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Julien Muffat, Yun Li, Bingbing Yuan, Maisam Mitalipova, Attya Omer, Sean Corcoran, Grisilda Bakiasi, Li-Huei Tsai, Patrick Aubourg, Richard M Ransohoff, Rudolf Jaenisch
Microglia, the only lifelong resident immune cells of the central nervous system (CNS), are highly specialized macrophages that have been recognized to have a crucial role in neurodegenerative diseases such as Alzheimer's, Parkinson's and adrenoleukodystrophy (ALD). However, in contrast to other cell types of the human CNS, bona fide microglia have not yet been derived from cultured human pluripotent stem cells. Here we establish a robust and efficient protocol for the rapid production of microglia-like cells from human (h) embryonic stem (ES) and induced pluripotent stem (iPS) cells that uses defined serum-free culture conditions...
September 26, 2016: Nature Medicine
Nicholas H Varvel, Jonas J Neher, Andrea Bosch, Wenyi Wang, Richard M Ransohoff, Richard J Miller, Raymond Dingledine
The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Thomas F Imperiale, Menggang Yu, Patrick O Monahan, Timothy E Stump, Rebeka Tabbey, Elizabeth Glowinski, David F Ransohoff
BACKGROUND: There is no validated, discriminating, and easy-to-apply tool for estimating risk of colorectal neoplasia. We studied whether the National Cancer Institute's (NCI's) Colorectal Cancer (CRC) Risk Assessment Tool, which estimates future CRC risk, could estimate current risk for advanced colorectal neoplasia among average-risk persons. METHODS: This cross-sectional study involved individuals age 50 to 80 years undergoing first-time screening colonoscopy...
January 2017: Journal of the National Cancer Institute
Nicholas Schwab, Tilman Schneider-Hohendorf, Heinz Wiendl, Ellen Cahir-McFarland, Richard M Ransohoff, Linda Lieberman, Tatiana Plavina
No abstract text is available yet for this article.
August 30, 2016: Neurology
Richard M Ransohoff
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron's environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier...
August 19, 2016: Science
Harvind S Chahal, Wenting Wu, Katherine J Ransohoff, Lingyao Yang, Haley Hedlin, Manisha Desai, Yuan Lin, Hong-Ji Dai, Abrar A Qureshi, Wen-Qing Li, Peter Kraft, David A Hinds, Jean Y Tang, Jiali Han, Kavita Y Sarin
Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression)...
2016: Nature Communications
Regan M Bernhard, Jonathan Chaponis, Richie Siburian, Patience Gallagher, Katherine Ransohoff, Daniel Wikler, Roy H Perlis, Joshua D Greene
Moral judgments are produced through the coordinated interaction of multiple neural systems, each of which relies on a characteristic set of neurotransmitters. Genes that produce or regulate these neurotransmitters may have distinctive influences on moral judgment. Two studies examined potential genetic influences on moral judgment using dilemmas that reliably elicit competing automatic and controlled responses, generated by dissociable neural systems. Study 1 (N = 228) examined 49 common variants (SNPs) within 10 candidate genes and identified a nominal association between a polymorphism (rs237889) of the oxytocin receptor gene (OXTR) and variation in deontological vs...
August 6, 2016: Social Cognitive and Affective Neuroscience
Richard M Ransohoff
Microglial research has entered a fertile, dynamic phase characterized by novel technologies including two-photon imaging, whole-genome transcriptomic and epigenomic analysis with complementary bioinformatics, unbiased proteomics, cytometry by time of flight (CyTOF; Fluidigm) cytometry, and complex high-content experimental models including slice culture and zebrafish. Against this vivid background of newly emerging data, investigators will encounter in the microglial research literature a body of published work using the terminology of macrophage polarization, most commonly into the M1 and M2 phenotypes...
July 26, 2016: Nature Neuroscience
Harvind S Chahal, Yuan Lin, Katherine J Ransohoff, David A Hinds, Wenting Wu, Hong-Ji Dai, Abrar A Qureshi, Wen-Qing Li, Peter Kraft, Jean Y Tang, Jiali Han, Kavita Y Sarin
Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2...
July 18, 2016: Nature Communications
Julia D Ransohoff, Shufeng Li, Kavita Y Sarin
No abstract text is available yet for this article.
June 29, 2016: JAMA Dermatology
Laura Hertwig, Isabell Hamann, Silvina Romero-Suarez, Jason M Millward, Rebekka Pietrek, Coralie Chanvillard, Hanna Stuis, Karolin Pollok, Richard M Ransohoff, Astrid E Cardona, Carmen Infante-Duarte
Fractalkine receptor (CX3CR1)-deficient mice develop very severe experimental autoimmune encephalomyelitis (EAE), associated with impaired NK cell recruitment into the CNS. Yet, the precise implications of NK cells in autoimmune neuroinflammation remain elusive. Here, we investigated the pattern of NK cell mobilization and the contribution of CX3CR1 to NK cell dynamics in the EAE. We show that in both wild-type and CX3CR1-deficient EAE mice, NK cells are mobilized from the periphery and accumulate in the inflamed CNS...
August 2016: European Journal of Immunology
David F Ransohoff, Harold C Sox
No abstract text is available yet for this article.
June 21, 2016: JAMA: the Journal of the American Medical Association
Amy Ransohoff, Douglas Wood, A Solomon Henry, Vasu Divi, A Colevas
BACKGROUND: Definitive assessment of primary site margin status following resection of head and neck cancer is necessary for prognostication, treatment determination and qualification for clinical trials. This retrospective analysis determined how often an independent reviewer can assess primary tumor margin status of head and neck cancer resections based on review of the pathology report, surgical operative report, and first follow-up note alone. METHODS: We extracted from the electronic medical record pathology reports, operative reports, and follow-up notes from head and neck cancer resections performed at Stanford Hospital...
June 2016: Oral Oncology
Katherine J Ransohoff, Mina S Ally, Marcia L Stefanick, Elizabeth Keiser, Katrina Spaunhurst, Kristopher Kapphahn, Sherry Pagoto, Catherine Messina, Haley Hedlin, JoAnn E Manson, Jean Y Tang
BACKGROUND: Sun exposure is a major risk factor for skin cancer; however, the relative contribution of ultraviolet (UV) exposure during childhood versus adulthood on skin cancer risk remains unclear. OBJECTIVE: Our goal was to determine the impact of residential UV, measured by AVerage daily total GLObal solar radiation (AVGLO), exposure during childhood (birth, 15 years) versus adulthood (35, 50 years, and present) on incident non-melanoma skin cancer (NMSC) and malignant melanoma (MM) in postmenopausal women...
June 2016: Cancer Causes & Control: CCC
Balint Otvos, Daniel J Silver, Erin E Mulkearns-Hubert, Alvaro G Alvarado, Soumya M Turaga, Mia D Sorensen, Patricia Rayman, William A Flavahan, James S Hale, Kevin Stoltz, Maksim Sinyuk, Qiulian Wu, Awad Jarrar, Sung-Hak Kim, Paul L Fox, Ichiro Nakano, Jeremy N Rich, Richard M Ransohoff, James Finke, Bjarne W Kristensen, Michael A Vogelbaum, Justin D Lathia
Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs)...
August 2016: Stem Cells
Birgit Obermeier, Ajay Verma, Richard M Ransohoff
In autoimmune neurologic disorders, the blood-brain barrier (BBB) plays a central role in immunopathogenesis, since this vascular interface is an entry path for cells and effector molecules of the peripheral immune system to reach the target organ, the central nervous system (CNS). The BBB's unique anatomic structure and the tightly regulated interplay of its cellular and acellular components allow for maintenance of brain homeostasis, regulation of influx and efflux, and protection from harm; these ensure an optimal environment for the neuronal network to function properly...
2016: Handbook of Clinical Neurology
Richard M Ransohoff
No abstract text is available yet for this article.
April 14, 2016: Nature
Rodrigo Jover, Michael Bretthauer, Evelien Dekker, Øyvind Holme, Michal F Kaminski, Magnus Løberg, Ann G Zauber, Miguel A Hernán, Iris Lansdorp-Vogelaar, Annike Sunde, Eleanor McFadden, Antoni Castells, Jaroslaw Regula, Enrique Quintero, Maria Pellisé, Carlo Senore, Mette Kalager, Mario Dinis-Ribeiro, Louise Emilsson, David F Ransohoff, Geir Hoff, Hans-Olov Adami
BACKGROUND: Current guidelines recommend surveillance colonoscopies after polyp removal depending on the number and characteristics of polyps, but there is a lack of evidence supporting the recommendations. This report outlines the rationale and design of two randomized trials and one observational study investigating evidence-based surveillance strategies following polyp removal. Study design and endpoints: The EPoS studies started to recruit patients in April 2015. EPoS study I randomizes 13 746 patients with low-risk adenomas (1 - 2 tubular adenomas size < 10 mm, low-grade dysplasia) to surveillance after 5 and 10 years, or 10 years only...
June 2016: Endoscopy
Bradley N Martin, Chenhui Wang, Cun-jin Zhang, Zizhen Kang, Muhammet Fatih Gulen, Jarod A Zepp, Junjie Zhao, Guanglin Bian, Jeong-su Do, Booki Min, Paul G Pavicic, Caroline El-Sanadi, Paul L Fox, Aoi Akitsu, Yoichiro Iwakura, Anasuya Sarkar, Mark D Wewers, William J Kaiser, Edward S Mocarski, Marc E Rothenberg, Amy G Hise, George R Dubyak, Richard M Ransohoff, Xiaoxia Li
Interleukin 1β (IL-1β) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1β during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1β production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1β, whereas ATP stimulation triggered T cell production of IL-1β via ASC-NLRP3-dependent caspase-8 activation...
May 2016: Nature Immunology
Andrea Crotti, Richard M Ransohoff
Microglia originate from erythromyeloid progenitors (EMPs) in the yolk sac and develop in the forming CNS. Microglia are fundamental for the development and function of a healthy brain. By contrast, their role in immune host defense of the CNS remains speculative, given the immune privilege of this organ. Alterations in microglia functionality are involved in brain aging, as well as in neurodegenerative disease severity and progression. The combination of their ontogeny with the influence of the complex environment of the CNS makes microglia a unique cell population...
March 15, 2016: Immunity
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