Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Arthritis Rheumatol ; 75(10): 1842-1849, 2023 10.
Article in English | MEDLINE | ID: mdl-37096447

ABSTRACT

OBJECTIVE: The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. METHODS: RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. RESULTS: The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84-0.95). CONCLUSION: The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.


Subject(s)
Dermatomyositis , Interferon Type I , Adult , Humans , Cross-Sectional Studies , Interferon Type I/genetics , Skin/metabolism , Interferon-Induced Helicase, IFIH1 , Autoantibodies
3.
J Invest Dermatol ; 141(12): 2876-2884.e4, 2021 12.
Article in English | MEDLINE | ID: mdl-34116063

ABSTRACT

Pachyonychia congenita (PC) is a genetic disorder of keratin that presents with nail dystrophy, painful palmoplantar keratoderma, and other clinical manifestations. We investigated the genotype‒structurotype‒phenotype correlations seen with mutations in keratin genes (keratin [K]6A, K6B, K6C, K16, K17) and utilized protein structure modeling of high-frequency mutations to examine the functional importance of keratin structural domains in PC pathogenesis. Participants of the International PC Research Registry underwent genetic testing and completed a standardized survey on their symptoms. Our results support previous reports associating oral leukokeratosis with K6A mutations and cutaneous cysts, follicular hyperkeratosis, and natal teeth with K17 mutations. Painful keratoderma was prominent with K6A and K16 mutations. Nail involvement was most common in patients with K6A mutation and least common in those with K6C mutation. Across keratin subtypes, patients with coil 2B mutations had the greatest impairment in ambulation, and patients with coil 1A mutations reported more emotional issues. Molecular modeling demonstrated that hotspot missense mutations in PC largely disrupted hydrophobic interactions or surface charge. The former may destabilize keratin dimers/tetramers, whereas the latter likely interferes with higher-order keratin filament formation. Understanding the pathologic alterations in keratin structure improves our knowledge of how PC genotype correlates with clinical phenotype, advancing insight into disease pathogenesis and therapeutic development.


Subject(s)
Genetic Association Studies , Keratins/genetics , Mutation , Pachyonychia Congenita/genetics , Humans , Keratin-16/genetics , Keratin-17/genetics , Keratin-6/genetics , Models, Molecular , Pachyonychia Congenita/psychology
4.
Neoreviews ; 22(1): e40-e51, 2021 01.
Article in English | MEDLINE | ID: mdl-33386313

ABSTRACT

The objective of this review is to help practitioners of neonatal and pediatric medicine become more familiar with diagnosing and managing neonatal skin conditions. This article will discuss normal neonatal skin care and benign and common rashes, as well as some of the serious dermatologic conditions that require specialists for further evaluation and/or treatment.


Subject(s)
Dermatology , Exanthema , Infant, Newborn, Diseases , Skin Diseases , Humans , Infant, Newborn , Infant, Newborn, Diseases/diagnosis , Infant, Newborn, Diseases/therapy , Skin Diseases/diagnosis , Skin Diseases/epidemiology , Skin Diseases/therapy
5.
Pediatr Dermatol ; 37(6): 1171-1172, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32970342

ABSTRACT

Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.


Subject(s)
Eosinophilia , Fasciitis , Adrenal Cortex Hormones , Child , Eosinophilia/drug therapy , Fasciitis/diagnosis , Fasciitis/drug therapy , Humans , Imatinib Mesylate/therapeutic use , Male
6.
Mol Biol Cell ; 28(2): 270-284, 2017 01 15.
Article in English | MEDLINE | ID: mdl-27881664

ABSTRACT

The endoplasmic reticulum (ER) mediates the folding, maturation, and deployment of the secretory proteome. Proteins that fail to achieve their native conformation are retained in the ER and targeted for clearance by ER-associated degradation (ERAD), a sophisticated process that mediates the ubiquitin-dependent delivery of substrates to the 26S proteasome for proteolysis. Recent findings indicate that inhibition of long-chain acyl-CoA synthetases with triacsin C, a fatty acid analogue, impairs lipid droplet (LD) biogenesis and ERAD, suggesting a role for LDs in ERAD. However, whether LDs are involved in the ERAD process remains an outstanding question. Using chemical and genetic approaches to disrupt diacylglycerol acyltransferase (DGAT)-dependent LD biogenesis, we provide evidence that LDs are dispensable for ERAD in mammalian cells. Instead, our results suggest that triacsin C causes global alterations in the cellular lipid landscape that disrupt ER proteostasis by interfering with the glycan trimming and dislocation steps of ERAD. Prolonged triacsin C treatment activates both the IRE1 and PERK branches of the unfolded protein response and ultimately leads to IRE1-dependent cell death. These findings identify an intimate relationship between fatty acid metabolism and ER proteostasis that influences cell viability.


Subject(s)
Endoplasmic Reticulum/metabolism , Lipid Droplets/physiology , Animals , Cell Line , Diacylglycerol O-Acyltransferase , Endoplasmic Reticulum/physiology , Endoplasmic Reticulum-Associated Degradation/physiology , Humans , Lipids/physiology , Membrane Proteins/metabolism , Polysaccharides/metabolism , Proteasome Endopeptidase Complex , Proteolysis , Triazenes , Ubiquitin/metabolism , Ubiquitination/physiology , Unfolded Protein Response/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...