570 results on '"Angela M. Christiano"'
Search Results
2. Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82
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Stephanie O. Erjavec, Sahar Gelfman, Alexa R. Abdelaziz, Eunice Y. Lee, Isha Monga, Anna Alkelai, Iuliana Ionita-Laza, Lynn Petukhova, and Angela M. Christiano
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Science - Abstract
Common variants have been discovered to be associated with Alopecia Areata; however, rare variants have been less well studied. Here, the authors use whole-exome sequencing to identify associated rare variants in the hair keratin gene KRT82. Further, they find that individuals with Alopecia Areata have reduced expression of KRT82 in the skin and hair follicle.
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- 2022
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3. Induction of T cell exhaustion by JAK1/3 inhibition in the treatment of alopecia areata
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Zhenpeng Dai, Tanya Sezin, Yuqian Chang, Eunice Y. Lee, Eddy Hsi Chun Wang, and Angela M. Christiano
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alopecia aerata (AA) ,T cell ,gamma chain cytokines ,JAK - STAT signaling pathway ,T cell exhaustion ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Alopecia areata (AA) is an autoimmune disease caused by T cell-mediated destruction of the hair follicle (HF). Therefore, approaches that effectively disrupt pathogenic T cell responses are predicted to have therapeutic benefit for AA treatment. T cells rely on the duality of T cell receptor (TCR) and gamma chain (γc) cytokine signaling for their development, activation, and peripheral homeostasis. Ifidancitinib is a potent and selective next-generation JAK1/3 inhibitor predicted to disrupt γc cytokine signaling. We found that Ifidancitinib robustly induced hair regrowth in AA-affected C3H/HeJ mice when fed with Ifidancitinib in chow diets. Skin taken from Ifidancitinib-treated mice showed significantly decreased AA-associated inflammation. CD44+CD62L- CD8+ T effector/memory cells, which are associated with the pathogenesis of AA, were significantly decreased in the peripheral lymphoid organs in Ifidancitinib-treated mice. We observed high expression of co-inhibitory receptors PD-1 on effector/memory CD8+ T cells, together with decreased IFN-γ production in Ifidancitinib-treated mice. Furthermore, we found that γc cytokines regulated T cell exhaustion. Taken together, our data indicate that selective induction of T cell exhaustion using a JAK inhibitor may offer a mechanistic explanation for the success of this treatment strategy in the reversal of autoimmune diseases such as AA.
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- 2022
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4. Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases
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Hideyuki Ujiie, David Rosmarin, Michael P. Schön, Sonja Ständer, Katharina Boch, Martin Metz, Marcus Maurer, Diamant Thaci, Enno Schmidt, Connor Cole, Kyle T. Amber, Dario Didona, Michael Hertl, Andreas Recke, Hanna Graßhoff, Alexander Hackel, Anja Schumann, Gabriela Riemekasten, Katja Bieber, Gant Sprow, Joshua Dan, Detlef Zillikens, Tanya Sezin, Angela M. Christiano, Kerstin Wolk, Robert Sabat, Khalaf Kridin, Victoria P. Werth, and Ralf J. Ludwig
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medical need ,skin ,inflammation ,atopic dermatitis ,psoriasis ,alopecia areata ,Medicine (General) ,R5-920 - Abstract
An estimated 20–25% of the population is affected by chronic, non-communicable inflammatory skin diseases. Chronic skin inflammation has many causes. Among the most frequent chronic inflammatory skin diseases are atopic dermatitis, psoriasis, urticaria, lichen planus, and hidradenitis suppurativa, driven by a complex interplay of genetics and environmental factors. Autoimmunity is another important cause of chronic skin inflammation. The autoimmune response may be mainly T cell driven, such as in alopecia areata or vitiligo, or B cell driven in chronic spontaneous urticaria, pemphigus and pemphigoid diseases. Rare causes of chronic skin inflammation are autoinflammatory diseases, or rheumatic diseases, such as cutaneous lupus erythematosus or dermatomyositis. Whilst we have seen a significant improvement in diagnosis and treatment, several challenges remain. Especially for rarer causes of chronic skin inflammation, early diagnosis is often missed because of low awareness and lack of diagnostics. Systemic immunosuppression is the treatment of choice for almost all of these diseases. Adverse events due to immunosuppression, insufficient therapeutic responses and relapses remain a challenge. For atopic dermatitis and psoriasis, a broad spectrum of innovative treatments has been developed. However, treatment responses cannot be predicted so far. Hence, development of (bio)markers allowing selection of specific medications for individual patients is needed. Given the encouraging developments during the past years, we envision that many of these challenges in the diagnosis and treatment of chronic inflammatory skin diseases will be thoroughly addressed in the future.
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- 2022
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5. Regulatory network analysis defines unique drug mechanisms of action and facilitates patient-drug matching in alopecia areata clinical trials
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James C. Chen, Zhenpeng Dai, and Angela M. Christiano
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Systems biology ,Alopecia areata ,Artificial intelligence ,Drug prediction ,Personalized medicine ,Biotechnology ,TP248.13-248.65 - Abstract
Not all therapeutics are created equal in regards to individual patients. The problem of identifying which compound will work best with which patient is a significant burden across all disease contexts. In the context of autoimmune diseases such as alopecia areata, several formulations of JAK/STAT inhibitors have demonstrated efficacy in clinical trials. All of these compounds demonstrate different rates of response, and here we observed that this coincided with different molecular effects on patients undergoing treatment. Using these data, we have developed a computational model that is capable of predicting which patient-drug pairs have the highest likelihood of response. We achieved this by integrating inferred mechanism of action data and gene regulatory networks derived from an independent patient cohort with baseline patient data prior to beginning treatment.
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- 2021
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6. Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs
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Catherine Do, Emmanuel L. P. Dumont, Martha Salas, Angelica Castano, Huthayfa Mujahed, Leonel Maldonado, Arunjot Singh, Sonia C. DaSilva-Arnold, Govind Bhagat, Soren Lehman, Angela M. Christiano, Subha Madhavan, Peter L. Nagy, Peter H. R. Green, Rena Feinman, Cornelia Trimble, Nicholas P. Illsley, Karen Marder, Lawrence Honig, Catherine Monk, Andre Goy, Kar Chow, Samuel Goldlust, George Kaptain, David Siegel, and Benjamin Tycko
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Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified. Results We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types. After excluding imprinting, the data pinpoint 15,112 high-confidence ASM differentially methylated regions, of which 1838 contain SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies are increased in cancers versus matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancer cells show increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor binding motifs are similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes track with de novo ASM. Allele-specific transcription factor binding from ChIP-seq is enriched among ASM loci, but most ASM differentially methylated regions lack such annotations, and some are found in otherwise uninformative “chromatin deserts.” Conclusions ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and transcription factor binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, cardiometabolic, neuropsychiatric, and neoplastic diseases.
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- 2020
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7. Engineering human skin model innervated with itch sensory neuron‐like cells differentiated from induced pluripotent stem cells
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Zongyou Guo, Chi‐Kun Tong, Joanna Jacków, Yanne S. Doucet, Hasan E. Abaci, Wangyong Zeng, Corey Hansen, Ryota Hayashi, Dominick DeLorenzo, Avina Rami, Alberto Pappalardo, Ellen A. Lumpkin, and Angela M. Christiano
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atopic dermatitis ,innervation ,iPSCs ,itch ,sensory neurons ,skin ,Chemical engineering ,TP155-156 ,Biotechnology ,TP248.13-248.65 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Atopic dermatitis (AD), driven by interleukins (IL‐4/IL‐13), is a chronic inflammatory skin disease characterized by intensive pruritus. However, it is unclear how immune signaling and sensory response pathways cross talk with each other. We differentiated itch sensory neuron‐like cells (ISNLCs) from iPSC lines. These ISNLCs displayed neural markers and action potentials and responded specifically to itch‐specific stimuli. These ISNLCs expressed receptors specific for IL‐4/IL‐13 and were activated directly by the two cytokines. We successfully innervated these ISNLCs into full thickness human skin constructs. These innervated skin grafts can be used in clinical applications such as wound healing. Moreover, the availability of such innervated skin models will be valuable to develop drugs to treat skin diseases such as AD.
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- 2022
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8. Tissue engineering of human hair follicles using a biomimetic developmental approach
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Hasan Erbil Abaci, Abigail Coffman, Yanne Doucet, James Chen, Joanna Jacków, Etienne Wang, Zongyou Guo, Jung U. Shin, Colin A. Jahoda, and Angela M. Christiano
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Science - Abstract
Human skin constructs hold potential for regenerative medicine, but the incorporation of hair follicles into such constructs is a challenge. Here, the authors use 3D printed molds to pattern hair follicle cell types in a physiological organization, and achieve human hair growth on the back of a mouse.
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- 2018
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9. Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata
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Zhenpeng Dai, James Chen, Yuqian Chang, and Angela M. Christiano
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Autoimmunity ,Inflammation ,Medicine - Abstract
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) are key intracellular mediators in the signal transduction of many cytokines and growth factors. Common γ chain cytokines and interferon-γ that use the JAK/STAT pathway to induce biological responses have been implicated in the pathogenesis of alopecia areata (AA), a T cell–mediated autoimmune disease of the hair follicle. We previously showed that therapeutic targeting of JAK/STAT pathways using the first-generation JAK1/2 inhibitor, ruxolitinib, and the pan-JAK inhibitor, tofacitinib, was highly effective in the treatment of human AA, as well as prevention and reversal of AA in the C3H/HeJ mouse model. To better define the role of individual JAKs in the pathogenesis of AA, in this study, we tested and compared the efficacy of several next-generation JAK-selective inhibitors in the C3H/HeJ mouse model of AA, using both systemic and topical delivery. We found that JAK1-selective inhibitors as well as JAK3-selective inhibitors robustly induced hair regrowth and decreased AA-associated inflammation, whereas several JAK2-selective inhibitors failed to restore hair growth in treated C3H/HeJ mice with AA. Unlike JAK1, which is broadly expressed in many tissues, JAK3 expression is largely restricted to hematopoietic cells. Our study demonstrates inhibiting JAK3 signaling is sufficient to prevent and reverse disease in the preclinical model of AA.
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- 2021
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10. Molecular signatures define alopecia areata subtypes and transcriptional biomarkers
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Ali Jabbari, Jane E. Cerise, James C. Chen, Julian Mackay-Wiggan, Madeleine Duvic, Vera Price, Maria Hordinsky, David Norris, Raphael Clynes, and Angela M. Christiano
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Alopecia areata ,Biomarkers ,Autoimmune ,Medicine ,Medicine (General) ,R5-920 - Abstract
Alopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis). Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis.
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- 2016
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11. Hair Follicle Dermal Cells Support Expansion of Murine and Human Embryonic and Induced Pluripotent Stem Cells and Promote Haematopoiesis in Mouse Cultures
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Jun Liu, Claire A. Higgins, Jenna C. Whitehouse, Susan J. Harris, Heather Crawford, Angela M. Christiano, Majlinda Lako, Nicholas Hole, and Colin A. B. Jahoda
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Internal medicine ,RC31-1245 - Abstract
In the hair follicle, the dermal papilla (DP) and dermal sheath (DS) support and maintain proliferation and differentiation of the epithelial stem cells that produce the hair fibre. In view of their regulatory properties, in this study, we investigated the interaction between hair follicle dermal cells (DP and DS) and embryonic stem cells (ESCs); induced pluripotent stem cells (iPSCs); and haematopoietic stem cells. We found that coculture of follicular dermal cells with ESCs or iPSCs supported their prolonged maintenance in an apparently undifferentiated state as established by differentiation assays, immunocytochemistry, and RT-PCR for markers of undifferentiated ESCs. We further showed that cytokines that are involved in ESC support are also expressed by cultured follicle dermal cells, providing a possible explanation for maintenance of ES cell stemness in cocultures. The same cytokines were expressed within follicles in situ in a pattern more consistent with a role in follicle growth activities than stem cell maintenance. Finally, we show that cultured mouse follicle dermal cells provide good stromal support for haematopoiesis in an established coculture model. Human follicular dermal cells represent an accessible and readily propagated source of feeder cells for pluripotent and haematopoietic cells and have potential for use in clinical applications.
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- 2018
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12. Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib
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Ali Jabbari, Zhenpeng Dai, Luzhou Xing, Jane E. Cerise, Yuval Ramot, Yackov Berkun, Gina A. Montealegre Sanchez, Raphaela Goldbach-Mansky, Angela M. Christiano, Raphael Clynes, and Abraham Zlotogorski
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Alopecia areata ,Interferon gamma ,JAK inhibitor ,CANDLE syndrome ,Autoimmune disease ,Baricitinib ,Gene expression profiling ,Autoinflammatory ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Alopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules. Methods: A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib. Findings: The patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment. Interpretation: Baricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.
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- 2015
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13. Contamination source modeling with SCRuB improves cancer phenotype prediction from microbiome data
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George I. Austin, Heekuk Park, Yoli Meydan, Dwayne Seeram, Tanya Sezin, Yue Clare Lou, Brian A. Firek, Michael J. Morowitz, Jillian F. Banfield, Angela M. Christiano, Itsik Pe’er, Anne-Catrin Uhlemann, Liat Shenhav, and Tal Korem
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Biomedical Engineering ,Molecular Medicine ,Bioengineering ,Applied Microbiology and Biotechnology ,Biotechnology - Published
- 2023
14. A multi-organ chip with matured tissue niches linked by vascular flow
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Kacey Ronaldson-Bouchard, Diogo Teles, Keith Yeager, Daniel Naveed Tavakol, Yimu Zhao, Alan Chramiec, Somnath Tagore, Max Summers, Sophia Stylianos, Manuel Tamargo, Busub Marcus Lee, Susan P. Halligan, Erbil Hasan Abaci, Zongyou Guo, Joanna Jacków, Alberto Pappalardo, Jerry Shih, Rajesh K. Soni, Shivam Sonar, Carrie German, Angela M. Christiano, Andrea Califano, Karen K. Hirschi, Christopher S. Chen, Andrzej Przekwas, and Gordana Vunjak-Novakovic
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MicroRNAs ,Liver ,Biomedical Engineering ,Medicine (miscellaneous) ,Heart ,Bioengineering ,Skin ,Computer Science Applications ,Biotechnology - Abstract
Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.
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- 2022
15. Jouni Uitto (1943–2022)
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John A. McGrath, Leena Bruckner-Tuderman, and Angela M. Christiano
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Cell Biology ,Dermatology ,Molecular Biology ,Biochemistry - Published
- 2023
16. Primary cicatricial alopecias are characterized by dysregulation of shared gene expression pathways
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Eddy H C Wang, Isha Monga, Brigitte N Sallee, James C Chen, Alexa R Abdelaziz, Rolando Perez-Lorenzo, Lindsey A Bordone, and Angela M Christiano
- Abstract
The primary forms of cicatricial (scarring) alopecia (PCA) are a group of inflammatory, irreversible hair loss disorders characterized by immune cell infiltrates targeting hair follicles (HFs). Lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and centrifugal cicatricial alopecia (CCCA) are among the main subtypes of PCAs. The pathogenesis of the different types of PCAs are poorly understood, and current treatment regimens yield inconsistent and unsatisfactory results. We performed high-throughput RNA-sequencing on scalp biopsies of a large cohort PCA patients to develop gene expression-based signatures, trained into machine-learning-based predictive models and pathways associated with dysregulated gene expression. We performed morphological and cytokine analysis to define the immune cell populations found in PCA subtypes. We identified a common PCA gene signature that was shared between LPP, FFA, and CCCA, which revealed a significant over-representation of mast cell (MC) genes, as well as downregulation of cholesterogenic pathways and upregulation of fibrosis and immune signaling genes. Immunohistological analyses revealed an increased presence of MCs in PCAs lesions. Our gene expression analyses revealed common pathways associated with PCAs, with a strong association with MCs. The indistinguishable differences in gene expression profiles and immune cell signatures between LPP, FFA, and CCCA suggest that similar treatment regimens may be effective in treating these irreversible forms of hair loss.
- Published
- 2022
17. Targeting the Jak/Signal Transducer and Activator of Transcription 3 Pathway with Ruxolitinib in a Mouse Model of Recessive Dystrophic Epidermolysis Bullosa–Squamous Cell Carcinoma
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J. Jackow, David Alvarez Cespedes, David M. Owens, Angela M. Christiano, Rolando Perez-Lorenzo, Corey Hansen, Avina Rami, Alberto Pappalardo, D. Delorenzo, Zongyou Guo, Arianna L. Kim, and R. Hayashi
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STAT3 Transcription Factor ,Ruxolitinib ,Collagen Type VII ,Skin Neoplasms ,Cutaneous squamous cell carcinoma ,Administration, Oral ,Dermatology ,Biochemistry ,stat ,Mice ,Cell Line, Tumor ,Nitriles ,Recessive dystrophic epidermolysis bullosa ,Animals ,Humans ,Medicine ,Basal cell ,Molecular Biology ,Janus Kinases ,business.industry ,Cell Biology ,Fibroblasts ,Xenograft Model Antitumor Assays ,Epidermolysis Bullosa Dystrophica ,Pyrimidines ,Mutation ,Carcinoma, Squamous Cell ,STAT protein ,Cancer research ,Pyrazoles ,business ,Signal Transduction ,medicine.drug - Published
- 2021
18. Prevalence estimates for lichen planopilaris and frontal fibrosing alopecia in a New York City health care system
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Fabian Jenkins, Lindsey Bordone, Eunice Y. Lee, Dahsan Gary, Angela M. Christiano, Jonathan Lavian, and Megan H. Trager
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Comorbidity ,Dermatology ,Young Adult ,Age Distribution ,Epidemiology ,Health care ,Prevalence ,medicine ,Humans ,Sex Distribution ,Child ,Aged ,Aged, 80 and over ,business.industry ,Frontal fibrosing alopecia ,Lichen Planus ,Infant ,Alopecia ,Middle Aged ,Lichen planopilaris ,medicine.disease ,Child, Preschool ,Female ,New York City ,business - Published
- 2021
19. An open-label study evaluating the efficacy of abatacept in alopecia areata
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Eddy Hsi Chun Wang, Raphael Clynes, B. Sallee, F. Sansaricq, Julian Mackay-Wiggan, Carey Kim, Angela M. Christiano, J.C. Chen, and Nhan Nguyen
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medicine.medical_specialty ,business.industry ,Abatacept ,Treatment outcome ,MEDLINE ,Dermatology ,Alopecia areata ,medicine.disease ,Clinical trial ,Open label study ,Severity of illness ,medicine ,Young adult ,business ,medicine.drug - Published
- 2021
20. Improved therapeutic efficacy of unmodified anti-tumor antibodies by immune checkpoint blockade and kinase targeted therapy in mouse models of melanoma
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Rolando Perez-Lorenzo, Raphael Clynes, Angela M. Christiano, and S. Erjavec
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0301 basic medicine ,anti-tumor antibodies ,medicine.medical_treatment ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,medicine ,melanoma ,business.industry ,Melanoma ,FOXP3 ,Cancer ,Immunotherapy ,medicine.disease ,targeted therapy ,Immune checkpoint ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,immunotherapy ,combination therapies ,business ,Research Paper - Abstract
The use of specific anti-tumor antibodies has transformed the solid cancer therapeutics landscape with the relative successes of therapies such as anti-HER2 in breast cancer, and anti-EGFR in HNSCC and colorectal cancer. However, these therapies result in toxicity and the emergence of resistant tumors. Here, we showed that removing immune suppression and enhancing stimulatory signals increased the anti-tumor activity of unmodified TA99 antibodies (anti-TYRP1) with a significant reduction of growth of solid tumors and lung metastases in mouse models of melanoma. Immune checkpoint blockade enhanced the efficacy of TA99, which was associated with greater CD8+/Foxp3+, NK1.1+ and dendritic cell infiltrates, suggestive of an increased anti-tumor innate and adaptive immune responses. Further, MEK inhibition in melanoma cell lines increased the expression of melanosomal antigens in vitro, and combining TA99 and MEKi in vivo resulted in enhanced tumor control. Moreover, we found an improved therapeutic effect when YUMM tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade (anti-PD1 and anti-CTLA4). Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which in combination with anti-tumor antibodies, generated a robust adaptive anti-tumor response that was sustained by immune checkpoint inhibition therapy. We postulate that combining anti-tumor antibodies with standard-of-care strategies such as immune checkpoint blockade or targeted therapy, will improve therapeutic outcomes in cancer.
- Published
- 2021
21. Regulatory network analysis defines unique drug mechanisms of action and facilitates patient-drug matching in alopecia areata clinical trials
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Angela M. Christiano, J.C. Chen, and Zhenpeng Dai
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Drug ,Artificial intelligence ,media_common.quotation_subject ,Biophysics ,Gene regulatory network ,Alopecia areata ,Context (language use) ,Disease ,Bioinformatics ,Biochemistry ,Structural Biology ,Genetics ,medicine ,ComputingMethodologies_COMPUTERGRAPHICS ,media_common ,Drug prediction ,business.industry ,medicine.disease ,Personalized medicine ,Computer Science Applications ,Clinical trial ,Cohort ,Systems biology ,business ,TP248.13-248.65 ,Research Article ,Biotechnology - Abstract
Graphical abstract, Not all therapeutics are created equal in regards to individual patients. The problem of identifying which compound will work best with which patient is a significant burden across all disease contexts. In the context of autoimmune diseases such as alopecia areata, several formulations of JAK/STAT inhibitors have demonstrated efficacy in clinical trials. All of these compounds demonstrate different rates of response, and here we observed that this coincided with different molecular effects on patients undergoing treatment. Using these data, we have developed a computational model that is capable of predicting which patient-drug pairs have the highest likelihood of response. We achieved this by integrating inferred mechanism of action data and gene regulatory networks derived from an independent patient cohort with baseline patient data prior to beginning treatment.
- Published
- 2021
22. Validation of Case Identification for Alopecia Areata Using International Classification of Diseases Coding
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Sara J. Li, Jonathan Lavian, Arash Mostaghimi, Angela M. Christiano, Eunice Yoojin Lee, Fernanda Polubriaginof, and Lindsey Bordone
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medicine.medical_specialty ,international classification of diseases ,Alopecia areata ,Physical examination ,Dermatology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,International Statistical Classification of Diseases and Related Health Problems ,database ,Ophiasis ,validation ,medicine.diagnostic_test ,business.industry ,Medical record ,Alopecia totalis ,ICD-10 ,medicine.disease ,030220 oncology & carcinogenesis ,Alopecia universalis ,positive predictive value ,Original Article ,business - Abstract
Background: Search algorithms used to identify patients with alopecia areata (AA) need to be validated prior to use in large databases. Objectives: The aim of the study is to assess whether patients with an International Statistical Classification of Diseases and Related Health Problems (ICD) 9 or 10 code for AA have a true diagnosis of AA. Materials and Methods: A multicenter retrospective review was performed at Columbia University Irving Medical Center, Brigham and Women's Hospital, and Massachusetts General Hospital to determine whether patients with an ICD 9 codes (704.01 - AA) or ICD 10 codes (L63.0 -Alopecia Totalis, L63.1 - Alopecia Universalis, L63.2 - Ophiasis, L63.8 - other AA, and L63.9 - AA, unspecified) for AA met diagnostic criteria for the disease. Results: Of 880 charts, 97.5% had physical examination findings consistent with AA, and 90% had an unequivocal diagnosis. AA was diagnosed by a dermatologist in 87% of the charts. The positive predictive value (PPV) of the ICD 9 code 704.01 was 97% (248/255). The PPV for the ICD 10 codes were 64% (75/118) for L63.0, 86% (130/151) for L63.1, 50% (1/2) for L63.2, 91% (81/89) for L63.8, and 93% (247/265) for L63.9. Overall, 89% (782/880) of patients with an ICD code for AA were deemed to have a true diagnosis of AA. Conclusions: Patients whose medical records contain an AA-associated ICD code have a high probability of having the condition.
- Published
- 2020
23. Forging the Future: 2018 Alopecia Areata Research Summit Summary Report
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Natasha Atanaskova Mesinkovska, Dory Kranz, David A. Norris, Angela M. Christiano, Jerry Shapiro, and Abby Ellison
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medicine.medical_specialty ,Nonprofit organization ,Alopecia Areata ,Endpoint Determination ,Dermatology ,Autoimmune skin disease ,Political science ,Outcome Assessment, Health Care ,medicine ,Humans ,Psoriasis ,Molecular Biology ,Clinical Trials as Topic ,geography ,Summit ,geography.geographical_feature_category ,integumentary system ,Extramural ,Arthritis, Psoriatic ,Cell Biology ,General Medicine ,Congresses as Topic ,Alopecia areata ,medicine.disease ,Hidradenitis Suppurativa ,Patient Satisfaction ,Family medicine ,Biotechnology - Abstract
Alopecia areata (AA) is a common autoimmune skin disease resulting in the loss of hair on the scalp and elsewhere on the body that affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National AA Foundation (NAAF) is a nonprofit organization that supports research to find a cure or acceptable treatment for AA, supports those with the disease, and educates the public about AA. NAAF conducts research summits every two years to review progress and create new directions in its funded and promoted research. This report from the seventh AA Research Summit, Forging the Future, held December 4-5, 2018 in New York City provides highlights of the research presented and future research priorities identified during targeted discussion sessions.
- Published
- 2020
24. Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing
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B. Sallee, J. Shin, Hasan E. Abaci, Angela M. Christiano, Z. Guo, Alberto Pappalardo, Eddy Hsi Chun Wang, Y. Doucet, Joanna Jacków, and Lauren Herron
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Drug ,Keratinocytes ,Receptors, CCR6 ,medicine.medical_treatment ,T cell ,media_common.quotation_subject ,Cell ,lcsh:Medicine ,Enzyme-Linked Immunosorbent Assay ,C-C chemokine receptor type 6 ,Real-Time Polymerase Chain Reaction ,Article ,03 medical and health sciences ,0302 clinical medicine ,Psoriasis ,medicine ,Humans ,lcsh:Science ,Cells, Cultured ,030304 developmental biology ,media_common ,Skin ,0303 health sciences ,Multidisciplinary ,integumentary system ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,lcsh:R ,Fibroblasts ,Th1 Cells ,medicine.disease ,Flow Cytometry ,Phenotype ,3. Good health ,Skin diseases ,medicine.anatomical_structure ,Cytokine ,030220 oncology & carcinogenesis ,Cancer research ,Cytokines ,Th17 Cells ,lcsh:Q ,business ,Infiltration (medical) ,Biomedical engineering - Abstract
Drug screening studies for inflammatory skin diseases are currently performed using model systems that only partially recapitulate human diseased skin. Here, we developed a new strategy to incorporate T cells into human 3D skin constructs (HSCs), which enabled us to closely monitor and quantitate T cell responses. We found that the epidermis promotes the activation and infiltration of T cells into the skin, and provides a directional cue for their selective migration towards the epidermis. We established a psoriatic HSC (pHSC) by incorporating polarized Th1/Th17 cells or CCR6+CLA+ T cells derived from psoriasis patients into the constructs. These pHSCs showed a psoriatic epidermal phenotype and characteristic cytokine profiles, and responded to various classes of psoriasis drugs, highlighting the potential utility of our model as a drug screening platform. Taken together, we developed an advanced immunocompetent 3D skin model to investigate epidermal-T cell interactions and to understand the pathophysiology of inflammatory skin diseases in a human-relevant and patient-specific context.
- Published
- 2020
25. Impaired autophagy promotes hair loss in the C3H/HeJ mouse model of alopecia areata
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Rupali Gund and Angela M. Christiano
- Subjects
Mice ,Mice, Inbred C3H ,Disease Models, Animal ,Alopecia Areata ,Monosaccharide Transport Proteins ,integumentary system ,Brief Report ,Autophagy ,Animals ,Lectins, C-Type ,Cell Biology ,Molecular Biology ,Genome-Wide Association Study - Abstract
Alopecia areata (AA) involves an aberrant immune attack on the hair follicle (HF), which leads to hair loss. Previous genetic data from our lab pointed to a connection between macroautophagy/autophagy and AA pathogenesis, and GWAS identified STX17, CLEC16A and BCL2L11/BIM as risk factors for AA. Additionally, AA patients have copy number deletions in region spanning the ATG4B gene. To test whether autophagy might contribute to disease pathogenesis in AA, we investigated autophagic activity in C3H/HeJ mouse model. We found that autophagy protein SQSTM1 accumulated in HF of AA mice, while in immune cells from AA skin-draining lymph nodes SQSTM1 was not altered, suggesting that autophagic activity is inhibited in the HF of AA mice. Induction of autophagy with Tat-BECN1 peptide attenuated AA, while treatment with the autophagy blocker chloroquine promoted disease, compared to untreated AA mice. Together, our findings suggest the involvement of impaired autophagy in disease pathogenesis of AA. Abbreviations: AA: alopecia areata; CQ: chloroquine; GWAS: genome-wide association studies; HF: hair follicle; MHC: major histocompatibility complex; SDLN: skin-draining lymph nodes
- Published
- 2022
- Full Text
- View/download PDF
26. CRISPR/Cas9-based targeted genome editing for correction of recessive dystrophic epidermolysis bullosa using iPS cells
- Author
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D. Delorenzo, Angela M. Christiano, Satoru Shinkuma, Hasan E. Abaci, Corey Hansen, Joanna Jacków, Zongyou Guo, Julio C. Salas-Alanis, Y. Doucet, R. Hayashi, Y. Kabata, and J. Shin
- Subjects
Exon ,Multidisciplinary ,integumentary system ,Genome editing ,Anchoring fibrils ,COL7A1 Gene ,Cancer research ,CRISPR ,Human skin ,Biological Sciences ,Stem cell ,Biology ,Induced pluripotent stem cell - Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disorder caused by mutations in the COL7A1 gene encoding type VII collagen (C7). The spectrum of severity depends on the type of mutation in the COL7A1 gene. C7 is the major constituent of anchoring fibrils (AFs) at the basement membrane zone (BMZ). Patients with RDEB lack functional C7 and have severely impaired dermal–epidermal stability, resulting in extensive blistering and open wounds on the skin that greatly affect the patient’s quality of life. There are currently no therapies approved for the treatment of RDEB. Here, we demonstrated the correction of mutations in exon 19 (c.2470insG) and exon 32 (c.3948insT) in the COL7A1 gene through homology-directed repair (HDR). We used the clustered regulatory interspaced short palindromic repeats (CRISPR) Cas9-gRNAs system to modify induced pluripotent stem cells (iPSCs) derived from patients with RDEB in both the heterozygous and homozygous states. Three-dimensional human skin equivalents (HSEs) were generated from gene-corrected iPSCs, differentiated into keratinocytes (KCs) and fibroblasts (FBs), and grafted onto immunodeficient mice, which showed normal expression of C7 at the BMZ as well as restored AFs 2 mo postgrafting. Safety assessment for potential off-target Cas9 cleavage activity did not reveal any unintended nuclease activity. Our findings represent a crucial advance for clinical applications of innovative autologous stem cell-based therapies for RDEB.
- Published
- 2019
27. Incidence estimates for lichen planopilaris and frontal fibrosing alopecia in a New York City health care system
- Author
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Eunice Y. Lee, Angela M. Christiano, Megan H. Trager, Dahsan Gary, Fabian Jenkins, Jonathan Lavian, and Lindsey Bordone
- Subjects
Adult ,Male ,medicine.medical_specialty ,Dermatology ,Data Warehousing ,Health care ,Epidemiology ,medicine ,Humans ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Frontal fibrosing alopecia ,Incidence (epidemiology) ,Incidence ,Lichen Planus ,ICD-10 ,Alopecia ,General Medicine ,Middle Aged ,medicine.disease ,body regions ,Distress ,Hair loss ,Female ,New York City ,business ,Cohort study - Abstract
Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are scarring alopecias that cause significant distress and psychological morbidity. Limited studies have been performed examining the epidemiology of FFA and LPP. We performed a retrospective case cohort analysis by querying for patients with the ICD 10 code L66.1 (LPP, FFA) between 2015 and 2018 using the Clinical Data Warehouse (CDW) at NewYork-Presbyterian Hospital and Columbia Doctors. We calculated the one-year incidence of LPP/FFA between January 1, 2018 to December 31, 2018 by identifying all patients without a previously recorded ICD code for L66.1 who presented as a new hair loss patient based on chart review. A total of 170 patients were identified with a new diagnosis of LPP or FFA in 2018 among 1,187,583 patients. The standardized incidence per 100,000 was 12.75 for LPP and FFA combined, 7.35 for LPP alone, and 5.41 for FFA alone. The incidence peaked in the 51 to 60 age range (3.36). The incidence was highest in non-Hispanic White patients (17.27), White patients of unknown ethnicity (26.26), and non-Hispanic Asian patients (17.27). In New York City, LPP and FFA are uncommon diseases that are most common in middle-aged females and non-Hispanic White patients.
- Published
- 2021
28. Author response for 'Engineering human skin model innervated with itch sensory neuron‐like cells differentiated from induced pluripotent stem cells'
- Author
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R. Hayashi, Hasan E. Abaci, Y. Doucet, D. Delorenzo, J. Jackow, Avina Rami, Chi-Kun Tong, Z. Guo, Angela M. Christiano, Corey Hansen, Wangyong Zeng, Alberto Pappalardo, and Ellen A. Lumpkin
- Subjects
medicine.anatomical_structure ,medicine ,Human skin ,Biology ,Induced pluripotent stem cell ,Neuroscience ,Sensory neuron - Published
- 2021
29. Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy
- Author
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Aakash V. Patel, S. Erjavec, Miguel Verbitsky, Lynn Petukhova, A.R. Abdelaziz, Ali Jabbari, Angela M. Christiano, Jane E. Cerise, Simone Sanna-Cherchi, Rachel K. Rigo, and Li Bian
- Subjects
0301 basic medicine ,Alopecia Areata ,DNA Copy Number Variations ,Genotype ,Population ,Gene Dosage ,Autophagy-Related Proteins ,Genome-wide association study ,Dermatology ,Biology ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Biochemistry ,Article ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Autophagy ,medicine ,Humans ,Copy-number variation ,education ,Molecular Biology ,Gene ,Genetic association ,Genetics ,education.field_of_study ,Scalp ,Gene Expression Profiling ,Alopecia areata ,medicine.disease ,Hair follicle ,Cysteine Endopeptidases ,030104 developmental biology ,Hair loss ,medicine.anatomical_structure ,Mutation ,Hair Follicle ,Genome-Wide Association Study ,Hair ,Transcription Factors - Abstract
Alopecia areata (AA) is a highly prevalent autoimmune disease that attacks the hair follicle and leads to hair loss that can range from small patches to complete loss of scalp and body hair. Our previous linkage and genome-wide association studies (GWAS) generated strong evidence for aetiological contributions from inherited genetic variants at different population frequencies, including both rare mutations and common polymorphisms. Additionally, we conducted gene expression (GE) studies on scalp biopsies of 96 patients and controls to establish signatures of active disease. In this study, we performed an integrative analysis on these two datasets to test the hypothesis that rare CNVs in patients with AA could be leveraged to identify drivers of disease in our AA GE signatures. We analysed copy number variants (CNVs) in a case-control cohort of 673 patients with AA and 16 311 controls independent of the case-control cohort of 96 research participants used in our GE study. Using an integrative computational analysis, we identified 14 genes whose expression levels were altered by CNVs in a consistent direction of effect, corresponding to gene expression changes in lesional skin of patients. Four of these genes were affected by CNVs in three or more unrelated patients with AA, including ATG4B and SMARCA2, which are involved in autophagy and chromatin remodelling, respectively. Our findings identified new classes of genes with potential contributions to AA pathogenesis.
- Published
- 2019
30. Pathomechanisms of immune-mediated alopecia
- Author
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Angela M. Christiano, Eddy Hsi Chun Wang, Alessandra Anzai, Valeria Aoki, and Eunice Y. Lee
- Subjects
0301 basic medicine ,Immunology ,Disease ,Pathogenesis ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immune privilege ,Hair cycle ,medicine ,Animals ,Humans ,Immunology and Allergy ,Invited Reviews ,integumentary system ,business.industry ,Alopecia ,General Medicine ,Alopecia areata ,Hair follicle ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Hair loss ,business ,Hair Follicle - Abstract
The hair follicle (HF) is a complex mini-organ that constantly undergoes dynamic cycles of growth and regression throughout life. While proper progression of the hair cycle requires homeostatic interplay between the HF and its immune microenvironment, specific parts of the HF, such as the bulge throughout the hair cycle and the bulb in the anagen phase, maintain relative immune privilege (IP). When this IP collapses, inflammatory infiltrates that aggregate around the bulge and bulb launch an immune attack on the HF, resulting in hair loss or alopecia. Alopecia areata (AA) and primary cicatricial alopecia (PCA) are two common forms of immune-mediated alopecias, and recent advancements in understanding their disease mechanisms have accelerated the discovery of novel treatments for immune-mediated alopecias, specifically AA. In this review, we highlight the pathomechanisms involved in both AA and CA in hopes that a deeper understanding of their underlying disease pathogenesis will encourage the development of more effective treatments that can target distinct disease pathways with greater specificity while minimizing adverse effects.
- Published
- 2019
31. Tissue engineering of human hair follicles using a biomimetic developmental approach
- Author
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Angela M. Christiano, Colin A.B. Jahoda, Hasan E. Abaci, Joanna Jacków, A. Coffman, Z. Guo, Etienne C. E. Wang, J.C. Chen, J. Shin, and Y. Doucet
- Subjects
0301 basic medicine ,Male ,Lymphoid Enhancer-Binding Factor 1 ,Cellular differentiation ,Developmental approach ,Science ,Transplantation, Heterologous ,General Physics and Astronomy ,Heterologous ,Mice, Nude ,Human skin ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Tissue engineering ,Biomimetics ,medicine ,Human Umbilical Vein Endothelial Cells ,otorhinolaryngologic diseases ,Animals ,Humans ,lcsh:Science ,Cells, Cultured ,Multidisciplinary ,Tissue Engineering ,integumentary system ,Alopecia ,Cell Differentiation ,General Chemistry ,Dermis ,3. Good health ,Cell biology ,Transplantation ,030104 developmental biology ,Dermal papillae ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Human hair growth ,lcsh:Q ,sense organs ,Hair Follicle - Abstract
Human skin constructs (HSCs) have the potential to provide an effective therapy for patients with significant skin injuries and to enable human-relevant drug screening for skin diseases; however, the incorporation of engineered skin appendages, such as hair follicles (HFs), into HSCs remains a major challenge. Here, we demonstrate a biomimetic approach for generation of human HFs within HSCs by recapitulating the physiological 3D organization of cells in the HF microenvironment using 3D-printed molds. Overexpression of Lef-1 in dermal papilla cells (DPC) restores the intact DPC transcriptional signature and significantly enhances the efficiency of HF differentiation in HSCs. Furthermore, vascularization of hair-bearing HSCs prior to engraftment allows for efficient human hair growth in immunodeficient mice. The ability to regenerate an entire HF from cultured human cells will have a transformative impact on the medical management of different types of alopecia, as well as chronic wounds, which represent major unmet medical needs., Human skin constructs hold potential for regenerative medicine, but the incorporation of hair follicles into such constructs is a challenge. Here, the authors use 3D printed molds to pattern hair follicle cell types in a physiological organization, and achieve human hair growth on the back of a mouse.
- Published
- 2018
32. Engineering human skin model innervated with itch sensory neuron-like cells differentiated from induced pluripotent stem cells
- Author
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Hasan E. Abaci, Chi-Kun Tong, Y. Doucet, D. Delorenzo, R. Hayashi, Zongyou Guo, Joanna Jacków, Angela M. Christiano, Avina Rami, Corey Hansen, Alberto Pappalardo, Ellen A. Lumpkin, and Wangyong Zeng
- Subjects
skin ,integumentary system ,atopic dermatitis ,Biomedical Engineering ,Pharmaceutical Science ,iPSCs ,Human skin ,Atopic dermatitis ,RM1-950 ,Biology ,medicine.disease ,innervation ,Sensory neuron ,medicine.anatomical_structure ,Chemical engineering ,itch ,sensory neurons ,medicine ,TP155-156 ,Therapeutics. Pharmacology ,Induced pluripotent stem cell ,Neuroscience ,TP248.13-248.65 ,Research Articles ,Biotechnology ,Research Article - Abstract
Atopic dermatitis (AD), driven by interleukins (IL‐4/IL‐13), is a chronic inflammatory skin disease characterized by intensive pruritus. However, it is unclear how immune signaling and sensory response pathways cross talk with each other. We differentiated itch sensory neuron‐like cells (ISNLCs) from iPSC lines. These ISNLCs displayed neural markers and action potentials and responded specifically to itch‐specific stimuli. These ISNLCs expressed receptors specific for IL‐4/IL‐13 and were activated directly by the two cytokines. We successfully innervated these ISNLCs into full thickness human skin constructs. These innervated skin grafts can be used in clinical applications such as wound healing. Moreover, the availability of such innervated skin models will be valuable to develop drugs to treat skin diseases such as AD.
- Published
- 2021
33. Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata
- Author
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James Ming Chen, Yuqian Chang, Angela M. Christiano, and Z. Dai
- Subjects
0301 basic medicine ,Ruxolitinib ,Alopecia Areata ,Pyridines ,Administration, Topical ,T cells ,Autoimmunity ,CD8-Positive T-Lymphocytes ,stat ,03 medical and health sciences ,0302 clinical medicine ,Piperidines ,Nitriles ,medicine ,Animals ,Pyrroles ,Protein Kinase Inhibitors ,Skin ,Inflammation ,Mice, Inbred C3H ,Tofacitinib ,Chemistry ,Macrophages ,JAK-STAT signaling pathway ,Janus Kinase 3 ,General Medicine ,Janus Kinase 1 ,Alopecia areata ,Janus Kinase 2 ,Triazoles ,medicine.disease ,Hair follicle ,030104 developmental biology ,medicine.anatomical_structure ,Pyrimidines ,NK Cell Lectin-Like Receptor Subfamily K ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,Azetidines ,Cytokines ,Pyrazoles ,Signal transduction ,Isonicotinic Acids ,Janus kinase ,medicine.drug ,Research Article - Abstract
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) are key intracellular mediators in the signal transduction of many cytokines and growth factors. Common γ chain cytokines and interferon-γ that use the JAK/STAT pathway to induce biological responses have been implicated in the pathogenesis of alopecia areata (AA), a T cell–mediated autoimmune disease of the hair follicle. We previously showed that therapeutic targeting of JAK/STAT pathways using the first-generation JAK1/2 inhibitor, ruxolitinib, and the pan-JAK inhibitor, tofacitinib, was highly effective in the treatment of human AA, as well as prevention and reversal of AA in the C3H/HeJ mouse model. To better define the role of individual JAKs in the pathogenesis of AA, in this study, we tested and compared the efficacy of several next-generation JAK-selective inhibitors in the C3H/HeJ mouse model of AA, using both systemic and topical delivery. We found that JAK1-selective inhibitors as well as JAK3-selective inhibitors robustly induced hair regrowth and decreased AA-associated inflammation, whereas several JAK2-selective inhibitors failed to restore hair growth in treated C3H/HeJ mice with AA. Unlike JAK1, which is broadly expressed in many tissues, JAK3 expression is largely restricted to hematopoietic cells. Our study demonstrates inhibiting JAK3 signaling is sufficient to prevent and reverse disease in the preclinical model of AA.
- Published
- 2021
34. A semisupervised model to predict regulatory effects of genetic variants at single nucleotide resolution using massively parallel reporter assays
- Author
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Zikun Yang, Iuliana Ionita-Laza, Lynn Petukhova, S. Erjavec, Angela M. Christiano, and Chen Wang
- Subjects
Statistics and Probability ,Locus (genetics) ,Context (language use) ,Genome-wide association study ,Computational biology ,Biology ,Biochemistry ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Nucleotide ,Epigenetics ,Enhancer ,Molecular Biology ,Massively parallel ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Haplotype ,Original Papers ,Computer Science Applications ,Computational Mathematics ,Computational Theory and Mathematics ,chemistry ,Functional genomics ,030217 neurology & neurosurgery - Abstract
Motivation Predicting regulatory effects of genetic variants is a challenging but important problem in functional genomics. Given the relatively low sensitivity of functional assays, and the pervasiveness of class imbalance in functional genomic data, popular statistical prediction models can sharply underestimate the probability of a regulatory effect. We describe here the presence-only model (PO-EN), a type of semisupervised model, to predict regulatory effects of genetic variants at sequence-level resolution in a context of interest by integrating a large number of epigenetic features and massively parallel reporter assays (MPRAs). Results Using experimental data from a variety of MPRAs we show that the presence-only model produces better calibrated predicted probabilities and has increased accuracy relative to state-of-the-art prediction models. Furthermore, we show that the predictions based on pretrained PO-EN models are useful for prioritizing functional variants among candidate eQTLs and significant SNPs at GWAS loci. In particular, for the costimulatory locus, associated with multiple autoimmune diseases, we show evidence of a regulatory variant residing in an enhancer 24.4 kb downstream of CTLA4, with evidence from capture Hi-C of interaction with CTLA4. Furthermore, the risk allele of the regulatory variant is on the same risk increasing haplotype as a functional coding variant in exon 1 of CTLA4, suggesting that the regulatory variant acts jointly with the coding variant leading to increased risk to disease. Availability and implementation The presence-only model is implemented in the R package ‘PO.EN’, freely available on CRAN. A vignette describing a detailed demonstration of using the proposed PO-EN model can be found on github at https://github.com/Iuliana-Ionita-Laza/PO.EN/ Supplementary information Supplementary data are available at Bioinformatics online.
- Published
- 2021
35. Immunogenic Catagen Initiates Alopecia Areata
- Author
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Jin Yong Kim and Angela M. Christiano
- Subjects
History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2021
36. Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression
- Author
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Alan J. Korman, Angela M. Christiano, Corey Hansen, Karen S. Sfanos, Janielle P. Maynard, Paula J. Hurley, Matthew G. Chaimowitz, Charles G. Drake, Charles J. Bieberich, Angelo M. De Marzo, Zoila A. Lopez-Bujanda, Radhika A. Patel, Joanna Jacków, Nivedita Chowdhury, Mark J. Selby, Nicholas J. Venturini, Aleksandar Obradovic, Michael C. Haffner, and Cory Abate-Shen
- Subjects
Male ,Cancer Research ,medicine.medical_treatment ,Prostate cancer ,Mice ,Castration Resistance ,Prostate ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Castration ,business.industry ,Myeloid-Derived Suppressor Cells ,Interleukin-8 ,Prostatic Neoplasms ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Blockade ,medicine.anatomical_structure ,Oncology ,Tumor progression ,Cancer research ,business - Abstract
Unlike several other tumor types, prostate cancer rarely responds to immune checkpoint blockade (ICB). To define tumor cell intrinsic factors that contribute to prostate cancer progression and resistance to ICB, we analyzed prostate cancer epithelial cells from castration-sensitive and -resistant samples using implanted tumors, cell lines, transgenic models and human tissue. We found that castration resulted in increased expression of interleukin-8 (IL-8) and its probable murine homolog Cxcl15 in prostate epithelial cells. We showed that these chemokines drove subsequent intratumoral infiltration of tumor-promoting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was largely abrogated when IL-8 signaling was blocked genetically or pharmacologically. Targeting IL-8 signaling in combination with ICB delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Our findings establish a novel mechanism by which castration mediates IL-8 secretion and subsequent PMN-MDSC infiltration, and highlight blockade of the IL-8/CXCR2 axis as a potential therapeutic intervention. Drake and colleagues demonstrate that castration in prostate cancer models promotes IL-8 secretion and immunosuppressive myeloid-derived suppressor cell migration, and that inhibiting this axis in combination with checkpoint blockade can mitigate tumor progression.
- Published
- 2020
37. Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82
- Author
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Stephanie O, Erjavec, Sahar, Gelfman, Alexa R, Abdelaziz, Eunice Y, Lee, Isha, Monga, Anna, Alkelai, Iuliana, Ionita-Laza, Lynn, Petukhova, and Angela M, Christiano
- Subjects
Keratins, Type II ,Alopecia Areata ,Keratins, Hair-Specific ,Exome Sequencing ,Genetic Variation ,Humans ,Genetic Predisposition to Disease ,Hair Follicle ,Hair ,Skin - Abstract
Alopecia areata is a complex genetic disease that results in hair loss due to the autoimmune-mediated attack of the hair follicle. We previously defined a role for both rare and common variants in our earlier GWAS and linkage studies. Here, we identify rare variants contributing to Alopecia Areata using a whole exome sequencing and gene-level burden analyses approach on 849 Alopecia Areata patients compared to 15,640 controls. KRT82 is identified as an Alopecia Areata risk gene with rare damaging variants in 51 heterozygous Alopecia Areata individuals (6.01%), achieving genome-wide significance (p = 2.18E-07). KRT82 encodes a hair-specific type II keratin that is exclusively expressed in the hair shaft cuticle during anagen phase, and its expression is decreased in Alopecia Areata patient skin and hair follicles. Finally, we find that cases with an identified damaging KRT82 variant and reduced KRT82 expression have elevated perifollicular CD8 infiltrates. In this work, we utilize whole exome sequencing to successfully identify a significant Alopecia Areata disease-relevant gene, KRT82, and reveal a proposed mechanism for rare variant predisposition leading to disrupted hair shaft integrity.
- Published
- 2020
38. Apcdd1 is a dual BMP/Wnt inhibitor in the developing nervous system and skin
- Author
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Etienne C. E. Wang, Keith D. Phan, Lăcrimioara Iancu, Gina M. DeStefano, Victor Luria, Amir Karger, John W. Cain, Jessica A. Weber, Neha Bhat, Bruce B. Riley, Anne H. O’Donnell-Luria, Samantha J. Butler, Angela M. Christiano, Alin Vonica, and Jinbai Guo
- Subjects
Embryo, Nonmammalian ,animal structures ,Mouse ,Xenopus ,1.1 Normal biological development and functioning ,Biology ,Xenopus Proteins ,Bi-functional protein ,Bone morphogenetic protein ,Medical and Health Sciences ,Article ,03 medical and health sciences ,Xenopus laevis ,0302 clinical medicine ,Protein Domains ,Underpinning research ,Wnt inhibitor ,Animals ,Gene ,Molecular Biology ,Zebrafish ,Wnt Signaling Pathway ,Apcdd1 ,030304 developmental biology ,Body Patterning ,0303 health sciences ,Wnt and BMP signaling Inhibitor ,Nonmammalian ,Membrane Glycoproteins ,Embryogenesis ,Wnt signaling pathway ,Cell Biology ,Biological Sciences ,biology.organism_classification ,Chicken ,Cell biology ,Embryo ,Bone Morphogenetic Proteins ,Embryonic development ,Signal transduction ,030217 neurology & neurosurgery ,Intracellular ,Homeostasis ,Biotechnology ,Developmental Biology - Abstract
Animal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling, here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish, and humans. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways central to animal development and human disease.Significance StatementApcdd1is a taxon-restricted gene that inhibits both BMP and Wnt intercellular signaling pathways in multiple organisms including mice, frog, zebrafish, and chicken. It encodes a bi-functional protein with a novel protein domain that can bind to Wnt and BMP receptors and block downstream signaling.
- Published
- 2020
39. Blockade of IL-7 signaling suppresses inflammatory responses and reverses alopecia areata in C3H/HeJ mice
- Author
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Eddy Hsi Chun Wang, Eunice Yoojin Lee, Lynn Petukhova, Z. Dai, Yuqian Chang, and Angela M. Christiano
- Subjects
Autoimmune disease ,0303 health sciences ,Multidisciplinary ,business.industry ,T cell ,Therapeutic effect ,Low dose ,Alopecia areata ,medicine.disease ,Hair follicle ,Blockade ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Cancer research ,Signal transduction ,business ,030304 developmental biology ,030215 immunology - Abstract
The interleukin-7 (IL-7) signaling pathway plays an important role in regulation of T cell function and survival. We detected overexpression of IL-7 in lesional skin from both humans and C3H/HeJ mice with alopecia areata (AA), a T cell-mediated autoimmune disease of the hair follicle. We found that exogenous IL-7 accelerated the onset of AA by augmenting the expansion of alopecic T cells. Conversely, blockade of IL-7 stopped the progression of AA and reversed early AA in C3H/HeJ mice. Mechanistically, we observed that IL-7Rα blockade substantially reduced the total number of most T cell subsets, but relative sparing of regulatory T cells (Tregs). We postulated that short-term anti-IL-7Rα treatment in combination with a low dose of Treg-tropic cytokines might improve therapeutic efficacy in AA. We demonstrated that short-term IL-7Rα blockade in combination with low doses of Treg-tropic cytokines enhanced therapeutic effects in the treatment of AA, and invite further clinical investigation.
- Published
- 2020
40. Medical comorbidities and sex distribution among patients with lichen planopilaris and frontal fibrosing alopecia: A retrospective cohort study
- Author
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Dahsan Gary, Fabian Jenkins, Megan H. Trager, Eunice Y. Lee, Lindsey Bordone, Angela M. Christiano, and Jonathan Lavian
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Dermatology ,Comorbidity ,Young Adult ,medicine ,Humans ,Forehead ,Sex Distribution ,Child ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Frontal fibrosing alopecia ,Gender distribution ,Lichen Planus ,Infant ,Retrospective cohort study ,Alopecia ,Middle Aged ,medicine.disease ,Lichen planopilaris ,Fibrosis ,Child, Preschool ,Female ,business ,Hair Follicle - Published
- 2020
41. Authors’ reply to: Comment on the article by Dr. Toshima about alopecia areata multiplex following autologous dermal micrograft injection
- Author
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Angela M. Christiano, Yuichi Kurihara, Y. Hayashi, Noriko Umegaki-Arao, S. Toshima, E.H.C. Wang, Hisashi Nomura, and Masayuki Amagai
- Subjects
medicine.medical_specialty ,Alopecia Areata ,business.industry ,MEDLINE ,Dermis ,Dermatology ,Alopecia areata ,Administration, Cutaneous ,medicine.disease ,Injections ,Infectious Diseases ,medicine.anatomical_structure ,Humans ,Medicine ,Multiplex ,business - Published
- 2020
42. JAK Inhibitors for Treatment of Alopecia Areata
- Author
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Eddy Hsi Chun Wang, Angela M. Christiano, Christina I. Tejeda, and B. Sallee
- Subjects
0301 basic medicine ,Drug ,Moderate to severe ,Alopecia Areata ,media_common.quotation_subject ,Dermatology ,Biochemistry ,Article ,Pathogenesis ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Janus Kinase Inhibitors ,In patient ,Molecular Biology ,Janus Kinases ,media_common ,business.industry ,Cell Biology ,Alopecia areata ,medicine.disease ,030104 developmental biology ,Hair loss ,Cancer research ,business - Abstract
The advancement of genetic and preclinical studies has uncovered the mechanisms involved in the pathogenesis of alopecia areata (AA). The development of targeted therapies using small molecules blocking specific pathways for the treatment of AA is underway. By repurposing Food and Drug Administration-approved small molecule JAK inhibitors as treatments for AA, it has been demonstrated that JAK inhibitors can effectively reverse hair loss in patients with moderate to severe AA. In this review, we summarize and discuss the current preclinical and clinical studies on JAK inhibitors, as well as the prospects of using JAK inhibitors for the treatment of AA.
- Published
- 2018
43. Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome
- Author
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Ambra Sartori, Angela M. Christiano, Lars E. French, Sandra S. Ring, Wolfram Jochum, Rebecca Higgins, Lukas Flatz, Daniel Hohl, Sergey Nikolaev, David Bomze, F.R. Fritzsche, Fabienne Hartmann, O. Hasan Ali, Arianna L. Kim, Andrey A. Yurchenko, Emmanouil T. Dermitzakis, Alexander A. Navarini, D. Bühler, O. Pavlova, and D.R. Bickers
- Subjects
0301 basic medicine ,Adult ,Male ,Patched Receptors ,endocrine system ,Skin Neoplasms ,Nevoid basal-cell carcinoma syndrome ,Dermatology ,medicine.disease_cause ,Article ,Loss of heterozygosity ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Medicine ,Humans ,Basal cell carcinoma ,Exome sequencing ,Mutation ,business.industry ,Siblings ,Haplotype ,Genetic disorder ,Basal Cell Nevus Syndrome ,Genomics ,medicine.disease ,3. Good health ,Patched-1 Receptor ,stomatognathic diseases ,030104 developmental biology ,Infectious Diseases ,Carcinoma, Basal Cell ,Cancer research ,business - Abstract
Background Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases NBCCS presents with a late onset of BCC development. Objective To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after 40 years of age. Two other siblings did not show signs of NBCCS. Results We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed Loss of Heterozygosity (LOH) of PTCH1 in eight out of nine tumors that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice-site mutation in PTCH1 (NM_001083605:exon9:c.763-6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harbored additional somatic loss-of-function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumor mutational burden (TMB) compared to BCCs of unrelated NBCCS patients while harboring a higher number of damaging PTCH1 mutations. Conclusions Our data suggests that a sequence of three genetic hits lead to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS.
- Published
- 2019
44. Production-scale fibronectin nanofibers promote wound closure and tissue repair in a dermal mouse model
- Author
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Jeffrey W. Ruberti, Sean P. Sheehy, Hasan E. Abaci, Jeffrey A. Paten, Leila F. Deravi, Simon P. Hoerstrup, Benjamin D. Pope, Karl Gledhill, Andrew K. Capulli, Kevin Kit Parker, Adrian T. Buganza, Y. Doucet, Patrick H. Campbell, Angela M. Christiano, Christophe O. Chantre, Stephanie Dauth, Seungkuk Ahn, Holly M. Golecki, University of Zurich, and Parker, Kevin Kit
- Subjects
Male ,0301 basic medicine ,Nanofibers ,Biophysics ,Adipose tissue ,610 Medicine & health ,2503 Ceramics and Composites ,Biocompatible Materials ,Bioengineering ,02 engineering and technology ,Administration, Cutaneous ,Regenerative medicine ,Article ,Biomaterials ,Extracellular matrix ,Mice ,03 medical and health sciences ,2211 Mechanics of Materials ,Tissue engineering ,Animals ,Skin ,Wound Healing ,1502 Bioengineering ,Tissue Engineering ,Tissue Scaffolds ,integumentary system ,biology ,Chemistry ,2502 Biomaterials ,Fibrillogenesis ,11359 Institute for Regenerative Medicine (IREM) ,021001 nanoscience & nanotechnology ,Fibronectins ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,Fibronectin ,030104 developmental biology ,Mechanics of Materials ,Nanofiber ,Ceramics and Composites ,biology.protein ,0210 nano-technology ,Wound healing ,1304 Biophysics - Abstract
Wounds in the fetus can heal without scarring. Consequently, biomaterials that attempt to recapitulate the biophysical and biochemical properties of fetal skin have emerged as promising pro-regenerative strategies. The extracellular matrix (ECM) protein fibronectin (Fn) in particular is believed to play a crucial role in directing this regenerative phenotype. Accordingly, Fn has been implicated in numerous wound healing studies, yet remains untested in its fibrillar conformation as found in fetal skin. Here, we show that high extensional (~1.2 × 10(5) s(−1)) and shear (~3 × 10(5) s(−1)) strain rates in rotary jet spinning (RJS) can drive high throughput Fn fibrillogenesis (~10 mL/min), thus producing nano fiber scaffolds that are used to effectively enhance wound healing. When tested on a full-thickness wound mouse model, Fn nanofiber dressings not only accelerated wound closure, but also significantly improved tissue restoration, recovering dermal and epidermal structures as well as skin appendages and adipose tissue. Together, these results suggest that bioprotein nanofiber fabrication via RJS could set a new paradigm for enhancing wound healing and may thus find use in a variety of regenerative medicine applications.
- Published
- 2018
45. Cicatricial Alopecia Research Foundation meeting, May 2016: Progress towards the diagnosis, treatment and cure of primary cicatricial alopecias
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Maria K. Hordinsky, Lloyd E. King, Raja K Sivamani, Craig Herbert Pratt, John P. Sundberg, Kurt S. Stenn, Angela M. Christiano, Tracy L. McGregor, Yolanda M. Lenzy, Amy J. McMichael, and Wilma F. Bergfeld
- Subjects
Central centrifugal cicatricial alopecia ,medicine.medical_specialty ,integumentary system ,business.industry ,Frontal fibrosing alopecia ,Dermatology ,Fibrous tissue ,Normal hair growth ,medicine.disease ,Lichen planopilaris ,Biochemistry ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Hair loss ,Diagnosis treatment ,030220 oncology & carcinogenesis ,Medicine ,business ,Molecular Biology ,Clinical evaluation - Abstract
Primary cicatricial alopecias (PCAs) are a group of skin diseases in which there is progressive and permanent destruction of hair follicles followed by replacement with fibrous tissue. Unfortunately, by the time patients seek clinical evaluation of their hair loss, the skin is already inflamed and/or scarred, so there is little hope for a return to their normal hair growth pattern. Clinical and basic science investigations are now focusing on three forms of human PCA: lichen planopilaris (LPP), frontal fibrosing alopecia (FFA) and central centrifugal cicatricial alopecia (CCCA). Transcriptome, lipidome and other new technologies are providing new insight into the pathogenesis of some of these diseases that are being validated and further investigated using spontaneous and genetically engineered mouse models.
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- 2018
46. Genome-Wide MicroRNA Analysis Implicates miR-30b/d in the Etiology of Alopecia Areata
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Roland Kruse, Silke Redler, Markus Böhm, Bettina Blaumeiser, Lynn Petukhova, Ulrike Blume-Peytavi, Markus M. Nöthen, Angela M. Christiano, Natalie Garcia Bartels, Hans Wolff, Andreas J. Forstner, Andrea Hofmann, David Broadley, Gerhard Lutz, Hermona Soreq, Alfredo De Rossi, Kathrin A. Giehl, Natalia V. Botchkareva, Aylar Tafazzoli, Regina C. Betz, and Marta Bertolini
- Subjects
0301 basic medicine ,Alopecia Areata ,Genome-wide association study ,Single-nucleotide polymorphism ,Dermatology ,Biology ,Biochemistry ,03 medical and health sciences ,Molecular Biology ,2708 ,Cell Biology ,microRNA ,medicine ,Humans ,SNP ,Gene ,Genetic association ,Genetics ,Qa-SNARE Proteins ,Interleukin-2 Receptor alpha Subunit ,Tenascin ,Alopecia areata ,medicine.disease ,MicroRNAs ,HEK293 Cells ,030104 developmental biology ,Hair loss ,Cancer research ,Human medicine ,Genome-Wide Association Study - Abstract
Alopecia areata (AA) is one of the most common forms of human hair loss. Although genetic studies have implicated autoimmune processes in AA etiology, understanding of the etiopathogenesis is incomplete. Recent research has implicated microRNAs, a class of small noncoding RNAs, in diverse autoimmune diseases. To our knowledge, no study has investigated the role of microRNAs in AA. In this study, gene-based analyses were performed for microRNAs using data of the largest genome-wide association meta-analysis of AA to date. Nominally, significant P-values were obtained for 78 of the 617 investigated microRNAs. After correction for multiple testing, three of the 78 microRNAs remained significant. Of these, miR-30b/d was the most significant microRNA for the follow-up analyses, which also showed lower expression in the hair follicle of AA patients. Target gene analyses for the three microRNAs showed 42 significantly associated target genes. These included IL2RA, TNXB, and ERBB3, which had been identified as susceptibility loci in previous genome-wide association studies. Using luciferase assay, site-specific miR-30b regulation of the AA risk genes IL2RA, STX17, and TNXB was validated. This study implicates microRNAs in the pathogenesis of AA. This finding may facilitate the development of future treatment strategies.
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- 2018
47. Novel therapies for alopecia areata: The era of rational drug development
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Angela M. Christiano, Etienne C. E. Wang, and Z. Dai
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0301 basic medicine ,medicine.medical_specialty ,Alopecia Areata ,business.industry ,Immunology ,Disease ,Alopecia areata ,Pharmacology ,medicine.disease ,030207 dermatology & venereal diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Drug Development ,Drug development ,Cytotoxic T-Lymphocyte-Associated Antigen 4 ,Alopecia universalis ,Humans ,Immunology and Allergy ,Medicine ,Personalized medicine ,skin and connective tissue diseases ,business ,Intensive care medicine - Abstract
Treatments for alopecia areata (AA) have evolved over the decades from broad and nonspecific therapies to those that are now more targeted and rationally selected. This was achieved by means of close cooperation and communication between clinicians and basic scientists, which resulted in the elucidation and understanding of the unique pathophysiology of AA. In this review we discuss this evolution and how novel therapies for AA have changed over the decades, what we have in our current arsenal of drugs for this potentially devastating disease, and what the future holds.
- Published
- 2018
48. Childhood alopecia areata-Data from the National Alopecia Areata Registry
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Vera H. Price, Madeleine Duvic, Iris Wohlmuth-Wieser, David A. Norris, Joyce S. Osei, Angela M. Christiano, and Maria K. Hordinsky
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Alopecia Areata ,Physical examination ,Comorbidity ,Dermatology ,Disease ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,Prevalence ,medicine ,Humans ,Registries ,Family history ,Child ,skin and connective tissue diseases ,integumentary system ,medicine.diagnostic_test ,business.industry ,Atopic dermatitis ,Alopecia areata ,medicine.disease ,United States ,body regions ,Child, Preschool ,030220 oncology & carcinogenesis ,Hair Disorder ,Pediatrics, Perinatology and Child Health ,Female ,Differential diagnosis ,business ,Congenital Alopecia - Abstract
Background/objectives Alopecia areata may occur at any age and is the third-most-common dermatosis in children. The objective of this study was to investigate the clinical and epidemiologic features of children and adolescents with alopecia areata based on the data of the National Alopecia Areata registry on children and adolescents. Methods Two thousand two hundred eighteen children and adolescents with alopecia areata self-enrolled in the National Alopecia Areata Registry and completed a web-based, self-administered, short-intake screening questionnaire (first tier). In the second tier, 643 patients participated in a clinical examination and completed a long-form questionnaire. Results Mean age of onset was 5.9 ± 4.1 years. With a female to male ratio of 1.5:1, alopecia areata was more prevalent in girls, but boys were significantly more likely to have a severe type (P = .009). One-fourth of all children had a positive family history, with 8% having more than three affected relatives. The disease most commonly associated with alopecia areata was atopic dermatitis (32.7%). Conclusion Childhood alopecia areata is more prevalent in girls than in boys, but boys have more extensive alopecia areata. Despite the low prevalence, congenital alopecia areata is an important differential diagnosis for neonatal hair loss. Alopecia areata runs in families, suggesting an underlying genetic background. One-quarter of the children reported at least one affected first-degree relative; 8% had more than three affected relatives.
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- 2018
49. Alopecia areata
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Angela M. Christiano, Jerry Shapiro, Nooshin Brinster, Lauren C. Strazzulla, Lorena Avila, Kristen Lo Sicco, and Eddy Hsi Chun Wang
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0301 basic medicine ,medicine.medical_specialty ,Disease ,Dermatology ,Syntaxin 17 ,030207 dermatology & venereal diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Quality of life (healthcare) ,Continuing medical education ,Severity of illness ,Medicine ,Intensive care medicine ,Diphenylcyclopropenone ,Modalities ,integumentary system ,business.industry ,Alopecia totalis ,Alopecia areata ,Hair follicle ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Hair loss ,chemistry ,Scalp ,030220 oncology & carcinogenesis ,Alopecia universalis ,business - Abstract
Alopecia areata (AA) is a common, inflammatory, nonscarring type of hair loss. Significant variations in the clinical presentation of AA have been observed, ranging from small, well-circumscribed patches of hair loss to a complete absence of body and scalp hair. Patients affected by AA encompass all age groups, sexes, and ethnicities, and may experience frustration with the unpredictable nature of their disease for which there is currently no definitive treatment. The cause of AA remains incompletely understood, though it is believed to result—at least in part—from a loss of immune privilege in the hair follicle, autoimmune-mediated hair follicle destruction, and the upregulation of inflammatory pathways. Patients with AA frequently experience marked impairment in psychological well-being, self-esteem, and may be more likely to suffer from psychiatric comorbidities. Part one of this two-part continuing medical education series describes the epidemiology, clinical evaluation, prognosis, and recent advancements in the understanding of the pathogenesis of AA.
- Published
- 2018
50. Building and Crossing the Translational Bridge: 2016 Alopecia Areata Research Summit Highlights
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Angela M. Christiano, Natasha Atanaskova Mesinkovska, Abby Ellison, John E. Harris, Maria K. Hordinsky, and Dory Kranz
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Nonprofit organization ,geography ,Summit ,geography.geographical_feature_category ,Extramural ,business.industry ,Strategic Initiative ,Treatment development ,Cell Biology ,Dermatology ,General Medicine ,Alopecia areata ,Public relations ,Autoimmune skin disease ,medicine.disease ,Political science ,medicine ,business ,Molecular Biology ,Biotechnology - Abstract
Alopecia areata (AA) is a common autoimmune skin disease that results in the loss of hair on the scalp and elsewhere on the body and affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National Alopecia Areata Foundation is a nonprofit organization that supports research to find a cure or acceptable treatment for AA, supports those with the disease, and educates the public about AA. The National Alopecia Areata Foundation conducts research summits every 2 years to review progress and create new directions in its funded and promoted research. The Foundation brings together scientists from all disciplines to get a broad and varied perspective. These AA research summits are part of the Foundation's main strategic initiative, the AA Treatment Development Program, to enhance the understanding of AA and accelerate progress toward a viable treatment.
- Published
- 2018
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