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Next-generation sequencing (NGS) is increasingly being utilized as an ancillary tool for diagnostically challenging melanocytic neoplasms. It is incumbent upon the pathology community to perform studies assessing the benefits and limitations of these tools in specific diagnostic scenarios. One of the most challenging diagnostic scenarios faced by skin pathologists involves accurate diagnosis of desmoplastic melanocytic neoplasms (DMNs). In this study, 20 expert melanoma pathologists rendered a diagnosis on 47 DMNs based on hematoxylin and eosin sections with demographic information. After submitting their diagnosis, the experts were given the same cases, but this time with comprehensive genomic sequencing results, and asked to render a diagnosis again. Identification of desmoplastic melanoma (DM) improved by 7%, and this difference was statistically significant ( P <0.05). In addition, among the 15 melanoma cases, in the pregenomic assessment, only 12 were favored to be DM by the experts, while after genomics, this improved to 14 of the cases being favored to be DM. In fact, some cases resulting in metastatic disease had a substantial increase in the number of experts recognizing them as DM after genomics. The impact of the genomic findings was less dramatic among benign and intermediate-grade desmoplastic tumors (BIDTs). Interobserver agreement also improved, with the Fleiss multirater Kappa being 0.36 before genomics to 0.4 after genomics. NGS has the potential to improve diagnostic accuracy in the assessment of desmoplastic melanocytic tumors. The degree of improvement will be most substantial among pathologists with some background and experience in bioinformatics and melanoma genetics.
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Secuenciación de Nucleótidos de Alto Rendimiento , Melanoma , Variaciones Dependientes del Observador , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/diagnóstico , Melanoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Femenino , Masculino , Reproducibilidad de los Resultados , Valor Predictivo de las Pruebas , Persona de Mediana Edad , Adulto , Anciano , Patólogos , Biomarcadores de Tumor/genéticaRESUMEN
OBJECTIVES: In precision medicine, where oncologic management is tailored to the individual's clinical and genetic profiles, advanced diagnostic testing provides prognostic information and guides management in a growing number of malignancies. There is a need to capture the work pathologists perform to meet this demand by providing medically relevant, timely, and accurate testing results. This work includes not only direct patient consults (interpretation of results and issuing reports) but the administrative and medical oversight as well as the research needed to provide the necessary quality assurance, quality control, direction, and framework for the laboratory. METHODS: An expert panel of Canadian pathologists involved in advanced diagnostics was convened to establish and beta test a model for workload assessment in advanced diagnostics. RESULTS: All aspects of the advanced diagnostics workload were detailed and applied to models based on members' experience, including medical oversight, administration, and the introduction of new testing and platforms. Models for biomarker testing were developed for simple and complex or multiplexed assays, and a detailed model was developed to assess the workload for next-generation sequencing-based assays. CONCLUSIONS: This paper provides the first detailed proposal for capturing an advanced diagnostic workload to enable appropriate pathologist allotment for performing all the steps required to run an advanced diagnostic service.
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Neoplasias , Medicina de Precisión , Canadá , Humanos , Oncología Médica , Neoplasias/genética , Medicina de Precisión/métodos , Carga de TrabajoRESUMEN
Thymoma-associated multiorgan autoimmunity disease can be seen in patients with thymomas and presents with features of graft versus host disease. Here, we report a case of a 52-year-old woman with a complex medical history including malignant thymoma, myasthenia gravis, Good's syndrome, and T cell large granular lymphocytic leukemia who presented with a diffuse pruritic rash ultimately found to be compatible with a cutaneous presentation of thymoma-associated multiorgan autoimmunity disease. The eruption heralded the recurrence of the malignant thymoma and the rash was ultimately found to be resistant to a multitude of therapies except for oral corticosteroids.
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Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III-IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.
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Treatment with programmed cell death 1 inhibitors is associated with a wide range of cutaneous immune-related adverse events, with lichenoid eruptions representing one of the major cutaneous toxicities. We describe the case of an 81-year-old man with metastatic melanoma treated with pembrolizumab who subsequently developed a delayed-onset generalized lichenoid dermatitis. After failing multiple lines of systemic immunosuppression, narrowband ultraviolet B (NBUVB) phototherapy three times per week for 17 sessions resulted in a significant clinical response in his cutaneous eruption and was well tolerated. NBUVB is a safe, lower-cost modality that induces local, skin-specific immunosuppression without the toxicities of traditional systemic immunosuppressive agents. To date, this is the first report of use of NBUVB in immune-related lichenoid dermatitis resistant to multiple standard therapies.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Erupciones Liquenoides/radioterapia , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Terapia Ultravioleta , Anciano de 80 o más Años , Humanos , Erupciones Liquenoides/inducido químicamente , Erupciones Liquenoides/inmunología , Erupciones Liquenoides/patología , Masculino , Melanoma/inmunología , Melanoma/secundario , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Muir-Torre syndrome (MTS) is a rare autosomal dominant condition characterized by the presence of at least one cutaneous sebaceous tumor and one visceral malignancy, arising mostly from the gastrointestinal tract. We present the case of a 63-year-old man with several cutaneous and visceral neoplasias in the context of MTS, and a pelvic lymph node lesion diagnosed initially as metastatic sebaceous carcinoma, but later identified as metastasis from a newly diagnosed prostatic adenocarcinoma. Histological similarities between these 2 lesions are discussed. A systematic literature review was conducted evaluating all published cases of patients with MTS in which metastases were reported. Eighteen articles were included in the final synthesis, representing 20 patients with a total of 26 metastases. Seventeen patients (85%) exhibited metastases originating from MTS-related neoplasms, whereas only 2 patients (11%) exhibited metastases from concomitant malignancies. Of the 85% of patients with metastases from MTS-related malignancies, most originated from noncutaneous sources (78% from visceral neoplasms and 22% from sebaceous carcinomas). When stratifying according to metastases, 23 cases (88%) originated from MTS-related lesions, whereas only 3 (12%) originated from unrelated malignancies. Our findings thus demonstrate that most metastases found in MTS patients (88%) do indeed originate from MTS-related neoplasms. Nevertheless, it remains imperative that a broad differential diagnosis is maintained when assessing a novel lesion, to avoid misdiagnoses, as in the present case, with significant therapeutic and prognostic implications.
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Adenocarcinoma/secundario , Síndrome de Muir-Torre/patología , Neoplasias de la Próstata/patología , Neoplasias de las Glándulas Sebáceas/patología , Adenocarcinoma/química , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biopsia , Toma de Decisiones Clínicas , Errores Diagnósticos , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Síndrome de Muir-Torre/metabolismo , Síndrome de Muir-Torre/terapia , Valor Predictivo de las Pruebas , Neoplasias de la Próstata/química , Neoplasias de la Próstata/terapia , Neoplasias de las Glándulas Sebáceas/química , Neoplasias de las Glándulas Sebáceas/terapiaRESUMEN
Melanoma is among the most aggressive cancers due to its tendency to metastasize early. Phenotype switching between a proliferative and an invasive state has been suggested as a critical process for metastasis, though the mechanisms that regulate state transitions are complex and remain poorly understood. Brother of Regulator of Imprinted Sites (BORIS), also known as CCCTC binding factor-Like (CTCFL), is a transcriptional modulator that becomes aberrantly expressed in melanoma. Yet, the role of BORIS in melanoma remains elusive. Here, we show that BORIS is involved in melanoma phenotype switching. Genetic modification of BORIS expression in melanoma cells combined with whole-transcriptome analysis indicated that BORIS expression contributes to an invasion-associated transcriptome. In line with these findings, inducible BORIS overexpression in melanoma cells reduced proliferation and increased migration and invasion, demonstrating that the transcriptional switch is accompanied by a phenotypic switch. Mechanistically, we reveal that BORIS binds near the promoter of transforming growth factor-beta 1 (TFGB1), a well-recognized factor involved in the transition towards an invasive state, which coincided with increased expression of TGFB1. Overall, our study indicates a pro-invasive role for BORIS in melanoma via transcriptional reprogramming.
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Idiopathic Atrophoderma of Pasini and Pierini should be considered on the differential in a patient presenting with an asymptomatic atrophic plaque on the skin. Differentiation from Linear Atrophoderma of Moulin and morphea remains a challenge; however, features of the presentation and tissue biopsy can help establish the diagnosis.
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Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene.
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Proteínas de Ciclo Celular/metabolismo , Melanoma/metabolismo , Proteínas Nucleares/metabolismo , Proteína Fosfatasa 2/metabolismo , Neoplasias Cutáneas/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Cromosomas Humanos X , Replicación del ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Células HEK293 , Humanos , Masculino , Melanoma/genética , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Pronóstico , Proteína Fosfatasa 2/genética , Factores SexualesRESUMEN
OBJECTIVE: To develop and validate a predictive score to avoid unnecessary screening and prophylactic antibiotic use in abortion clinics by identifying a group of women who are at very low risk for Chlamydia trachomatis (CT) infection. METHODS: This population-based retrospective study includes 1000 women who underwent surgical abortion between January and September 2010. The main outcome measure was the rate of CT infection among women seeking an induced abortion according to sociodemographic and clinical data. The score was developed by using two-thirds of the data set as the derivation sample to identify the strongest predictors of CT. A receiver operating characteristic curve established cutoffs and applied the score to the remaining one-third (validation sample). RESULTS: The rate of CT infection was 6.7%. Three criteria were independently associated with CT: gestation more than 10 weeks (adjusted odds ratio [aOR], 1.96; 95% confidence interval [95% CI], 1.06-3.64), not using contraception (aOR, 2.70; 95% CI, 1.41-5.16), and having 0 or 1 child (aOR, 3.46; 95% CI, 1.34-8.93). The CT score was based on these 3 criteria. The low-risk group was derived from values of the score (probability of CT, 1.3% [95% CI, 0-3.0]). Application of these criteria to the validation data set confirmed the diagnostic accuracy of the score (probability of CT, 0%). Sensitivity was 100% and specificity was 26.9% for the score in the validation data set. When applied to the validation data set, the score avoided 25.4% of CT tests and screened 100% of CT-infected women before surgical abortion. CONCLUSIONS: This easy-to-calculate score may prove useful for avoiding CT test in 25% of patients seeking surgical abortion.
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Aborto Inducido , Infecciones por Chlamydia/diagnóstico , Chlamydia trachomatis/aislamiento & purificación , Tamizaje Masivo , Procedimientos Innecesarios , Aborto Inducido/efectos adversos , Adulto , Instituciones de Atención Ambulatoria , Femenino , Francia , Política de Salud , Humanos , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Embarazo , Derivación y Consulta , Estudios RetrospectivosRESUMEN
OBJECTIVE: The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. METHODOLOGY: We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CASES: Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. CONCLUSION: TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.
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Factor Nuclear 1-beta del Hepatocito/genética , Riñón Displástico Multiquístico/genética , Mutación , Páncreas/anomalías , Adulto , Pie Equinovaro/genética , Femenino , Edad Gestacional , Heterocigoto , Humanos , Riñón Displástico Multiquístico/diagnóstico por imagen , Riñón Displástico Multiquístico/patología , Oligohidramnios/genética , Páncreas/diagnóstico por imagen , Páncreas/patología , Fenotipo , Embarazo , Ultrasonografía PrenatalRESUMEN
Cutaneous melanoma is associated with strong prognostic phenotypic features, such as gender, Breslow's thickness and ulceration, although the biological significance of these variables is largely unknown. It is likely that these features are surrogates of important biological events rather than directly promoting cutaneous melanoma progression. In this article, we address the molecular mechanisms that drive these phenotypic changes. Furthermore, we present a comprehensive overview of recurrent genetic abnormalities, both germline and somatic, in relation to cutaneous melanoma subtypes, ultraviolet exposure and anatomical localization, as well as pre-existing and targeted therapy-induced mutations that may contribute to resistance. The increasing knowledge of critically important oncogenes and tumor-suppressor genes is promoting a transition in melanoma diagnosis, in which single-gene testing will be replaced by multiplex and multidimensional analyses that combine classical histopathological characteristics with the molecular profile for the prognostication and selection of melanoma therapy.
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Petechiae, one of the classic signs of asphyxia, are thought to be more frequently observed in cases of hanging where part of the body is supporting the victim's weight, ie, cases of incomplete hanging. However, there is very little evidence-based medicine to support this claim. The present study is intended to evaluate the relationship between petechiae and the type of hanging (complete vs. incomplete). Furthermore, several other variables were analyzed to determine if they contribute significantly to the presence of petechiae. An 8.5-year retrospective study of 206 cases of death by hanging reviewed autopsy reports for the presence of petechiae. For each case, the following information was also compiled: gender and age, height and weight, body mass index, the type of hanging (complete or incomplete suspension), the type of ligature used (narrow or wide), and whether or not the victim had received cardiopulmonary resuscitation maneuvers. Statistical analysis revealed that the incidence was higher among incomplete hanging victims compared with cases of complete suspension and that the incidence of petechiae varied inversely with the height of the victims. The other factors were not shown to contribute significantly to the presence of petechiae.
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Asfixia/patología , Traumatismos del Cuello/patología , Púrpura/patología , Adolescente , Adulto , Factores de Edad , Estatura , Índice de Masa Corporal , Peso Corporal , Reanimación Cardiopulmonar , Niño , Femenino , Patologia Forense , Humanos , Incidencia , Modelos Logísticos , Masculino , Estudios Retrospectivos , SuicidioRESUMEN
The FoxP3 (forkhead box P3) gene is an X-linked gene that is submitted to inactivation. It is an essential transcription factor in CD4(+)CD25(+)FoxP3 regulatory T cells, which are therapeutic targets in disseminated cutaneous melanoma. Moreover, FoxP3 is an important tumor suppressor gene in carcinomas and has putative cancer suppressor gene function in cutaneous melanoma as well. Therefore understanding the structure and function of the FoxP3 gene is crucial to gaining insight into the biology of melanoma to better develop immunotherapeutics and future therapeutic strategies.
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Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Animales , Humanos , Melanoma/genética , Neoplasias Cutáneas/genéticaRESUMEN
Smothering is defined as an obstruction of the air passages above the level of the epiglottis, including the nose, mouth, and pharynx. This is in contrast to choking, which is considered to be due to an obstruction of the air passages below the epiglottis. The manner of death in smothering can be homicidal, suicidal, or an accident. Accidental smothering is considered to be a rare event among middle-aged adults, yet many cases still occur. Presented here is the case of a 39-year-old woman with a history of bipolar disease who was found dead on her living room floor by her neighbors. Her hands were covered in scratches and her pet cat was found disemboweled in the kitchen with its tail hacked off. On autopsy her stomach was found to be full of cat intestines, adipose tissue, and strips of fur-covered skin. An intact left kidney and adipose tissue were found lodged in her throat just above her epiglottis. After a complete investigation, the cause of death was determined to be asphyxia by smothering due to animal tissue.
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Asfixia/etiología , Trastorno Bipolar/psicología , Gatos , Cuerpos Extraños/patología , Mascotas , Adulto , Obstrucción de las Vías Aéreas/etiología , Animales , Asfixia/patología , Femenino , Cuerpos Extraños/complicaciones , Patologia Forense , Contenido Digestivo , HumanosRESUMEN
Despite a dramatic increase in the worldwide prevalence of overweight and obese people in recent years, the implication of this epidemic on forensic practice has barely been studied. Over a one-year period, all autopsy cases performed on adult victims in the province of Quebec (Canada) were retrospectively reviewed (582 cases). In the forensic population, manner of death differed in relation to BMI: underweight people most commonly died of natural causes, whereas normal weight, overweight and obese individuals most commonly died as the result of an accident. Results also revealed an over-representation of underweight victims and under-representation of overweight victims in the forensic population compared to the population of both Quebec and Canada. The latter is particularly worrisome considering it suggests that overweight corpses are less frequently referred for an autopsy. It is important to emphasize to forensic teams that just because an obese person is more likely to suffer from health problems that can lead to death, does not mean a natural death has occurred. Obese people are equally susceptible to unnatural causes of death and it is crucial to maintain an adequate level of suspicion while investigating the cases of these individuals.
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Índice de Masa Corporal , Causas de Muerte , Sobrepeso/epidemiología , Delgadez/epidemiología , Accidentes/mortalidad , Adolescente , Adulto , Anciano , Femenino , Medicina Legal , Homicidio/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Quebec/epidemiología , Estudios Retrospectivos , Distribución por Sexo , Suicidio/estadística & datos numéricosRESUMEN
The pathophysiology of hanging is still poorly understood. This article presents a review of eight animal models: four models of isolated occlusion of the vessels of the neck (group 1), one model of combined tracheal and vessel occlusion (group 2), and three models of true animal hanging (group 3). Occlusion of the airway passages in group 2 did not accelerate respiratory arrest compared to group 1. Cessation of cerebral blood flow, rather than airway obstruction, seems to be the main cause of respiratory decline. In general, muscular movements ceased after 1-3.5 min and early generalized tonic-clonic convulsions were described. Complete circulatory collapse seems to occur between 4 and 8.5 min. These observations from animal models of hanging are compared with the data collected from filmed human hangings. Avenues to improve animal models are discussed.
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Asfixia/fisiopatología , Modelos Animales , Traumatismos del Cuello/fisiopatología , Animales , Presión Sanguínea/fisiología , Isquemia Encefálica/fisiopatología , Gatos , Circulación Cerebrovascular/fisiología , Constricción Patológica/fisiopatología , Perros , Electroencefalografía , Frecuencia Cardíaca/fisiología , Movimiento/fisiología , Parálisis/fisiopatología , Conejos , Ratas , Respiración , Convulsiones/fisiopatologíaRESUMEN
In cases of hanging, the exact mechanism leading to death has yet to be elucidated. Most of our contemporary knowledge is still based on writings from the end of the 19th and the beginning of the 20th century. This article reviews the historic experiments that shaped our current theories. Medico-legal textbooks written in English and French from 1870 to 1930 were reviewed. Various animals, such as rabbits, mice, and dogs, have been used to develop animal models of hanging. Limited human studies on cadavers and judicial hangings have provided some additional insight into the pathophysiology of death by hanging. The main pathophysiological theories described were respiratory asphyxia, interruption to cerebral blood flow because of occlusion of vessels in the neck, and cardiac inhibition secondary to nerve stimulation. The relative contributions of each of these theories to death in cases of hanging is still debated today.
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Asfixia/fisiopatología , Traumatismos del Cuello/fisiopatología , Obstrucción de las Vías Aéreas/fisiopatología , Animales , Constricción Patológica , Patologia Forense , Humanos , Cuello/irrigación sanguínea , Convulsiones/fisiopatologíaRESUMEN
Mutations in mitochondrial DNA (mtDNA) are associated with a broad spectrum of clinical disorders. The segregation pattern of pathogenic mtDNAs is an important determinant of both the onset and the severity of the disease phenotype, but the mechanisms controlling mtDNA segregation remain poorly understood. To investigate this, we previously generated heteroplasmic mice containing two different mtDNA haplotypes and showed that BALB/c mtDNA was invariably selected over NZB mtDNA in blood and spleen. Here, we have characterized this process in hematopoietic tissues and tested whether it involves the presentation of mtDNA-encoded peptides by MHC class Ib molecules. Selection against NZB mtDNA was widespread across different hematopoietic cell lineages and proportional to heteroplasmy levels. Backcrossing heteroplasmic mice with CAST/Ei, a strain in which the MHC class Ib molecule H2-M3 is silent, completely abolished selection against NZB mtDNA in the spleen. To test whether this effect depended on an intact immune system, we generated heteroplasmic mice missing functional copies of Tap1, beta2m or Rag1 to impair presentation or recognition of mtDNA-encoded peptides. The kinetics of selection against NZB mtDNA were unaltered in these mice compared with their wild-type littermates. We conclude that mtDNA selection in hematopoietic tissues is not based on an immune mechanism, but likely involves metabolic signaling.