RESUMEN
Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.
Asunto(s)
Quinasa 1 de Quinasa de Quinasa MAP/genética , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Humanos , Quinasa 1 de Quinasa de Quinasa MAP/metabolismo , Melanoma/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Neoplasias Cutáneas/metabolismoRESUMEN
Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.
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División Celular/fisiología , Melanoma/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Células del Estroma/metabolismo , Animales , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Proliferación Celular , Modelos Animales de Enfermedad , Exoma/genética , Femenino , Humanos , Inmunoterapia , RatonesRESUMEN
Psoriasis is a chronic skin disease associated with considerable physical and psychological comorbidities. Stress and emotional disturbances have been implicated in both triggering the onset and exacerbation of psoriasis. In order to determine the level of perceived stress and mood alterations in patients with psoriasis and their association with disease severity, 300 individuals completed diverse validated questionnaires assessing stress and psychological mood. Evaluation of perception of disease was also measured. A significant association between psoriasis severity and mood, emotional disturbances and an impact on assessments of the quality of life were observed. Particularly, Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale and Hospital Anxiety and Depression Scale for Depression detected a significant risk for depression in relation to the disease severity. The association between depression features, anxiety and perceived stress with psoriasis severity is important and can influence the appropriate management of psoriasis.
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Ansiedad/psicología , Depresión/psicología , Emociones , Psoriasis/psicología , Estrés Psicológico/psicología , Adolescente , Adulto , Afecto , Anciano , Anciano de 80 o más Años , Ansiedad/diagnóstico , Ansiedad/epidemiología , Comorbilidad , Costo de Enfermedad , Depresión/diagnóstico , Depresión/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/diagnóstico , Psoriasis/epidemiología , Calidad de Vida , Factores de Riesgo , Índice de Severidad de la Enfermedad , España/epidemiología , Estrés Psicológico/diagnóstico , Estrés Psicológico/epidemiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Self-healing cutaneous mucinosis (SHCM) is an idiopathic localized cutaneous mucinosis mainly described in children and characterized clinically by an acute onset of papules and nodules that exhibit a spontaneous resolution in a period ranging from weeks to few months. Histologically, a diffuse mucin deposition in the dermis and/or hypodermis associated with a proliferation of spindle-shaped cells and some large epithelioid gangliocyte-like mononuclear cells is usually observed. An uncommon adult variant of SHCM has also been reported; however, the clinicopathological features described in these patients are extremely heterogeneous and differ significantly from the juvenile variant of the disease, often showing exclusively dermal involvement. We report a case of a 37-year-old female patient with multiple asymptomatic nodules located on the legs and arms that resolved spontaneously in a period of 2 years, showing the typical subcutaneous features of the juvenile variant of SHCM at the histological examination (ie, mucinous areas associated with dense bands of fibrosis containing arborizing thin-walled vessels, spindle-shaped fibroblasts, and some gangliocyte-like cells). To the best of our knowledge, this is the first report of SHCM showing the classic pattern of deep-seated subcutaneous involvement of the disease in an adult patient. We also review the cases of adult-onset SHCM reported in the literature.
Asunto(s)
Mucinosis/patología , Piel/patología , Cicatrización de Heridas , Adulto , Factores de Edad , Biopsia , Femenino , Humanos , Fenotipo , Remisión EspontáneaRESUMEN
The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.
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Daño del ADN , Melanoma/patología , Rayos Ultravioleta , Animales , Humanos , Ratones , Pronóstico , Análisis de SupervivenciaRESUMEN
In the version of this article originally published, Extended Data Fig. 3 was incorrect. A duplicate of Extended Data Fig. 4 was uploaded in place of Extended Data Fig. 3. Extended Data Fig. 3 has now been uploaded. The error has been fixed in the PDF and HTML versions of this article.
RESUMEN
Telangiectasias are the clinical manifestation of diverse processes affecting blood vessels. Herein we report the case of a 60-year-old man presenting long-standing asymptomatic annular telangiectatic lesions with whitish centers. The histopathologic examination revealed thickened blood dermal vessel walls in the superficial dermis showing reduplication of the basement membrane resembling cutaneous collagenous vasculopathy (CCV). We suggest that this atypical clinicopathological presentation may represent either a localized annular variant of CCV or a previously unreported clinical form of multiple cutaneous telangiectasias.
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Telangiectasia/patología , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cutáneas Vasculares/patologíaAsunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Fusión Génica , Síndrome Hipereosinofílico/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Papulosis Linfomatoide/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Neoplasias Cutáneas/tratamiento farmacológico , Factores de Escisión y Poliadenilación de ARNm/genética , Adulto , Biopsia , Humanos , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/genética , Inmunohistoquímica , Hibridación Fluorescente in Situ , Papulosis Linfomatoide/diagnóstico , Papulosis Linfomatoide/genética , Masculino , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Resultado del TratamientoRESUMEN
The typical finding in primary syphilis stage is a unique, painless chancre with indurated borders. We report a case of primary syphilis presenting as erosive and crusted balanoposthitis with an underlying chancre, penile edema, and bilateral inguinal lymphadenopathy in a heterosexual man.
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Balanitis/microbiología , Edema/microbiología , Enfermedades del Pene/microbiología , Sífilis/microbiología , Treponema pallidum/aislamiento & purificación , Antibacterianos/uso terapéutico , Balanitis/diagnóstico , Balanitis/tratamiento farmacológico , Edema/diagnóstico , Edema/tratamiento farmacológico , Prepucio/microbiología , Ácido Fusídico/uso terapéutico , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Pomadas , Penicilina G Benzatina/uso terapéutico , Enfermedades del Pene/diagnóstico , Enfermedades del Pene/tratamiento farmacológico , Reacción en Cadena en Tiempo Real de la Polimerasa , Sífilis/diagnóstico , Sífilis/tratamiento farmacológico , Serodiagnóstico de la Sífilis , Treponema pallidum/genéticaRESUMEN
We studied the dynamics of a single sonoluminescing bubble (SBSL) in a liquid hammer device. In particular, we investigated the phosphoric acid-xenon system, in which pulses up to four orders of magnitude brighter than SBSL in water systems (about 10;{12} photons per pulse) have been previously reported [Chakravarty, Phys. Rev. E 69, 066317 (2004)]. We used stroboscopic photography and a Mie scattering technique in order to measure the radius evolution of the bubbles. Under adequate conditions we may position a bubble at the bottom of the tube (cavity) and a second bubble trapped at the middle of the tube (upper bubble). During its collapse, the cavity produces the compression of the liquid column. This compression drives impulsively the dynamics of the upper bubble. Our measurements reveal that the observed light emissions produced by the upper bubble are generated at its second collapse. We employed a simple numerical model to investigate the conditions that occur during the upper bubble collapse. We found good agreement between numerical and experimental values for the light intensity (fluence) and light pulse widths. Results from the model show that the light emission is increased mainly due to an increase in noble gas ambient radius and not because the maximum temperature increases. Even for the brightest pulses obtained ( 2x10;{13} photons, about 20W of peak power) the maximum temperatures computed for the upper bubble are always lower than 20000K .
RESUMEN
We present theoretical calculations of an argon bubble in a liquid solution of 85%wt sulfuric acid and 15%wt water in single-bubble sonoluminescence. We used a model without free parameters to be adjusted. We predict from first principles the region in parameter space for stable bubble evolution, the temporal evolution of the bubble radius, the maximum temperature, pressures, and the light spectra due to thermal emissions. We also used a partial differential equation based model (hydrocode) to compute the temperature and pressure evolutions at the center of the bubble during maximum compression. We found the behavior of this liquid mixture to be very different from water in several aspects. Most of the models in sonoluminescence were compared with water experimental results.