RESUMEN
The normal colon epithelium is transformed into its neoplastic counterpart through a series of genetic alterations in driver genes including activating mutations in PIK3CA. Treatment often involves surgery followed by 5-fluorouracil (5-FU) based therapy, which has limited efficiency and serious side effects. We sought to determine whether fisetin, a dietary flavonoid, alone or in combination with 5-FU affected tumorigenesis in the mammalian intestine. We first determined the effect of fisetin, 5-FU or their combination on PIK3CA-mutant and PIK3CA wild-type colon cancer cells by assessing cell viability, colony formation, apoptosis and effects on PI3K/AKT/mTOR signaling. Treatment of PIK3CA-mutant cells with fisetin and 5-FU reduced the expression of PI3K, phosphorylation of AKT, mTOR, its target proteins, constituents of mTOR signaling complex and this treatment increased the phosphorylation of AMPKα. We then determined whether fisetin and 5-FU together or singly affected tumorigenesis in ApcMin/+ mice that also express constitutively active PI3K in the distal small intestine and colon. Tumor incidence was markedly lower in fisetin-treated FC1 3K1 ApcMin/+ mice that also express constitutively active PI3K in distal small intestine and colon, as compared to control animals, indicating that fisetin is a strong preventive agent. In addition, the combination of fisetin and 5-FU also reduced the total number of intestinal tumors. Fisetin could be used as a preventive agent plus an adjuvant with 5-FU for the treatment of PIK3CA-mutant colorectal cancer.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias Colorrectales/tratamiento farmacológico , Flavonoides/administración & dosificación , Fluorouracilo/administración & dosificación , Mutación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Sinergismo Farmacológico , Flavonoides/farmacología , Flavonoles , Fluorouracilo/farmacología , Células HCT116 , Células HT29 , Humanos , Ratones , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inflammation, and the organization of collagen in the breast tumor microenvironment, is an important mediator of breast tumor progression. However, a direct link between markers of inflammation, collagen organization, and patient outcome has yet to be established. A tumor microarray of 371 invasive breast carcinoma biopsy specimens was analyzed for expression of inflammatory markers, including cyclooxygenase 2 (COX-2), macrophages, and several collagen features in the tumor nest (TN) or the tumor-associated stroma (TS). The tumor microarray cohort included females, aged 18 to 80 years, with a median follow-up of 8.4 years. High expression of COX-2 (TN), CD68 (TS), and CD163 (TN and TS) predicted worse patient overall survival (OS). This notion was strengthened by the finding from the multivariate analysis that high numbers of CD163+ macrophages in the TS is an independent prognostic factor. Overall collagen deposition was associated with high stromal expression of COX-2 and CD163; however, total collagen deposition was not a predictor for OS. Conversely, local collagen density, alignment and perpendicular alignment to the tumor boundary (tumor-associated collagen signature-3) were predictors of OS. These results suggest that in invasive carcinoma, the localization of inflammatory cells and aligned collagen orientation predict poor patient survival. Additional clinical studies may help validate whether therapy with selective COX-2 inhibitors alters expression of CD68 and CD163 inflammatory markers.
Asunto(s)
Neoplasias de la Mama/metabolismo , Colágeno/metabolismo , Ciclooxigenasa 2/metabolismo , Macrófagos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Macrófagos/patología , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: High mammographic density has been correlated with a 4-fold to 6-fold increased risk of developing breast cancer, and is associated with increased stromal deposition of extracellular matrix proteins, including collagen I. The molecular and cellular mechanisms responsible for high breast tissue density are not completely understood. METHODS: We previously described accelerated tumor formation and metastases in a transgenic mouse model of collagen-dense mammary tumors (type I collagen-α1 (Col1α1)(tm1Jae) and mouse mammary tumor virus - polyoma virus middle T antigen (MMTV-PyVT)) compared to wild-type mice. Using ELISA cytokine arrays and multi-color flow cytometry analysis, we studied cytokine signals and the non-malignant, immune cells in the collagen-dense tumor microenvironment that may promote accelerated tumor progression and metastasis. RESULTS: Collagen-dense tumors did not show any alteration in immune cell populations at late stages. The cytokine signals in the mammary tumor microenvironment were clearly different between wild-type and collagen-dense tumors. Cytokines associated with neutrophil signaling, such as granulocyte monocyte-colony stimulated factor (GM-CSF), were increased in collagen-dense tumors. Depleting neutrophils with anti-Ly6G (1A8) significantly reduced the number of tumors, and blocked metastasis in over 80 % of mice with collagen-dense tumors, but did not impact tumor growth or metastasis in wild-type mice. CONCLUSION: Our study suggests that tumor progression in a collagen-dense microenvironment is mechanistically different, with pro-tumor neutrophils, compared to a non-dense microenvironment.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Colágeno/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Microambiente Tumoral , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/inmunología , Colágeno/genética , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Expresión Génica , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Mamarias Experimentales , Ratones , Ratones Transgénicos , Células Mieloides/inmunología , Células Mieloides/metabolismo , Metástasis de la Neoplasia , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Tomografía de Emisión de Positrones , Bazo/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Carga Tumoral , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Hospital readmissions are estimated to cost $17.4 billion per year in the Medicare population alone, with readmission rates as high as 30% for patients undergoing complex abdominal surgery. Improved transitional care and self-monitoring may reduce preventable readmissions for such high-risk populations. In this study, we will conduct a single-institution randomized controlled trial (RCT) to assess the effect of a novel transitional care mobile app, MobiMD, on hospital readmission in complex abdominal surgery patients. METHODS: Three hundred patients will be randomized 1:1 to standard of care (SOC) versus SOC plus MobiMD app in a parallel, single-blinded, two-arm RCT. Eligible patients are those who undergo complex abdominal surgery in the division of Surgical Oncology, Colorectal Surgery or Transplant Surgery. The MobiMD app provides push notification reminders directly to the patient's smart device, prompting them to enter clinical data and patient-reported outcomes. Clinical data collected via the MobiMD app include vital signs, red flag symptoms, daily wound and surgical drain images, ostomy output, drain output, medication compliance, and wound care compliance. These data are reviewed daily by a physician. The primary outcome is the proportion of participants readmitted to the hospital within 30 days of surgery. Secondary outcomes are 90-day hospital readmission, emergency department and urgent care visits, complication severity, and total readmission cost. DISCUSSION: If effective, mobile health apps such as MobiMD could be routinely integrated into surgical transitional care programs to minimize unnecessary hospital readmissions, emergency department visits and healthcare resource utilization. Clinical trials identifier: NCT04540315.
Asunto(s)
Aplicaciones Móviles , Telemedicina , Cuidado de Transición , Servicio de Urgencia en Hospital , Humanos , Readmisión del Paciente , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Poorly coordinated transitions of care in complex abdominal surgery patients contribute to frequent hospital readmissions and inflated healthcare spending. Mobile health (mHealth) transitional care technologies may reduce surgical readmissions yet remain understudied in high-risk surgical populations. METHODS: We conducted a single-group, prepost study of a mHealth transitional care app in 50 complex surgical patients. Eligible patients were adults undergoing complex abdominal surgery in the divisions of Surgical Oncology and Colorectal Surgery. The main outcome was app engagement, calculated by notification response rate (number of participant-entered datapoints divided by the total number of app-requested datapoints) over the 30-day postoperative period. Secondary outcomes included changes in engagement over time and by individual app feature. RESULTS: A total of 85% (50/59) of eligible patients enrolled. Most participants were male (58%, n = 29), and mean age was 50 years (range 24-80 years). Overall notification response rate was 28%. Among the 58% of participants (29/50) who engaged with the app at least once after discharge (app users), the average notification response rate was 45%. The mean notification response rate among app users decreased over time from 50% to 32% between weeks 1 and 4 after hospital discharge. Engagement with individual app features ranged from 48-81%, with highest engagement for symptom reports and lowest engagement for wound care instructions. CONCLUSION: mHealth transitional care is feasible in complex surgical patients using only patients' existing smart devices. Randomized controlled trials are required to determine the impact on hospital readmissions, surgical outcomes, patient satisfaction, and overall resource utilization.
Asunto(s)
Aplicaciones Móviles , Telemedicina , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Participación del Paciente , Transferencia de Pacientes , Proyectos Piloto , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the effect of aspirin dose on the incidence of all gestational age preeclampsia and preterm preeclampsia. DATA SOURCES: Electronic databases (Cochrane, PubMed, Scopus, ClinicalTrials.gov and the Web of Science) were searched for articles published between January 1985 and March 2019 with no language restrictions. METHODS: We followed the PRIMSA guidelines and utilized Covidence software. Articles were screened by 2 independent reviewers, with discrepancies settled by an independent 3rd party. Study selection criteria were randomized trials comparing aspirin for prevention of all gestational age and preterm preeclampsia to placebo or no antiplatelet treatment in women aged 15-55 years with moderate or high-risk factors according to the list of risk factors from American College of Obstetricians and Gynecologists and United States Preventive Services Task Force guidelines. The quality of trials was assessed using the Cochrane risk of bias tool. The data were pooled using a random-effects meta-analysis comparing aspirin at doses of <81, 81, 100, and 150 mg. Pre-specified outcomes were all gestational age and preterm preeclampsia. RESULTS: Of 1,609 articles screened, 23 randomized trials, which included 32,370 women, fulfilled the inclusion criteria. In preterm preeclampsia, women assigned at random to 150 mg experienced a significant 62% reduction in risk of preterm preeclampsia (RR = 0.38; 95% CI: 0.20-0.72; P = 0.011). Aspirin doses <150 mg produced no significant reductions. The number needed to treat with 150 mg of aspirin was 39 (95% CI: 23-100). There was a maximum 30% reduction in risk of all gestational age preeclampsia at all aspirin doses. CONCLUSIONS: In this meta-analysis, based on indirect comparisons, aspirin at a dose greater than the current, recommended 81 mg was associated with the highest reduction in preterm preeclampsia. Our meta-analysis is limited due to the deficiency of homogeneous high evidence data available in the literature to date; however, it may be prudent for clinicians to consider that the optimal aspirin dose may be higher than the current guidelines advise. Future research to compare the efficacy aspirin doses greater than 81 mg is recommended. STUDY REGISTRATION: PROSPERO, CRD42019127951 (University of York, UK; http://www.crd.york.ac.uk/PROSPERO/).
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Preeclampsia/epidemiología , Preeclampsia/prevención & control , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Embarazo , Factores de Riesgo , Adulto JovenRESUMEN
PURPOSE: Estimating cancer risk associated with interplanetary space travel is complicated. Human exposure data to high atomic number, high-energy (HZE) radiation is lacking, so data from low linear energy transfer (low-LET) γ-ray radiation is used in risk models, with the assumption that HZE and γ-ray radiation have comparable biological effects. This assumption has been challenged by reports indicating that HZE radiation might produce more aggressive tumors. The goal of this research is to test whether high-LET HZE radiation induced tumors are more aggressive. MATERIALS AND METHODS: Murine models of mammary and liver cancer were used to compare the impact of exposure to 0.2Gy of 300MeV/n silicon ions, 3 Gy of γ-rays or no radiation. Numerous measures of tumor aggressiveness were assessed. RESULTS: For the mammary cancer models, there was no significant change in the tumor latency or metastasis in silicon-irradiated mice compared to controls. For the liver cancer models, we observed an increase in tumor incidence but not tumor aggressiveness in irradiated mice. CONCLUSION: Tumors in the HZE-irradiated mice were not more aggressive than those arising from exposure to low-LET γ-rays or spontaneously. Thus, enhanced aggressiveness does not appear to be a uniform characteristic of all tumors in HZE-irradiated animals.