroma ,Mice, Transgenic ,Biology ,Schwannoma ,Mice ,Germline mutation ,Hearing ,Ganglia, Spinal ,Genetics ,medicine ,otorhinolaryngologic diseases ,Animals ,Humans ,Neurofibromatosis type 2 ,Molecular Biology ,Genetics (clinical) ,Neurofibromin 2 ,Cranial nerves ,Genetic disorder ,General Medicine ,Anatomy ,Exons ,Neuroma, Acoustic ,Articles ,Vestibulocochlear Nerve ,medicine.disease ,Neuroma ,Disease Models, Animal ,Auditory brainstem response ,Mutation ,Cell Adhesion Molecules - Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disorder resulting from germline mutations in the NF2 gene. Bilateral vestibular schwannomas, tumors on cranial nerve VIII, are pathognomonic for NF2 disease. Furthermore, schwannomas also commonly develop in other cranial nerves, dorsal root ganglia and peripheral nerves. These tumors are a major cause of morbidity and mortality, and medical therapies to treat them are limited. Animal models that accurately recapitulate the full anatomical spectrum of human NF2-related schwannomas, including the characteristic functional deficits in hearing and balance associated with cranial nerve VIII tumors, would allow systematic evaluation of experimental therapeutics prior to clinical use. Here, we present a genetically engineered NF2 mouse model generated through excision of the Nf2 gene driven by Cre expression under control of a tissue-restricted 3.9kbPeriostin promoter element. By 10 months of age, 100% of Postn-Cre; Nf2(flox/flox) mice develop spinal, peripheral and cranial nerve tumors histologically identical to human schwannomas. In addition, the development of cranial nerve VIII tumors correlates with functional impairments in hearing and balance, as measured by auditory brainstem response and vestibular testing. Overall, the Postn-Cre; Nf2(flox/flox) tumor model provides a novel tool for future mechanistic and therapeutic studies of NF2-associated schwannomas.
- Published
- 2014
33. Gene networks in Drosophila melanogaster: integrating experimental data to predict gene function
- Author
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Jeff R. Gehlhausen, Rupali P Patwardhan, Justen Andrews, Brian D. Eads, Mehmet Dalkilic, Sumit Middha, James C. Costello, and Scott Beason
- Subjects
Candidate gene ,Gene regulatory network ,Genomics ,Computational biology ,Databases, Genetic ,Protein Interaction Mapping ,Melanogaster ,Animals ,Cluster Analysis ,Gene Regulatory Networks ,Databases, Protein ,Gene ,Oligonucleotide Array Sequence Analysis ,Genetics ,biology ,Gene Expression Profiling ,Research ,Computational Biology ,biology.organism_classification ,Gene expression profiling ,Systems Integration ,Drosophila melanogaster ,Functional genomics ,Algorithms - Abstract
The first computational interaction network built from Drosophila melanogaster protein-protein and genetic interaction data allows the functional annotation of orphan genes and reveals clusters of functionally-related genes., Background Discovering the functions of all genes is a central goal of contemporary biomedical research. Despite considerable effort, we are still far from achieving this goal in any metazoan organism. Collectively, the growing body of high-throughput functional genomics data provides evidence of gene function, but remains difficult to interpret. Results We constructed the first network of functional relationships for Drosophila melanogaster by integrating most of the available, comprehensive sets of genetic interaction, protein-protein interaction, and microarray expression data. The complete integrated network covers 85% of the currently known genes, which we refined to a high confidence network that includes 20,000 functional relationships among 5,021 genes. An analysis of the network revealed a remarkable concordance with prior knowledge. Using the network, we were able to infer a set of high-confidence Gene Ontology biological process annotations on 483 of the roughly 5,000 previously unannotated genes. We also show that this approach is a means of inferring annotations on a class of genes that cannot be annotated based solely on sequence similarity. Lastly, we demonstrate the utility of the network through reanalyzing gene expression data to both discover clusters of coregulated genes and compile a list of candidate genes related to specific biological processes. Conclusions Here we present the the first genome-wide functional gene network in D. melanogaster. The network enables the exploration, mining, and reanalysis of experimental data, as well as the interpretation of new data. The inferred annotations provide testable hypotheses of previously uncharacterized genes.
- Published
- 2009
34. DATA-DRIVEN ONTOLOGIES
- Author
-
Daniel R. Schrider, Jeff R. Gehlhausen, James C. Costello, and Mehmet Dalkilic
- Subjects
Source code ,Process (engineering) ,Computer science ,media_common.quotation_subject ,Gene regulatory network ,Ontology (information science) ,Data science ,Data-driven ,Annotation ,ComputingMethodologies_PATTERNRECOGNITION ,Extant taxon ,ComputingMethodologies_GENERAL ,Function (engineering) ,media_common - Abstract
Gene networks are important tools in studying gene-gene relationships and gene function. Understanding the relationships within these networks is an important challenge. Ontologies are a critical tool in helping deal with these data. The use of the Gene Ontology, for example, has become routine in methods for validation, discovery, etc. Here we present a novel algorithm that synthesizes an ontology by considering both extant annotation terms and also the connections between genes in gene networks. The process is efficient and produces easily inspectable ontologies. Because the relationships drawn between terms are heavily influenced by data, we call these "Data-Driven" Ontologies. We apply this algorithm to both discover new relationships between biological processes and as a tool to compare sets of genes across microrarray experiments. Supplemental data and source code are available at: http://www.ddont.org
- Published
- 2008
35. Abstract 355: Generation of a murine model of Neurofibromatosis Type 2 that accurately recapitulates the spontaneous development of vestibular and spinal schwannomas found in NF2 patients
- Author
-
Matthew Shew, Su Jung Park, Charles W. Yates, Jeff R. Gehlhausen, and Wade Clapp
- Subjects
Vestibular system ,Cancer Research ,Pathology ,medicine.medical_specialty ,Tumor suppressor gene ,Hearing loss ,business.industry ,Schwannoma ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Dorsal root ganglion ,Peripheral nervous system ,Conditional gene knockout ,otorhinolaryngologic diseases ,medicine ,medicine.symptom ,Neurofibromatosis type 2 ,business - Abstract
Neurofibromatosis type 2 (NF2) is a genetic disease resulting from germline loss of the NF2 tumor suppressor gene. The hallmark of NF2 is hearing and vestibular loss of function in young adults caused by the development of vestibular schwannomas, which occur bilaterally in nearly all patients and are associated with homozygous loss of NF2. Individuals affected with NF2 also acquire schwannomas of other cranial, spinal and peripheral nerves. Importantly, non-familial schwannomas, the most common tumor of the peripheral nervous system, are also caused by bi-allelic loss of NF2 gene function. A major limitation in the identification of genetic and pharmacologic targets for schwannomas has been the lack of a robust preclinical model that accurately recapitulates human NF2 disease. In order to develop a more robust model, we intercrossed a mouse expressing Cre Recombinase under the control of the 3.9PeriCre promoter with an Nf2 conditional knockout mouse previously generated by Dr. Marco Giovannini to conditionally ablate Nf2 in neural crest-derived cell populations. Histological analysis of the dorsal root ganglion (DRG) and proximal spinal nerves of 3.9PeriCre+;Nf2flox/flox mice revealed that intercrossed mice spontaneously develop tumors between 8 and 10 months at every single spinal level. Microscopic analysis implicated these tumors as schwannomas, as they display a dense pattern of cellularity consistent with the established criteria of GEM schwannoma, including S100β1 positivity. Quantitation of the DRG volume indicated that 3.9PeriCre+ mice have a statistically significant increase when compared to 3.9PeriCre- littermates. FDG-PET studies corroborated this finding, as comparative studies showed an increase in the metabolic activity of paraspinal tumors found in 3.9PeriCre+ mice. Auditory Brainstem Response testing has revealed that 3.9PeriCre+ mice acquire an age-dependent increase in hearing threshold by 8 months when compared to age-matched 3.9PeriCre- controls. Histological analysis of Cranial Nerve VIII confirmed that the hearing loss was directly associated with the development of vestibular schwannomas. To test for concomitant vestibular loss of function, three different behavioral studies (contact righting, trunk curl, and swim) were performed to isolate and test the integrity of the vestibular sense in 3.9PeriCre;Nf2flox/flox mice. These studies indicated that 3.9PeriCre+ mice develop vestibular deficits, as all three studies identified highly significant differences between the two genotypes. Collectively, these genetically engineered mice acquire a physiologic phenotype that closely recapitulates important features of human NF2 disease and provides opportunities for testing putative therapeutic targets using genetic intercrosses or novel small molecule inhibitors. Citation Format: Jeff R. Gehlhausen, Su Jung Park, Matthew Shew, Wade Clapp, Charles Yates. Generation of a murine model of Neurofibromatosis Type 2 that accurately recapitulates the spontaneous development of vestibular and spinal schwannomas found in NF2 patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2013-355
- Published
- 2013
36. The tumor suppressor CDKN3 controls mitosis
- Author
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Yanwen Chen, Grzegorz Nalepa, Amalia S. Lehmann, Jamie L. Renbarger, Jeff R. Gehlhausen, Rikki Enzor, Xianlin Yang, Wade Clapp, Su Jung Park, Dilip Dey, Xiaowei Guan, Shi Chen, Luis F. Parada, Ying-Ying He, Feng Chun Yang, Yanzhu Yang, and Jill S. Barnholtz-Sloan
- Subjects
Mitosis ,Polo-like kinase ,Cyclin B ,Biology ,Mass Spectrometry ,Article ,03 medical and health sciences ,0302 clinical medicine ,CDC2 Protein Kinase ,Humans ,Phosphorylation ,Kinetochores ,Research Articles ,Cyclin-Dependent Kinase Inhibitor Proteins ,030304 developmental biology ,Centrosome ,0303 health sciences ,urogenital system ,Kinase ,Kinetochore ,Correction ,Cell Biology ,Cell cycle ,Cyclin-Dependent Kinases ,3. Good health ,Cell biology ,Spindle checkpoint ,Mitotic exit ,030220 oncology & carcinogenesis ,Dual-Specificity Phosphatases ,RNA Interference ,030217 neurology & neurosurgery ,HeLa Cells ,Signal Transduction - Abstract
A genome-wide screen of phosphatases that control mitosis identified CDKN3, which acts through the CDC2 signaling axis., Mitosis is controlled by a network of kinases and phosphatases. We screened a library of small interfering RNAs against a genome-wide set of phosphatases to comprehensively evaluate the role of human phosphatases in mitosis. We found four candidate spindle checkpoint phosphatases, including the tumor suppressor CDKN3. We show that CDKN3 is essential for normal mitosis and G1/S transition. We demonstrate that subcellular localization of CDKN3 changes throughout the cell cycle. We show that CDKN3 dephosphorylates threonine-161 of CDC2 during mitotic exit and we visualize CDC2pThr-161 at kinetochores and centrosomes in early mitosis. We performed a phosphokinome-wide mass spectrometry screen to find effectors of the CDKN3-CDC2 signaling axis. We found that one of the identified downstream phosphotargets, CKβ phosphorylated at serine 209, localizes to mitotic centrosomes and controls the spindle checkpoint. Finally, we show that CDKN3 protein is down-regulated in brain tumors. Our findings indicate that CDKN3 controls mitosis through the CDC2 signaling axis. These results have implications for targeted anticancer therapeutics.
- Published
- 2013
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