RESUMO
BACKGROUND: Psychological distress is a significant problem among patients with a diagnosis of cancer and is associated with elevated risk for mortality; however, not all patients with a diagnosis of cancer experience significant psychological distress. Cancer-related pain has been associated with greater psychological distress among patients with a cancer diagnosis (current or previous). The current study aimed to examine potential theoretical mechanisms (i.e., cognitive fusion, experiential avoidance, and functional impairment) as proposed by the psychological flexibility model, for the association between cancer-related pain and psychological distress. We hypothesized that cancer-related pain would be indirectly positively associated with psychological distress among patients with a cancer diagnosis (current or previous) through psychological inflexibility (i.e., cognitive fusion and experiential avoidance) related to pain and functional impairment, in serial. METHOD: Sixty-one adult outpatients diagnosed with cancer completed self-report assessments of cancer-related pain, psychological inflexibility related to pain, pain-related functional impairment, and psychological distress. RESULTS: Cancer-related pain was positively associated with psychological distress indirectly through greater pain-related psychological inflexibility (i.e., cognitive fusion and experiential avoidance) and functional impairment, in serial. Alternative models were explored but unsupported. CONCLUSION: Consistent with the psychological flexibility model, psychological inflexibility and functional impairment may be potential mechanisms underlying the association between cancer-related pain and psychological distress among patients with a cancer diagnosis (current or previous).
Assuntos
Dor do Câncer/psicologia , Modelos Psicológicos , Neoplasias/psicologia , Angústia Psicológica , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , AutorrelatoRESUMO
Pateamine A is a naturally occurring metabolite extracted from the marine sponge Mycale hentscheli. It exhibits potent cytotoxicity towards cancer cell lines and has been shown to target protein translation initiation via inhibition of the function of eukaryotic initiation factor 4A proteins. We have synthesised a simplified analogue of pateamine A, consisting of the skeletal core of the natural product but with the thiazole heterocycle replaced by a triazole. The convergent design of the synthesis features a base-induced opening of a δ-valerolactone to access the Z,E-dienoate moiety, Julia-Kocienski olefination and copper-catalysed azide-alkyne cycloaddition. Bioactivity testing of the simplified pateamine A analogue (3) indicated a significant reduction in cytotoxicity, compared to natural pateamine A. We propose that this reduced activity is due mainly to the substitution of the thiazole for the triazole heterocycle. This supports the hypothesis that the thiazole of pateamine A is important for binding to its biological target.
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Compostos de Epóxi/química , Macrolídeos/química , Tiazóis/química , Triazóis/química , Triazóis/síntese química , Azidas/química , Catálise , Técnicas de Química Sintética , Cobre/químicaRESUMO
We previously found that a population of colonic stromal cells that constitutively express high levels of prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2) altered their location in the lamina propria in response to injury in a Myd88-dependent manner (Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., and Stappenbeck, T. S. (2007) J. Clin. Invest. 117, 258-269). At the time of this study, the identity of these cells and the mechanism by which they expressed high levels of Ptgs2 were unknown. Here we found that these colonic stromal cells were mesenchymal stem cells (MSCs). These colonic MSCs expressed high Ptgs2 levels not through interaction with bacterial products but instead as a consequence of mRNA stabilization downstream of Fgf9 (fibroblast growth factor 9), a growth factor that is constitutively expressed by the intestinal epithelium. This stabilization was mediated partially through a mechanism involving endogenous CUG-binding protein 2 (CUGbp2). These studies suggest that Fgf9 is an important factor in the regulation of Ptgs2 in colonic MSCs and may be a factor involved in its constitutive expression in vivo.
Assuntos
Colo/citologia , Ciclo-Oxigenase 2/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Proteínas CELF , Linhagem Celular , Células Cultivadas , Ciclo-Oxigenase 2/genética , Fator 9 de Crescimento de Fibroblastos/farmacologia , Flavonoides/farmacologia , Citometria de Fluxo , Humanos , Immunoblotting , Imuno-Histoquímica , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células Estromais/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
The colonic epithelial lining undergoes constant replacement, driven by epithelial stem cells in crypts of Lieberkühn. Stem cells lost because of damage or disease can be replaced by adjacent crypts that undergo fission. The close proximity of an extraordinary number of luminal microbes creates a challenge for this repair process; infection must be prevented while immune system activation and epithelial stem cell genetic damage must be minimized. To understand the factors that modulate crypt/stem cell replacement in the mouse colon, we developed an in vivo acute injury system analogous to punch biopsy of the skin. In contrast to epidermal stem cells, colonic epithelial progenitors did not migrate over the wound bed. Instead, their proliferative expansion was confined to crypts adjacent to wound beds and was delayed to the latter phase of healing. This increased epithelial proliferation was coincident with the infiltration of Trem2 expressing macrophages and increased expression of IL-4 and IL-13 in the wound bed. Interestingly, Trem2(-/-) mice displayed slow and incomplete wound healing of colonic mucosal injuries. We found the latter phase of healing in Trem2(-/-) mice showed a diminished burst of epithelial proliferation, increased expression of IFN-gamma and TNF-alpha, diminished expression of IL-4 and IL-13, and increased markers of classical macrophage activation. Ablation of these cytokines in injured WT and Trem2(-/-) mice demonstrated that their expression ultimately determined the rate and nature of wound healing. These studies show that Trem2 signaling is an important pathway to promote healing of wounds in the colon where stem cell replacement is necessary.
Assuntos
Colo/fisiologia , Glicoproteínas de Membrana/fisiologia , Mucosa/fisiologia , Receptores Imunológicos/fisiologia , Transdução de Sinais , Células-Tronco/fisiologia , Cicatrização/fisiologia , Animais , Proliferação de Células , Citocinas/análise , Células Epiteliais , Macrófagos/química , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Modelos Animais , Mucosa/patologia , Receptores Imunológicos/genética , Cicatrização/imunologiaRESUMO
Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.
Assuntos
Autofagia/genética , Proteínas de Transporte/metabolismo , Celulas de Paneth/metabolismo , Alelos , Animais , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/genética , Linhagem Celular , Doença de Crohn/genética , Doença de Crohn/patologia , Exocitose/genética , Homozigoto , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Celulas de Paneth/patologiaRESUMO
Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant disorders of skeletal muscle. Susceptibility to MH is only apparent after exposure to volatile anesthetics and/or depolarizing muscle relaxants. CCD patients present with diffuse muscular weakness but are also at risk of MH. Mutations in RYR1 (19q13.1), encoding a skeletal muscle calcium release channel (ryanodine receptor), account for the majority of MH and CCD cases. Fifteen RYR1 N-terminal mutations are considered causative of MH susceptibility, five of which are also associated with CCD. In the first extensive UK population survey, eight of 15 mutations were detected in 85 out of 297 (29%) unrelated MH susceptible cases, with G2434R detected in 53 cases (18%). Mutation type was shown to affect significantly MH phenotypes (in vitro contracture test (IVCT) response to caffeine, halothane, and ryanodine). RYR1 mutations associated with both CCD and MH (R163C, R2163H, R2435H) had more severe caffeine and halothane response phenotypes than those associated with MH alone. Mutations near the amino terminal (R163C, G341R) had a relatively greater effect on responses to caffeine than halothane, with a significantly increased caffeine:halothane tension ratio compared to G2434R of the central domain. All phenotypes were more severe in males than females, and were also affected by muscle specimen size and viability. Discordance between RYR1 genotype and IVCT phenotype was observed in seven families (nine individuals), with five false-positives and four false-negatives. This represents the most extensive study of MH patient clinical and genetic data to date and demonstrates that RYR1 mutations involved in CCD are those associated with one end of the spectrum of MH IVCT phenotypes.