RESUMEN
OBJECTIVES: The current gold standard treatment for port-wine stains (PWS) is pulsed dye laser (PDL). However, multiple treatment sessions may be necessary and complete resolution is often not achieved. Neoangiogenesis can occur soon after treatment and is thought to be a major factor contributing to treatment failure. Adjuvant antiangiogenic topical therapies may therefore improve the efficacy of pulsed dye laser treatment of port-wine stains. MATERIAL AND METHODS: Following PRISMA guidelines, we searched PubMed, Embase, Web of Science, and clinicaltrials.gov using "port-wine stain," "nevus flammeus," "capillary malformation," "sturge weber," and "pulsed dye laser" as keywords and medical subject heading (MeSH) terms. Articles were included if they (1) were a randomized controlled trial (RCT); (2) studied patients with PWS; and (3) investigated topical adjuvant therapies with PDL. Bias was assessed using the Critical Appraisal Skills Programme (CASP) Randomized Controlled Trial Standard Checklist. RESULTS: 1835 studies were identified, with six studies meeting inclusion criteria. The total number of patients studied was 103 (range: 9-23), with 8-36 week follow-up. The average age ranged from 11 to 33.5 years old. Three studies examined adjuvant topical sirolimus (n = 52), two examined timolol (n = 29), and one studied imiquimod (n = 22). Two of three RCTs reported no improvement through colorimetric analysis with topical sirolimus; however, one of these studies did show a significant improvement through Investigator Global Assessment (IGA) score. The last sirolimus study showed significant improvement through digital photographic image scoring (DPIA). Studies examining topical timolol reported no change in PWS appearance compared to placebo. The addition of 5% adjuvant imiquimod cream did lead to significant improvement. A variety of outcome measures were used. Imiquimod and sirolimus led to mild cutaneous adverse events, while timolol caused no side effects. None of the adverse events led to treatment discontinuation. Study quality was moderate in three, high in two, and low in one. CONCLUSION: The efficacy of adjuvant topical therapy was unclear. Limitations included variation in concentration and duration of adjuvant therapies, differences in follow-up time, and inconsistent outcome measure reporting. Given their potential clinical promise, larger prospective studies examining topical adjuvant therapies should be considered.
Asunto(s)
Láseres de Colorantes , Mancha Vino de Oporto , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Mancha Vino de Oporto/tratamiento farmacológico , Imiquimod/uso terapéutico , Timolol/uso terapéutico , Láseres de Colorantes/uso terapéutico , Sirolimus/uso terapéutico , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Tedizolid phosphate is an oxazolidinone antibacterial agent approved for the treatment of Gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate treatment in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to those of the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration-time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the MIC susceptibility breakpoint of 0.5 µg/ml for Staphylococcus and Streptococcus sp. was 100%. As most participants from the PN012 trial were cured, no significant exposure-efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar those in adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.
Asunto(s)
Oxazolidinonas , Enfermedades Cutáneas Bacterianas , Adolescente , Adulto , Antibacterianos/uso terapéutico , Niño , Humanos , Probabilidad , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , TetrazolesRESUMEN
Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84-1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83-0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.
Asunto(s)
Diagnóstico por Computador , Interpretación de Imagen Asistida por Computador , Linfocitos Infiltrantes de Tumor/inmunología , Aprendizaje Automático , Melanoma/inmunología , Microscopía , Neoplasias Cutáneas/inmunología , Adulto , Anciano , Automatización de Laboratorios , Biopsia , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Humanos , Recuento de Linfocitos , Masculino , Melanoma/mortalidad , Melanoma/patología , Melanoma/terapia , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. OBJECTIVE: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. METHODS: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). RESULTS: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α-coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN-γ, OASL, and TH2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17-regulated gene expression (IL17F and IL36A/IL36B/IL36G). CONCLUSION: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36-targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.
Asunto(s)
Ictiosis/inmunología , Síndrome de Netherton/inmunología , Linfocitos T/inmunología , Células Th17/inmunología , Uniones Estrechas/genética , Adolescente , Adulto , Anciano , Niño , Dermatoglifia del ADN , Femenino , Proteínas Filagrina , Genoma , Humanos , Ictiosis/genética , Interleucina-1/genética , Interleucina-17/genética , Metabolismo de los Lípidos/genética , Activación de Linfocitos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Síndrome de Netherton/genética , Transcriptoma , Adulto JovenRESUMEN
Transgender individuals may transition to their identified gender through social, hormonal, and procedural methods by using a multidisciplinary team of health care providers, including dermatologists. In this review, we discuss the medical and aesthetic dermatologic needs related to the transitioning of transgender patients and provide therapeutic and procedural recommendations. In addition to routine cutaneous conditions, dermatologists may need to treat hormonal therapy-related complications. Acumen for genital dermatology and familiarity with gender reassignment surgery is important for the dermatologist caring for a transgender patient. From a structural standpoint, transgender beauty poses a unique aesthetic task. We identify key differences in the facial structure and physique of males versus those of females. Dermatologists may have a tremendous impact on the lives of transgender individuals who seek to realize their gender identity.
Asunto(s)
Técnicas Cosméticas , Estética , Personas Transgénero , Tejido Adiposo/trasplante , Alopecia/inducido químicamente , Alopecia/tratamiento farmacológico , Contorneado Corporal , Distribución de la Grasa Corporal , Rellenos Dérmicos/efectos adversos , Rellenos Dérmicos/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Cara/anatomía & histología , Cara/cirugía , Femenino , Identidad de Género , Hormonas Esteroides Gonadales/efectos adversos , Hormonas Esteroides Gonadales/farmacología , Remoción del Cabello/métodos , Hirsutismo/inducido químicamente , Hirsutismo/tratamiento farmacológico , Humanos , Masculino , Neurotoxinas/uso terapéutico , Complicaciones Posoperatorias/terapia , Procedimientos de Cirugía Plástica , Caracteres Sexuales , Cirugía de Reasignación de Sexo , Piel/efectos de los fármacos , Personas Transgénero/psicologíaRESUMEN
The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/ß-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Receptores Frizzled/metabolismo , Neoplasias Experimentales/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinación , Vía de Señalización Wnt , Animales , Proteínas de Unión al ADN/genética , Receptores Frizzled/genética , Células HEK293 , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Ratones , Neoplasias Experimentales/genética , Proteínas Oncogénicas/genética , Proteínas Proto-Oncogénicas/genética , Ubiquitina Tiolesterasa/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The incidence of allergic contact dermatitis (ACD) reactions to personal care products has progressively increased, affecting women more so than men. Fragrances and preservatives are the major sensitizers behind cosmetic-induced ACD, due to their ubiquitous presence in these products, though emulsifiers, ultraviolet filters, and botanical allergens have been implicated as well. While patch testing is the standard for diagnosing ACD, many cosmetic-specific antigens are not currently included within the commercially available kits. Therefore, patch testing for potential cosmetic-induced ACD should be supplemented with additional compounds commonly found in personal use products. Effective treatment of ACD must involve accurate identification and removal of the offending agent.
Asunto(s)
Alérgenos/efectos adversos , Cosméticos/efectos adversos , Dermatitis Alérgica por Contacto , Pruebas del Parche/métodos , Perfumes/efectos adversos , Conservadores Farmacéuticos/efectos adversos , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/terapia , HumanosRESUMEN
Mixed lineage leukemia (MLL) and its metazoan Trithorax orthologs have been linked with the epigenetic maintenance of transcriptional activity. To identify mechanisms by which MLL perpetuates active transcription in dividing cells, we investigated its role during M phase of the cell cycle. Unlike other chromatin-modifying enzymes examined, we found that MLL associates with gene promoters packaged within condensed mitotic chromosomes. Genome-wide location analysis identified a globally rearranged pattern of MLL occupancy during mitosis in a manner favoring genes that were highly transcribed during interphase. Knockdown experiments revealed that MLL retention at gene promoters during mitosis accelerates transcription reactivation following mitotic exit. MLL tethers Menin, RbBP5, and ASH2L to its occupied sites during mitosis, but is dispensable for preserving histone H3K4 methylation. These findings implicate mitotic bookmarking as a component of Trithorax-based gene regulation, which may facilitate inheritance of active gene expression states during cell division.
Asunto(s)
Cromatina/metabolismo , Mitosis/fisiología , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Activación Transcripcional , Animales , Cromatina/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Células HeLa , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Interfase/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Nodular fasciitis (NF) is a clonal self-limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well-documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6-USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Fascitis/genética , Proteínas de Fusión Oncogénica/genética , Fosfoproteínas Fosfatasas/genética , Proteínas Proto-Oncogénicas/genética , Ubiquitina Tiolesterasa/genética , Adulto , Carcinogénesis/genética , Hibridación Genómica Comparativa , Fascitis/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , ARN Mensajero/genéticaRESUMEN
Plasma membrane proteins that enter cells by clathrin-independent endocytosis (CIE) are sorted either to lysosomes for degradation or recycled back to the plasma membrane. Expression of some MARCH E3 ubiquitin ligases promotes trafficking of CIE cargo proteins to lysosomes by ubiquitylating the proteins. Here, we show that co-expression of the ubiquitin-specific protease TRE17/USP6 counteracts the MARCH-dependent targeting of CIE cargo proteins, but not that of transferrin receptor, to lysosomes, leading to recovery of the stability and cell surface level of the proteins. The ubiquitylation of CIE cargo proteins by MARCH8 was reversed by TRE17, suggesting that TRE17 leads to deubiquitylation of CIE cargo proteins. The effects of TRE17 were dependent on its deubiquitylating activity and expression of TRE17 alone led to a stabilization of surface major histocompatibility complex class I (MHCI) molecules, a CIE cargo, suggesting that deubiquitylation of endogenous CIE cargo proteins promotes their stability. This study demonstrates that cycles of ubiquitylation and deubiquitylation can determine whether CIE cargo proteins are degraded or recycled.
Asunto(s)
Clatrina/metabolismo , Endocitosis/fisiología , Proteínas Proto-Oncogénicas/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Clatrina/genética , Endocitosis/genética , Técnica del Anticuerpo Fluorescente , Células HeLa , Humanos , Transporte de Proteínas/genética , Transporte de Proteínas/fisiología , Proteínas Proto-Oncogénicas/genética , Ubiquitina Tiolesterasa/genética , UbiquitinaciónRESUMEN
Fibroma of tendon sheath is a benign (myo)fibroblastic neoplasm of the tenosynovial soft tissues, typically affecting the distal extremities. It is classically described as a paucicellular, densely collagenized tumor; however, cellular variants have been described. A subset of cellular fibromas of tendon sheath shares similar histological features with nodular fasciitis. As nodular fasciitis very frequently harbors rearrangement of ubiquitin-specific peptidase 6 (USP6), we hypothesized that cellular fibromas of tendon sheath with nodular fasciitis-like features may also contain USP6 rearrangements. Cases of fibroma of tendon sheath (n=19), including cellular (n=9) and classic (n=10) variants, were evaluated for USP6 rearrangement by fluorescence in situ hybridization studies. A subset of cases was tested for MYH9 rearrangements and MYH9-USP6 and CDH11-USP6 fusion products. Classic fibroma of tendon sheath occurred in 5 males and 5 females (median age 67 years, range 23-77 years) as soft tissue masses of the hand (n=4), finger (n=3), forearm (n=1) and foot (n=2). Cellular fibroma of tendon sheath occurred in 5 males and 4 females in a younger age group (median age 32 years, range 12-46 years) as small soft tissue masses of the finger (n=5), hand (n=3) and wrist (n=1). USP6 rearrangements were detected in 6/9 cellular fibromas of tendon sheath. Among cellular fibromas of tendon sheath with USP6 rearrangements, no MYH9 rearrangements were detected. By RT-PCR, neither the MYH9-USP6 or the CDH11-USP6 fusion products were detected in any case. Neither USP6 nor MYH9 rearrangement were detected in any classic fibroma of tendon sheath. We report for the first time the presence of USP6 rearrangements in a subset of cellular fibroma of tendon sheath. Based on the similar morphological and molecular genetic features, we suspect that a subset of cellular fibromas of tendon sheath are under-recognized examples of tenosynovial nodular fasciitis, driven by alternate USP6 fusion genes. Further investigation will delineate how these lesions should best be classified.
Asunto(s)
Biomarcadores de Tumor/genética , Fascitis/genética , Fibroma/genética , Reordenamiento Génico , Tumor de Células Gigantes de las Vainas Tendinosas/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias de los Tejidos Blandos/genética , Tendones/patología , Ubiquitina Tiolesterasa/genética , Adolescente , Adulto , Anciano , Cadherinas/genética , Niño , Fascitis/patología , Femenino , Fibroma/patología , Fusión Génica , Predisposición Genética a la Enfermedad , Tumor de Células Gigantes de las Vainas Tendinosas/patología , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Motoras Moleculares/genética , Cadenas Pesadas de Miosina/genética , Fenotipo , Neoplasias de los Tejidos Blandos/patología , Adulto JovenRESUMEN
AIMS: Biphenotypic sinonasal sarcoma (SNS) is a locally aggressive tumour that occurs in the sinonasal region. PAX3-MAML3 has recently been identified as a recurrent fusion gene event in this entity; however, a subset of tumours harbour alternative PAX3 rearrangement without the involvement of MAML3. In this study we sought to characterize the molecular profile of a large series of cases, with a special emphasis on tumours with alternative fusions. METHODS AND RESULTS: Forty-four examples of SNS were screened by fluorescence in-situ hybridization and reverse transcription polymerase chain reaction to better characterize its molecular profile and identify potential novel fusion genes. Twenty-four were positive for PAX3-MAML3 (55%), 15 showed rearrangements of PAX3 without MAML3 involvement (34%), one showed rearrangement of MAML3 without PAX3 involvement, and four were negative for the involvement of either gene (9%). Among 15 cases with PAX3 involvement only, three were found to harbour PAX3-FOXO1. Two of these cases arose in the nasal cavities of female patients (aged 31 and 47 years), and one showed bilateral involvement of the nasal cavities of a 35-year-old male. A fourth case involved the skull base of a 47-year-old male, and was positive for PAX3-NCOA1. Patients with fusion-negative tumours were slightly older. CONCLUSION: More than half of the SNSs in this series were positive for PAX3-MAML3. However, a subset of tumours may harbour alternative PAX3 fusion genes or show no involvement of PAX3. Except for a possible weak association between age and molecular profile, the overall morphological and immunophenotypic features of all cases seem to be similar. Because of the rarity of these tumours, the impact of the molecular profile on the clinical course of these tumours remains to be determined.
Asunto(s)
Neoplasias de los Senos Paranasales/genética , Sarcoma/genética , Adulto , Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Coactivador 1 de Receptor Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción Paired Box/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores , Factores de Transcripción/genéticaRESUMEN
Ewing sarcoma is a rare and deadly pediatric bone cancer for which survival rates and treatment options have stagnated for decades. Ewing sarcoma has not benefited from immunotherapy due to poor understanding of how its immune landscape is regulated. We recently reported that ubiquitin-specific protease 6 (USP6) functions as a tumor suppressor in Ewing sarcoma, and identified it as the first cell-intrinsic factor to modulate the Ewing sarcoma immune tumor microenvironment (TME). USP6 induces intratumoral infiltration and activation of multiple innate immune lineages in xenografted nude mice. Here we report that natural killer (NK) cells are essential for its tumor-inhibitory functions, as NK cell depletion reverses USP6-mediated suppression of Ewing sarcoma xenograft growth. USP6 expression in Ewing sarcoma cells directly stimulates NK cell activation and degranulation in vitro, and functions by increasing surface levels of multiple NK cell-activating ligands. USP6 also induces surface upregulation of the receptor for the apoptosis-inducing ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), providing an additional route for enhanced sensitivity to NK cell killing. Furthermore, USP6-expressing Ewing sarcoma and NK cells participate in a paracrine immunostimulatory feedforward loop, wherein IFNγ secreted by activated NK cells feeds back on USP6/Ewing sarcoma cells to induce synergistic expression of chemokines CXCL9 and CXCL10. Remarkably, expression of USP6 in subcutaneous Ewing sarcoma xenografts induces systemic activation and maturation of NK cells, and induces an abscopal response in which growth of distal tumors is inhibited, coincident with increased infiltration and activation of NK cells. This work reveals how USP6 reprograms the Ewing sarcoma TME to enhance antitumor immunity, and may be exploited for future therapeutic benefit. Significance: This study provides novel insights into the immunomodulatory functions of USP6, the only cancer cell-intrinsic factor demonstrated to regulate the immune TME in Ewing sarcoma. We demonstrate that USP6-mediated suppression of Ewing sarcoma tumorigenesis is dependent on NK cells. USP6 directly activates NK cell cytolytic function, inducing both intratumoral and systemic activation of NK cells in an Ewing sarcoma xenograft model.
Asunto(s)
Neoplasias Óseas , Tumores Neuroectodérmicos Periféricos Primitivos , Sarcoma de Ewing , Humanos , Animales , Ratones , Factor Intrinseco , Ligandos , Ratones Desnudos , Factor Inductor de la Apoptosis , Proteasas Ubiquitina-Específicas , Microambiente Tumoral , Ubiquitina TiolesterasaRESUMEN
BACKGROUND: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. METHODS: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. RESULTS: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. CONCLUSIONS: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials.
RESUMEN
One of the earliest morphogenetic processes in the development of many animals is epiboly. In the zebrafish, epiboly ensues when the animally localized blastoderm cells spread, thin over, and enclose the vegetally localized yolk. Only a few factors are known to function in this fundamental process. We identified a maternal-effect mutant, betty boop (bbp), which displays a novel defect in epiboly, wherein the blastoderm margin constricts dramatically, precisely when half of the yolk cell is covered by the blastoderm, causing the yolk cell to burst. Whole-blastoderm transplants and mRNA microinjection rescue demonstrate that Bbp functions in the yolk cell to regulate epiboly. We positionally cloned the maternal-effect bbp mutant gene and identified it as the zebrafish homolog of the serine-threonine kinase Mitogen Activated Protein Kinase Activated Protein Kinase 2, or MAPKAPK2, which was not previously known to function in embryonic development. We show that the regulation of MAPKAPK2 is conserved and p38 MAP kinase functions upstream of MAPKAPK2 in regulating epiboly in the zebrafish embryo. Dramatic alterations in calcium dynamics, together with the massive marginal constrictive force observed in bbp mutants, indicate precocious constriction of an F-actin network within the yolk cell, which first forms at 50% epiboly and regulates epiboly progression. We show that MAPKAPK2 activity and its regulator p38 MAPK function in the yolk cell to regulate the process of epiboly, identifying a new pathway regulating this cell movement process. We postulate that a p38 MAPKAPK2 kinase cascade modulates the activity of F-actin at the yolk cell margin circumference allowing the gradual closure of the blastopore as epiboly progresses.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/fisiología , Morfogénesis , Proteínas Serina-Treonina Quinasas/fisiología , Pez Cebra/crecimiento & desarrollo , Actinas/metabolismo , Animales , Calcio/metabolismo , Movimiento Celular , Yema de Huevo , Desarrollo Embrionario , Gástrula , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Mutantes , Proteínas Serina-Treonina Quinasas/metabolismo , Pez Cebra/embriología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer. Among the ESS32, LOXHD1, encoding a stereociliary protein, is the most highly expressed gene through an alternative transcription start site. Deletion or silencing of EWSR1::FLI1 bound upstream de novo enhancer results in loss of the LOXHD1 short isoform, altering EWSR1::FLI1 and HIF1α pathway genes and resulting in decreased proliferation/invasion of EwS cells. These observations implicate LOXHD1 as a biomarker and a determinant of EwS metastasis and suggest new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.
Asunto(s)
Proteínas Portadoras , Elementos de Facilitación Genéticos , Proteínas de Fusión Oncogénica , Sarcoma de Ewing , Adolescente , Proteínas Portadoras/genética , Línea Celular Tumoral , Niño , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologíaRESUMEN
Aneurysmal bone cyst (ABC) is a pediatric osseous tumor characterized by extensive destruction of the surrounding bone. The molecular mechanisms underlying its pathogenesis are completely unknown. Recent work showed that translocation of the TRE17/USP6 locus occurs in over 60% of ABC cases resulting in TRE17 overexpression. Immature osteoblasts are presumed to be the cell type harboring translocation of TRE17 in at least a subset of ABCs. However, the effects of TRE17 overexpression on transformation and osteoblast function are unknown. TRE17 encodes a ubiquitin-specific protease (USP) and a TBC (TRE2-Bub2-Cdc16) domain that promotes activation of the Arf6 GTPase. Here we report that TRE17 potently inhibits the maturation of MC3T3 pre-osteoblasts in a USP-dependent and Arf6-independent manner. Notably, we find that TRE17 function is mediated through an autocrine mechanism. Transcriptome analysis of TRE17-expressing cells reveals dysregulation of several pathways with established roles in osteoblast maturation. In particular, signaling through the bone morphogenetic protein (BMP) pathway, a key regulator of osteogenesis, is profoundly altered. TRE17 simultaneously inhibits the expression of BMP-4 while augmenting the BMP antagonist, Gremlin-1. Osteoblastic maturation is restored in TRE17-expressing cells by the addition of exogenous BMP-4, thus establishing a functional role for BMP-4 during TRE17-induced transformation. Because bone homeostasis involves a precise balance between the activities of osteoblasts and osteoclasts, our studies raise the possibility that attenuated osteoblast maturation caused by TRE17 overexpression may contribute to the bone loss/destruction observed in ABC.
Asunto(s)
Comunicación Autocrina , Quistes Óseos Aneurismáticos/patología , Proteínas Morfogenéticas Óseas/metabolismo , Endopeptidasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Oncogenes/fisiología , Osteoblastos/patología , Factor 6 de Ribosilación del ADP , Factores de Ribosilacion-ADP/genética , Factores de Ribosilacion-ADP/metabolismo , Fosfatasa Alcalina/metabolismo , Animales , Biomarcadores/metabolismo , Western Blotting , Quistes Óseos Aneurismáticos/enzimología , Quistes Óseos Aneurismáticos/genética , Proteínas Morfogenéticas Óseas/genética , Diferenciación Celular , Proliferación Celular , Transformación Celular Neoplásica , Medios de Cultivo Condicionados/farmacología , Ensayo de Cambio de Movilidad Electroforética , Endopeptidasas/genética , Perfilación de la Expresión Génica , Células HeLa , Humanos , Ratones , Mutagénesis Sitio-Dirigida , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoblastos/metabolismo , Transporte de Proteínas , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Ubiquitina Tiolesterasa , Proteasas Ubiquitina-EspecíficasRESUMEN
Nodular fasciitis (NF) is a relatively common mass-forming and self-limited subcutaneous pseudosarcomatous myofibroblastic proliferation of unknown pathogenesis. Due to its rapid growth and high mitotic activity, NF is often misdiagnosed as a sarcoma. While studying the USP6 biology in aneurysmal bone cyst and other mesenchymal tumors, we identified high expression levels of USP6 mRNA in two examples of NF. This finding led us to further examine the mechanisms underlying USP6 overexpression in these lesions. Upon subsequent investigation, genomic rearrangements of the USP6 locus were found in 92% (44 of 48) of NF. Rapid amplification of 5'-cDNA ends identified MYH9 as the translocation partner. RT-PCR and direct sequencing revealed the fusion of the MYH9 promoter region to the entire coding region of USP6. Control tumors and tissues were negative for this fusion. Xenografts of cells overexpressing USP6 in nude mice exhibited clinical and histological features similar to human NF. The identification of a sensitive and specific abnormality in NF holds the potential to be used diagnostically. Considering the self-limited nature of the lesion, NF may represent a model of 'transient neoplasia', as it is, to our knowledge, the first example of a self-limited human disease characterized by a recurrent somatic gene fusion event.
Asunto(s)
Fascitis/genética , Fascitis/patología , Fusión Génica , Proteínas Motoras Moleculares/genética , Cadenas Pesadas de Miosina/genética , Proteínas Proto-Oncogénicas/genética , Ubiquitina Tiolesterasa/genética , Adolescente , Adulto , Anciano , Animales , Secuencia de Bases , Cadherinas/metabolismo , Niño , Preescolar , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Femenino , Perfilación de la Expresión Génica , Reordenamiento Génico , Genoma Humano/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteínas Motoras Moleculares/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma/diagnóstico , Translocación Genética , Trasplante Heterólogo , Ubiquitina Tiolesterasa/metabolismo , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Early reports on cancer patients with coronavirus disease 2019 (COVID-19) corroborated speculation that cancer patients are at increased risk for becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing severe COVID-19. However, cancer patients are a heterogeneous population and their corresponding risk may be different. AIM: To compare COVID-19 presentation in patients with active malignancy to those with a history of cancer to determine the impact of cancer status on COVID-19 outcomes in the two groups. METHODS AND RESULTS: Of the 6724 patients who were hospitalized at NYU Langone Health (3/16/20-7/31/20) and tested positive for SARS-CoV-2, 580 had either active cancer (n = 221) or a history of cancer (n = 359). We compared the baseline clinicodemographic characteristics and hospital courses of the two groups. We studied the relationship between cancer status and the rate of admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), and all-cause mortality. The two groups had similar laboratory results associated with COVID-19 infection, incidence of venous thromboembolism, and incidence of severe COVID-19. Active cancer status was not associated with the rate of ICU admission (p = .307) or use of IMV (p = .236), but was significantly associated with worse all-cause mortality in both univariate and multivariate analysis with odds ratios of 1.48 (95% confidence interval [CI]: 1.04-2.09; p = .028) and 1.71 (95% CI: 1.12-2.63; p = .014), respectively. CONCLUSION: Active cancer patients had worse survival outcomes compared to patients with a history of cancer despite similar COVID-19 disease characteristics in the two groups. Our data suggest that cancer care should continue with minimal interruptions during the pandemic to bring about response and remission as soon as possible.