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INTRODUCTION: Recent studies have evaluated patient perception of physician attire; however, few studies have considered physician perceptions of workplace attire. This study aimed to assess current trends regarding attire preferences among surgeons. METHODS: A national, population-based survey was distributed via email and "X" (Twitter). Participants were asked to complete an online questionnaire regarding their perception of the white coat, preferred attire in clinical settings, and reasons for choice of attire. RESULTS: Of 481 participants, 172 (36%) were attendings, 164 (34%) were residents, 125 (26%) were medical students, and 20 (4%) were fellows. Those who practiced in the Midwest region were more likely to wear a white coat daily (35.1% versus 28.5% South, 23.5% Northeast, 20.0% West, P < 0.05). Late career surgeons (practicing >20 y) were more likely to wear a white coat in the hospital and wear it daily (56% versus 36% of middle-career surgeons, 34% early-career surgeons, and 26% in training, P < 0.05). Women surgeons more frequently wore a white coat in clinic (64% versus 54% men, P < 0.05), reported that wearing a white coat was influenced by their program's culture (61% versus 46% of men surgeons, P < 0.05), that they would stop wearing a white coat if other members of their department stopped (50% versus 35% of men, P < 0.05), and that they believe the white coat helps distinguish female doctors from nurses (61% versus 50% of men surgeons, P < 0.05). CONCLUSIONS: This study demonstrates generational, regional, and gender differences among surgeons in their perception of the white coat at a national level.
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Recent studies have shown that chronic use of prescription or illicit opioids leads to an increased risk of cardiovascular events and pulmonary arterial hypertension. Indices of vascular age and arterial stiffness are also shown to be increased in opioid-dependent patients, with the effects being more marked in women. There are currently no studies investigating sex-specific vascular dysfunction in opioid use, and the mechanisms leading to opioid-induced vascular damage remain unknown. We hypothesized that exposure to exogenous opioids causes sex-specific vascular remodeling that will be more pronounced in female. Acknowledging the emerging roles of cofilins and extracellular signal-regulated kinases (ERKs) in mediating actin dynamics, we investigated the effects of morphine on these molecules. Twenty-four hour exposure to morphine increased inactivated cofilin and activated ERKs in resistance arteries from female mice, which may promote stress fiber over-assembly. We also performed continuous intraluminal infusion of morphine in pressurized resistance arteries from male and female mice using culture pressure myographs. We observed that morphine reduced the vascular diameter in resistance arteries from female, but not male mice. These results have significant implications for the previously unexplored role of exogenous opioids as a modifiable cardiovascular risk factor, especially in women.
Assuntos
Fatores de Despolimerização de Actina/metabolismo , Analgésicos Opioides/toxicidade , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hemodinâmica/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Morfina/toxicidade , Remodelação Vascular/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Masculino , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/patologia , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fosforilação , Ratos Sprague-Dawley , Fatores Sexuais , Transdução de SinaisRESUMO
Radotinib (Supect™) was developed to treat chronic myeloid leukemia (CML) as a BCR-ABL1 tyrosine kinase inhibitor (TKI). Other TKIs, including imatinib and nilotinib, were also developed for treatment of CML, and recent studies were increasing about the therapeutic effects of other TKIs on solid tumors. However, the effect of radotinib on solid tumors has not yet been investigated. In this study, radotinib killed CML cell line K562 directly; however, radotinib did not enhance NK cell cytotoxicity against K562 cells. Because K562 is known as a Fas-negative cell line, we investigated whether radotinib could regulate cell cytotoxicity against various Fas-expressing solid cancer cell lines. Radotinib dramatically increased NK cell cytotoxicity against various Fas-expressing solid cancer cells, including lung, breast, and melanoma cells. Additionally, the efficiency of radotinib-enhanced cytotoxicity was lower in Fas siRNA-transfected cells than in negative controls, suggesting that Fas signaling might be involved in the radotinib-enhanced NK cell cytotoxicity. This study provides the first evidence that radotinib could be used as an effective and strong therapeutic to treat solid tumors via upregulation of NK cell cytotoxicity, suggesting that radotinib has indirect killing mechanisms via upregulation of antitumor innate immune responses as well as direct killing activities for CML cells.
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Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pirazinas/uso terapêutico , Receptor fas/metabolismo , Antineoplásicos/farmacologia , Apoptose , Benzamidas/farmacologia , Citotoxicidade Imunológica , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Imunidade Inata , Células K562 , Ativação Linfocitária , Pirazinas/farmacologia , RNA Interferente Pequeno/genética , Receptor fas/genéticaRESUMO
This study aimed to evaluate the levels of three major hydroxycholesterols (24-, 25-, and 27-hydroxycholesterols) in the serum and cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS), as well as to show their role in the pathogenesis of ALS experimental models. The level of 25-hydroxycholesterol were higher in untreated ALS patients (n = 30) than in controls without ALS (n = 33) and ALS patients treated with riluzole (n = 9) both in their serum and CSF. The level of 25-hydroxycholesterol in the serum of ALS patients were significantly associated with their disease severity and rate of progression. In the motor neuron-like cell line (NSC34) with the human mutant G93A superoxide dismutase 1 gene (mSOD1-G93A), 25-hydroxycholesterol induced motor neuronal death/ apoptosis via glycogen synthase kinase-3ß and liver X receptor pathways; riluzole treatment attenuated these effects. The expressions of enzymes that synthesize 25-hydroxycholesterol were significantly increased in the brains of early symptomatic mSOD1G93A mice. Our data, obtained from patients with ALS, a cellular model of ALS, and an animal model of ALS, suggests that 25-hydroxycholesterol could be actively involved in the pathogenesis of ALS, mostly in the early symptomatic disease stage, by mediating neuronal apoptosis.
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Esclerose Lateral Amiotrófica/metabolismo , Hidroxicolesteróis/metabolismo , Adulto , Idoso , Esclerose Lateral Amiotrófica/patologia , Animais , Humanos , Camundongos , Pessoa de Meia-IdadeRESUMO
Interleukin (IL)-32α, the shortest isoform of proinflammatory cytokine IL-32, is associated with various inflammatory diseases and cancers. However, its involvement in human melanoma is not understood. To determine the effect of IL-32α in melanoma, IL-32α levels were examined in human melanoma cell lines that exhibit different migratory abilities. IL-32α levels were higher in human melanoma cell lines with more migratory ability. An IL-32α-overexpressing G361 human melanoma cell line was generated to investigate the effect of IL-32α on melanoma migration. IL-32α-overexpressing G361 cells (G361-IL-32α) exhibit an increased migratory ability compared to vector control cells (G361-vector). To identify factors involved in IL-32α-induced migration, we compared expression of E-cadherin in G361-vector and G361-IL-32α cells. We observed decreased levels of E-cadherin in G361-IL-32α cells, resulting in F-actin polymerization. To further investigate signaling pathways related to IL-32α-induced migration, we treated G361-vector and G361-IL-32α cells with PD98059, a selective MEK inhibitor. Inhibition of Erk1/2 by PD98059 restored E-cadherin expression and decreased IL-32α-induced migration. In addition, cell invasiveness of G361-IL-32α cells was tested using an in vivo lung metastasis model. As results, lung metastasis was significantly increased by IL-32α overexpression. Taken together, these data indicate that IL-32α induced human melanoma migration via Erk1/2 activation, which repressed E-cadherin expression. Our findings suggest that IL-32α is a novel regulator of migration in melanoma.
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Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Interleucinas/metabolismo , Neoplasias Pulmonares/secundário , Melanoma/patologia , Animais , Antígenos CD , Apoptose , Proliferação de Células , Regulação para Baixo , Humanos , Neoplasias Pulmonares/metabolismo , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system and is mediated by complement-dependent cytotoxicity (CDC) of NMO-specific immunoglobulin G (IgG) antibodies (NMO-IgG). Glycyrrhizic acid (GA) has numerous pharmacological effects including inhibition of the complement pathway. We aimed to study the influence of GA on NMO-IgG-induced CDC. NMO-IgG samples from 7 patients with NMO, together with human complement, induced CDC in an aquaporin 4 M23-overexpressing glial cell line, an in vitro NMO model. GA attenuated NMO-IgG-induced CDC in a dose-dependent manner. The mechanism of the GA-related CDC inhibition was sequentially dissected and found to involve inhibition of C1q binding to NMO-IgG. Consequently, GA attenuates NMO-IgG-induced CDC and may be a promising novel therapeutic agent against NMO.
Assuntos
Astrócitos/efeitos dos fármacos , Complemento C1q/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Fatores Imunológicos/farmacologia , Neuromielite Óptica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Adulto , Astrócitos/imunologia , Astrócitos/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Ácido Glicirrízico/uso terapêutico , Humanos , Imunoglobulina G/imunologia , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Neuromielite Óptica/patologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Interleukin-18 (IL-18) was recently reported to have a pro-tumor effect in various cancers. Increased IL-18 levels in the serum of cancer patients correlated with malignancy, and IL-18 acts a crucial factor for cell migration in gastric cancer and melanoma. Claudins, which are the most important tight junction proteins, are also linked with cancer progression and metastasis. However, the relationship between claudins and IL-18 is not well-understood. Here, we show that the migratory ability of MCF-7 cells was reduced when endogenous IL-18 expression was inhibited with IL-18 siRNA. Moreover, exogenous IL-18 enhanced breast cancer cell migration and suppressed the expression of the tight junction proteins claudin-1, claudin-3, claudin-4, and claudin-12 in MCF-7 cells. Knockdown of claudin-3, claudin-4, and claudin-12, but not claudin-1, increased breast cancer migration with maximal effects observed in claudin-12 siRNA-transfected cells. To investigate whether the mitogen-activated protein kinase (MAPK) signaling pathway is involved in IL-18-induced cell migration and claudin-12 expression, cells were pretreated with SB203580 (an inhibitor of p38 MAPK) or PD98059 (an inhibitor of ERK1/2) prior to the addition of IL-18. Although pretreatment of MCF-7 cells with SB203580 blocked both the enhanced cell migration and the decreased claudin-12 expression, PD98059 only blocked cell migration and did not affect claudin-12 expression. In addition, exogenous IL-18 induced rapid phosphorylation of p38 MAPK. These results suggest that IL-18 is an important factor inducing breast cancer cell migration through down-regulation of claudin-12 and activation of the p38 MAPK pathway.
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Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Claudinas/fisiologia , Interleucina-18/fisiologia , Sistema de Sinalização das MAP Quinases , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Movimento Celular/fisiologia , Claudina-1/antagonistas & inibidores , Claudina-1/genética , Claudina-1/fisiologia , Claudina-3/antagonistas & inibidores , Claudina-3/genética , Claudina-3/fisiologia , Claudina-4/antagonistas & inibidores , Claudina-4/genética , Claudina-4/fisiologia , Claudinas/antagonistas & inibidores , Claudinas/genética , Regulação para Baixo/efeitos dos fármacos , Feminino , Flavonoides/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Imidazóis/farmacologia , Interleucina-18/antagonistas & inibidores , Interleucina-18/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/genética , Proteínas Recombinantes/farmacologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/fisiologiaRESUMO
The active metabolite of vitamin D(3), 1α,25(OH)(2)D(3) , displays anticancer effects by regulating cell cycle and apoptosis in many cancer cells. However, it has not been determined whether 1α,25(OH)(2)D(3) increases the susceptibility of cancer cells to NK cells. Here, we investigated the anticancer effect of 1α,25(OH)(2)D(3) in human melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1α,25(OH)(2)D(3)-resistant melanoma cells (G-361 and SK-MEL-5) treated with 1α,25(OH)(2)D(3) showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1α,25(OH)(2)D(3) showed significantly increased caspase activity. In addition to Fas up-regulation, expression of heat shock protein 60 (Hsp60) was elevated by 1α,25(OH)(2) D(3) . Increased expression of Hsp60 by 1α,25(OH)(2)D(3) was related to not only up-regulation of Fas expression but also to NK susceptibility of G-361 cells. Taken together, our data suggest that 1α,25(OH)(2)D(3) acts as an anticancer agent by increasing expression of Fas on the surface of melanoma cells through Hsp60 induction and strengthens caspase sensitivity to Fas-mediated apoptotic pathway by NK cells. 1α,25(OH)(2)D(3) treatment may therefore have a preventive role in melanoma occurrence or potentiate the anticancer effects of NK-cell immune therapy.
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Calcitriol/farmacologia , Chaperonina 60/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Melanoma/tratamento farmacológico , Receptor fas/metabolismo , Apoptose/imunologia , Western Blotting , Caspase 3/metabolismo , Caspase 8/metabolismo , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Citometria de Fluxo , Humanos , Melanoma/imunologia , Melanoma/metabolismo , Interferência de RNA , RNA Interferente PequenoRESUMO
IL-32 was recently identified as a proinflammatory cytokine that is induced by IL-18 in natural killer (NK) cells and is highly correlated with inflammatory disorders. However, the relationship between IL-32 and tumor progression is still unknown. In this study, we investigated whether overexpression of IL-32 affects susceptibility of chronic myeloid leukemia (CML) cells to NK cells. Interestingly, IL-32α-overexpressing CML cell lines, K562, Kcl22, and BV173, showed higher NK cell-mediated killing. Flow cytometry analysis revealed that overexpression of IL-32α induced increased expression of Fas and UL16-binding protein 2 (ULBP2) in CML cells. The direct relationship between overexpression of surface molecules by IL-32α and increased NK cell-mediated killing was confirmed by Fas or ULBP2 siRNA transfection. IL-32α-induced Fas and ULBP2 expression are regulated p38 MAPK. In addition, the transcription factor Ets1 plays a key role in ULBP2 specific expression by IL-32α overexpression in ULBP family members. Taken together, these data show that IL-32α stimulates Fas and ULBP2 expression via activation of p38 MAPK, which increases NK susceptibility of CML cells. Enhanced NK cell susceptibility of CML cells by IL-32α overexpression may improve the efficiency of NK cell-based immunotherapy.
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Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucinas/metabolismo , Células Matadoras Naturais/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Receptor fas/metabolismo , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Citometria de Fluxo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Interleucinas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor fas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Heat-killed lactic acid bacteria (LAB) are known to be important immunomodulators that stimulate tumor necrosis factor-α (TNF-α) and nitric oxide (NO) production as well as increase phagocytic activity in macrophages. NK cells play a critical role in innate immune response and induce spontaneous killing of tumor cells and virus-infected cells. However, the effect of heat-killed LAB on NK cells is still unclear. In this study, we investigated the effect of heat-killed Lactobacillus acidophilus La205 (La205) on NK cytolytic activity. We found that heat-killed La205 directly stimulated NK cytolytic activity in dose- and time-dependent manners. To determine the mechanism underlying heat-killed La205-enhanced NK cytotoxicity, the expression of NK activating receptors was tested. Heat-killed La205 did not affect the expression of NK activating receptors. To investigate whether NK degranulation is related to heat-killed La205-enhanced NK cytotoxicity, NK degranulation inhibitor concanamycin A (CMA) was used. CMA effectively blocked heat-killed La205-induced NK cytotoxicity, and an assay for detection of a degranulation marker, CD107a, showed that heat-killed La205 increased granule exocytosis approximately 2-fold in comparison to non-treated NK cells. In addition, heat-killed La205 dramatically elevated mRNA expression of granulysin, a component of the cytolytic granule contents, in NK cells. However, other granule contents, including perforin and granzymes, were not changed by heat-killed La205. From these data, we concluded that heat-killed La205 stimulated NK cytolytic activity through enhancement of granule exocytosis, and granulysin may be a critical mediator in heat-killed La205-induced granule exocytosis.
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Grânulos Citoplasmáticos/imunologia , Citotoxicidade Imunológica/imunologia , Exocitose/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Lactobacillus acidophilus/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Relação Dose-Resposta Imunológica , Regulação da Expressão Gênica/imunologia , Granzimas/genética , Granzimas/metabolismo , HumanosRESUMO
Natural killer (NK) cells play an important role in the innate immune response. Interleukin-18 (IL-18) is a well-known interferon-gamma (IFN-gamma inducing factor, which stimulates immune response in NK and T cells. Sphingosine kinase (SPHK) catalyzes the formation of sphingosine 1-phosphate (S1P), which acts as a second messenger to function as an anti-apoptotic factor and proliferation stimulator of immune cells. In this study, to elucidate whether SPHK is involved in IL-18-induced IFN-gamma production, we measured IL-18-induced IFN-gamma production after pre-treatment with SPHK inhibitor (SKI) in NK-92MI cells. We found that IL-18-induced IFN-gamma expression was blocked by SKI pre-treatment in both mRNA and protein levels. In addition, the increased IFN-gamma production by stimulation with IL-18 is mediated through both SPHK and p38 MAPK. To determine the upstream signals of SKI and p38 MAPK in IL-18-induced IFN-gamma production, phosphorylation levels of p38 MAPK was measured after SKI pre-treatment. As a result, inhibition of SPHK by SKI blocked phosphorylation of p38 MAPK, showing that SPHK activation by IL-18 is an upstream signal of p38 MAPK activation. Inhibition of SPHK by SKI also inhibited IL-18-induced IFN-gamma production in human primary NK cells. In conclusion, SPHK activation is an essential factor for IL-18-induced IFN-gamma production via p38 MAPK.
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Interferon gama/antagonistas & inibidores , Interleucina-18/fisiologia , Células Matadoras Naturais/imunologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Humanos , Interferon gama/biossíntese , Interleucina-18/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Lisofosfolipídeos/biossíntese , Fosforilação/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Inibidores de Proteínas Quinases/farmacologia , Esfingosina/análogos & derivados , Esfingosina/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
Interleukin-18 (IL-18) was discovered as an interferon-gamma-inducing factor and had a critical role in inflammatory and immune response. It stimulates natural killer (NK) and T cells and enhances Th1 immune response. These activated immune cells eliminate cancer cells and virus-infected cells effectively. However, IL-18 has also been found to promote tumor progression. Higher expression or secretion level of IL-18 is detected in various cancer cells in comparison with normal control, and IL-18 is able to induce angiogenesis, migration/metastasis, proliferation and immune escape. These dual effects and the mechanism of IL-18 need to be investigated further as it relates to cancer.