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1.
Epileptic Disord ; 2024 May 28.
Article in English | MEDLINE | ID: mdl-38804823

ABSTRACT

OBJECTIVE: Hypothalamic hamartomas are congenital lesions that typically present with gelastic seizures, refractory epilepsy, neurodevelopmental delay, and severe cognitive impairment. Surgical procedures have been reported to be effective in removing the hamartomas, however, they are associated with significant morbidity. Therefore, it is not considered a safe therapeutic modality. Image-guided robotic radiosurgery (CyberKnife® Radiosurgery System) has been shown to provide good outcomes without lasting complications. METHODS: This series of cases describes the clinical, radiological, radiotherapeutic, and postsurgical outcomes of five patients with epileptic encephalopathies secondary to hypothalamic hamartomas who were treated with CyberKnife®. RESULTS: All patients exhibited refractory epilepsy with gelastic seizures and were unsuitable candidates for surgical resection The prescribed dose ranged between 16 and 25 Gy, delivered in a single fraction for four patients and five fractions for one patient while adhering strictly to visual pathway constraints. After radiosurgery, four patients maintained seizure control (one with an Engel class Ia, three with an Engel class 1d), and another presented sporadic, nondisabling gelastic seizures (with an Engel class IIa). After 24-26 months of follow-up, in three patients, their intelligence quotient scores increased. No complications were reported. SIGNIFICANCE: This report suggests that Cyberknife may be a good option for treating hypothalamic hamartoma, particularly in cases where other noninvasive alternatives are unavailable. Nevertheless, additional studies are essential in order to evaluate the effectiveness of the technique in these cases.

2.
Cell Rep ; 35(3): 109011, 2021 04 20.
Article in English | MEDLINE | ID: mdl-33882306

ABSTRACT

Pulmonary neuroendocrine cells (PNECs) have crucial roles in airway physiology and immunity by producing bioactive amines and neuropeptides (NPs). A variety of human diseases exhibit PNEC hyperplasia. Given accumulated evidence that PNECs represent a heterogenous population of cells, we investigate how PNECs differ, whether the heterogeneity is similarly present in mouse and human cells, and whether specific disease involves discrete PNECs. Herein, we identify three distinct types of PNECs in human and mouse airways based on single and double positivity for TUBB3 and the established NP markers. We show that the three PNEC types exhibit significant differences in NP expression, homeostatic turnover, and response to injury and disease. We provide evidence that these differences parallel their distinct cell of origin from basal stem cells (BSCs) or other airway epithelial progenitors.


Subject(s)
Cell Lineage/genetics , Epithelial Cells/pathology , Neuroendocrine Cells/pathology , Stem Cells/pathology , Tubulin/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation , Epithelial Cells/classification , Epithelial Cells/metabolism , Female , Gene Expression Regulation , Humans , Hyperplasia/genetics , Hyperplasia/metabolism , Hyperplasia/pathology , Infant , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N1 Subtype/pathogenicity , Lung , Male , Mice , Mice, Transgenic , Neuroendocrine Cells/classification , Neuroendocrine Cells/metabolism , Neuropeptides/genetics , Neuropeptides/metabolism , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , Signal Transduction , Stem Cells/classification , Stem Cells/metabolism , Sudden Infant Death/genetics , Sudden Infant Death/pathology , Transcription Factors/genetics , Transcription Factors/metabolism , Tubulin/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
3.
Clin Pharmacol Ther ; 110(1): 69-81, 2021 07.
Article in English | MEDLINE | ID: mdl-33423293

ABSTRACT

Inflammation of the airway involves the recruitment of highly active immune cells to combat and clear microbes and toxic factors; however, this inflammatory response can result in unintended damage to lung tissue. Tissue damage resulting from inflammation is often mitigated by resolving factors that limit the scope and duration of the inflammatory response. Both inflammatory and resolving processes require the actions of a vast array of lipid mediators that can be rapidly synthesized through a variety of airway resident and infiltrating immune cells. Eicosanoids and endocannabinoids represent two major classes of lipid mediators that share synthetic enzymes and have diverse and overlapping functions. This review seeks to provide a summary of the major bioactive eicosanoids and endocannabinoids, challenges facing researchers that study them, and their roles in modulating inflammation and resolution. With a special emphasis on cystic fibrosis, a variety of therapeutics are discussed that have been explored for their potential anti-inflammatory or proresolving impact toward alleviating excessive airway inflammation and improving lung function.


Subject(s)
Eicosanoids/metabolism , Endocannabinoids/metabolism , Lung/pathology , Animals , Anti-Inflammatory Agents/pharmacology , Cystic Fibrosis/pathology , Cystic Fibrosis/therapy , Humans , Inflammation/pathology , Inflammation/therapy
4.
CES med ; 34(2): 103-113, mayo-ago. 2020. tab, graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1285736

ABSTRACT

Resumen Objetivo: Caracterizar los pacientes diagnosticados con tumores del sistema nervioso central en el Instituto Neurológico de Colombia durante el periodo 2010-2015. Métodos: Estudio descriptivo retrospectivo. Para los tumores primarios se usó la clasificación de la Organización Mundial de la Salud y para los metastásicos se usó la Clasificación Internacional de Enfermedades en Oncología. Resultados: Se identificaron 288 pacientes, 194 de ellos con tumores primarios y 94 tumores metastásicos. No se lograron clasificar los tumores primarios en el 23,7 % de los casos y para los metastásicos no se obtuvo la clasificación morfológica (histológica) en el 35,1 % de los casos. Los hombres presentaron con mayor frecuencia tumores de comportamiento maligno tipo glioblastoma NEO (no especificado de otra manera) (14,9 %) y en las mujeres predominaron los tumores de comportamiento benigno tipo meningioma (23,2 %). En mayores de 65 años, tanto el glioblastoma NEO como el meningioma fueron más frecuentes en mujeres con 17,4 % y 28,3 %, respectivamente. Entre los pacientes con tumores metastásicos, de acuerdo con la clasificación topográfica, los tumores primarios más frecuentes se localizaron en pulmón (39,4 %) y mama (17 %). No se identificó el sitio primario de metástasis en el 11,7 % de los casos. La histología más comúnmente identificada fue el adenocarcinoma (14,9 %), seguido del carcinoma (8,5 %). Conclusiones: Para una vigilancia efectiva de la enfermedad es necesario realizar un monitoreo epidemiológico y clínico de tumores primarios y metastásicos, mediante el uso de registros institucionales de cáncer, incluyendo datos topográficos, histológicos y moleculares, según disponibilidad.


Abstract Objective: The aim of this study was to characterize patients with a diagno- sis of a central nervous system (CNS) tumors at the Instituto Neurologico de Colombia during the period between 2010 to 2015. Methods: A retrospective descriptive study was conducted. The Classification of the World Health Organization was used for CNS primary tumors whereas the International Classification of Diseases for oncology (ICD-O) was used for CNS metastatic tumors. Results: 288 patients were identified, 194 of them with primary tumors of CNS and 94 with metastatic tu- mors from systemic cancer. It was not possible to classify primary tumors in 23.7% of the cases and regarding the metastatic tumors it was not possible to obtain the classification in 35.1 % of the cases. Men presented more frequently tumors of ma- lignant behavior such as glioblastoma NOS (not otherwise specified) (14.9 %) while in women benign behavior tumors such as meningioma predominated (23.2 %). For population older than 65 years old, both glioblastoma NOS and meningioma were more frequent in women with 17.4 % and 28.3 %, respectively. In patients with CNS metastatic tumors, according to the topographic classification, the most frequent primary tumors were lung (39.4 %), followed by breast (17 %). Its origin was not iden- tified in 11.7 % of the cases. The most identified histology was adenocarcinoma (14.9 %), followed by carcinoma (8.5 %). Conclusion: For disease surveillance, it is necessary to complete epidemiological and clinical monitoring of primary and metastatic tumors of the CNS by using institutional cancer registries including topographic, histological and molecular data according to availability.

5.
Sci Rep ; 9(1): 15703, 2019 10 31.
Article in English | MEDLINE | ID: mdl-31673002

ABSTRACT

Intestinal helminth infections elicit Th2-type immunity, which influences host immune responses to additional threats, such as allergens, metabolic disease, and other pathogens. Th2 immunity involves a shift of the CD4+ T-cell population from type-0 to type-2 (Th2) with increased abundance of interleukin (IL)-4 and IL-13. This study sought to investigate if existing gut-restricted intestinal helminth infections impact bacterial-induced acute airway neutrophil recruitment. C57BL/6 mice were divided into four groups: uninfected; helminth-Heligmosomoides polygyrus infected; Pseudomonas aeruginosa infected; and coinfected. Mice infected with H. polygyrus were incubated for 2 weeks, followed by P. aeruginosa intranasal inoculation. Bronchial alveolar lavage, blood, and lung samples were analyzed. Interestingly, infection with gut-restricted helminths resulted in immunological and structural changes in the lung. These changes include increased lung CD4+ T cells, increased Th2 cytokine expression, and airway goblet cell hyperplasia. Furthermore, coinfected mice exhibited significantly more airspace neutrophil infiltration at 6 hours following P. aeruginosa infection and exhibited an improved rate of survival compared with bacterial infected alone. These results suggest that chronic helminth infection of the intestines can influence and enhance acute airway neutrophil responses to P. aeruginosa infection.


Subject(s)
Helminthiasis/pathology , Intestinal Diseases, Parasitic/pathology , Lung/microbiology , Nematospiroides dubius/isolation & purification , Neutrophils/immunology , Pseudomonas aeruginosa/metabolism , Animals , Helminthiasis/immunology , Helminthiasis/microbiology , Inflammation Mediators/metabolism , Intestinal Diseases, Parasitic/immunology , Intestinal Diseases, Parasitic/microbiology , Lung/metabolism , Mice , Mice, Inbred C57BL , Nematospiroides dubius/pathogenicity , Th2 Cells/immunology
6.
Immunity ; 51(6): 1102-1118.e7, 2019 12 17.
Article in English | MEDLINE | ID: mdl-31757673

ABSTRACT

Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.


Subject(s)
Adrenergic Neurons/cytology , Asthma/pathology , Dopamine/metabolism , Dopaminergic Neurons/cytology , Lung/pathology , Th2 Cells/immunology , Adolescent , Adult , Age Factors , Aged , Animals , Asthma/immunology , Cells, Cultured , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Interleukin-2/metabolism , Interleukin-4/immunology , Lung/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Neurogenesis/physiology , Receptors, Dopamine D4/metabolism , STAT5 Transcription Factor/metabolism , Sympathetic Nervous System/cytology
7.
Rev. neurol. (Ed. impr.) ; 69(4): 145-151, 16 ago., 2019. tab, graf
Article in English | IBECS | ID: ibc-184072

ABSTRACT

Introduction. Psychogenic non-epileptic seizures (PNES) are paroxysmal changes in behavior that resemble epileptic seizures, although they have no electrophysiological correlation or clinical evidence of epilepsy. Aim. To compare clinical and sociodemographic characteristics of patients diagnosed with PNES-alone and PNES-andepilepsy. Patients and methods. A cross-sectional study of consecutive patients diagnosed with PNES in a 20-month period was carried out. A video-EEG was performed in all patients. Socio-demographical, clinical and semiological characteristics were compared between those patients with and without concomitant epilepsy. Results. Sixty-five patients were included, 35 (53.9%) had PNES-alone and 30 (46.1%) had PNES-and-epilepsy. The proportion of women in the study was 70.8%. The median age at seizure onset was 16 years. A late start was recorded in PNES-alone group (23 years) compared to PNES-and-epilepsy group (11 years), however, it was not significant. There was a lower frequency of antiepileptic drugs use in the PNES-alone group compared with the PNES-and-epilepsy group. The most frequent semiological features were the gradual onset of events (69.2%) and the duration longer than two minutes (63.1%). Conclusion. The waxing and waning pattern during paroxysmal events suggest a non-epileptic origin. However, it is not uncommon to find patients with concomitant epileptic seizures


Introducción. Las crisis psicógenas no epilépticas (CPNE) son cambios paroxísticos en el comportamiento que se asemejan a las crisis epilépticas, aunque no tienen correlación electrofisiológica ni evidencia clínica de epilepsia. Objetivo. Comparar las características clínicas y sociodemográficas entre pacientes diagnosticados con CPNE, con y sin epilepsia concomitante. Pacientes y métodos. Estudio transversal de pacientes consecutivamente diagnosticados de CPNE durante un período de 20 meses. A todos los participantes se les realizó un videoelectroencefalograma (video-EEG). Se compararon las características sociodemográficas, clínicas y semiológicas entre los que presentaban y los que no presentaban epilepsia concomitante. Resultados. Se incluyó a 65 pacientes, 35 con CPNE (53,9%), y 30 con CPNE y epilepsia (46,1%). La edad mediana en el inicio del video-EEG fue de 33 años, y un 70,8% eran mujeres. La edad mediana de inicio de las crisis fue de 16 años. En el grupo de CPNE hubo un inicio más tardío (23 años) en comparación con el grupo de CNPE y epilepsia (11 años), pero la diferencia no fue significativa. La proporción de pacientes en terapia con fármacos antiepilépticos fue significativamente mayor en el grupo con CPNE y epilepsia comparado con el grupo con CPNE. Las características semiológicas más frecuentemente encontradas fueron el inicio gradual de las crisis (69,2%) y una duración de más de dos minutos (63,1%). Conclusión. La variabilidad en los síntomas sugiere un origen no epiléptico de los eventos paroxísticos, los cuales se presentan frecuentemente en pacientes con epilepsia


Subject(s)
Humans , Male , Female , Adolescent , Young Adult , Adult , Middle Aged , Epilepsy/diagnosis , Cross-Sectional Studies , Diagnosis, Differential , Socioeconomic Factors , Colombia
8.
Am J Respir Cell Mol Biol ; 60(6): 687-694, 2019 06.
Article in English | MEDLINE | ID: mdl-30571139

ABSTRACT

Mucus overproduction is a major contributor to morbidity and mortality in asthma. Mucus overproduction is induced by orchestrated actions of multiple factors that include inflammatory cytokines and γ-aminobutyric acid (GABA). GABA is produced only by pulmonary neuroendocrine cells (PNECs) in the mouse lung. Recent studies in a neonatal mouse model of allergic inflammation have shown that PNECs play an essential role in mucus overproduction by GABA hypersecretion. Whether PNECs mediate dysregulated GABA signaling for mucus overproduction in asthma is unknown. In this study, we characterized the cellular source of GABA in the lungs of nonhuman primates and humans and assessed GABA secretion and signaling in primate disease models. We found that like in mice, PNECs were the major source of GABA in primate lungs. In addition, an infant nonhuman primate model of asthma exhibited an increase in GABA secretion. Furthermore, subjects with asthma had elevated levels of expression of a subset of GABA type α (GABAα) and type ß (GABAß) receptors in airway epithelium compared with those of healthy control subjects. Last, employing a normal human bronchial epithelial cell model of preinduced mucus overproduction, we showed pharmaceutical blockade of GABAα and GABAß receptor signaling reversed the effect of IL-13 on MUC5AC gene expression and goblet cell proliferation. Together, our data demonstrate an evolutionarily conserved intraepithelial GABA signaling that, in concert with IL-13, plays an essential role in mucus overproduction. Our findings may offer new strategies to ameliorate mucus overproduction in patients with asthma by targeting PNEC secretion and GABA signaling.


Subject(s)
Goblet Cells/pathology , Lung/pathology , Neuroendocrine Cells/metabolism , gamma-Aminobutyric Acid/metabolism , Acute Lung Injury/pathology , Animals , Asthma/pathology , Bronchi/pathology , Disease Models, Animal , Epithelial Cells/metabolism , Humans , Hyperplasia , Interleukin-13/metabolism , Macaca mulatta , Mucus/metabolism , Receptors, GABA/metabolism , Signal Transduction
9.
Am J Respir Cell Mol Biol ; 59(2): 237-245, 2018 08.
Article in English | MEDLINE | ID: mdl-29447458

ABSTRACT

Metastatic disease is the primary cause of death of patients with lung cancer, but the mouse models of lung adenocarcinoma do not accurately recapitulate the tumor microenvironment or metastatic disease observed in patients. In this study, we conditionally deleted E-cadherin in an autochthonous lung adenocarcinoma mouse model driven by activated oncogenic Kras and p53 loss. Loss of E-cadherin significantly accelerated lung adenocarcinoma progression and decreased survival of the mice. Kras;p53;E-cadherin mice had a 41% lung tumor burden, invasive grade 4 tumors, and a desmoplastic stroma just 8 weeks after tumor initiation. One hundred percent of the mice developed local metastases to the lymph nodes or chest wall, and 38% developed distant metastases to the liver or kidney. Lung adenocarcinoma cancer cell lines derived from these tumors also had high migratory rates. These studies demonstrate that the Kras;p53;E-cadherin mouse model better emulates the tumor microenvironment and metastases observed in patients with lung adenocarcinoma than previous models and may therefore be useful for studying metastasis and testing new lung cancer treatments in vivo.


Subject(s)
Adenocarcinoma/pathology , Cadherins/metabolism , Lung Neoplasms/pathology , Neoplasm Metastasis , Proto-Oncogene Proteins p21(ras)/metabolism , Adenocarcinoma/genetics , Animals , Disease Models, Animal , Liver Neoplasms/pathology , Lung Neoplasms/genetics , Mice, Inbred C57BL , Neoplasm Metastasis/genetics , Proto-Oncogene Proteins p21(ras)/genetics
10.
Curr Allergy Asthma Rep ; 18(2): 10, 2018 02 16.
Article in English | MEDLINE | ID: mdl-29453651

ABSTRACT

PURPOSE OF REVIEW: Asthma is a chronic airway disease that affects more than 300 million people worldwide. Current treatment focuses on symptomatic relief by temporally dampening inflammation and relaxing the airway. Novel combative strategies against asthma and hopefully a cure are yet to be developed. The goal of this review is to summarize recent literature on neurotrophins (NTs) in experimental models and clinical settings of asthma research. RECENT FINDINGS: We highlight studies of early phases of asthma that collectively reveal a profound impact of elevated NT levels following initial detrimental insults on long-term airway dysfunction. We hope this review will foster insights into the complex interaction between NTs, nerves, immune cells, and airway structural cells during a critical time window of development and disease susceptibility. Future studies are required to better understand the role of NTs in asthma pathophysiology and to evaluate whether NTs and their receptors may serve as new drug targets.


Subject(s)
Asthma/physiopathology , Brain-Derived Neurotrophic Factor/metabolism , Nerve Growth Factors/metabolism , Animals , Humans
11.
FASEB J ; 31(10): 4335-4346, 2017 10.
Article in English | MEDLINE | ID: mdl-28619712

ABSTRACT

Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve-airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ∼3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas ß2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.-Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.


Subject(s)
Asthma/prevention & control , Bronchial Hyperreactivity/metabolism , Muscle, Smooth/metabolism , Receptor, Muscarinic M3/metabolism , Acetylcholine/metabolism , Animals , Bronchial Hyperreactivity/diagnosis , Disease Models, Animal , Disease Progression , Mice, Knockout , Muscle Contraction/drug effects , Muscle Contraction/physiology , Muscle, Smooth/drug effects , Receptor, Muscarinic M3/antagonists & inhibitors , Respiratory System/drug effects
12.
FASEB J ; 31(9): 4117-4128, 2017 09.
Article in English | MEDLINE | ID: mdl-28566470

ABSTRACT

Pulmonary neuroendocrine cells (PNECs) are the only innervated airway epithelial cells. To what extent neural innervation regulates PNEC secretion and function is unknown. Here, we discover that neurotrophin 4 (NT4) plays an essential role in mucus overproduction after early life allergen exposure by orchestrating PNEC innervation and secretion of GABA. We found that PNECs were the only cellular source of GABA in airways. In addition, PNECs expressed NT4 as a target-derived mechanism underlying PNEC innervation during development. Early life allergen exposure elevated the level of NT4 and caused PNEC hyperinnervation and nodose neuron hyperactivity. Associated with aberrant PNEC innervation, the authors discovered that GABA hypersecretion was required for the induction of mucin Muc5ac expression. In contrast, NT4-/- mice were protected from allergen-induced mucus overproduction and changes along the nerve-PNEC axis without any defects in inflammation. Last, GABA installation restored mucus overproduction in NT4-/- mice after early life allergen exposure. Together, our findings provide the first evidence for NT4-dependent neural regulation of PNEC secretion of GABA in a neonatal disease model. Targeting the nerve-PNEC axis may be a valid treatment strategy for mucus overproduction in airway diseases, such as childhood asthma.-Barrios, J., Patel, K. R., Aven, L., Achey, R., Minns, M. S., Lee, Y., Trinkaus-Randall, V. E., Ai, X. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion.


Subject(s)
Allergens/immunology , Gene Expression Regulation/immunology , Hypersensitivity/metabolism , Mucus/metabolism , Neuroendocrine Cells/metabolism , Ovalbumin/immunology , Animals , Calcium , Mice, Inbred C57BL , gamma-Aminobutyric Acid/genetics , gamma-Aminobutyric Acid/metabolism
13.
Proc Natl Acad Sci U S A ; 111(28): 10299-304, 2014 Jul 15.
Article in English | MEDLINE | ID: mdl-24982195

ABSTRACT

Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxia-inducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma.


Subject(s)
Adenocarcinoma/enzymology , Cell Movement , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Lung Neoplasms/enzymology , Membrane Glycoproteins/biosynthesis , Protein-Tyrosine Kinases/biosynthesis , Receptor, trkB/biosynthesis , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Cell Line, Tumor , Gene Knockdown Techniques , Humans , Hypoxia-Inducible Factor 1/genetics , Hypoxia-Inducible Factor 1/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Membrane Glycoproteins/genetics , Mice, Mutant Strains , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Receptor, trkB/genetics , Signal Transduction/genetics
14.
EMBO J ; 33(5): 468-81, 2014 Mar 03.
Article in English | MEDLINE | ID: mdl-24497554

ABSTRACT

Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Movement , Lung Neoplasms/pathology , Neoplasm Metastasis/pathology , Phosphoproteins/metabolism , Transcription Factors/metabolism , Acyltransferases , Adaptor Proteins, Signal Transducing/genetics , Animals , Cell Cycle Proteins , Disease Models, Animal , Gene Knockdown Techniques , Humans , Lung/pathology , Mice , Phosphoproteins/genetics , Transcription Factors/genetics , YAP-Signaling Proteins
15.
Am J Respir Cell Mol Biol ; 48(3): 288-98, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23204392

ABSTRACT

The regeneration of alveolar epithelial cells is a critical aspect of alveolar reorganization after lung injury. Although alveolar Type II (AT2) cells have been described as progenitor cells for alveolar epithelia, more remains to be understood about how their progenitor cell properties are regulated. A nuclear, chromatin-bound green fluorescence protein reporter (H2B-GFP) was driven from the murine surfactant protein-C (SPC) promoter to generate SPC H2B-GFP transgenic mice. The SPC H2B-GFP allele allowed the FACS-based enrichment and gene expression profiling of AT2 cells. Approximately 97% of AT2 cells were GFP-labeled on Postnatal Day 1, and the percentage of GFP-labeled AT2 cells decreased to approximately 63% at Postnatal Week 8. Isolated young adult SPC H2B-GFP(+) cells displayed proliferation, differentiation, and self-renewal capacity in the presence of lung fibroblasts in a Matrigel-based three-dimensional culture system. Heterogeneity within the GFP(+) population was revealed, because cells with distinct alveolar and bronchiolar gene expression arose in three-dimensional cultures. CD74, a surface marker highly enriched on GFP(+) cells, was identified as a positive selection marker, providing 3-fold enrichment for AT2 cells. In vivo, GFP expression was induced within other epithelial cell types during maturation of the distal lung. The utility of the SPC H2B-GFP murine model for the identification of AT2 cells was greatest in early postnatal lungs and more limited with age, when some discordance between SPC and GFP expression was observed. In adult mice, this allele may allow for the enrichment and future characterization of other SPC-expressing alveolar and bronchiolar cells, including putative stem/progenitor cell populations.


Subject(s)
Chromatin/metabolism , Epithelial Cells/metabolism , Fibroblasts/metabolism , Green Fluorescent Proteins/metabolism , Lung/metabolism , Pulmonary Surfactant-Associated Protein C/metabolism , Alleles , Animals , Antigens, Differentiation, B-Lymphocyte/genetics , Antigens, Differentiation, B-Lymphocyte/metabolism , Bronchioles/cytology , Bronchioles/metabolism , Cell Differentiation/genetics , Cell Growth Processes/genetics , Cells, Cultured , Chromatin/genetics , Epithelial Cells/cytology , Female , Fibroblasts/cytology , Gene Expression , Gene Expression Profiling/methods , Green Fluorescent Proteins/genetics , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/metabolism , Lung/cytology , Lung Injury/genetics , Lung Injury/metabolism , Lung Injury/pathology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Promoter Regions, Genetic , Pulmonary Alveoli/cytology , Pulmonary Alveoli/metabolism , Pulmonary Surfactant-Associated Protein C/biosynthesis , Pulmonary Surfactant-Associated Protein C/genetics , Regeneration/genetics , Respiratory Mucosa/cytology , Respiratory Mucosa/metabolism
16.
J Agric Food Chem ; 58(4): 2100-10, 2010 Feb 24.
Article in English | MEDLINE | ID: mdl-20121190

ABSTRACT

The anthocyanin-rich extract (ARE) of the fruit from Pourouma cecropiifolia , a tropical plant native to the Amazon region, showed moderate cytotoxicity toward different cancer cell lines when evaluated by MTT assays. This extract was fractionated using Sephadex LH-20 chromatography to obtain three fractions (F1-F3), the composition of which was analyzed by HPLC-PDA and LC-ESI/MS. F1 was composed primarily of the monomeric anthocyanins delphinidin-3-O-beta-glucopyranoside, cyanidin-3-O-beta-glucopyranoside, and cyanidin-3-O-(6''-malonyl)glucopyranoside. F2 contained the isomeric flavonols quercetin 3-O-alpha-rhamnopyranosyl-(1-->6)-beta-galactopyranoside and quercetin 3-O-alpha-rhamnopyranosyl-(1-->6)-beta-glucopyranoside, the structures of which were confirmed by (1)H and (13)C NMR. F3 contained polymeric pigments, which were analyzed using tandem ESI/MS with an ion trap-TOF. The structures of two proanthocyanidin and two flavanol-anthocyanin condensed pigments were suggested on the basis of their MS(n) fragmentation patterns. After cell viability assays were performed, only fraction F3 showed a cell growth-inhibitory effect similar to the one found for ARE. F3 significantly reduced the viability of HEp-2 larynx, MKN-45 gastric carcinoma, and MCF-7 breast cancer cells; in contrast, the pure compounds did not show promising cytotoxicity toward the cancer cells evaluated.


Subject(s)
Anthocyanins/isolation & purification , Anthocyanins/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Ericaceae/chemistry , Plant Extracts/chemistry , Breast Neoplasms , Carcinoma, Hepatocellular , Cell Line, Tumor , Cell Survival/drug effects , Chromatography, High Pressure Liquid , Ecosystem , Female , Flavonols/isolation & purification , Fruit/chemistry , Humans , Liver Neoplasms , Magnetic Resonance Spectroscopy , Mass Spectrometry , Tropical Climate
17.
J Agric Food Chem ; 54(2): 509-16, 2006 Jan 25.
Article in English | MEDLINE | ID: mdl-16417313

ABSTRACT

Volatile extracts from pulp, peels, leaves, and seeds of champa (Campomanesia lineatifolia R. and P.) were obtained by continuous liquid-liquid extraction with pentane/dichloromethane (1:1), and their chemical composition was determined by using HRGC and HRGC-MS. Differences between C. lineatifolia volatile extracts with regard to the identified compounds are presented; however, in all of them the beta-triketones were detected as major constituents (between 50 and 60% of total extract). An odor profile description of volatiles isolated in all of the extracts was obtained by HRGC-O. These analyses showed that beta-triketones contributed to the fruity, floral, and green odor notes in the flavor of fruit. Application of AEDA to pulp volatile extract revealed 2,5-dimethyl-4-methoxy-3(2H)-furanone, 2-phenylethanol, and 2,3-dihydro-5-hydroxy-6,8,8-trimethyl-2-phenyl-4H-1-benzopyran-4,7(8H)-dione (champanone C) to have the highest flavor dilution factors. In a similar way, (E)-cinnamyl alcohol, 2,5-dimethyl-4-methoxy-3(2H)-furanone, and 2,3-dihydro-5-hydroxy-6,8,8-trimethyl-2-phenyl-4H-1-benzopyran-4,7(8H)-dione (champanone C) were identified as key odorant compounds in the fruit peel volatile extract. This is the first time that the volatile composition in champa is reported and also the sensory odor importance of beta-triketones.


Subject(s)
Fruit/chemistry , Myrtaceae/chemistry , Odorants/analysis , Chromatography, Gas , Furans/analysis , Gas Chromatography-Mass Spectrometry , Humans , Ketones/analysis , Smell , Taste , Terpenes/analysis , Volatilization
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