RESUMEN
We present a case of herpes zoster ophthalmicus (HZO) with a rare complication of orbital apex syndrome (OAS) manifesting as optic perineuritis with multiple cranial nerve palsies. A 65-year-old with COPD presented to the hospital with a vesicular rash involving his left eyelid. He was admitted for HZO and a concurrent COPD exacerbation. The HZO was treated with antivirals and the COPD exacerbation was treated with corticosteroids. On hospital day three, he developed left-sided ptosis, ophthalmoplegia, and a mid-dilated fixed pupil. MRI of the brain demonstrated enhancement of the left optic nerve sheath, rectus muscles, and periorbital soft tissues. He was diagnosed with OAS and treated with an increased dose of corticosteroids. After two months, his orbital symptoms resolved. This case is unique because the patient developed HZO in the setting of corticosteroid treatment for a COPD exacerbation, and his HZO progressed to OAS despite proper initiation of antiviral therapy.
Asunto(s)
Herpes Zóster Oftálmico , Oftalmoplejía , Enfermedad Pulmonar Obstructiva Crónica , Masculino , Humanos , Anciano , Herpes Zóster Oftálmico/complicaciones , Herpes Zóster Oftálmico/tratamiento farmacológico , Herpes Zóster Oftálmico/diagnóstico , Oftalmoplejía/tratamiento farmacológico , Oftalmoplejía/etiología , Oftalmoplejía/diagnóstico , Antivirales/uso terapéutico , Síndrome , Corticoesteroides/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/complicacionesRESUMEN
The mechanisms of Myc-driven liver tumorigenesis are inadequately understood. Herein we show that Myc-driven hepatocellular carcinoma (HCC) is dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion. However, Myc-induced tumors develop selectively from the rare Shp2-positive hepatocytes in Shp2-deficent liver, and Myc-driven oncogenesis depends on an intact Ras-Erk signaling promoted by Shp2 to sustain Myc stability. Despite a stringent requirement of Shp2 cell autonomously, Shp2 deletion induces an immunosuppressive environment, resulting in defective clearance of tumor-initiating cells and aggressive tumor progression. The basal Wnt/ß-catenin signaling is upregulated in Shp2-deficient liver, which is further augmented by Myc transfection. Ablating Ctnnb1 suppresses Myc-induced HCC in Shp2-deficient livers, revealing an essential role of ß-catenin. Consistently, Myc overexpression and CTNNB1 mutations are frequently co-detected in HCC patients with poor prognosis. These data elucidate complex mechanisms of liver tumorigenesis driven by cell-intrinsic oncogenic signaling in cooperation with a tumor-promoting microenvironment generated by disrupting the specific oncogenic pathway.
Asunto(s)
Carcinoma Hepatocelular/patología , Hepatocitos/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/fisiología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Análisis de la Célula Individual/métodos , Microambiente Tumoral , Animales , Biomarcadores de Tumor , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Hepatocitos/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas c-myc/genética , Transcriptoma , Vía de Señalización Wnt , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: While commonly seen in syndromic craniosynostosis, the incidence of Chiari malformation (CM) in nonsyndromic craniosynostosis has been reported at 5% and there is a lack of understanding of the pathophysiology and management of CM in this patient population. CASE DESCRIPTION: We present a 5-year-old male patient who underwent a sagittal craniosynostosis repair at the age of 5 months and returned at the age of 5 years with daily headaches associated with behavioral changes. He was found to have pan-synostoses and radiographic evidence of increased intracranial pressure, including a Chiari malformation. Neurologic and genetic workup was unremarkable. A cranial vault reconstruction was performed, and subsequent imaging demonstrated resolution of previously noted Chiari malformation. CONCLUSIONS: In our case, we provided a unique window into the underlying pathophysiology for CM in patients with concurrent nonsyndromic craniosynostosis that we hope will add to the current foundation of literature supporting the intricate relation between cranial vault compliance and Chiari malformation or hindbrain herniation. Furthermore, we provide insight into the management of acquired CM and support isolated cranial vault reconstruction in those who do not appear to have symptomatic suboccipital compression.
Asunto(s)
Malformación de Arnold-Chiari/cirugía , Craneosinostosis/cirugía , Procedimientos Neuroquirúrgicos/métodos , Procedimientos de Cirugía Plástica/métodos , Cráneo/cirugía , Malformación de Arnold-Chiari/etiología , Malformación de Arnold-Chiari/psicología , Trastornos de la Conducta Infantil/etiología , Trastornos de la Conducta Infantil/psicología , Preescolar , Craneosinostosis/complicaciones , Craneosinostosis/psicología , Cefalea/etiología , Humanos , Presión Intracraneal , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
PURPOSE: This study tested the hypothesis that stress conditions that simulated percutaneous thermal ablation (PTA), transarterial embolization (TAE), or transarterial chemoembolization stimulated enrichment of hepatocellular carcinoma (HCC) cancer stem cells (hCSCs) and that hCSC inhibitors can suppress this effect. MATERIALS AND METHODS: Human HCC cell lines HepG2 and PLC/PRF/5 were subjected to a 46.5°C heat bath for 10 minutes or to 1% hypoxia for 72 hours without fetal bovine serum and with or without doxorubicin. Cells were then treated with a ß-catenin inhibitor (FH535 or XAV939), a PI3 kinase inhibitor (Ly294002), or niclosamide, a US Food and Drug Administration-approved antihelminthic drug that acts as a mitochondrial decoupler and mixed inhibitor. Surviving cells were analyzed for hCSC markers by flow cytometry, for stemness by colony-forming assay or sphere-forming assay, and for proliferative capacity by MTT assay (where MTT is 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide). Expression of proteins related to CSC renewal and proliferation were analyzed by immunoblotting and immunostaining. RESULTS: Conditions that simulated PTA, TAE, and transarterial chemoembolization resulted in an enrichment of cells bearing hCSC markers (CD133, CD44, and EpCAM). Cells surviving heat stress exhibited higher colony- or sphere-forming capacity and a greater proliferative state. These effects could be suppressed by niclosamide and inhibitors of ß-catenin and PI3 kinase. CONCLUSIONS: Stress conditions induced by locoregional therapies stimulated hCSC enrichment and proliferation, which could be suppressed by niclosamide and inhibitors of pathways important for hCSC renewal. Future studies will determine whether combining locoregional therapies with adjuvant hCSC inhibitors reduces HCC recurrence.
Asunto(s)
Técnicas de Ablación/efectos adversos , Carcinoma Hepatocelular/terapia , Proliferación Celular/efectos de los fármacos , Quimioembolización Terapéutica/efectos adversos , Embolización Terapéutica/efectos adversos , Calor/efectos adversos , Neoplasias Hepáticas/terapia , Células Madre Neoplásicas/efectos de los fármacos , Microambiente Tumoral , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Respuesta al Choque Térmico , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fenotipo , Transducción de Señal , Hipoxia TumoralRESUMEN
BACKGROUND & AIMS: Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogens or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), ß-catenin and PIK3CA. METHODS: We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and ΔN90-ß-catenin (MET/CAT), or c-Met and PIK3CAH1047R (MET/PIK), into WT and Shp2hep-/- mice. We compared liver tumor loads and investigated the pathogenesis and molecular mechanisms involved using multidisciplinary approaches. RESULTS: Despite the induction of oxidative and metabolic stresses, Shp2 deletion in hepatocytes suppressed hepatocarcinogenesis driven by overexpression of oncoproteins MET/CAT or MET/PIK. Shp2 loss inhibited proliferative signaling from c-Met, Wnt/ß-catenin, Ras/Erk and PI3K/Akt pathways, but triggered cell senescence following exogenous expression of the oncogenes. CONCLUSIONS: Shp2, acting downstream of RTKs, is positively required for hepatocyte-intrinsic tumorigenic signaling from these oncoproteins, even if Shp2 deficiency induces a tumor-promoting hepatic microenvironment. These data suggest a new and more effective therapeutic strategy for HCCs driven by oncogenic RTKs and other upstream molecules, by inhibiting Shp2 and also suppressing any tumor-enhancing stromal factors produced because of Shp2 inhibition. LAY SUMMARY: Primary liver cancer is a malignant disease with poor prognosis, largely because there are limited systemic therapies available. We show here that a cytoplasmic tyrosine phosphatase Shp2 is required for liver tumorigenesis. This tumorigenesis is driven by two oncoproteins that are implicated in human liver cancer. This, together with our previous studies, uncovers the complexity of liver tumorigenesis, by elucidating the pro- and anti-tumor effects of Shp2 in mouse models. This data can be used to guide new therapies.
Asunto(s)
Carcinogénesis/genética , Hepatocitos/metabolismo , Neoplasias Hepáticas Experimentales/genética , Fosfatidilinositol 3-Quinasas/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas c-met/genética , beta Catenina/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Fosfatidilinositol 3-Quinasa Clase I , Hepatocitos/patología , Immunoblotting , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , ARN Neoplásico/genética , Eliminación de Secuencia , Transducción de Señal , beta Catenina/metabolismoRESUMEN
BACKGROUND: The natural history of unrepaired craniosynostosis is not well defined. Delayed surgical intervention carries greater risk of postoperative complications and its functional benefits for older patients are poorly characterized. The authors reviewed patients in whom children presented beyond 1 year of age to better understand the natural history of craniosynostosis, and the risk-benefit relationship for delayed reconstruction. METHODS: After institutional IRB approval the authors conducted a retrospective review of patients who presented after 1 year of age with craniosynostosis. Type of craniosynostosis, age at evaluation, medical history, surgical findings, developmental abnormalities, ophthalmologic findings, and clinical course were reviewed. RESULTS: Ten patients with delayed presentation for craniosynostosis were identified. The mean age at presentation was 6.8 yearsâ±â4.2 years (range, 3-17 years). Seven of 10 patients presented with developmental delay. Five patients presented with debilitating headaches. Five patients presented with comorbid Chiari malformations, 3 of whom required surgical decompression. Two patients had papilledema. Four patients underwent intracranial pressure monitoring, with elevated pressures found in 3 patients. Six patients underwent delayed cranial vault remodeling. There were no peri- or postoperative complications, including infection or residual bony defects, in those undergoing delayed operation. CONCLUSIONS: Children who present in a delayed fashion with unrepaired craniosynostosis have high rates of debilitating headaches, developmental delays, head shape anomalies, and Chiari malformation. Five patients reporting preoperative headaches noted subjective improvements in headaches following delayed operation. Cranial reconstruction can be safely performed at an older age and is appropriate to consider in carefully selected patients for aesthetic and/or functional concerns.
Asunto(s)
Craneosinostosis/cirugía , Descompresión Quirúrgica/métodos , Manejo de la Enfermedad , Cráneo/cirugía , Niño , Craneosinostosis/diagnóstico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Cráneo/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
We report a case of confirmed Mycoplasma pneumoniae infection in the setting of unilateral anterior uveitis and perineuritis without coexisting systemic manifestations. We hypothesize a causal association between acute M. pneumoniae infection and this patient's ocular presentation. Delay in identification of M. pneumoniae infection in this case prompted treatment with systemic and topical steroids for presumed autoimmune etiology. The rapid resolution of symptoms without concurrent antibiotic treatment suggests a possible postinfectious autoimmune component that may be responsive to steroid treatment.
Asunto(s)
Infecciones Bacterianas del Ojo/microbiología , Mycoplasma pneumoniae/aislamiento & purificación , Neuritis Óptica/microbiología , Neumonía por Mycoplasma/microbiología , Uveítis Anterior/microbiología , Enfermedad Aguda , Adolescente , Infecciones Bacterianas del Ojo/diagnóstico , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Imagen por Resonancia Magnética , Neuritis Óptica/diagnóstico , Neuritis Óptica/tratamiento farmacológico , Papiledema/diagnóstico , Papiledema/tratamiento farmacológico , Papiledema/microbiología , Neumonía por Mycoplasma/diagnóstico , Neumonía por Mycoplasma/tratamiento farmacológico , Prednisolona/uso terapéutico , Uveítis Anterior/diagnóstico , Uveítis Anterior/tratamiento farmacológicoRESUMEN
Anemia is a frequently observed adverse effect in cancer patients who receive chemotherapy or drugs designed to block specific oncogenic signaling pathways, although the underlying mechanisms are poorly understood. An article first published online (Zhu HH, Luo X, Zhang K, et al. Proc Natl Acad Sci USA 2015;112:13342-13347) presented data indicating that cell type-specific pathway cross-talk is likely an important mechanism to consider. Shp2 and Pten, two master regulators of central cytoplasmic signaling pathways, oppose each other in myeloproliferation and leukemogenesis, but cooperate in promoting erythropoiesis. Thus, genetic ablation or pharmacologic inhibition of Shp2 suppresses the leukemogenic effect of Pten loss, yet simultaneously induces severe anemia in mice with Pten deficiency in blood cells.
Asunto(s)
Anemia/genética , Eritropoyesis/genética , Leucemia/genética , Transducción de Señal/genética , Anemia/inducido químicamente , Anemia/metabolismo , Animales , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Eritropoyesis/efectos de los fármacos , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Ratones , Ratones Noqueados , Modelos Genéticos , Mutación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Piridonas/farmacología , Piridonas/toxicidad , Pirimidinonas/farmacología , Pirimidinonas/toxicidad , Factores de Riesgo , Transducción de Señal/efectos de los fármacosAsunto(s)
Anomalías Múltiples/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Proteínas de Homeodominio/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Fenotipo , Anomalías Múltiples/patología , Secuencia de Bases , Niño , Trastornos Generalizados del Desarrollo Infantil/patología , Femenino , Estudios de Asociación Genética , Humanos , Datos de Secuencia Molecular , Análisis de Secuencia de ADNRESUMEN
The ability of adult stem cells to reside in a quiescent state is crucial for preventing premature exhaustion of the stem cell pool. However, the intrinsic epigenetic factors that regulate spermatogonial stem cell quiescence are largely unknown. Here, we investigate in mice how DNA methyltransferase 3-like (DNMT3L), an epigenetic regulator important for interpreting chromatin context and facilitating de novo DNA methylation, sustains the long-term male germ cell pool. We demonstrated that stem cell-enriched THY1(+) spermatogonial stem/progenitor cells (SPCs) constituted a DNMT3L-expressing population in postnatal testes. DNMT3L influenced the stability of promyelocytic leukemia zinc finger (PLZF), potentially by downregulating Cdk2/CDK2 expression, which sequestered CDK2-mediated PLZF degradation. Reduced PLZF in Dnmt3l KO THY1(+) cells released its antagonist, Sal-like protein 4A (SALL4A), which is associated with overactivated ERK and AKT signaling cascades. Furthermore, DNMT3L was required to suppress the cell proliferation-promoting factor SALL4B in THY1(+) SPCs and to prevent premature stem cell exhaustion. Our results indicate that DNMT3L is required to delicately balance the cycling and quiescence of SPCs. These findings reveal a novel role for DNMT3L in modulating postnatal SPC cell fate decisions.
Asunto(s)
Células Madre Adultas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/fisiología , Regulación del Desarrollo de la Expresión Génica , Espermatogonias/metabolismo , Alelos , Animales , Proliferación Celular , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Heterocigoto , Masculino , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/metabolismo , Testículo/metabolismo , Factores de Transcripción/metabolismo , Dedos de ZincRESUMEN
DNA methyltransferase 3-like (DNMT3L) is one of the key players in de novo DNA methylation of imprinting control elements and retrotransposons, which occurs after genome-wide epigenetic erasure during germ cell development. In this review, we summarise the biochemical properties of DNMT3L and discuss the possible mechanisms behind DNMT3L-mediated imprinting establishment and retrotransposon silencing in germ cells. We also discuss possible connections between DNMT3L and non-coding RNA-mediated epigenetic remodelling, the roles of DNMT3L in germ cell development and the implications in stem cell and cancer research.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/metabolismo , Epigénesis Genética , Genoma , Células Germinativas/enzimología , Retroelementos/genética , Animales , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , Impresión Genómica , Células Germinativas/citología , Células Germinativas/crecimiento & desarrollo , Histona Desacetilasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Ratones , Neoplasias/enzimología , Neoplasias/patología , Células Madre/citología , Células Madre/enzimologíaRESUMEN
Visual experience and deprivation bidirectionally modify the NR2A and NR2B subunit composition of NMDARs, and these changes in turn modify the properties of synaptic plasticity in the visual cortex. Deprivation-induced lowering of the NR2A/2B ratio can occur by altering either NR2A or NR2B protein levels, but how a reduction in synaptic activity regulates these changes in a subunit-specific manner is poorly understood. Here, we find that visual deprivation in juvenile mice by dark-rearing or monocular lid suture reduces the NR2A/2B ratio in the deprived cortex in temporally distinct phases--initially by increasing NR2B protein levels, and later by decreasing NR2A protein levels. Brief dark-exposure of juvenile rats likewise produces an increase in NR2B expression. Furthermore, we are able to model the early increase in NR2B by blocking NMDARs in vitro, and we find that translation of NR2B is likely a major point of regulation. Translation of NR2A is not regulated in this manner. Therefore, the differential translational regulation of NR2A and NR2B may contribute to experience-dependent modification of NMDAR subunit composition.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Corteza Visual/metabolismo , Amaurosis Fugax/metabolismo , Análisis de Varianza , Animales , Animales Recién Nacidos , Western Blotting , Oscuridad , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Lóbulo Frontal/metabolismo , Lateralidad Funcional/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Estimulación Luminosa/métodos , Embarazo , Privación Sensorial/fisiología , Factores de Tiempo , Corteza Visual/ultraestructuraRESUMEN
Expression of N-methyl d-aspartate (NMDA) receptor-dependent homosynaptic long term depression at synapses in the hippocampus and neocortex requires the persistent dephosphorylation of postsynaptic protein kinase A substrates. An attractive mechanism for expression of long term depression is the loss of surface AMPA (alpha-amino-3-hydroxy-5-methylisoxazale-4-propionate) receptors at synapses. Here we show that a threshold level of NMDA receptor activation must be exceeded to trigger a stable loss of AMPA receptors from the surface of cultured hippocampal neurons. NMDA also causes displacement of protein kinase A from the synapse, and inhibiting protein kinase A (PKA) activity mimics the NMDA-induced loss of surface AMPA receptors. PKA is targeted to the synapse by an interaction with the A kinase-anchoring protein, AKAP79/150. Disruption of the PKA-AKAP interaction is sufficient to cause a long-lasting reduction in synaptic AMPA receptors in cultured neurons. In addition, we demonstrate in hippocampal slices that displacement of PKA from AKADs occludes synaptically induced long term depression. These data indicate that synaptic anchoring of PKA through association with AKAPs plays an important role in the regulation of AMPA receptor surface expression and synaptic plasticity.