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CONTEXT: The COVID-19 pandemic highlighted the significance of public health laboratories across the United States, while also revealing weaknesses in the laboratory system. OBJECTIVE: To identify actionable recommendations for building a more resilient public health laboratory system based on previously published lessons learned from COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In April 2023, the Association of Public Health Laboratories, in cooperation with RAND , convened a 1.5-day after action review workshop of approximately 30 public health laboratory stakeholders to reevaluate priorities, improve processes, and affect policies. MAIN OUTCOME MEASURES: Analysis of workshop discussions identified 5 priority areas and 19 recommendations related to clarifying laboratories' unique role and promoting workforce capacity/agility, technology, and collaboration with governmental and nongovernmental partners. RESULTS: Within the identified priority areas, workshop participants described how the recommendations would address challenges encountered during COVID-19 and contribute to strengthening the system. CONCLUSIONS: As the risk of novel infectious diseases persists and grows, the importance of maintaining laboratory response capabilities is likely to increase. Addressing the system's weaknesses will require active engagement of laboratories and the many stakeholders who depend on them, along with consistent, adequate funding to strengthen and sustain capabilities.
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COVID-19 , Laboratorios , Salud Pública , SARS-CoV-2 , COVID-19/epidemiología , COVID-19/prevención & control , Humanos , Estados Unidos , Salud Pública/métodos , Salud Pública/tendencias , Laboratorios/organización & administración , Laboratorios/normas , Pandemias/prevención & controlRESUMEN
INTRODUCTION: Human papillomavirus (HPV) is an epidemic currently affecting 80 million people in the United States. The HPV virus can be passed from one person to another via sexual intercourse, oral sex, open mouth kissing and skin-to-skin contact. In some cases, the infection is not eliminated by the immune system and can cause cancer of the head and neck, cervix, anus, and genitals. There has been a rise in oropharyngeal cancer (OPC) associated with HPV, which can be missed on conventional dental screening examinations. Dentists should engage in promoting HPV vaccination as a primary measure for OPC prevention. The goal of this HPV pilot program was to educate and offer same day HPV vaccination to dental patients by using a multidisciplinary approach in a hospital setting. METHODS: Patients 18 through 26 years of age who presented to the Erie County Medical Center's dental clinic were approached and educated on HPV. Eligible patients received a direct recommendation for the HPV vaccine. Those interested in same day vaccination were referred to the division of infectious diseases' YOU Center for Wellness. A retrospective chart review was completed for patients who were HPV educated from March 5, 2020, through December 15, 2021. Charts were evaluated for age, sex, race, ethnicity, reason for visit, HPV vaccine referral, and HPV vaccine administration. RESULTS: 326 patients were included in the chart review. The prominent sex, race, and ethnicity were male, Black or African American, and non-Hispanic origin. The median age was 23. Most patients presented to the dental clinic for an emergency visit and were not previously vaccinated against HPV. 110 patients were unvaccinated, and 44 patients were referred to the division of infectious disease for same day vaccination. Of these 44, 24 patients initiated the vaccination process. Five patients received all three doses, three patients received two doses, and 16 patients received one dose. CONCLUSION: This pilot program successfully vaccinated 24 patients with at least a single dose of the HPV vaccine. This multidisciplinary model can be implemented in other health care settings.
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Children with attention-deficit/hyperactivity disorder (ADHD) experience a host of social problems, in addition to significant impairments in behavioral inhibition, working memory, and self-control. Behavioral inhibition and working memory difficulties have been linked with social functioning deficits, but to date, most studies have examined these neurocognitive problems either in isolation or as an aggregate measure in relation to social problems, and none has considered the role of self-control. Thus, it remains unclear whether all of these executive functions are linked with social problems or if the link can be more parsimoniously explained by construct overlap. Fifty-eight children with ADHD and 63 typically developing (TD) children completed tests assessing self-control, behavioral inhibition, and working memory; parents and teachers rated children's social functioning. Examination of potential indirect effects with the bootstrapping procedure indicated that working memory mediated the relation between group membership (ADHD, TD) and child social functioning based on teacher but not parent ratings. Behavioral inhibition and self-control did not have direct relations with either parent- or teacher-rated social functioning. These findings point to important differences regarding how executive functioning difficulties manifest at school compared to home, as well as the specific executive function components that predict ADHD-related social difficulties.
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The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions.
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Neoplasias Renales , Tumor de Wilms , Humanos , Neoplasias Renales/terapia , Recurrencia Local de Neoplasia , Tumor de Wilms/terapia , Biomarcadores , BiologíaAsunto(s)
Enfermedades Autoinmunes , Síndrome Linfoproliferativo Autoinmune , Trastornos Linfoproliferativos , Humanos , Niño , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/tratamiento farmacológico , Síndrome Linfoproliferativo Autoinmune/genética , Sirolimus/efectos adversos , Receptor fas/genética , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/tratamiento farmacológico , ApoptosisRESUMEN
PURPOSE: Malignant rhabdoid tumour (MRT) is a rare and aggressive childhood malignancy that occurs in the kidneys or central nervous system and is associated with very poor prognosis. Chemoresistance is a major issue in the treatment of this malignancy leading to an urgent need for a greater understanding of its underlying mechanisms in MRT and novel treatment strategies for MRT patients. The balance between oxidative stress mediated by reactive oxygen species (ROS) and the antioxidant system has become a subject of interest in cancer therapy research. Studies have implicated key players of the antioxidant system in chemotherapeutic including the well-known antioxidant glutathione (GSH) and the transcription factor nuclear erythroid-related factor-2 (Nrf2). METHODS: This study evaluated the role of these components in the response of MRT cells to treatment with the commonly used chemotherapeutic agent, cisplatin. RESULTS: This study characterised the basal levels of GSH, ROS and Nrf2 in a panel of MRT cell lines and found a correlation between the expression profile of the antioxidant defence system and cisplatin sensitivity. Results showed that treatment with ROS scavenger N-acetylcysteine (NAC) protected cells from cisplatin-induced ROS and apoptosis. Interestingly, depleting GSH levels with the inhibitor buthionine sulphoximine (BSO) enhanced cisplatin-induced ROS and sensitised cells to cisplatin. Lastly, targeting Nrf2 with the small molecule inhibitor ML385 or by siRNA diminished GSH levels, enhanced ROS and sensitised resistant MRT cells to cisplatin. CONCLUSIONS: These results suggest that targeting the Nrf2/GSH antioxidant system may present a novel therapeutic strategy to combat chemoresistance in rhabdoid tumours.
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Cisplatino , Tumor Rabdoide , Humanos , Niño , Cisplatino/farmacología , Antioxidantes/farmacología , Tumor Rabdoide/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Glutatión/metabolismo , Butionina Sulfoximina , Apoptosis , Línea Celular TumoralRESUMEN
As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.
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Infecciones por Adenovirus Humanos , Coinfección , Dependovirus , Hepatitis , Niño , Humanos , Enfermedad Aguda , Infecciones por Adenovirus Humanos/epidemiología , Infecciones por Adenovirus Humanos/virología , Coinfección/epidemiología , Coinfección/virología , Dependovirus/genética , Dependovirus/aislamiento & purificación , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/virología , Hepatitis/epidemiología , Hepatitis/virología , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 6/aislamiento & purificación , Enterovirus Humano A/aislamiento & purificación , Virus Helper/aislamiento & purificaciónRESUMEN
BACKGROUND: Outcomes in pediatric ulcerative colitis (UC) are heterogeneous and predictors of disease course eagerly sought. Mucosal atrophy (MA) is characterized by histological abnormalities of colonic intestinal glands. OBJECTIVE: To determine the prevalence of MA in a national inception cohort of pediatric UC and its impact on outcomes. METHODS: Irish children < 16 years old with UC are diagnosed at a single referral center. At diagnosis, patients underwent phenotyping by Paris classification and activity assessment by Pediatric Ulcerative Colitis Activity Index. Biopsies from all colonic segments were evaluated for MA. Patients were followed prospectively. The primary outcome was corticosteroid-free remission at 1 year. Secondary outcomes included relapse, treatment escalation, and colectomy by 2 years. RESULTS: Of 251 pediatric patients with UC (mean age 11.8 years, 55% male), 38 (15%) had MA on diagnostic biopsy. Baseline characteristics were similar between groups with/without MA and there was no difference in steroid-free remission or rates of moderate-severe UC at 1 year. Patients with MA had higher use of steroids (29% vs 15%, P = 0.04) and immunomodulators (40% vs 21%, P = 0.04) at 6 months, higher biologic use at 1 year (34% vs 16%, P = 0.03), earlier first relapse (mean ± SD 29.4 ± 26.1 vs 46.7 ± 43.4 weeks after diagnosis, P = 0.02), and higher colectomy rates by 2 years (21% vs 8%, P = 0.01). CONCLUSIONS: Children with MA at diagnosis had higher colectomy rates despite earlier treatment escalation and similar baseline severity scores. We identify MA as a promising new prognostic marker in children with newly diagnosed UC.
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Colitis Ulcerosa , Humanos , Masculino , Niño , Adolescente , Femenino , Estudios de Cohortes , Resultado del Tratamiento , Colitis Ulcerosa/cirugía , Colitis Ulcerosa/diagnóstico , Colectomía , RecurrenciaRESUMEN
The surgical resection of malignant tumors often leads to severe bone and soft-tissue deficits that can result in difficulty swallowing, impaired speech, and facial disfigurement. Prosthetic rehabilitation of these patients becomes an integral part of the patient's recovery and allows for improvement in quality of life. This clinical report describes a patient who underwent an anterior maxillectomy secondary to squamous cell carcinoma. After the insertion of a polymethyl methacrylate (PMMA) interim resection prosthesis, the patient developed a severe allergic stomatitis reaction in the oral cavity and oropharynx. By using the patch test approach, true PMMA allergy was diagnosed along with a suitable PMMA replacement for the prosthesis. A subsequent prosthesis was fabricated from urethane dimethacrylate in place of the standard PMMA.
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Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with infantile-onset chronic diarrhea. Genomic deletions in chromosome 16, encompassing a sequence termed the 'intestine-critical region (ICR)', were recently identified as the cause of an autosomal recessive congenital enteropathy. The regulatory sequence within the ICR is flanked by an unannotated open reading frame termed PERCC1, which plays a role in enteroendocrine cell (EEC) function. We investigated two unrelated children with idiopathic congenital diarrhea requiring home parenteral nutrition attending the Irish Intestinal Failure Program. Currently 12 and 19-years old, these Irish male patients presented with watery diarrhea and hypernatremic dehydration in infancy. Probands were phenotyped by comprehensive clinical investigations, including endoscopic biopsies and serum gastrin level measurements. Following negative exome sequencing, PCR and Sanger sequencing of the entire coding region and intron boundaries of PERCC1 were performed for each proband and their parents. In both patients, serum gastrin levels were low and failed to increase following a meal challenge. While no deletions involving the ICR were detected, targeted sequencing of the PERCC1 gene revealed a shared homozygous c.390C > G stop gain variant. We report clinical and molecular findings in two unrelated patients harboring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene in association with CODE. That both parenteral nutrition dependent children with unexplained diarrhea at our institution harbored a PERCC1 mutation underscores the importance of its inclusion in exome sequencing interpretation.
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Codón sin Sentido , Gastrinas , Adolescente , Adulto , Niño , Humanos , Masculino , Adulto Joven , Diarrea/genética , Gastrinas/genética , Mutación , FenotipoRESUMEN
Malignant rhabdoid tumour (MRT) is a rare and aggressive paediatric tumour that typically arises in the kidneys or central nervous system (CNS). The malignancy often affects patients under the age of three and is associated with an extremely poor survival rate, with most deaths occurring within the first year of presentation. Thus, there is an unmet and urgent medical need for novel therapeutic strategies for this malignancy. One of the major issues when treating MRT patients is the emergence of chemoresistance. Autophagy has become an area of focus in the study of chemoresistance due to its reported dual role as both a pro-survival and pro-death mechanism. The role of autophagy in the chemotherapeutic response of MRT remains largely unknown. A greater understanding of the role of autophagy may lead to the development of therapeutic strategies to enhance chemotherapeutic effect and improve the clinical outcome of MRT patients. This study evaluated the cellular response to cisplatin, a representative chemotherapeutic agent used in the treatment of MRT, and the role of autophagy in mediating cisplatin resistance. Our results demonstrated that cisplatin induced apoptosis and autophagy concomitantly in a panel of MRT cell lines. Furthermore, inhibition of caspase-induced apoptosis with Z-VAD-FMK also inhibited autophagy levels demonstrating a complex interplay between these two pathways. In addition, blocking autophagy at the early stages of the autophagic process using the pharmacological inhibitor SAR405 or through the genetic knockdown of critical autophagic protein ATG5 by siRNA did not sensitise cells to cisplatin-induced apoptosis. Collectively, these results suggest that induction of autophagy does not appear to elicit a pro-survival effect in the chemotherapeutic response of MRT cells.
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Antineoplásicos , Tumor Rabdoide , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Autofagia , Niño , Cisplatino/farmacología , Cisplatino/uso terapéutico , Humanos , Tumor Rabdoide/tratamiento farmacológico , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologíaRESUMEN
Malignant rhabdoid tumour (MRT) is a rare, aggressive paediatric malignancy most commonly diagnosed in those below the age of three. MRTs can arise in soft tissue but are more often associated with the central nervous system or kidney. Unfortunately, the prognosis upon diagnosis with MRT is poor. Given the resistance of MRT to current treatment protocols including cisplatin, and the vulnerability of this young patient population to aggressive therapies, there is a need for novel treatment options. Several members of the inhibitor of apoptosis protein (IAP) family including Xlinked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/cIAP2), livin and survivin have been implicated in chemotherapy resistance in various malignancies. We have previously demonstrated expression of these IAP family members in a panel of MRT cell lines. In the present study, sensitivity of this same panel of MRT cell lines to small-molecule mediated inhibition of the IAPs via the survivin inhibitor YM155 and the XIAP/cIAP1/cIAP2 inhibitor BV6 was demonstrated. Additionally, both BV6 and the XIAP inhibitor embelin synergistically enhanced cisplatin mediated apoptotic cell death in MRT cell lines, with enhanced caspase-3 cleavage. Importantly, we have demonstrated, for the first time, expression of XIAP, its target caspase-3 and its endogenous inhibitor SMAC in rhabdoid tumour patient tissue. In conclusion, this study provides pre-clinical evidence that IAP inhibition may be a new therapeutic option in MRT.
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Cisplatino , Proteínas Inhibidoras de la Apoptosis , Tumor Rabdoide , Antineoplásicos/uso terapéutico , Caspasa 3/metabolismo , Línea Celular Tumoral , Niño , Cisplatino/farmacología , Cisplatino/uso terapéutico , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/metabolismo , Tumor Rabdoide/tratamiento farmacológico , SurvivinRESUMEN
OBJECTIVE: A growing body of research provides reliable evidence of moderate to large magnitude deficits in the visuospatial (VS) working memory (WM) of children with attention-deficit/hyperactivity disorder (ADHD), relative to typically developing (TD) children. Studies of ADHD-related Visuo-spatial Working Memory (VS-WM) functioning most often present sequential presentations of VS stimuli and examine general performance characteristics. Only a few studies have examined the effects of varying VS-WM task parameters on performance in children with ADHD, despite evidence from basic-cognitive research that indicates methodological heterogeneity in VS-WM task parameters yields significant performance variability that is associated with underlying mechanistic processes. This study is the first to examine the effect of the task parameters path characteristics and path crossings on performance in children with ADHD and TD children. METHOD: School-aged children with ADHD (n = 50) and TD children (n = 59) completed a VS-WM task that varied by path lengths and path crossings. RESULTS: Multilevel analyses indicated a negative effect of relatively long paths on VS-WM performance of both TD children and children with ADHD, and a negative effect of increasing path crossings that appears to be unique to TD children and dependent on path length. CONCLUSIONS: Overall, findings appear to suggest that school-aged children engage in dynamic rehearsal of VS information (i.e., mental rehearsal of path sequences), rather than static rehearsal (i.e., rehearsal of a gestalt). Moreover, ADHD-related VS-WM deficits are most likely to yield real-world impairments when information is presented with relatively long path lengths. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Trastorno por Déficit de Atención con Hiperactividad , Memoria a Corto Plazo , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Humanos , Aprendizaje , Trastornos de la Memoria/complicaciones , Pruebas NeuropsicológicasRESUMEN
This report presents a case in which oral soft tissue lesions were the first signs of multiple myeloma (MM) following a solid-organ transplantation. A 75-year-old man presented with bilateral primary oral gingival masses in the posterior mandible approximately 2 months after tooth extractions. A panoramic radiograph appeared normal and did not reveal "punched-out" lytic lesions of the bone, a classic sign of MM. A biopsy of the gingival masses was performed, and the resulting diagnosis was a plasma cell neoplasm. After a hematologic screening, positron emission tomography/computed tomography, and bone marrow biopsy, the diagnosis of MM with extensive disease was confirmed. Oral manifestations of MM are common, making the patient's oral health history an integral part of diagnosis. Although the isolated gingival hypertrophy observed in the present case is an atypical oral presentation, an understanding of the maxillofacial manifestations of MM is important to ensure diagnosis in the early stages of disease.
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Trasplante de Riñón , Mieloma Múltiple , Anciano , Biopsia , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Mandíbula/patología , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/patología , Radiografía PanorámicaRESUMEN
PURPOSE: The purpose of the report is to present a rare case of clinical management of a 26-year-old patient with fibrodysplasia ossificans progressiva (FOP), and discuss treatment options and possible outcomes. SUMMARY: FOP is a rare autosomal dominant genetic disorder of the connective tissue that affects one in two million people. It is characterized by multiple areas of progressive heterotopic endochondral ossifications. The symptoms typically begin with painful soft tissue swellings in the patient's first decade, which frequently occur after minor trauma, but may also happen spontaneously. The soft tissue swellings eventually form hard bony masses that cause joint limitations, growth defects, skeletal deformities, and chronic pain. The results are severely limiting to the activities of daily living and overall quality of life with the average life expectancy being 40 years of age. Medical and dental treatment, including the use of general anesthesia, may be complicated by increased risk of ossification of the soft tissues in the airway and lungs. The following case report focuses on a 26-year-old Caucasian female, with FOP. The patient presented to the Erie County Medical Center Dental clinic in Spring 2019 with generalized dental pain. She reported a history of multiple dental infections over many years which were periodically treated with antibiotics. A thorough intraoral exam and radiographs were not able to be completed upon initial presentation due to severe trismus and mobility limitations. The patient was a wheelchair user, verbal, and maintained a completely liquid diet by mouth. The patient also had a medical history significant for dysphagia and aspiration. After a substantial pre-operative optimization process, the patient was brought to the operating room for full mouth dental extractions. At the 2-week follow-up from surgery the patient showed excellent healing. CONCLUSION: While there are greater potential risks with placing a patient with FOP patient under general anesthesia, proper management of dental disease can relieve the patient from recurrent infections and discomfort.
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Miositis Osificante , Actividades Cotidianas , Adulto , Atención Odontológica , Femenino , Humanos , Miositis Osificante/complicaciones , Miositis Osificante/diagnóstico , Miositis Osificante/terapia , Calidad de VidaRESUMEN
HK1 deficient Haemolytic Anaemia in association with a Neurological Phenotype & co-existing Meckel-Gruber due to CEP290 in a Romani family.
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Anemia Hemolítica/diagnóstico , Anemia Hemolítica/genética , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Trastornos de la Motilidad Ciliar/diagnóstico , Trastornos de la Motilidad Ciliar/genética , Proteínas del Citoesqueleto/genética , Encefalocele/diagnóstico , Encefalocele/genética , Hexoquinasa/genética , Mutación , Fenotipo , Enfermedades Renales Poliquísticas/diagnóstico , Enfermedades Renales Poliquísticas/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Alelos , Sustitución de Aminoácidos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , LinajeRESUMEN
Replication-competent virus has not been detected in individuals with mild to moderate coronavirus disease 2019 (COVID-19) more than 10 days after symptom onset. It is unknown whether these findings apply to nursing home residents. Of 273 specimens collected from nursing home residents >10 days from the initial positive test, none were culture positive.
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COVID-19 , SARS-CoV-2 , Humanos , Casas de Salud , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción ReversaRESUMEN
Human cancer typically results from the stochastic accumulation of multiple oncogene-activating and tumor-suppressor gene-inactivating mutations. However, this process takes time and especially in the context of certain pediatric cancer, fewer but more 'impactful' mutations may in short order produce the full-blown cancer phenotype. This is well exemplified by the highly aggressive malignant rhabdoid tumor (MRT), where the only gene classically showing recurrent inactivation is SMARCB1, a subunit member of the BAF chromatin-remodeling complex. This is true of all three presentations of MRT including MRT of kidney (MRTK), MRT of the central nervous system (atypical teratoid rhabdoid tumor-ATRT) and extracranial, extrarenal rhabdoid tumor (EERT). Our reverse modeling of rhabdoid tumors with isogenic cell lines, either induced or not induced, to express SMARCB1 showed widespread differential chromatin remodeling indicative of altered BAF complex activity with ensuant histone modifications when tested by chromatin immunoprecipitation followed by sequencing (ChIP-seq). The changes due to reintroduction of SMARCB1 were preponderantly at typical enhancers with tandem BAF complex occupancy at these sites and related gene activation, as substantiated also by transcriptomic data. Indeed, for both MRTK and ATRT cells, there is evidence of an overlap between SMARCB1-dependent enhancer activation and tissue-specific lineage-determining genes. These genes are inactive in the tumor state, conceivably arresting the cells in a primitive/undifferentiated state. This epigenetic dysregulation from inactivation of a chromatin-remodeling complex subunit contributes to an improved understanding of the complex pathophysiological basis of MRT, one of the most lethal and aggressive human cancers.
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Linfoma Anaplásico de Células Grandes , Quinasa de Linfoma Anaplásico/genética , Brentuximab Vedotina , Niño , Humanos , Estudios Longitudinales , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Terapia Molecular DirigidaRESUMEN
The paucity of recurrent mutations has hampered efforts to understand and treat neuroblastoma. Alternative splicing and splicing-dependent RNA-fusions represent mechanisms able to increase the gene product repertoire but their role in neuroblastoma remains largely unexplored. Here we investigate the presence and possible roles of aberrant splicing and splicing-dependent RNA-fusion transcripts in neuroblastoma. In addition, we attend to establish whether the spliceosome can be targeted to treat neuroblastoma. Through analysis of RNA-sequenced neuroblastoma we show that elevated expression of splicing factors is a strong predictor of poor clinical outcome. Furthermore, we identified >900 primarily intrachromosomal fusions containing canonical splicing sites. Fusions included transcripts from well-known oncogenes, were enriched for proximal genes and in chromosomal regions commonly gained or lost in neuroblastoma. As a proof-of-principle that these fusions can generate altered gene products, we characterized a ZNF451-BAG2 fusion, producing a truncated BAG2-protein which inhibited retinoic acid induced differentiation. Spliceosome inhibition impeded neuroblastoma fusion expression, induced apoptosis and inhibited xenograft tumor growth. Our findings elucidate a splicing-dependent mechanism generating altered gene products in neuroblastoma and show that the spliceosome is a potential target for clinical intervention.