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Given the limited efficacy of clinical approaches that rely on ex vivo generated dendritic cells (DCs), it is imperative to design strategies that harness specialized DC subsets in situ. This requires delineating the expression of surface markers by DC subsets among individuals and tissues. Here, we performed a multiparametric phenotypic characterization and unbiased analysis of human DC subsets in blood, tonsil, spleen, and skin. We uncovered previously unreported phenotypic heterogeneity of human cDC2s among individuals, including variable expression of functional receptors such as CD172a. We found marked differences in DC subsets localized in blood and lymphoid tissues versus skin, and a striking absence of the newly discovered Axl+ DCs in the skin. Finally, we evaluated the capacity of anti-receptor monoclonal antibodies to deliver vaccine components to skin DC subsets. These results offer a promising path for developing DC subset-specific immunotherapies that cannot be provided by transcriptomic analysis alone.
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Antígenos de Diferenciação/imunologia , Variação Biológica Individual , Células Dendríticas/imunologia , Fenótipo , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Imunológicos/imunologia , Pele/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacocinética , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação/genética , Biomarcadores/análise , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/biossíntese , Citofotometria/métodos , Células Dendríticas/citologia , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Imunoterapia , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Especificidade de Órgãos , Tonsila Palatina/citologia , Tonsila Palatina/imunologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/deficiência , Receptores Proteína Tirosina Quinases/genética , Receptores Imunológicos/genética , Pele/citologia , Baço/citologia , Baço/imunologia , Receptor Tirosina Quinase AxlRESUMO
BACKGROUND: Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations in COL7A1, which encodes type VII collagen (C7). Beremagene geperpavec (B-VEC) is a topical investigational herpes simplex virus type 1 (HSV-1)-based gene therapy designed to restore C7 protein by delivering COL7A1. METHODS: We conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain). RESULTS: Primary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P = 0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P<0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was -0.88 with B-VEC and -0.71 with placebo (adjusted least-squares mean difference, -0.61; 95% CI, -1.10 to -0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills. CONCLUSIONS: Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.).
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Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Terapia Genética , Humanos , Administração Tópica , Colágeno Tipo VII/administração & dosagem , Colágeno Tipo VII/efeitos adversos , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/metabolismo , Prurido/induzido quimicamente , Cicatrização/efeitos dos fármacos , Cicatrização/genética , Terapia Genética/efeitos adversos , Terapia Genética/métodosRESUMO
Breast cancer becomes invasive when carcinoma cells invade through the basement membrane (BM)-a nanoporous layer of matrix that physically separates the primary tumour from the stroma. Single cells can invade through nanoporous three-dimensional matrices due to protease-mediated degradation or force-mediated widening of pores via invadopodial protrusions. However, how multiple cells collectively invade through the physiological BM, as they do during breast cancer progression, remains unclear. Here we developed a three-dimensional in vitro model of collective invasion of the BM during breast cancer. We show that cells utilize both proteases and forces-but not invadopodia-to breach the BM. Forces are generated from a combination of global cell volume expansion, which stretches the BM, and local contractile forces that act in the plane of the BM to breach it, allowing invasion. These results uncover a mechanism by which cells collectively interact to overcome a critical barrier to metastasis.
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BACKGROUND: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. OBJECTIVE: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. METHODS: Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. RESULTS: Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P = .002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P = .02), and 5.7-fold greater odds of death compared to medium-impact variants (P = .05). LIMITATIONS: Cross-sectional design. CONCLUSION: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.
Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Estudos de Associação Genética , Humanos , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Masculino , Feminino , Colágeno Tipo VII/genética , Adulto , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Pré-Escolar , Fenótipo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Genótipo , Índice de Gravidade de Doença , Genes RecessivosRESUMO
BACKGROUND: A spectrum of skin disease severity exists in patients with recessive dystrophic epidermolysis bullosa (RDEB). OBJECTIVE: To characterize the patient-reported outcomes and quality of life (QOL) in patients with RDEB. METHODS: A cross-sectional study of patients with RDEB surveyed through the global EBCare Registry. Patient-reported outcomes included skin disease severity, wound characteristics, pain, itch, extracutaneous symptoms, and medications. QOL was measured by using the validated Quality of Life in Epidermolysis Bullosa instrument. RESULTS: A total of 85 patients with RDEB reported 1226 wounds (937 recurrent wounds and 289 chronic open wounds). Overall skin disease severity was self-reported as mild (26%; 22/83), moderate (48%; 40/83), or severe (25%; 21/83). Worsening skin disease severity was significantly associated with larger wounds, increased opiate use, anemia, gastrostomy tube use, infections, osteoporosis, and squamous cell carcinoma. Larger wound size was associated with worse quality of life scores. LIMITATIONS: All data were self-reported from an online epidermolysis bullosa patient registry. CONCLUSIONS: This study shows a significant correlation between larger wound size with worsening skin disease severity and quality of life in participants with RDEB. Worsening skin disease severity significantly correlated with key clinical manifestations. These results show that patients with RDEB are able to self-report their skin disease severity and wounds.
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Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Estudos Transversais , Epidermólise Bolhosa/epidemiologia , Epidermólise Bolhosa/terapia , Epidermólise Bolhosa Distrófica/epidemiologia , Epidermólise Bolhosa Distrófica/terapia , Humanos , Recidiva Local de Neoplasia , Medidas de Resultados Relatados pelo Paciente , Qualidade de VidaRESUMO
INTRODUCTION: Dystrophic epidermolysis bullosa is a debilitating skin condition, without curative treatment. Previous research has focused on the recessive variant, which is known to cause severe disease. Limited work focusing on the clinical manifestations and outcomes of dominant dystrophic epidermolysis bullosa is found (DDEB). METHODS: Analysis of an online survey of 42 DDEB patients. RESULTS: Self-reported severity of disease did not correlate with size of the wound or number of dressing changes, but did correlate with severity of pain reported in the last 12 months (3.4 mild vs 6.8 severe disease, P = 0.0002). Patients with severe DDEB also reported more severe internal disease symptoms, such as difficulty swallowing (62.5%, P = 0.01) and greater analgesic use during dressing changes (4.4% mild vs 81.3% severe, P = <0.001). DISCUSSION: Patient perception of disease severity in DDEB appears to be most impacted by pain, presence of chronic open wounds, difficulty swallowing, difficulty walking, and anal strictures. As research on DDEB increases, future studies focused on these symptoms might be the most impactful for DDEB patients. However, distinguishing DDEB from other subtypes remains a challenge.
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Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Estudos Transversais , Epidermólise Bolhosa/terapia , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/terapia , Humanos , Medidas de Resultados Relatados pelo Paciente , Qualidade de VidaRESUMO
As more therapeutic clinical trials focus on treatment of individual wounds in patients with recessive dystrophic epidermolysis bullosa, it has become crucial to understand the baseline clinical characteristics of these wounds. To investigate these features, we administered an RDEB-specific wound survey. Forty participants reported on location, size, pain, infection frequency, wound type, and duration of 189 wounds; a subset of 22 participants reported on pruritus in 63 wounds. Increased wound size was significantly associated with increased pain, increased pruritus, longer wound duration, increased infection frequency, and patients with mutations resulting in truncated type VII collagen.
Assuntos
Epidermólise Bolhosa Distrófica , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/genética , Humanos , Mutação , CicatrizaçãoRESUMO
In this study, we generated a new set of monoclonal antibodies (mAbs) to bovine and human type VII collagen (COL7) by immunizing mice with bovine cornea-derived basement membrane zone (BMZ) fraction. The four mAbs, tentatively named as COL7-like mAbs, showed speckled subepidermal staining in addition to linear BMZ staining of normal human skin and bovine cornea, a characteristic immunofluorescence feature of COL7, but showed no reactivity with COL7 by in vitro biochemical analyses. Taking advantage of the phenomenon that COL7-like mAbs did not react with mouse BMZ, we compared immunofluorescence reactivity between wild-type and COL7-rescued humanized mice and found that COL7-like mAbs reacted with BMZ of COL7-rescued humanized mice. In ELISAs, COL7-like mAbs reacted with intact triple-helical mammalian recombinant protein (RP) of COL7 but not with bacterial RP. Furthermore, COL7-like mAbs did not react with COL7 within either cultured DJM-1 cells or basal cells of skin of a bullous dermolysis of the newborn patient. These results confirmed that COL7-like mAbs reacted with human and bovine COL7. The epitopes for COL7-like mAbs were considered to be present only on mature COL7 after secretion from keratinocytes and deposition to BMZ and to be easily destroyed during immunoblotting procedure. Additional studies indicated association of the speckled subepidermal staining with both type IV collagen and elastin. These unique anti-COL7 mAbs should be useful in studies of both normal and diseased conditions, particularly dystrophic epidermolysis bullosa, which produces only immature COL7.
Assuntos
Membrana Basal/metabolismo , Colágeno Tipo VII/imunologia , Colágeno Tipo VII/metabolismo , Animais , Anticorpos Monoclonais/biossíntese , Bovinos , Células HEK293 , Humanos , CamundongosRESUMO
BACKGROUND: Bullous dermolysis of the newborn (BDN) is a subtype of dystrophic epidermolysis bullosa (DEB) characterized by skin fragility and blister formation at birth that typically resolves within the first year of life. Abnormal intraepidermal retention of type VII collagen (C7) has been reported as a characteristic feature of BDN, but few studies have investigated the specificity of this finding. METHODS: We retrospectively reviewed pathology reports of patients diagnosed with DEB using immunofluorescence mapping from January 2001 to January 2015. For cases describing intraepidermal accumulation of C7, we collected information on patient characteristics, including genetic testing results, clinical outcome, and concurrent electron microscopy findings, where available. RESULTS: Of the 143 cases of DEB with immunofluorescence mapping, eight patients had intracytoplasmic epidermal retention of C7. Of these eight patients, two were lost to follow-up, four had complete resolution of bullae, and two had marked improvement with rare residual bullae. Concurrent electron microscopic findings available for three patients were consistent with BDN. CONCLUSIONS: Our review of immunofluorescence mapping findings in patients with DEB found that 5.6% had abnormal intracytoplasmic epidermal retention of C7, a finding previously reported in BDN. All such patients with clinical outcomes available had resolution or marked improvement of bullae, consistent with clinical outcomes expected in BDN.
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Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/metabolismo , Pele/patologia , Epidermólise Bolhosa Distrófica/patologia , Feminino , Imunofluorescência/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Microscopia Eletrônica , Estudos RetrospectivosRESUMO
Basement membranes can be a barrier to tumour growth, but basement membrane molecules, including laminins, are also important autocrine factors produced by cancers to promote tumorigenesis. Many studies have shown the importance of laminin 332 (previously known as laminin 5) in this process, especially in squamous cell carcinoma. Through interactions with several cell-surface receptors (including alpha6beta4 and alpha3beta1 integrins, epidermal growth factor receptor and syndecan 1) and other basement membrane components (including type VII collagen), laminin 332 drives tumorigenesis through phosphatidylinositol-3 kinase (PI3K) and RAC1 activation, promoting tumour invasion and cell survival. The extracellular interactions of laminin 332 appear amenable to antibody-mediated therapies.
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Carcinoma de Células Escamosas/metabolismo , Moléculas de Adesão Celular/fisiologia , Laminina/fisiologia , Animais , Adesão Celular , Movimento Celular , Colágeno Tipo VII/metabolismo , Humanos , Laminina/química , Camundongos , Modelos Biológicos , Transdução de Sinais , CalininaRESUMO
Importance: Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating, often fatal, inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. Support and palliation are the only current therapies. Objective: To evaluate the safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with RDEB. Design, Setting, and Participants: Single-center phase 1 clinical trial conducted in the United States of 4 patients with severe RDEB with a measured area of wounds suitable for grafting of at least 100 cm2. Patients with undetectable type VII collagen keratinocyte expression were excluded. Interventions: Autologous keratinocytes isolated from biopsy samples collected from 4 patients with RDEB were transduced with good manufacturing practice-grade retrovirus carrying full-length human COL7A1 and assembled into epidermal sheet grafts. Type VII collagen gene-corrected grafts (approximately 35 cm2) were transplanted onto 6 wounds in each of the patients (n = 24 grafts). Main Outcomes and Measures: The primary safety outcomes were recombination competent retrovirus, cancer, and autoimmune reaction. Molecular correction was assessed as type VII collagen expression measured by immunofluorescence and immunoelectron microscopy. Wound healing was assessed using serial photographs taken at 3, 6, and 12 months after grafting. Results: The 4 patients (mean age, 23 years [range, 18-32 years]) were all male with an estimated body surface area affected with RDEB of 4% to 30%. All 24 grafts were well tolerated without serious adverse events. Type VII collagen expression at the dermal-epidermal junction was demonstrated on the graft sites by immunofluorescence microscopy in 9 of 10 biopsy samples (90%) at 3 months, in 8 of 12 samples (66%) at 6 months, and in 5 of 12 samples (42%) at 12 months, including correct type VII collagen localization to anchoring fibrils. Wounds with recombinant type VII collagen graft sites displayed 75% or greater healing at 3 months (21 intact graft sites of 24 wound sites; 87%), 6 months (16/24; 67%), and 12 months (12/24; 50%) compared with baseline wound sites. Conclusions and Relevance: In this preliminary study of 4 patients with RDEB, there was wound healing in some type VII collagen gene-corrected grafts, but the response was variable among patients and among grafted sites and generally declined over 1 year. Long-term follow-up is necessary for these patients, and controlled trials are needed with a broader range of patients to better understand the potential long-term efficacy of genetically corrected autologous epidermal grafts. Trial Registration: clinicaltrials.gov Identifier: NCT01263379.
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Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/terapia , Técnicas de Transferência de Genes , Queratinócitos/transplante , Cicatrização , Adolescente , Adulto , Colágeno Tipo VII/metabolismo , Colágeno Tipo VII/uso terapêutico , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/metabolismo , Epidermólise Bolhosa Distrófica/patologia , Humanos , Masculino , Vírus da Leucemia Murina de Moloney/genética , Pirimidinas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Retalhos Cirúrgicos , Fatores de Tempo , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/terapia , Adulto JovemRESUMO
Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.
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Penfigoide Mucomembranoso Benigno/diagnóstico , Penfigoide Mucomembranoso Benigno/terapia , Humanos , Guias de Prática Clínica como Assunto , Registros , Resultado do TratamentoAssuntos
Betacoronavirus/imunologia , Consenso , Infecções por Coronavirus/prevenção & controle , Epidermólise Bolhosa/terapia , Pandemias/prevenção & controle , Equipe de Assistência ao Paciente/normas , Pneumonia Viral/prevenção & controle , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Epidermólise Bolhosa/imunologia , Humanos , Comunicação Interdisciplinar , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Guias de Prática Clínica como Assunto , SARS-CoV-2RESUMO
Definitive correction of disease causing mutations in somatic cells by homologous recombination (HR) is an attractive therapeutic approach for the treatment of genetic diseases. However, HR-based somatic gene therapy is limited by the low efficiency of gene targeting in mammalian cells and replicative senescence of primary cells ex vivo, forcing investigators to explore alternative strategies such as retro- and lentiviral gene transfer, or genome editing in induced pluripotent stem cells. Here, we report correction of mutations at the LAMA3 locus in primary keratinocytes derived from a patient affected by recessive inherited Herlitz junctional epidermolysis bullosa (H-JEB) disorder using recombinant adenoassociated virus (rAAV)-mediated HR. We identified a highly recombinogenic AAV serotype, AAV-DJ, that mediates efficient gene targeting in keratinocytes at clinically relevant frequencies with a low rate of random integration. Targeted H-JEB patient cells were selected based on restoration of adhesion phenotype, which eliminated the need for foreign sequences in repaired cells, enhancing the clinical use and safety profile of our approach. Corrected pools of primary cells assembled functional laminin-332 heterotrimer and fully reversed the blistering phenotype both in vitro and in skin grafts. The efficient targeting of the LAMA3 locus by AAV-DJ using phenotypic selection, together with the observed low frequency of off-target events, makes AAV-DJ based somatic cell targeting a promising strategy for ex vivo therapy for this severe and often lethal epithelial disorder.
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Epidermólise Bolhosa Juncional/genética , Terapia Genética/métodos , Recombinação Homóloga/genética , Laminina/genética , Animais , Colágeno Tipo VII/genética , Dependovirus/genética , Epidermólise Bolhosa Juncional/patologia , Epidermólise Bolhosa Juncional/terapia , Xenoenxertos , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , MutaçãoRESUMO
Basement membrane abnormalities have often been observed in kidney cysts of polycystic kidney disease (PKD) patients and animal models. There is an abnormal deposition of extracellular matrix molecules, including laminin-α3,ß3,γ2 (laminin-332), in human autosomal dominant PKD (ADPKD). Knockdown of PKD1 paralogs in zebrafish leads to dysregulated synthesis of the extracellular matrix, suggesting that altered basement membrane assembly may be a primary defect in ADPKD. In this study, we demonstrate that laminin-332 is aberrantly expressed in cysts and precystic tubules of human autosomal recessive PKD (ARPKD) kidneys as well as in the kidneys of PCK rats, an orthologous ARPKD model. There was aberrant expression of laminin-γ2 as early as postnatal day 2 and elevated laminin-332 protein in postnatal day 30, coinciding with the formation and early growth of renal cysts in PCK rat kidneys. We also show that a kidney cell line derived from Oak Ridge polycystic kidney mice, another model of ARPKD, exhibited abnormal lumen-deficient and multilumen structures in Matrigel culture. These cells had increased proliferation rates and altered expression levels of laminin-332 compared with their rescued counterparts. A function-blocking polyclonal antibody to laminin-332 significantly inhibited their abnormal proliferation rates and rescued their aberrant phenotype in Matrigel culture. Furthermore, abnormal laminin-332 expression in cysts originating from collecting ducts and proximal tubules as well as in precystic tubules was observed in a human end-stage ADPKD kidney. Our results suggest that abnormal expression of laminin-332 contributes to the aberrant proliferation of cyst epithelial cells and cyst growth in genetic forms of PKD.
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Moléculas de Adesão Celular/biossíntese , Proliferação de Células , Doenças Renais Císticas/patologia , Rim Policístico Autossômico Recessivo/metabolismo , Animais , Membrana Basal/patologia , Linhagem Celular , Pré-Escolar , Humanos , Doenças Renais Císticas/metabolismo , Laminina/biossíntese , Masculino , Camundongos , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/metabolismo , Ratos , CalininaRESUMO
BACKGROUND: Several new targeted genes and clinical subtypes have been identified since publication in 2008 of the report of the last international consensus meeting on diagnosis and classification of epidermolysis bullosa (EB). As a correlate, new clinical manifestations have been seen in several subtypes previously described. OBJECTIVE: We sought to arrive at an updated consensus on the classification of EB subtypes, based on newer data, both clinical and molecular. RESULTS: In this latest consensus report, we introduce a new approach to classification ("onion skinning") that takes into account sequentially the major EB type present (based on identification of the level of skin cleavage), phenotypic characteristics (distribution and severity of disease activity; specific extracutaneous features; other), mode of inheritance, targeted protein and its relative expression in skin, gene involved and type(s) of mutation present, and--when possible--specific mutation(s) and their location(s). LIMITATIONS: This classification scheme critically takes into account all published data through June 2013. Further modifications are likely in the future, as more is learned about this group of diseases. CONCLUSION: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and molecular features of each EB subtype, and has sufficient flexibility incorporated in its structure to permit further modifications in the future.
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Epidermólise Bolhosa/classificação , Epidermólise Bolhosa/genética , Predisposição Genética para Doença/epidemiologia , Consenso , Epidermólise Bolhosa/diagnóstico , Feminino , Regulação da Expressão Gênica , Humanos , Incidência , Masculino , Prognóstico , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND/PURPOSE: Dystrophic epidermolysis bullosa (DEB), a rare genetic skin disease caused by loss-of-function mutations in COL7A1, the gene encoding type VII collagen (COL7), is characterized by skin blistering, scarring, and extracutaneous manifestations that markedly reduce patient quality-of-life. Beremagene geperpavec-svdt ('B-VEC') is a gene therapy employing a non-integrating, replication-defective herpes simplex virus type 1 (HSV-1)-based vector encoding two copies of full-length human COL7A1 to restore COL7 protein after topical administration to DEB wounds. B-VEC was approved in the United States in 2023 as the first topical gene therapy and the first approved treatment for DEB. However, few providers have experience with use of this gene therapy. METHODS: Data was obtained through literature review and the experience of providers who participated in the B-VEC clinical study or initiated treatment after B-VEC approval. RESULTS: This review discusses the burden of disease, describes the clinical trial outcomes of B-VEC, and provides physician and patient/caregiver recommendations as a practical guide for the real-world use of B-VEC, which can be administered in-office or at the patient's home. CONCLUSIONS: By continuing to optimize the practical aspects of B-VEC administration, the focus will continue to shift to patient-centric considerations and improved patient outcomes.