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1.
Cancer Lett ; 574: 216384, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37716465

RESUMO

There are well demonstrated differences in tumor cell metabolism between right sided (RCC) and left sided (LCC) colon cancer, which could underlie the robust differences observed in their clinical behavior, particularly in metastatic disease. As such, we utilized liquid chromatography-mass spectrometry to perform an untargeted metabolomics analysis comparing frozen liver metastasis (LM) biobank samples derived from patients with RCC (N = 32) and LCC (N = 58) to further elucidate the unique biology of each. We also performed an untargeted RNA-seq and subsequent network analysis on samples derived from an overlapping subset of patients (RCC: N = 10; LCC: N = 18). Our biobank redemonstrates the inferior survival of patients with RCC-derived LM (P = 0.04), a well-established finding. Our metabolomic results demonstrate increased reactive oxygen species associated metabolites and bile acids in RCC. Conversely, carnitines, indicators of fatty acid oxidation, are relatively increased in LCC. The transcriptomic analysis implicates increased MEK-ERK, PI3K-AKT and Transcription Growth Factor Beta signaling in RCC LM. Our multi-omic analysis reveals several key differences in cellular physiology which taken together may be relevant to clinical differences in tumor behavior between RCC and LCC liver metastasis.


Assuntos
Carcinoma de Células Renais , Neoplasias do Colo , Neoplasias Renais , Neoplasias Hepáticas , Humanos , Multiômica , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias Hepáticas/genética , Redes e Vias Metabólicas
2.
Clin Biomech (Bristol, Avon) ; 92: 105565, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34999389

RESUMO

BACKGROUND: Minimally invasive percutaneous polymethyl methacrylate cement augmentation procedures offer numerous clinical advantages for patients with periacetabular osteolytic metastatic bone defects in contrast to open reconstructive procedures that are associated with many complications. Several techniques, such as Ablation-Osteoplasty-Reinforcement-Internal Fixation (AORIF), cementoplasty alone, and screw fixation alone are currently used. There is no consensus on optimal skeletal reinforcement of diseased bones. The purpose of this study was to determine the most effective technique of percutaneous acetabular augmentation for joint preservation, with respect to resilience on cyclic loading and fracture pattern at maximal load to failure. METHODS: Five cohorts of hemipelvis composite bones with uniform periacetabular defects and various types of reinforcement techniques were utilized to simulate osteolytic metastasis in the weight bearing dome of the acetabulum. Five groups of hemipelves underwent finite element analysis and biomechanical testing for load to failure, energy absorption to failure, stress relaxation on cyclic loading, and fracture locations. RESULTS: The combination of screws and bone cement augmentation demonstrated significant higher energy absorption than the cement or screw only groups (p < 0.05), and better protection of acetabulum from displaced intraarticular fractures than the screws alone oror cement only groups (p < 0.05). Resilience to cyclic loading was higheest in the screw with cement fixation group than the screw only repair (p < 0.01), though not the cement fixation only group. INTERPRETATION: These data support the hypothesis that cementoplasty combined with screw augmentation such as the AORIF technique provides the best protection of acetabulum from massive metastatic cancer-induced acetabular fractures compared to augmentation with screws or cement alone.


Assuntos
Acetábulo , Neoplasias , Acetábulo/cirurgia , Fenômenos Biomecânicos , Cimentos Ósseos/uso terapêutico , Parafusos Ósseos , Fixação Interna de Fraturas/métodos , Humanos
3.
Ther Adv Musculoskelet Dis ; 12: 1759720X20966135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343723

RESUMO

Naringin is a naturally occurring flavonoid found in plants of the Citrus genus that has historically been used in traditional Chinese medical regimens for the treatment of osteoporosis. Naringin modulates signaling through numerous molecular pathways critical to musculoskeletal development, cellular differentiation, and inflammation. Administration of naringin increases in vitro expression of bone morphogenetic proteins (BMPs) and activation of the Wnt/ß-catenin and extracellular signal-related kinase (Erk) pathways, thereby promoting osteoblastic proliferation and differentiation from stem cell precursors for bone formation. Naringin also inhibits osteoclastogenesis by both modifying RANK/RANKL interactions and inducing apoptosis in osteoclasts in vitro. In addition, naringin acts on the estrogen receptor in bone to mimic the native bone-preserving effects of estrogen, with few systemic side effects on other estrogen-sensitive tissues. The efficacy of naringin therapy in reducing the osteolysis characteristic of common musculoskeletal pathologies such as osteoporosis, degenerative joint disease, and osteomyelitis, as well as inflammatory conditions affecting bone such as diabetes mellitus, has been extensively demonstrated in vitro and in animal models. Naringin thus represents a naturally abundant, cost-efficient agent whose potential for use in novel musculoskeletal biotherapies warrants re-visiting and further exploration through human studies. Here, we review the cellular mechanisms of action that have been elucidated regarding the action of naringin on bone resident cells and the bone microenvironment, in vivo evidence of naringin's osteostimulative and chondroprotective properties in the setting of osteolytic bone disease, and current limitations in the development of naringin-containing translational therapies for common musculoskeletal conditions.

4.
Bone ; 141: 115568, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32745687

RESUMO

Bone and joint infections are devastating afflictions. Although medical interventions and advents have improved their care, bone and joint infections still portend dismal outcomes. Indeed, bone and joint infections are associated with extremely high mortality and morbidity rates and, generally, occur secondary to the aggressive pathogen Staphylococcus aureus. The consequences of bone and joint infections are further compounded by the fact that although they are aggressively treated, they frequently recur and result in massive bone and articular cartilage loss. Here, we review the literature and chronicle the fact that the fundamental cellular components of the musculoskeletal system can be internally infected with Staphylococcus aureus, which explains the ready recurrence of bone and joint infections even after extensive administration of antibiotic therapy and debridement and offer potential treatment solutions for further study. Moreover, we review the ramifications of intracellular infection and expound that the massive bone and articular cartilage loss is caused by the sustained proinflammatory state induced by infection and offer potential combination therapies for further study to protect bone and cartilage.


Assuntos
Artrite Infecciosa , Osteomielite , Infecções Estafilocócicas , Antibacterianos/uso terapêutico , Artrite Infecciosa/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus
7.
Cell Rep ; 24(13): 3441-3454.e12, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257206

RESUMO

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.


Assuntos
Caderinas/genética , Variações do Número de Cópias de DNA , Receptores de Superfície Celular/genética , Síndrome de Tourette/genética , Adulto , Polaridade Celular , Criança , Feminino , Humanos , Masculino , Linhagem , Síndrome de Tourette/patologia
8.
Cell ; 174(3): 505-520, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30053424

RESUMO

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.


Assuntos
Mapeamento Cromossômico/métodos , Transtornos do Neurodesenvolvimento/genética , Biologia de Sistemas/métodos , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Neurobiologia/métodos , Neuropsiquiatria
9.
Am J Physiol Cell Physiol ; 306(4): C343-53, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24259420

RESUMO

The in vitro perfused rectal gland of the dogfish shark (Squalus acanthias) and filter-grown monolayers of primary cultures of shark rectal gland (SRG) epithelial cells were used to analyze the signal transduction pathway by which C-type natriuretic peptide (CNP) stimulates chloride secretion. CNP binds to natriuretic receptors in the basolateral membrane, elevates cellular cGMP, and opens cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels in the apical membrane. CNP-provoked chloride secretion was completely inhibitable by the nonspecific protein kinase inhibitor staurosporine and the PKA inhibitor H89 but insensitive to H8, an inhibitor of type I and II isoforms of cGMP-dependent protein kinase (cGKI and cGKII). CNP-induced secretion could not be mimicked by nonhydrolyzable cGMP analogs added alone or in combination with the protein kinase C activator phorbolester, arguing against a role for cGK or for cGMP-induced PKC signaling. We failed to detect a dogfish ortholog of cGKII by molecular cloning and affinity chromatography. However, inhibitors of the cGMP-inhibitable isoform of phosphodiesterase (PDE3) including milrinone, amrinone, and cilostamide but not inhibitors of other PDE isoenzymes mimicked the effect of CNP on chloride secretion in perfused glands and monolayers. CNP raised cGMP and cAMP levels in the SRG epithelial cells. This rise in cAMP as well as the CNP and amrinone-provoked chloride secretion, but not the rise in cGMP, was almost completely blocked by the Gαi-coupled adenylyl cyclase inhibitor somatostatin, arguing against a role for cGMP cross-activation of PKA in CNP action. These data provide molecular, functional, and pharmacological evidence for a CNP/cGMP/PDE3/cAMP/PKA signaling cascade coupled to CFTR in the SRG.


Assuntos
Cloretos/metabolismo , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Cação (Peixe)/metabolismo , Proteínas de Peixes/metabolismo , Peptídeo Natriurético Tipo C/metabolismo , Glândula de Sal/enzimologia , Inibidores de Adenilil Ciclases , Adenilil Ciclases/metabolismo , Animais , Células Cultivadas , Clonagem Molecular , Proteína Quinase Dependente de GMP Cíclico Tipo I/antagonistas & inibidores , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Proteína Quinase Dependente de GMP Cíclico Tipo II/antagonistas & inibidores , Proteína Quinase Dependente de GMP Cíclico Tipo II/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Ativação do Canal Iônico , Masculino , Inibidores da Fosfodiesterase 3/farmacologia , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Receptores do Fator Natriurético Atrial/metabolismo , Glândula de Sal/efeitos dos fármacos , Sistemas do Segundo Mensageiro , Fatores de Tempo
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