RESUMEN
BACKGROUND: The temporal in vivo response of epithelial cells to a viral challenge and its association with viral clearance and clinical outcomes has been largely unexplored in asthma. OBJECTIVE: To determine gene expression profiles over time in nasal epithelial cells (NECs) challenged in vivo with rhinovirus-16 (RV16) and compare to nasal symptoms and viral clearance. METHODS: Patients with stable mild to moderate asthma (n = 20) were challenged intranasally with RV16. Nasal brush samples for RNA sequencing were taken 7 days prior to infection and 3, 6 and 14 days post-infection, and blood samples 4 days prior to infection and day 6 post-infection. Viral load was measured in nasal lavage fluid at day 3, 6 and 14. RESULTS: Top differentially (>2.5-fold increase) expressed gene sets in NECs post-RV16 at days 3 and 6, compared with baseline, were interferon alpha and gamma response genes. Patients clearing the virus within 6 days (early resolvers) had a significantly increased interferon response at day 6, whereas those having cleared the virus by day 14 (late resolvers) had significantly increased responses at day 3, 6 and 14. Interestingly, patients not having cleared the virus by day 14 (non-resolvers) had no enhanced interferon responses at any of these days. The daily Cold Symptom Scores (CSS) peaked at days 3 to 5 and correlated positively with interferon response genes at day 3 (R = 0.48), but not at other time-points. Interferon response genes were also enhanced in blood at day 6 after RV16 challenge. CONCLUSION AND CLINICAL RELEVANCE: This study shows that viral load and clearance varies markedly over time in mild to moderate asthma patients exposed to a fixed RV16 dose. The host's nasal interferon response to RV16 at day 3 is associated with upper respiratory tract symptoms. The temporal interferon response in nasal epithelium associates with viral clearance in the nasal compartment.
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Asma , Bronquios , Interferón-alfa/inmunología , Interferón gamma/inmunología , Mucosa Nasal , Infecciones por Picornaviridae , Rhinovirus/inmunología , Adulto , Asma/inmunología , Asma/patología , Asma/virología , Bronquios/inmunología , Bronquios/patología , Bronquios/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mucosa Nasal/inmunología , Mucosa Nasal/patología , Mucosa Nasal/virología , Infecciones por Picornaviridae/inmunología , Infecciones por Picornaviridae/patologíaRESUMEN
BACKGROUND: Radiotherapy may lead to side effects that undermine patients' quality of life (QOL). Although mind-body practices like qigong appear to improve QOL in cancer survivors, little is known about their benefits for patients who are receiving radiotherapy. Thus, in the current randomized controlled trial, the authors examined the efficacy of a qigong intervention on QOL in women with breast cancer during and after treatment. METHODS: Ninety-six women with breast cancer were recruited from a cancer center in Shanghai, China, and were randomized to a qigong group (N = 49) or a waitlist control group (N = 47). Women in the qigong group attended 5 weekly classes over 5 or 6 weeks of radiotherapy. QOL outcomes (ie, depressive symptoms, fatigue, sleep disturbance, and overall QOL) and cortisol slopes were assessed at baseline, during treatment, at the end of treatment, 1 month later, and 3 months later. RESULTS: The mean age of the women was 46 years (range, 25-64 years). Seven percent of women had stage 0 disease, 25% had stage I disease, 40% had stage II disease, and 28% had stage III disease. Fifty-four percent of women underwent mastectomy. Multilevel analyses revealed that women in the qigong group reported less depressive symptoms over time than women in the control group (P = .05). Women who had elevated depressive symptoms at the start of radiotherapy reported less fatigue (P < .01) and better overall QOL (P < .05) in the qigong group compared with the control group, and these findings were clinically significant. No significant differences were observed for sleep disturbance or cortisol slopes. CONCLUSIONS: The current results indicated that qigong may have therapeutic effects in the management of QOL among women who are receiving radiotherapy for breast cancer. Benefits were particularly evident for patients who had preintervention elevated levels of depressive symptoms.
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Neoplasias de la Mama/fisiopatología , Neoplasias de la Mama/radioterapia , Ejercicios Respiratorios , Calidad de Vida , Adulto , Fatiga/fisiopatología , Femenino , Humanos , Hidrocortisona/sangre , Persona de Mediana Edad , Cooperación del Paciente , Trastornos del Sueño-Vigilia/fisiopatología , Listas de EsperaRESUMEN
For pharmacokinetics characterization of a therapeutic insulin dimer, an ultrasensitive plasma method was required due to the expected low circulating levels in humans. A bioanalytical strategy combining immunoprecipitation enrichment with liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis of the intact protein offers the opportunity to resolve the analyte from endogenous and exogenous insulin and insulin analogs. Nonetheless, interference from complex background matrix was observed limiting reliable measurements at the low concentration range. A sample preparation approach incorporating protein precipitation and immunoprecipitation was developed and optimized to further reduce sample complexity prior to LC-MS/MS analysis. This approach enabled a deeper level of selectivity and presented a cleaner mass spectrometric detection that may otherwise be confounded. Sample preparation was automated to allow high throughput analysis. The method reached a limit of quantitation at 0.3 ng/mL (25 pM), and a linear dynamic range from 0.3 to 300 ng/mL. Results were highly reproducible, with intra-day and inter-day precision and bias below 11%. Furthermore, the organic solvent treatment involved in protein precipitation is expected to improve assay resistance to the bias introduced by endogenous protein binding such as that exerted by anti-drug antibodies. The method was successfully applied to support clinical pharmacokinetics studies. This approach may potentially be adapted to bioanalysis of low abundance proteins.
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Insulina , Espectrometría de Masas en Tándem , Cromatografía Liquida/métodos , Humanos , Proteínas , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson's disease (PD). OBJECTIVE: To explore the use of the electronic medical records (EMRs) to identify participants with PD. METHODS: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants. Questionnaires were completed to ascertain Ashkenazi Jewish (AJ) ancestry and family history of PD. RESULTS: Among 837 participants with PD, 82% were 65 years and older and 72% had a family history of AJ ancestry. Among those with AJ ancestry, 15.6% reported having relatives with PD. The frequency of observed mutations for LRRK2 and GBA genes combined was approximately 15.4%. The frequency of observed LRRK2 mutation was 6.1% overall and 7.2% from those with AJ ancestry; and for GBA mutation was 9.3% overall and 11.2% from those with AJ ancestry. CONCLUSION: Although the frequency of observed mutations in this study was lower than anticipated, mutation carriers were enriched among those with a family history of AJ ancestry increasing nearly 2-3-fold, from 3% -7% (LRRK2) and 4% -11% (GBA). The identification (and selection) of PD patients through EMRs prior to genotyping is a viable approach, to establish a genetically defined cohort of patients with PD for clinical research.
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Enfermedad de Parkinson , Registros Electrónicos de Salud , Estudios de Factibilidad , Glucosilceramidasa/genética , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación , Enfermedad de Parkinson/genéticaRESUMEN
The goal of this investigation was to examine clinical translation of glucose responsiveness of MK-2640, which is a novel insulin saccharide conjugate that can bind the insulin receptor or mannose receptor C type 1 (MRC1), the latter dependent upon glucose concentration. In a rising dose study in 36 healthy adults under euglycemic clamp conditions, rising exposures revealed saturation of MK-2640 clearance, likely due to saturation of clearance by MRC1. Potency of MK-2640 was ~25-fold reduced relative to regular human insulin. In a randomized, 2-period crossover trial in 16 subjects with type 1 diabetes mellitus to evaluate glucose-responsiveness of i.v. administered MK-2640, we were unable to demonstrate a glucose-dependent change in MK-2640 clearance, although a significant glucose-dependent augmentation of glucose infusion rate was observed. These pharmacokinetic (PK) and pharmacodynamic (PD) data provide crucial insights into next steps for developing an insulin saccharide conjugate as a clinically effective glucose-responsive insulin analog.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/análogos & derivados , Administración Intravenosa , Adolescente , Adulto , Antígenos CD/efectos de los fármacos , Estudios Cruzados , Diabetes Mellitus Tipo 1/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Insulina/efectos adversos , Insulina/farmacocinética , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Receptor de Insulina/efectos de los fármacos , Adulto JovenRESUMEN
Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.
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Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/sangre , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacocinética , Trastornos Migrañosos/sangre , Trastornos Migrañosos/tratamiento farmacológico , Piridinas/sangre , Piridinas/farmacocinética , Pirroles/sangre , Pirroles/farmacocinética , Adulto , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Relación Dosis-Respuesta a Droga , Pruebas con Sangre Seca , Femenino , Humanos , Persona de Mediana Edad , Piridinas/administración & dosificación , Pirroles/administración & dosificación , Encuestas y CuestionariosRESUMEN
This study examined the effects of yoga on quality of life (QOL) and psychosocial outcomes in women with breast cancer undergoing radiotherapy. Sixty-one women were randomly assigned to either a yoga or a wait-list group. Yoga classes were taught biweekly during the 6 weeks of radiotherapy. Participants completed measures of QOL, fatigue, benefit finding (finding meaning in the cancer experience), intrusive thoughts, sleep disturbances, depressive symptoms, and anxiety before radiotherapy and then again 1 week, 1 month, and 3 months after the end of radiotherapy. General linear model analyses revealed that compared to the control group, the yoga group reported significantly better general health perception (p = .005) and physical functioning scores (p = .04) 1 week postradiotherapy; higher levels of intrusive thoughts 1 month postradiotherapy (p = .01); and greater benefit finding 3 months postradiotherapy (p = .01). There were no other group differences in other QOL subscales for fatigue, depression, or sleep scores. Exploratory analyses indicated that intrusive thoughts 1 month after radiotherapy were significantly positively correlated with benefit finding 3 months after radiotherapy (r = .36, p = .011). Our results indicated that the yoga program was associated with statistically and clinically significant improvements in aspects of QOL.
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Calidad de Vida , Yoga , Neoplasias de la Mama/psicología , Depresión , Fatiga , Femenino , HumanosRESUMEN
PURPOSE: To determine the prevalence rate of health behaviors in testis cancer survivors and to determine whether the rate of health behaviors in survivors was significantly different than those of their age-matched relative controls and a population-based control group matched for age, sex, education, and income. PATIENTS AND METHODS: The health behaviors of 162 testis cancer survivors were compared with their age-matched relative controls (n = 74) and an age-, sex-, education-, and income-matched population-based control group (n ranged from 1,123 to 9,775). Health behaviors were assessed with the telephone-administered Behavioral Risk Factor and Surveillance Survey. RESULTS: Nearly one in five testis cancer survivors reported current smoking and one third reported problem drinking. Only 11% reported having at least five servings of fruits and vegetables per day. Compared with their relative controls, the survivors were more likely to engage in regular exercise. For those participants who drank, survivors were twice as likely to engage in problem drinking and averaged a higher number of drinks compared to their Centers for Disease Control (CDC) controls. Survivors were also half as likely to have at least five servings of fruits and vegetables per day compared with the CDC controls. CONCLUSION: The overall picture regarding testis cancer survivors' health behaviors was mixed compared with the relative and CDC control groups. Our results suggest that reduced alcohol use and increased fruit and vegetable consumption may be important targets for future disease prevention in testis cancer survivors.
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Conductas Relacionadas con la Salud , Conocimientos, Actitudes y Práctica en Salud , Estilo de Vida , Sobrevivientes/psicología , Neoplasias Testiculares/psicología , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/psicología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Colesterol/sangre , Estudios Transversales , Dieta , Ejercicio Físico , Frutas , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Medición de Riesgo , Factores de Riesgo , Conducta de Reducción del Riesgo , Fumar/epidemiología , Fumar/psicología , Sobrevivientes/estadística & datos numéricos , Neoplasias Testiculares/epidemiología , Factores de Tiempo , Estados Unidos/epidemiología , Verduras , Adulto JovenRESUMEN
AIM: To examine whether acupuncture can prevent prolonged postoperative ileus (PPOI) after intraperitoneal surgery for colon cancer. METHODS: Ninety patients were recruited from the Fudan University Cancer Hospital, Shanghai, China. After surgery, patients were randomized to receive acupuncture (once daily, starting on postoperative day 1, for up to six consecutive days) or usual care. PPOI was defined as an inability to pass flatus or have a bowel movement by 96 h after surgery. The main outcomes were time to first flatus, time to first bowel movement, and electrogastroenterography. Secondary outcomes were quality of life (QOL) measures, including pain, nausea, insomnia, abdominal distension/fullness, and sense of well-being. RESULTS: No significant differences in PPOI on day 4 (P = 0.71) or QOL measures were found between the groups. There were also no group differences when the data were analyzed by examining those whose PPOI had resolved by day 5 (P = 0.69) or day 6 (P = 0.88). No adverse events related to acupuncture were reported. CONCLUSION: Acupuncture did not prevent PPOI and was not useful for treating PPOI once it had developed in this population.
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Colectomía/efectos adversos , Neoplasias del Colon/cirugía , Electroacupuntura , Ileus/prevención & control , Adulto , Anciano , Defecación , Femenino , Motilidad Gastrointestinal , Humanos , Ileus/etiología , Ileus/fisiopatología , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/etiología , Dolor Postoperatorio/prevención & control , Náusea y Vómito Posoperatorios/etiología , Náusea y Vómito Posoperatorios/prevención & control , Estudios Prospectivos , Calidad de Vida , Recuperación de la Función , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Trastornos del Inicio y del Mantenimiento del Sueño/prevención & control , Factores de Tiempo , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Huachansu, a Chinese medicine that comes from dried toad venom from the skin glands of Bufo gargarizans or B. melanostictus, has been used in the treatment of various cancers in China. The authors conducted a pilot study, using a phase 1 trial design, of huachansu in patients with advanced cancer. METHODS: Huachansu was administered intravenously for 14 days followed by 7 days off (1 cycle). Without significant adverse events or progressive disease, treatment continued beyond 2 cycles. The dose of huachansu was escalated as follows with 3 patients per cohort: 10 (level 1), 20 (level 2), 40 (level 3), 60 (level 4), and 90 (level 5) mL/m(2). RESULTS: Fifteen patients (hepatocellular cancer, n = 11; nonsmall cell lung cancer, n = 2; pancreatic cancer, n = 2) were enrolled in the trial, and no dose-limiting toxicities (DLTs) were found. Eleven patients had no drug-related toxicity greater than grade 1. Six (40%) had stable disease (median duration, 6.0 months; range, 3.5-11.1 months). One of these patients (with hepatocellular cancer) had 20% regression (duration, 11 months) (dose level 1). Quality of life improved for patients with stable disease. Plasma bufalin concentration reached maximal levels at the end of the 2-hour infusion and was proportional to the amount of drug being administered (0.81-3.38 ng/mL). CONCLUSIONS: No DLT was observed with the use of huachansu at doses up to 8x higher than typically used in China. Six patients had prolonged stable disease or minor tumor shrinkage.