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AAV vector-mediated gene therapy has been proposed as a feasible strategy for several eye diseases. However, AAV antibodies in the serum prior to treatment hinder the transduction efficiency and thus the therapeutic effect. Therefore, it is necessary to evaluate AAV antibodies in the serum before gene therapy. As large animals, goats are more closely related to humans than rodents and more economically available than nonhuman primates. Here, we first evaluated the AAV2 antibody serum level in rhesus monkeys before AAV injection. Then, we optimized a cell-based neutralizing antibody assay for detecting AAV antibodies in the serum of Saanen goats and evaluated the consistency of the cell-based neutralizing antibody assay and ELISA for goat serum antibody evaluation. The cell-based neutralizing antibody assay showed that the percentage of macaques with low antibody levels was 42.86%; however, there were no macaques with low antibody levels when the serum was evaluated by ELISA. The proportion of goats with low antibody levels was 56.67% according to the neutralizing antibody assay and 33. 33% according to the ELISA, and McNemar's test showed that the results of the two assays were not significantly different (P = 0.754), but that their consistency is poor (Kappa = 0.286, P = 0.114). Moreover, longitudinal evaluation of serum antibodies before and after intravitreal injection of AAV2 in goats revealed that the level of AAV antibodies increased and transduction inhibition subsequently increased, as reported in humans, indicating that transduction inhibition should be taken into account at different stages of gene therapy. In summary, starting with an evaluation of monkey serum antibodies, we optimized a detection method of goat serum antibodies, providing an alternative large animal model for gene therapy, and our serum antibody measurement method may be applied to other large animals.
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Anticorpos Neutralizantes , Cabras , Humanos , Animais , Cabras/genética , Terapia Genética/métodos , Injeções Intravítreas , Macaca mulatta , Dependovirus/genética , Vetores Genéticos , Anticorpos Antivirais/genéticaRESUMO
Retinal fundus diseases can lead to irreversible visual impairment without timely diagnoses and appropriate treatments. Single disease-based deep learning algorithms had been developed for the detection of diabetic retinopathy, age-related macular degeneration, and glaucoma. Here, we developed a deep learning platform (DLP) capable of detecting multiple common referable fundus diseases and conditions (39 classes) by using 249,620 fundus images marked with 275,543 labels from heterogenous sources. Our DLP achieved a frequency-weighted average F1 score of 0.923, sensitivity of 0.978, specificity of 0.996 and area under the receiver operating characteristic curve (AUC) of 0.9984 for multi-label classification in the primary test dataset and reached the average level of retina specialists. External multihospital test, public data test and tele-reading application also showed high efficiency for multiple retinal diseases and conditions detection. These results indicate that our DLP can be applied for retinal fundus disease triage, especially in remote areas around the world.
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Algoritmos , Aprendizado Profundo , Fundo de Olho , Redes Neurais de Computação , Fotografação/métodos , Doenças Retinianas/diagnóstico , Retinopatia Diabética/diagnóstico , Glaucoma/diagnóstico , Humanos , Degeneração Macular/diagnóstico , Curva ROCRESUMO
Optic neuropathies are leading causes of irreversible visual impairment and blindness, currently affecting more than 100 million people worldwide. Glaucoma is a group of optic neuropathies attributed to progressive degeneration of retinal ganglion cells (RGCs). We have previously demonstrated an increase in survival of RGCs by the activation of macrophages, whereas the inhibition of macrophages was involved in the alleviation on endotoxin-induced inflammation by antagonist of growth hormone-releasing hormone (GHRH). Herein, we hypothesized that GHRH receptor (GHRH-R) signaling could be involved in the survival of RGCs mediated by inflammation. We found the expression of GHRH-R in RGCs of adult rat retina. After optic nerve crush, subcutaneous application of GHRH agonist MR-409 or antagonist MIA-602 promoted the survival of RGCs. Both the GHRH agonist and antagonist increased the phosphorylation of Akt in the retina, but only agonist MR-409 promoted microglia activation in the retina. The antagonist MIA-602 reduced significantly the expression of inflammation-related genes Il1b, Il6, and Tnf Moreover, agonist MR-409 further enhanced the promotion of RGC survival by lens injury or zymosan-induced macrophage activation, whereas antagonist MIA-602 attenuated the enhancement in RGC survival. Our findings reveal the protective effect of agonistic analogs of GHRH on RGCs in rats after optic nerve injury and its additive effect to macrophage activation, indicating a therapeutic potential of GHRH agonists for the protection of RGCs against optic neuropathies especially in glaucoma.
Assuntos
Hormônio Liberador de Hormônio do Crescimento/agonistas , Macrófagos/patologia , Neuroproteção , Traumatismos do Nervo Óptico/patologia , Células Ganglionares da Retina/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/antagonistas & inibidores , Inflamação/genética , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Neuroproteção/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Endogâmicos F344 , Receptores de Neuropeptídeos/metabolismo , Receptores de Hormônios Reguladores de Hormônio Hipofisário/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Fator de Transcrição STAT3/metabolismo , Sermorelina/análogos & derivados , Sermorelina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismo , Zimosan/farmacologiaRESUMO
BACKGROUND: Previous studies reported that mild inflammation promotes retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve (ON) injury with involvement of infiltrating macrophages and neutrophils. Here we aimed to evaluate the involvement and regulation of the main inflammatory chemokine pathway CXCL5/CXCR2 in the inflammation-mediated RGC survival and axonal regeneration in mice after ON injury. METHODS: The expressions and cellular locations of CXCL5 and CXCR2 were confirmed in mouse retina. Treatment effects of recombinant CXCL5 and CXCR2 antagonist SB225002 were studied in the explant culture and the ON injury model with or without lens injury. The number of RGCs, regenerating axons, and inflammatory cells were determined, and the activation of Akt andSTAT3 signaling pathways were evaluated. RESULTS: Cxcr2 and Cxcl5 expressions were increased after ON and lens injury. Addition of recombinant CXCL5 promoted RGC survival and neurite outgrowth in retinal explant culture with increase in the number of activated microglia, which was inhibited by SB225002 or clodronate liposomes. Recombinant CXCL5 also alleviated RGC death and promoted axonal regeneration in mice after ON injury, and promoted the lens injury-induced RGC protection with increase in the number of activated CD68+ cells. SB225002 inhibited lens injury-induced cell infiltration and activation, and attenuated the promotion effect on RGC survival and axonal regeneration through reduction of lens injury-induced Akt activation. CONCLUSIONS: CXCL5 promotes RGC survival and axonal regeneration after ON injury and further enhances RGC protection induced by lens injury with CD68+ cell activation, which is attenuated by CXCR2 antagonist. CXCL5/CXCR2 could be a potential therapeutic target for RGC survival promotion after ON injury.
Assuntos
Quimiocina CXCL5/biossíntese , Mediadores da Inflamação/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Receptores de Interleucina-8B/biossíntese , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Mediadores da Inflamação/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Traumatismos do Nervo Óptico/patologia , Compostos de Fenilureia/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidoresRESUMO
Inflammation is a critical pathophysiological process that modulates neuronal survival in the central nervous system after disease or injury. However, the effects and mechanisms of macrophage activation on neuronal survival remain unclear. In the present study, we co-cultured adult Fischer rat retinas with primary peritoneal macrophages or zymosan-treated peritoneal macrophages for 7 days. Immunofluorescence analysis revealed that peritoneal macrophages reduced retinal ganglion cell survival and neurite outgrowth in the retinal explant compared with the control group. The addition of zymosan to peritoneal macrophages attenuated the survival and neurite outgrowth of retinal ganglion cells. Conditioned media from peritoneal macrophages also reduced retinal ganglion cell survival and neurite outgrowth. This result suggests that secretions from peritoneal macrophages mediate the inhibitory effects of these macrophages. In addition, increased inflammation- and oxidation-related gene expression may be related to the enhanced retinal ganglion cell degeneration caused by zymosan activation. In summary, this study revealed that primary rat peritoneal macrophages attenuated retinal ganglion cell survival and neurite outgrowth, and that macrophage activation further aggravated retinal ganglion cell degeneration. This study was approved by the Animal Ethics Committee of the Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong Province, China, on March 11, 2014 (approval no. EC20140311(2)-P01).
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Gene therapy has been proposed as a feasible strategy for RGC survival and optic nerve regeneration. Some preclinical and clinical studies revealed intraocular inflammation after intravitreal injection of adeno-associated virus (AAV) by slit-lamp or indirect ophthalmoscope. Here we evaluate the longitudinal profile of immediate inflammatory responses after AAV2 injection in rat retina and vitreous body by optical coherence tomography (OCT). Adult Fischer F344 rats were intravitreally injected once with saline, AAV2 or zymosan. Retinal thickness and cell infiltration were recorded by OCT longitudinally for 2 months and verified by histological analysis. The transduction rate of single intravitreal AAV2 injection was 21.3 ± 4.9% of whole retina, and the transduction efficiency on RGCs was 91.5 ± 2.5% in the transduced area. Significant increase in cell infiltration was observed from Day 1-3 after AAV2 injection, compared to very few infiltrating cells observed in the saline-injected group. The infiltrating cells ceased at Day 5 after intravitreal injection and remained absent at 2 months. The thicknesses of total and inner retina were increased along Day 1-3 after AAV2 injection, but reverted to normal afterwards. The surviving RGCs in the AAV2-injected groups at Day 14 showed no significant difference compared to saline-injected group. In summary, this study revealed the immediate inflammatory responses and retinal edema after intravitreal AAV2 injection in normal rats, without influencing long-term retinal thickness and RGC survival. OCT can be implemented for the time-lapse in vivo evaluation of inflammatory response after AAV-mediated gene therapy through intravitreal injection.
Assuntos
Dependovirus , Terapia Genética/métodos , Doenças do Nervo Óptico/terapia , Células Ganglionares da Retina/patologia , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Injeções Intravítreas , Doenças do Nervo Óptico/diagnóstico , Ratos , Ratos Endogâmicos F344 , Tomografia de Coerência Óptica , Transdução GenéticaRESUMO
The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.
Assuntos
Diferenciação Celular/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Regeneração/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Regulação para Baixo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/fisiologia , Mioblastos/fisiologia , Regulação para Cima/fisiologiaRESUMO
Neuron survival is critical for the maintenance of central nervous system physiology upon diseases or injury. We previously demonstrated that the blockage of phosphatidylinositol 3-kinase/Akt and Janus kinase/STAT3 pathways promotes retinal ganglion cell (RGC) survival and axonal regeneration via macrophage activation; yet, the complexity of the inflammatory regulation for neural repair indicates the involvement of additional unresolved signaling pathways. Here we report the effects and underlying mechanism of casein kinase-II (CK2) inhibition on RGC survival and axonal regeneration in rats after optic nerve (ON) injury. Adult rats received intravitreal injection of CK2 inhibitors, TBB (4,5,6,7-Tetrabromo-2-azabenzimidazole) and DMAT (2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole), after ON transection and peripheral nerve (PN) grafting. Intravitreal application of TBB and DAMT effectively suppressed the CK2 phosphorylation activity in the retina, and enhanced RGC survival and axonal regeneration in vivo. Meanwhile, the numbers of infiltrating macrophages were increased. Removal of macrophages by clodronate liposomes significantly abolished the CK2 inhibition-induced RGC survival and axonal regeneration. Clodronate liposomes also weakened the RGC protective effects by TBB and DMAT in vitro. In summary, this study revealed that inhibition of CK2 enhances RGC survival and axonal regeneration via macrophage activation in rats. CK2 could be a therapeutic target for RGC protection after ON injury.
Assuntos
Axônios/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Traumatismos do Nervo Óptico/tratamento farmacológico , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Macrófagos/patologia , Traumatismos do Nervo Óptico/patologia , Inibidores de Proteínas Quinases , Ratos , Transdução de SinaisRESUMO
By exploiting the polymer/silica hybrid and the air trench waveguide structures, we demonstrate a new type of low-power consuming and high-speed thermal-optic (TO) switch. Such a design provides an effective means to shorten the switching time of the TO switches, as well as to reduce the power consumption at the same time. This TO switch operated with less than 150 µs of switching time via a polymer/silica hybrid waveguide structure. Meanwhile, the power consumption was reduced to be 3.4 mW by introducing the air trench structure.
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OBJECTIVE: This study aimed to identify predictors of changes in diurnal cortisol patterns during the 8-month follow up period for young breast cancer survivors. Among the potential predictors were tumor size, lymph node metastasis, changes in sleep problems, habitual time of awakening and bedtime, physical activity levels, body mass index (BMI), and depressive levels across 8 months. METHODS: The participants were 62 breast cancer women who were aged 40 years and below, and had completed active breast cancer treatment. The longitudinal data were collected at four points: baseline assessment (T0) and three follow-ups after baseline: T1 (in the 2nd month), T2 (in the 5th month), and T3 (in the 8th month). The participants collected their salivary cortisol at home at six time points: upon waking, 30 and 45min after waking, and at 1200h, 1700h, and 2100h. They also completed several questionnaires: the Medical Outcomes Study Sleep scale; the Beck Depression Inventory-II, physical activity levels on a 10-point scale, time of going to bed, time of awakening, and total sleep hours. RESULTS: This study found that the main predictors of changes toward flatter diurnal cortisol patterns during the 8-month follow ups were greater tumor sizes, increases of BMI scores, and habitually later times of awakening. CONCLUSIONS: While greater tumor sizes represent biological vulnerability of disruption of cortisol circadian rhythm, maintaining an appropriate BMI and good sleep habits could be a protective factor for normal cortisol regulation, which likely helps to reduce early mortality in young breast cancer survivors.
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Neoplasias da Mama/patologia , Ritmo Circadiano , Hidrocortisona/metabolismo , Estilo de Vida , Distúrbios do Início e da Manutenção do Sono/metabolismo , Sono , Sobreviventes , Vigília , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Feminino , Humanos , Estudos Longitudinais , Atividade Motora , Estadiamento de Neoplasias , Saliva/química , Carga TumoralRESUMO
In this paper, a low-power 1 × 2 polymeric thermo-optic switch operating at the polymer optical fiber low-loss window of 650 nm was studied. The characteristic parameters of the switch were carefully designed and simulated. The fabrication was done by using standard semiconductor fabrication techniques such as spin-coating, photolithography, and dry etching. The device was fabricated based on poly(methyl methacrylate) (PMMA)-based materials with the Mach-Zehnder interferometer (MZI) structure. The device shows an extinction ratio of over 23.4 dB at 650 nm with a very low-power consumption of 5.3 mW. The measured switching rise time and fall time are 464.4 and 448.0 µs, respectively.
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The objectives of this study were to identify the antioxidants and antioxidant axtivity in 27 of Taiwan's indigenous vegetables. Lycium chinense (Lc), Lactuca indica (Li), and Perilla ocymoides (Po) contained abundant quercetin (Que), while Artemisia lactiflora (Al) and Gynura bicolor (Gb) were rich in morin and kaempferol, respectively. Additionally, Nymphoides cristata (Nc) and Sechium edule (Se)-yellow had significantly higher levels of myricetin (Myr) than other tested samples. Cyanidin (Cyan) and malvidin (Mal) were abundant in Gb, Abelmoschus esculentus Moench (Abe), Po, Anisogonium esculentum (Retz.) Presl (Ane), Ipomoea batatas (Ib)-purple, and Hemerocallis fulva (Hf)-bright orange. Relatively high levels of Trolox equivalent antioxidant capacity (TEAC), oxygen radical absorption capacity (ORAC), and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenger were generated from extracts of Toona sinensis (Ts) and Po. Significant and positive correlations between antioxidant activity and polyphenols, anthocyanidins, Que, Myr, and morin were observed, indicating that these phytochemicals were some of the main components responsible for the antioxidant activity of tested plants. The much higher antioxidant activity of Po, Ts, and Ib (purple leaf) may be related to their higher Cyan, Que, and polyphenol content.
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Antioxidantes/análise , Extratos Vegetais/química , Verduras/química , Antocianinas/análise , Cromatografia Líquida de Alta Pressão , Flavonoides/análise , Quempferóis/análise , Folhas de Planta/química , Polifenóis/análise , Espécies Reativas de Oxigênio , TaiwanRESUMO
The purpose of this study was to explore whether stress from individual's and partner's depression, anxiety, sleep disturbances, insecure attachment and meaning in life were predictors of diurnal cortisol patterns in breast cancer survivors and their spouses. Thirty-four couple dyads participated in this eight-month follow-up study. The breast cancer survivors and their spouses completed the Medical Outcomes Study Sleep scale, the Beck Depression Inventory-II, the State Trait Anxiety Inventory, the Experiences in Close Relationships-Revised scale and the Meaning in Life Questionnaire, and they collected salivary cortisol at home at the time of awakening, 30 and 45 min after waking and at 1200 h, 1700 h and 2100 h. Diurnal cortisol slopes of survivors and spouses are positively correlated. But the factors associated with diurnal cortisol patterns are different between survivors and spouses. For survivors, neither survivor individuals' nor spouses' psychosocial factors were the predictors of survivors' diurnal cortisol patterns. For spouses, the survivors' higher anxious attachment style was the main predictor of spouses' flatter diurnal cortisol patterns. In conclusion, for spouses, psychophysiological stress responses are mainly influenced by breast cancer survivors' insecure attachment. Future couple supportive care interventions can address survivors' attachment styles in close relationships in order to improve neuroendocrine functions for both breast cancer survivors and their spouses.
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Neoplasias da Mama/fisiopatologia , Catexia , Ritmo Circadiano , Depressão/epidemiologia , Hidrocortisona/metabolismo , Saliva/química , Cônjuges/psicologia , Estresse Psicológico/fisiopatologia , Sobreviventes , Adulto , Idoso , Ansiedade/epidemiologia , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Emoções , Relações Familiares , Humanos , Hidrocortisona/análise , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/fisiopatologia , Autorrelato , Transtornos do Sono-Vigília/epidemiologia , Estresse Psicológico/etiologia , Sobreviventes/psicologia , Taiwan , Adulto JovemRESUMO
Gastric cancer is one of the leading causes of cancer death in the world and nearly all patients who respond initially to cisplatin later develop drug resistance, indicating multi-drug resistance is an essential aspect of the failure of treatment. Phenethyl isothiocyanate (PEITC) has been implicated in inhibiting metastasis of several types of human cancer. However, the effect and potential mechanism of PEITC reversed multi-drug resistance of human gastric cancer is not fully clear. We have identified the role of PEITC in multi-drug resistance reversal of human gastric cancer SGC7901/DDP cell line. PEITC inhibited cisplatin-resistant human SGC7901/DDP cell growth in a dose-dependent manner, causing increased apoptosis, ROS generation, glutathione depletion, accumulation of Rhodamine-123, decreased expression of P-glycoprotein and cell cycle arrest. mRNA and protein expression of the multi-drug resistance gene (MDR1), multi-drug resistance-associated protein (MRP1), excision repair cross-complementing gene 1 (ERCC1), survivin, and Mad2 was decreased, and phosphorylation of Akt and transcriptional activation of NF-κB were suppressed. PEITC may be useful as the therapeutic strategy for overcoming multi-drug resistance through suppressing the PI3K-Akt pathway in human gastric cancer.
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Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Isotiocianatos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/genética , Endonucleases/metabolismo , Glutationa/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Mad2/genética , Proteínas Mad2/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , SurvivinaRESUMO
OBJECTIVE: This study examined whether the changes in sleep problems, attachment styles, meaning in life, and salivary cortisol over the course of 14 months were the predictors of changes in depressive symptoms in women with breast cancer at post-treatment stage. METHODS: The study included 76 participants who completed active breast cancer treatment with longitudinal data collected at five points, including baseline assessment (T0) and the four follow-ups after baseline: T1 (in the 2nd month), T2 (in the 5th month), T3 (in the 8th month), and T4 (in the 14th month). The self-reported questionnaires included the Medical Outcomes Study Sleep (MOS-Sleep) scale; the Beck Depression Inventory-II (BDI-II); the Experiences in Close Relationships-Revised (ECR-R) scale for measuring anxiety and avoidance dimensions of attachment style; and the Meaning in Life Questionnaire (MLQ), consisting of the MLQ-Presence scale and the MLQ-Search scale. The participants collected their salivary cortisol at home at six time points: upon waking, 30 and 45 min after waking, and at 1200 h, 1700 h, and 2100 h. RESULTS: Higher scores on for anxiety-related attachment style and the sleep problems index at baseline were associated with more severe initial depressive symptoms after the age, BMI, cancer, and treatment variables were controlled. The presence of meaning in life at baseline was negatively correlated with initial depressive symptoms. Moreover, the decreases in the presence of meaning in life over the course of 14 months predicted more severe depressive symptoms. In addition, the persistent increases of cortisol level at 2100 h across 14-month follow-ups predicted worsening depressive symptoms. CONCLUSIONS: Lacking presence of meaning in life as a predictor for severe depressive symptoms demonstrates that breast cancer survivors who lack psychological well-being are more likely to be depressed. The persistent elevation of cortisol levels at night also indicates breast cancer survivors to be at high risk of depression.
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Adaptação Psicológica , Depressão/metabolismo , Depressão/psicologia , Hidrocortisona/metabolismo , Distúrbios do Início e da Manutenção do Sono/metabolismo , Distúrbios do Início e da Manutenção do Sono/psicologia , Sobreviventes/psicologia , Neoplasias da Mama/psicologia , Depressão/complicações , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Fatores de Risco , Saliva/metabolismo , Distúrbios do Início e da Manutenção do Sono/complicações , Fatores de TempoRESUMO
BACKGROUND: Neuroendocrine dysregulation influenced by psychosocial stress is related to breast cancer recurrence. Very few studies examine the impacts of psychotherapy on diurnal cortisol patterns among breast cancer survivors. METHODS: Forty-eight breast cancer patients who completed active cancer treatment were randomly assigned to receive either 8 weekly body-mind-spirit (BMS) group therapy sessions or 1 educational (EDU) session. Self-report measures included the Beck Depression Inventory-II (BDI-II), and the Meaning in Life questionnaire (MLQ) including two subscales: MLQ-Presence and MLQ-Search. Salivary cortisol levels were collected by the subjects in their homes at the time of awakening, 30 and 45 min after awakening, and at 12.00, 17.00, and 21.00 h. Measurement time points include baseline, the 2nd month (completion of BMS therapy), the 5th month, and the 8th month. RESULTS: There were no significant differences in BDI-II scores (p>0.05) and MLQ-Presence scores (p >0.05) between BMS and EDU groups at baseline or across the three follow-ups. Nevertheless, greater MLQ-Search scores were found in the BMS group compared to the EDU group during the 5th month of follow-up (p <0.01). The higher level of cortisol at 21.00 h (p < 0.01) and a flatter diurnal cortisol pattern were more likely to occur in EDU than in BMS participants (p < 0.05) at the 8th month of follow-up. CONCLUSION: BMS group therapy likely contributed to enhancing an active search for meaning in life toward more opportunities for personal growth and to maintaining stable cortisol responses to everyday life stress for breast cancer survivors.
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Neoplasias da Mama/psicologia , Ritmo Circadiano/fisiologia , Hidrocortisona/metabolismo , Terapias Mente-Corpo , Psicoterapia Breve/métodos , Sobreviventes/psicologia , Adaptação Psicológica , Adolescente , Adulto , Idoso , Análise de Variância , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Depressão/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Escalas de Graduação Psiquiátrica , Saliva/química , Estresse Psicológico/metabolismo , Estresse Psicológico/terapia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1-q11.2 and two pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMRbeta), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMRbeta through interleukin-31 signaling. In one family, we identified a point mutation in the IL31RA gene, c.1562C>T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5. The identification of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology.
Assuntos
Alelos , Amiloidose Familiar/genética , Mutação/genética , Subunidade beta de Receptor de Oncostatina M/genética , Filogenia , Receptores de Interleucina/genética , Dermatopatias/genética , Sequência de Bases , Chile , Análise Mutacional de DNA , Ligação Genética , Haplótipos/genética , Humanos , Dados de Sequência Molecular , Proteínas Mutantes/genética , Reprodutibilidade dos Testes , TaiwanRESUMO
The recombinant thymine-DNA glycosylase (TDG) from Aeropyrum pernix (A. pernix) was expressed in Escherichia coli. The enzymatic activity of recombinant A. pernix TDG (ApeTDG) was characterized using oligonucleotides containing a thymine/uracil base as substrate. ApeTDG had distinct glycosylase activity on T/G mismatch. The optimal temperature and pH for thymine removal were 65-70 degrees C and pH 7.0-8.5, respectively. High concentration of NaCl inhibited the thymine removal. Divalent ions had different influence on the thymine removal by ApeTDG. Ca(2+) and Mg(2+) had no inhibition on the enzymic activity, but Ni(2+), Co(2+), Cu(2+), Mn(2+), and Zn(2+) completely inhibited the excision reaction. As derived from a hyperthermophilic archaea, ApeTDG protein was heat-resistant at 75 degrees C. ApeTDG also had a relatively weak DNA glycosylase activity on uracil base, with the following order: U/C>U/G approximately U/T>U/U approximately U/I approximately U/AP approximately U/->U/A. Additional mismatch located at 3' of T/G had less inhibition on the thymine removal than that located at 5' of T/G, and two additional mismatches located at each side of T/G completely inhibited the excision of thymine. Together, these data suggest that ApeTDG is a TDG protein with weak UDG activity.
Assuntos
Aeropyrum/enzimologia , Proteínas Arqueais/química , Proteínas Arqueais/metabolismo , Timina DNA Glicosilase/química , Timina DNA Glicosilase/metabolismo , Aeropyrum/metabolismo , Proteínas Arqueais/isolamento & purificação , Sequência de Bases , Concentração de Íons de Hidrogênio , Dados de Sequência Molecular , Temperatura , Timina/química , Timina/metabolismo , Timina DNA Glicosilase/isolamento & purificaçãoRESUMO
In the title complex, [Cu(2)Cl(4)(C(17)H(22)N(2))(2)], the Cu(II) cation is coordinated by a N,N'-dibenzyl-propane-1,2-diamine ligand and two Cl(-) anions, and a Cl(-) anion from an adjacent mol-ecule further bridges to the Cu(II) cation in the apical position, with a longer Cu-Cl distance of 2.9858â (18)â Å, forming a centrosymmetric dimeric complex in which each Cu(II) cation is in a distorted square-pyramidal geometry. Intra-molecular N-Hâ¯Cl hydrogen bonding is observed in the dimeric complex.
RESUMO
The asymmetric unit of the title complex, [Ni(C(16)H(20)N(2))(2)(H(2)O)(2)]Cl(2)·C(3)H(7)NO, consists of two Ni(II) atoms, each lying on an inversion center, two Cl anions, two N,N'-dibenzyl-ethane-1,2-diamine ligands, two coordinated water mol-ecules and one N,N-dimethyl-formamide solvent mol-ecule. Each Ni(II) atom is six-coordinated in a distorted octa-hedral coordination geometry, with the equatorial plane formed by four N atoms and the axial positions occupied by two water mol-ecules. The complex mol-ecules are linked into a chain along [001] by N-Hâ¯Cl, N-Hâ¯O and O-Hâ¯Cl hydrogen bonds. The C atoms and H atoms of the solvent mol-ecule are disordered over two sites in a ratio of 0.52â (2):0.48â (2).