RESUMO
BACKGROUND: Physical frailty is relevant to adverse outcomes, but appropriate procedures for screening populations are lacking. We hypothesized that frailty is associated with multiple somatic symptoms because frail elderly people might have several somatic symptoms attributed to deterioration of multiple organs. OBJECTIVE: To examine the association between multiple somatic symptoms and frailty. METHODS: We conducted a cross-sectional study and enrolled 1818 participants aged ≥60 years from Japanese national medical check-up in 2015. Frailty status was categorized into frail, pre-frail or non-frail based on the definition of the Fried frailty phenotype model. Sixteen self-reported subjective somatic symptoms were recorded at the timing of medical check-up. Odds ratio (OR) and 95% confidence interval (CI) of frail or pre-frail were analyzed using number of somatic symptoms. RESULTS: Out of total of 1818 subjects, 44 (2.4%) frail subjects, 635 (34.9%) pre-frail subjects and 1139 (62.7%) non-frail subjects were detected. More than two somatic symptoms were significantly associated with the frail phenotype (OR 6.20, 95% CI 2.95, 13.03, P < 0.001) and were associated with the pre-frail phenotype (OR 2.06, 95% CI 1.69, 2.51, P < 0.001). Associations remained significant after multi-adjustment for age, sex, past medical cardiovascular diseases and depressive mood The number of somatic symptoms ≥2 was thought to be the optimal cut-off point to predict frail with a sensitivity of 79.6%, specificity of 61.5%. CONCLUSIONS: Our study shows that multiple somatic symptoms are independently associated with frailty. Using more than two multiple somatic symptoms as a prescreening tool for frailty may be appropriate.
Assuntos
Idoso Fragilizado/estatística & dados numéricos , Fragilidade/epidemiologia , Sintomas Inexplicáveis , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Estudos Transversais , Depressão/complicações , Feminino , Idoso Fragilizado/psicologia , Avaliação Geriátrica/métodos , Humanos , Vida Independente , Japão/epidemiologia , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl(+/+) HSPCs, and transduction of C-CBL mutants into c-Cbl(-/-) HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.
Assuntos
Genes Supressores de Tumor , Leucemia Mieloide/genética , Proteínas Mutantes/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Desequilíbrio Alélico , Sequência de Aminoácidos , Animais , Sequência de Bases , Cromossomos Humanos Par 11/genética , Feminino , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutação , Células NIH 3T3 , Transplante de Neoplasias , Oncogenes/genética , Fosforilação , Conformação Proteica , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-cbl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-cbl/química , Proteínas Proto-Oncogênicas c-cbl/deficiência , Ubiquitinação , Dissomia Uniparental/genética , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Bortezomib therapy is now indispensable for multiple myeloma, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. The development of orally active proteasome inhibitors with distinct mechanisms of action is therefore eagerly awaited. Previously, we identified homopiperazine derivatives as a novel class of proteasome inhibitors with a different mode of proteasome binding from bortezomib. In this study, we show that K-7174, one of proteasome inhibitory homopiperazine derivatives, exhibits a therapeutic effect, which is stronger when administered orally than intravenously, without obvious side effects in a murine myeloma model. Moreover, K-7174 kills bortezomib-resistant myeloma cells carrying a ß5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. K-7174 induces transcriptional repression of class I histone deacetylases (HDAC1, -2, and -3) via caspase-8-dependent degradation of Sp1, the most potent transactivator of class I HDAC genes. HDAC1 overexpression ameliorates the cytotoxic effect of K-7174 and abrogates histone hyperacetylation without affecting the accumulation of ubiquitinated proteins in K-7174-treated myeloma cells. Conversely, HDAC inhibitors enhance the activity of K-7174 with an increase in histone acetylation. These results suggest that class I HDACs are critical targets of K-7174-induced cytotoxicity. It is highly anticipated that K-7174 increases the tolerability and convenience of patients by oral administration and has the clinical utility in overcoming bortezomib resistance as a single agent or in combination with HDAC inhibitors.
Assuntos
Anisóis/farmacologia , Azepinas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/biossíntese , Mieloma Múltiplo/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular Tumoral , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Pirazinas/farmacologiaRESUMO
Bortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-kappaB activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8-dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment.
Assuntos
Ácidos Borônicos/uso terapêutico , Histona Desacetilases/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/enzimologia , Pirazinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Ácidos Borônicos/administração & dosagem , Bortezomib , Caspase 8/metabolismo , Linhagem Celular Tumoral , Depsipeptídeos/administração & dosagem , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Técnicas de Silenciamento de Genes , Histona Desacetilase 1/genética , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/classificação , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Pirazinas/administração & dosagem , RNA Interferente Pequeno/genética , Fator de Transcrição Sp1/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Introduction. Family physicians have more opportunities to attend athletic competitions as medical staff at first-aid centers because of the increasing popularity of endurance sports. Case. A 38-year-old man who participated in a triathlon race experienced difficulty in breathing after swimming and was moved to a first-aid center. His initial oxygen saturation was 82% and a thoracic computed tomography scan showed bilateral ground glass opacity in the peripheral lungs. His diagnosis was noncardiogenic pulmonary edema associated with exercise or swimming: exercise-induced pulmonary edema (EIPE) or swimming-induced pulmonary edema (SIPE). Treatment with furosemide and corticosteroid relieved his symptoms of pulmonary edema. Discussion. Noncardiogenic pulmonary edema associated with endurance sports is not common, but knowledge about EIPE/SIPE or neurogenic pulmonary edema associated with hyponatremia, which is called Ayus-Arieff syndrome, is crucial. Knowledge and caution for possible risk factors, such as exposure to cold water or overhydration, are essential for both medical staff and endurance athletes. Conclusion. To determine the presence of pulmonary edema associated with strenuous exercise, oxygen saturation should be used as a screening tool at a first-aid center. To avoid risks for EIPE/SIPE, knowledge about these diseases is essential for medical staff and for athletes who perform extreme exercise.
RESUMO
The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.