RESUMO
BACKGROUND: When cancer treatments have similar oncologic outcomes, the number of days with in-person healthcare contact (""contact days'') can help contextualize expected time use with each treatment. We assessed contact days in a completed randomized clinical trial. PATIENTS AND METHODS: We conducted a secondary analysis of the CCTG LY.12 RCT that evaluated 2-3 cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates and survival. We calculated patient-level "contact days" by analyzing trial forms. The study period was from assignment to progression or transplant. Days without healthcare contact were considered "home days''. We compared measures of contact days across arms. RESULTS: The study period was longer in the GDP arm (median 50, vs. 47 days, P = .007). Contact days were comparable in both arms (median 18 vs 19, P = 0.79), but home days were higher in the GDP arm (median 33 vs 28, P < .001). The proportion of contact days was lower in the GDP arm (34%, vs. 38%, P = .009). The GDP arm experienced more contact days related to planned outpatient chemotherapy (median, 10 vs. 8 days), but the DHAP arm experienced many more inpatient contact days (median, 11 vs. 0 days). CONCLUSIONS: Measures of time use, such as contact days, can be extracted from RCTs. In LY.12, despite comparable oncologic outcomes, GDP was associated with fewer contact days. Such information can guide decision-making for patients with hematological cancers, who already face significant healthcare contact.
Assuntos
Cisplatino , Neoplasias , Humanos , Cisplatino/efeitos adversos , Desoxicitidina/efeitos adversos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Neoplasias/tratamento farmacológicoRESUMO
Extracellular vesicles (EVs) are newly recognized as important vectors for carrying and spreading antibiotic resistance genes (ARGs). However, the ARGs harbored by EVs in ambient environments and the transfer potential are still unclear. In this study, the prevalence of ARGs and mobile genetic elements (MGEs) in EVs and their microbial origins were studied in indoor dust from restaurants, kindergarten, dormitories, and vehicles. The amount of EVs ranged from 3.40 × 107 to 1.09 × 1011 particles/g dust. The length of EV-associated DNA fragments was between 21 bp and 9.7 kb. Metagenomic sequencing showed that a total of 241 antibiotic ARG subtypes encoding resistance to 16 common classes were detected in the EVs from all four fields. Multidrug, quinolone, and macrolide resistance genes were the dominant types. 15 ARG subtypes were exclusively carried and even enriched in EVs compared to the indoor microbiome. Moreover, several ARGs showed co-occurrence with MGEs. The EVs showed distinct taxonomic composition with their original dust microbiota. 30.23% of EV-associated DNA was predicted to originate from potential pathogens. Our results indicated the widespread of EVs carrying ARGs and virulence genes in daily life indoor dust, provided new insights into the status of extracellular DNA, and raised risk concerns on their gene transfer potential.
Assuntos
Antibacterianos , Vesículas Extracelulares , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Poeira , Genes Bacterianos , MacrolídeosRESUMO
BACKGROUND: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. METHODS: CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). RESULTS: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. CONCLUSIONS: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.
Assuntos
Antígeno B7-H1/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Lapatinib/uso terapêutico , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Metástase Neoplásica , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Estudos RetrospectivosRESUMO
Accumulated evidence demonstrates that Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, the precise role of PERK in JEV-induced apoptosis and encephalitis remains unknown. Here, we report that JEV infection activates the PERK-ATF4-CHOP apoptosis pathway both in vitro and in vivo PERK activation also promotes the formation of stress granule, which in turn represses JEV-induced apoptosis. However, PERK inhibitor reduces apoptosis, indicating that JEV-activated PERK predominantly induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway. Among JEV proteins that have been reported to induce ER stress, only JEV NS4B can induce PERK activation. PERK has been reported to form an active molecule by dimerization. The coimmunoprecipitation assay shows that NS4B interacts with PERK. Moreover, glycerol gradient centrifugation shows that NS4B induces PERK dimerization. Both the LIG-FHA and the LIG-WD40 domains within NS4B are required to induce PERK dimerization, suggesting that JEV NS4B pulls two PERK molecules together by simultaneously interacting with them via different motifs. PERK deactivation reduces brain cell damage and encephalitis during JEV infection. Furthermore, expression of JEV NS4B is sufficient to induce encephalitis via PERK in mice, indicating that JEV activates PERK primarily via its NS4B to cause encephalitis. Taken together, our findings provide a novel insight into JEV-caused encephalitis.IMPORTANCE Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, whether the PERK pathway of ER stress response plays important roles in JEV-induced apoptosis and encephalitis remains unknown. Here, we found that JEV infection activates ER stress sensor PERK in neuronal cells and mouse brains. PERK activation induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway upon JEV infection. Among the JEV proteins prM, E, NS1, NS2A, NS2B, and NS4B, only NS4B activates PERK. Moreover, activated PERK participates in apoptosis and encephalitis induced by JEV and NS4B. These findings provide a novel therapeutic approach for JEV-caused encephalitis.
Assuntos
Vírus da Encefalite Japonesa (Espécie)/patogenicidade , Encefalite Japonesa/metabolismo , Neurônios/citologia , Proteínas não Estruturais Virais/metabolismo , eIF-2 Quinase/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Apoptose , Sítios de Ligação , Linhagem Celular , Modelos Animais de Doenças , Vírus da Encefalite Japonesa (Espécie)/metabolismo , Encefalite Japonesa/virologia , Estresse do Retículo Endoplasmático , Fator de Iniciação 2 em Eucariotos/metabolismo , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos , Neurônios/metabolismo , Neurônios/virologia , Multimerização Proteica , Transdução de Sinais , Fator de Transcrição CHOP/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , eIF-2 Quinase/químicaRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Although 5-year survival rates in the first-line setting range from 60% to 70%, up to 50% of patients become refractory to or relapse after treatment. Published analyses of large-scale outcome data from patients with refractory DLBCL are limited. SCHOLAR-1, an international, multicohort retrospective non-Hodgkin lymphoma research study, retrospectively evaluated outcomes in patients with refractory DLBCL which, for this study, was defined as progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or relapsed at ≤12 months from autologous stem cell transplantation. SCHOLAR-1 pooled data from 2 phase 3 clinical trials (Lymphoma Academic Research Organization-CORAL and Canadian Cancer Trials Group LY.12) and 2 observational cohorts (MD Anderson Cancer Center and University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence). Response rates and overall survival were estimated from the time of initiation of salvage therapy for refractory disease. Among 861 patients, 636 were included on the basis of refractory disease inclusion criteria. For patients with refractory DLBCL, the objective response rate was 26% (complete response rate, 7%) to the next line of therapy, and the median overall survival was 6.3 months. Twenty percent of patients were alive at 2 years. Outcomes were consistently poor across patient subgroups and study cohorts. SCHOLAR-1 is the largest patient-level pooled retrospective analysis to characterize response rates and survival for a population of patients with refractory DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Cooperação Internacional , Linfoma Difuso de Grandes Células B/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Estudos Observacionais como Assunto/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The EORTC QLQ-C30 and the Brief Pain Inventory (BPI) are validated tools for measuring quality of life (QOL) and the impact of pain in patients with advanced cancer. Interpretation of these instrument scores can be challenging and it is difficult to know what numerical changes translate to clinically significant impact in patients' lives. To address this issue, our study sought to establish the minimal clinically important differences (MCID) for these two instruments in a prospective cohort of patients with advanced cancer and painful bone metastases. METHODS: Both anchor-based and distribution-based methods were used to estimate the MCID scores from patients enrolled in a randomized phase III trial evaluating two different re-irradiation treatment schedules. For the anchor-based method, the global QOL item from the QLQ-C30 was chosen as the anchor. Spearman correlation coefficients were calculated for all items and only those items with moderate or better correlation (|r| ≥ 0.30) with the anchor were used for subsequent analysis. A 10-point difference in the global QOL score was used to classify improvement and deterioration, and the MCID scores were calculated for each of these categories. These results were compared with scores obtained by the distribution-method, which estimates the MCID purely from the statistical characteristics of the sample population. RESULTS: A total of 375 patients were included in this study with documented pain responses and completed QOL questionnaires at 2 months. 9/14 items in the QLQ-C30 and 6/10 items in the BPI were found to have moderate or better correlation with the anchor. For deterioration, statistically significant MCID scores were found in all items of the QLQ-C30 and BPI. For improvement, statistically significant MCID scores were found in 7/9 items of the QLQ-C30 and 2/6 items of the BPI. The MCID scores for deterioration were uniformly higher than the MCIDs for improvement. Using the distribution-based method, there was good agreement between the 0.5 standard deviation (SD) values and anchor-based scores for deterioration. For improvement, there was less agreement and the anchor-based scores were lower than the 0.5 SD values obtained from the distribution-based method. CONCLUSION: We present MCID scores for the QLQ-C30 and BPI instruments obtained from a large cohort of patients with advanced cancer undergoing re-irradiation for painful bone metastases. The results from this study were compared to other similar studies which showed larger MCID scores for improvement compared to deterioration. We hypothesize that disease trajectory and patient expectations are important factors in understanding the contrasting results. The results of this study can guide clinicians and researchers in the interpretation of these instruments.
Assuntos
Neoplasias Ósseas/complicações , Diferença Mínima Clinicamente Importante , Dor/diagnóstico , Qualidade de Vida/psicologia , Reirradiação/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: The lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum HER2, CAIX, and TIMP-1. METHODS: MA.31 accrued 652 patients; 537 (82%) were centrally confirmed HER2+. Biomarkers were categorized for univariate and multivariable predictive investigations with a median cut-point, ULN cut-points (15 ng/ml for HER2; 506 pg/ml for CAIX; 454 pg/ml for TIMP-1), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariable analysis examined continuous and categorical effects of biomarkers on PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. RESULTS: Serum was banked for 472 (72%) of 652 patients. Higher serum HER2 (>median; >15; >30; or >100 ng/ml; p = 0.05-0.002); higher CAIX (>median; >506 pg/ml; p = 0.02; p = 0.001); and higher TIMP-1 (> median; > 454 pg/ml; p = 0.001; p = 0.02) had shorter univariate PFS. In multivariable analysis, higher continuous TIMP-1 was associated with significantly shorter PFS: HR = 1.001 (95% CI = 1.00-01.002; p = 0.004). Continuous serum HER2 and CAIX were not significantly associated with PFS. HER2 of 15 ng/ml or higher had shorter PFS (p = 0.02); higher categorical CAIX had shorter PFS (p = 0.01-0.08). Interaction terms of HER2, CAIX, and TIMP-1 with treatment were not significant; the predictive test power was low. CONCLUSIONS: Higher levels of serum TIMP-1, CAIX, and HER2 were significant prognostic biomarkers of shorter PFS. We found no significant interaction between serum biomarkers and response to lapatinib versus trastuzumab. Evaluation of TIMP-1 and CAIX-targeted therapy in addition to HER2-targeted therapy appears warranted in patients with elevated serum levels of these biomarkers.
Assuntos
Antígenos de Neoplasias/sangue , Neoplasias da Mama/tratamento farmacológico , Anidrase Carbônica IX/sangue , Quinazolinas/administração & dosagem , Receptor ErbB-2/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Trastuzumab/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/sangue , Intervalo Livre de Doença , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Quinazolinas/farmacologia , Análise de Sobrevida , Trastuzumab/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
Current evidence demonstrated certain beneficial effects of medicinal herbs as an adjuvant therapy for post-stroke depression (PSD) in China; Chai-hu (Chinese Thorowax Root, Radix Bupleuri) is an example of a medicinal plant for Liver-Qi regulation (MPLR) in the treatment of PSD. Despite several narrative reports on the antidepressant properties of MPLR, it appears that there are no systematic reviews to summarize its outcome effects. Therefore, the aim of this review was to assess the effectiveness and safety of MPLR adjuvant therapy in patients with PSD. Seven databases were extensively searched from January 2000 until July 2016. Randomized control trials (RCTs) involving patients with PSD that compared treatment with and without MPLR were taken into account. The pooled effect estimates were calculated based on Cochrane Collaboration's software RevMan 5.3. Finally, 42 eligible studies with 3612 participants were included. Overall, MPLR adjuvant therapy showed a significantly higher effective rate (RR = 1.23; 95% CI = 1.19, 1.27; p < 0.00001) compared to those without. Moreover, the administration of MPLR was superior to abstainers regarding Hamilton Depression Scale (HAMD) score changes after 3 weeks (WMD = -4.83; 95% CI = -6.82, -2.83; p < 0.00001), 4 weeks (WMD = -3.25; 95% CI = -4.10, -2.40; p < 0.00001), 6 weeks (WMD = -4.04; 95% CI = -5.24, -2.84; p < 0.00001), 8 weeks (WMD = -4.72; 95% CI = -5.57, -3.87; p < 0.00001), and 12 weeks (WMD = -3.07; 95% CI = -4.05, -2.09; p < 0.00001). In addition, there were additive benefits in terms of response changes for the National Institutes of Health Stroke Scale (NIHSS) and other self-rating scores. No frequently occurring or serious adverse events were reported. We concluded that there is supporting evidence that adjuvant therapy with MPLR is effective in reducing the depressive symptoms and enhancing quality of life for patients with PSD. More well-designed RCTs are necessary to explore the role of MPLR in the treatment of PSD. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Fígado/patologia , Plantas Medicinais/efeitos dos fármacos , Qi , Acidente Vascular Cerebral/complicações , Antidepressivos/uso terapêutico , Humanos , Qualidade de Vida , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
PURPOSE: The objective of our study was to determine the optimal cut points for classification of pain scores as mild, moderate, and severe based on interference with function and quality of life (QOL). METHODS: We evaluated 822 patients who completed the Brief Pain Inventory (BPI) and/or the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30) prior to receiving repeat radiation therapy for previously irradiated painful bone metastases. Optimal cut points for mild, moderate, and severe pain were determined by the MANOVA that yielded the largest F ratio for the between category effect on the seven interference items of BPI and the six functional domains of QOL (physical, role, emotional, cognitive, social functioning, and global QOL) as indicated by Pillai's Trace, Wilk's λ, and Hostelling's Trace F statistics. RESULTS: For BPI and for QOL domains separately, the two largest F ratios for Wilk's λ, Pillai's Trace, and Hotelling's Trace F statistics were from the cut points 4, 8 and 6, 8. When combining both, the optimal cut points were 4, 8 with 1-4 (mild), 5-8 (moderate), and 9-10 (severe). With this classification, the mean scores of all the seven interference items in BPI and the six functional domains were all highly statistically different. Patients with severe pain survived significantly shorter than those with mild and moderate pain (p < 0.0001). CONCLUSION: Our analysis supports the classification of pain scores as follows: 1-4 as mild pain, 5-8 as moderate pain, and 9-10 as severe pain. This may facilitate conduct of future clinical trials.
Assuntos
Neoplasias Ósseas/complicações , Medição da Dor/métodos , Dor/classificação , Qualidade de Vida , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Adulto JovemRESUMO
PURPOSE: Previous studies have determined optimal cut points (CPs) for the classification of pain severity as mild, moderate, or severe using only the Brief Pain Inventory (BPI) or the BPI in conjunction with a quality of life (QOL) tool. The purpose of our study was to determine the optimal CPs based on correlation with only QOL outcomes. METHODS: We conducted an analysis of 298 patients treated with radiation therapy for painful bone metastases on a phase III randomized trial. Prior to treatment, patients provided their worst pain score on a scale of 0 (no pain) to 10 (worst possible pain), as well as completed the European Organization of Cancer Research and Treatment (EORTC) QOL Questionnaire Bone Metastases module (QLQ-BM22) and the EORTC QOL Questionnaire Core-15 Palliative (QLQ-C15-PAL). Optimal CPs were determined to be those that yielded the largest F ratio for the between category effect on each subscale of the QLQ-BM22 and QLQ-C15-PAL using the multivariate analysis of variance (MANOVA). RESULTS: The two largest F ratios for Wilk's λ, Pillai's Trace, and Hotelling's Trace were for CPs 5,6 and 5,7. Combining both, the optimal CPs to differentiate between mild, moderate, and severe pain were 5 and 7. Pain scores of 1-5, 6, and 7-10 were classified as mild, moderate, and severe, respectively. Patients with severe pain experienced greater functional interference and poorer QOL when compared to those with mild pain. CONCLUSION: Our results suggest that, based on the impact of pain on QOL measures, pain scores should be classified as follows: 1-5 as mild pain, 6 as moderate pain, and 7-10 as severe pain. Optimal CPs vary depending on the type of outcome measurement used.
Assuntos
Neoplasias Ósseas/secundário , Medição da Dor/métodos , Qualidade de Vida/psicologia , Idoso , Feminino , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Inquéritos e QuestionáriosRESUMO
PURPOSE: Validated tools for evaluating quality of life (QOL) in patients with bone metastases include the EORTC QLQ-BM22 and QLQ-C15-PAL modules. A statistically significant difference in metric scores may not be clinically significant. To aid in their interpretation, we performed analyses to determine the minimal clinically important differences (MCID) for these QOL instruments. METHODS: Both anchor-based and distribution-based methods were used to determine the MCID among patients with bone metastases enrolled in a randomized phase III trial. For the anchor-based approach, overall QOL as measured by the QLQ-C15-PAL module was used as the anchor and only the subscales with moderate or better correlation were used for subsequent MCID analysis. In the anchor-based approach, patients were classified as improved, stable or deteriorated by the change in the overall QOL score from baseline to follow-up after 42 days. The MCID and confidence interval was then calculated for all subscales. In the distribution-based approach, the MCID was expressed as a proportion of the standard deviation and standard error measurement from the subscale score distribution. RESULTS: A total of 204 patients completed the questionnaires at baseline and follow-up. Only the dyspnea and insomnia subscales did not have at least moderate correlation with the overall QOL anchor. Using the anchor-based approach, 10/11 subscales had an MCID score significantly different than 0 for improvement and 3/11 subscales had a significant MCID score for deterioration. The magnitude of MCID scores was higher for improvement in comparison with deterioration. For improvement, the anchor-based approach showed good agreement with the distribution-based approach when using 0.5 SD as the MCID. However, there was greater lack of agreement between these approaches for deterioration. CONCLUSION: We present the MCID scores for the EORTC QLQ-BM22 and QLQ-C15-PAL QOL instruments. The results of this study can guide clinicians in the interpretation of these instruments. CLINICAL TRIALS REGISTRY: NCT01248585.
Assuntos
Neoplasias Ósseas/radioterapia , Diferença Mínima Clinicamente Importante , Perfil de Impacto da Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Cuidados Paliativos , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: The study aims to know the effect of electroacupuncture (EA) in maintenance of the homeostasis of the neuroendocrine system in hepatectomy rats and the involvement of arginine vasopressin (AVP) signaling in hypothalamus after EA was observed. MATERIALS AND METHODS: Rats were randomly assigned to four groups, including the intact group, model group, sham-EA group, and EA group. EA was given during the perioperative period at the Zusanli (ST36) and Sanyinjiao (SP6) points after hepatectomy. The serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were detected via radioimmunoassay. The expression of AVP, arginine vasopressin receptor 1a (AVPR1a), arginine vasopressin receptor 1b (AVPR1b), and glucocorticoid receptor (GR) was detected by Western blot after surgery. RESULTS: Compared with the intact group, the ACTH and CORT levels in the serum of model group were increased, whereas the ACTH and CORT levels were decreased in the EA group compared with the model group. Moreover, AVP and AVPR1b protein levels in the pituitary gland were increased in the model group and decreased in the EA group. Further, a distinct increase in the AVP and AVPR1a protein levels was observed in the model group, whereas they were significantly decreased in the EA group. Blockade of AVPR1b by nelivaptan reduced the increase of ACTH and CORT. D [Leu(4) , Lys(8) ] vasopressin can inhibit the effect of EA in rectification of the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. CONCLUSIONS: EA application at ST36 and SP6 can ameliorate the hyperactivity of the HPA axis via AVP signaling during the perioperative period.
Assuntos
Arginina Vasopressina/metabolismo , Eletroacupuntura/métodos , Regulação da Expressão Gênica/fisiologia , Hepatectomia , Hipercinese/terapia , Sistema Hipotálamo-Hipofisário/metabolismo , Receptores de Vasopressinas/metabolismo , Pontos de Acupuntura , Hormônio Adrenocorticotrópico/sangue , Análise de Variância , Animais , Arginina Vasopressina/genética , Arginina Vasopressina/farmacologia , Corticosterona/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatectomia/efeitos adversos , Hipercinese/etiologia , Camundongos , Neuropeptídeos , RNA Mensageiro/metabolismo , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Receptores de Vasopressinas/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Venous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide-prednisone to observation for 332 patients with MM post-autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty-three patients had biomarker data, including D-dimer, factor VIII and thrombin anti-thrombin (TAT) levels collected post-ASCT at baseline and 2 months after intervention investigating in-vivo thrombin generation. Differences between the time-points included a significant reduction over time in D-dimer, factor VIII and TAT levels in the observation group and sustained elevation of D-dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide-prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide-prednisone arm, with a trend to increase in D-dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide-prednisone maintenance therapy post-ASCT for MM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antitrombina III/análise , Fator VIII/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Peptídeo Hidrolases/análise , Trombina/biossíntese , Trombofilia/induzido quimicamente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Prednisona/administração & dosagem , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Trombofilia/sangue , Transplante Autólogo , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/prevenção & controleRESUMO
Electrically powered solitons are particle-like field configurations in out-of-equilibrium nematics that have garnered significant interest. However, their random generation and lack of controllable motion have limited their application. Here, we present a reconfigurable optoelectronic approach capable of regulating the entire lifecycle of solitons by utilizing multi-strategy digital light projection to construct delicate patterning of virtual electrode. We demonstrate that optically actuated domains with diverse geometry enable the generation of multiple solitons and further allow in-situ formation of individual soliton by matching the light pattern to its dimension. Exquisitely engineered light intensity of patterns facilitates modulation of soliton velocity and transformation of propagating direction. The utilization of a light-guided channel enables the on-demand control of soliton trajectories along customized paths. Furthermore, dynamic light patterns that vary in space and time allow for collective motion such as migration, mimicking phototaxis in biological systems. This reconfigurable manipulation strategy, grounded in the photoconductive effect, proves highly versatile and effective in directing soliton dynamics, heralding the potential for their programmable control and offering a significant advantage in multitasking scenarios.
RESUMO
INTRODUCTION: Although contact days-days with health-care contact outside home-are increasingly adopted as a measure of time toxicity and treatment burden, they could also serve as a surrogate of treatment-related harm. We sought to assess the association between contact days and patient-reported outcomes and the prognostic ability of contact days. METHODS: We conducted a secondary analysis of CO.17 that evaluated cetuximab vs supportive care in patients with advanced colorectal cancer. CO.17 collected European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 instrument data. We assessed the association between number of contact days in a window and changes in physical function and global health status and the association between number of contact days in the first 4 weeks with overall survival. RESULTS: There was a negative association between the number of contact days and change in physical function (per each additional contact day: at 4 weeks, 1.50-point decrease; 8 weeks, 1.06-point decrease; P < .0001 for both) but not with global health status. This negative association was seen in patients receiving cetuximab but not supportive care. More contact days in the first 4 weeks was associated with worse overall survival for all participants and patients receiving cetuximab (per each additional contact day: all participants, adjusted hazard ratio [HR] = 1.07, 95% confidence interval [CI] = 1.05 to 1.10; and cetuximab, adjusted HR = 1.08, 95% CI = 1.05 to 1.11; P < .0001 for both). CONCLUSIONS: In this secondary analysis of a clinical trial, more contact days early in the course were associated with declines in physical function and worse survival in all participants and in participants receiving cancer-directed treatment. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00079066.
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Cetuximab , Neoplasias Colorretais , Qualidade de Vida , Humanos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/tratamento farmacológico , Masculino , Feminino , Cetuximab/efeitos adversos , Cetuximab/uso terapêutico , Cetuximab/administração & dosagem , Pessoa de Meia-Idade , Idoso , Prognóstico , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários , Fatores de Tempo , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Nível de Saúde , Desempenho Físico FuncionalRESUMO
Exposure to ozone has been associated with metabolic disorders in humans, but the underlying mechanism remains unclear. In this study, the role of the gut-liver axis and the potential mechanism behind the metabolic disorder were investigated by histological examination, microbiome and metabolome approaches in mice during the subacute (4-week) and subchronic (12-week) exposure to 0.5 ppm and 2.5 ppm ozone. Ozone exposure resulted in slowed weight gain and reduced hepatic lipid contents in a dose-dependent manner. After exposure to ozone, the number of intestinal goblet cells decreased, while the number of tuft cells increased. Tight junction protein zonula occludens-1 (ZO-1) was significantly downregulated, and the apoptosis of epithelial cells increased with compensatory proliferation, indicating a compromised chemical and physical layer of the intestinal barrier. The hepatic and cecal metabolic profiles were altered, primarily related to lipid metabolism and oxidative stress. The abundance of Muribaculaceae increased dose-dependently in both colon and cecum, and was associated with the decrease of metabolites such as bile acids, betaine, and L-carnitine, which subsequently disrupted the intestinal barrier and lipid metabolism. Overall, this study found that subacute and subchronic exposure to ozone induced metabolic disorder via disturbing the gut-liver axis, especially the intestinal barrier. These findings provide new mechanistic understanding of the health risks associated with environmental ozone exposure and other oxidative stressors.
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Microbiota , Ozônio , Humanos , Camundongos , Animais , Fígado/metabolismo , Metaboloma , Lipídeos , Ozônio/toxicidadeAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único , Canadá , Predisposição Genética para Doença/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Quimioterapia de Manutenção , Melfalan/administração & dosagem , Prednisona/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Talidomida/administração & dosagem , Transplante AutólogoRESUMO
The practice of utilizing animal manures on land is widespread in agriculture, but it has raised concerns about the possible spread of antibiotic resistance genes (ARGs) and the potential risk it poses to public health through food production. Fermentation bed culture is an effective circular agricultural practice commonly utilized in pig farming that minimizes the environmental impact of livestock farming. However, this method generates a significant amount of fermentation bed waste (FBW), which can be turned into organic fertilizer for land application. The objective of this research was to examine the impacts of amending agricultural soil samples with swine manure-derived FBW on microbial communities, mobile genetic elements (MGEs), and ARG profiles over different periods. The study findings indicated that the amendment of swine manure-derived FBW significantly increased the diversity and abundance of ARGs and MGEs during the early stages of amendment, but this effect diminished over time, and after 12 months of FBW amendments, the levels returned to those comparable to control samples. The shift in the bacterial communities played a significant role in shaping the patterns of ARGs. Actinobacteriota, Proteobacteria, and Bacteroidetes were identified as the primary potential hosts of ARGs through metagenomic binning analysis. Furthermore, the pH of soil samples was identified as the most important property in driving the composition of the bacterial community and soil resistome. These findings provided valuable insights into the temporal patterns and dissemination risks of ARGs in FBW-amended agriculture soil, which could contribute to the development of effective strategies to manage the dissemination risks of FBW-derived ARGs.
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Microbiota , Solo , Suínos , Animais , Solo/química , Antibacterianos/farmacologia , Esterco/análise , Fermentação , Genes Bacterianos , Microbiologia do Solo , Agricultura , Bactérias/genéticaRESUMO
Studies on targeting cancer stem cells (CSCs) have not yielded satisfactory results regarding solid tumor treatments; one of the reasons for this is the difficulty associated with the identification of a relatively specific antigen in solid tumors. CD14, which is mainly expressed in certain immune cells, is associated with tumor recurrence, growth, metastasis and resistance to treatment, which is in conformity with the characteristics of CSCs. It was thus hypothesized that esophageal CSCs (ECSCs) express CD14. In the present study, paraffinembedded sections of human esophageal carcinoma were used to determine the coexpression of CD14 and the ECSC marker aldehyde dehydrogenase1 (ALDH1) using immunofluorescence. CD14+ cells were then isolated using immunomagnetic separation for stemness detection, including proliferation, migration, invasion and tumorigenicity. Cell Counting Kit8 (CCK8), EdU and colonyformation assays were utilized to investigate the proliferative ability, the metastatic capacity was examined using Transwell and woundhealing assays and a xenograft assay was performed to investigate the tumorigenic ability. It was indicated that the ALDH1labeled ECSCs expressed CD14 and primary CD14+ cells possessed the characteristics of CSCs. On the whole, the results of the present study suggest the potential utility of CD14 as a novel surface marker for ECSCs.
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Neoplasias Esofágicas , Recidiva Local de Neoplasia , Humanos , Família Aldeído Desidrogenase 1 , Biomarcadores/metabolismo , Neoplasias Esofágicas/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , AnimaisRESUMO
PURPOSE: The time spent in pursuing treatments for advanced cancer can be substantial. We have previously proposed a pragmatic and patient-centered metric of these time costs-which we term time toxicity-as any day with physical health care system contact. This includes outpatient visits (eg, bloodwork, scans, etc), emergency department visits, and overnight stays in a health care facility. Herein, we sought to assess time toxicity in a completed randomized controlled trial (RCT). METHODS: We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions versus supportive care alone in 572 patients with advanced colorectal cancer. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 v 4.6 months). Subsequent analyses reported that benefit was restricted to patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing trial forms. We considered days without health care contact as home days. We compared medians of time measures across arms and stratified results by K-ras status. RESULTS: In the overall population, median time toxic days were higher in the cetuximab arm (28 v 10, P < .001) although median home days were not statistically different between arms (140 v 121, P = .09). In patients with K-ras-mutated tumors, cetuximab was associated with almost numerically equal home days (114 days v 112 days, P = .571) and higher time toxicity (23 days v 11 days, P < .001). In patients with K-ras wild-type tumors, cetuximab was associated with more home days (186 v 132, P < .001). CONCLUSION: This proof-of-concept feasibility study demonstrates that measures of time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS benefit with cetuximab, home days were statistically similar across arms. Such data can supplement traditional survival end points in RCTs. Further work should refine and validate the measure prospectively.[Media: see text].