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Objective: Rural and emerging adult women report low physical activity (PA) levels. This study identified differences in current self-reported PA levels and perceived resources among US university women from metropolitan, micropolitan, and rural areas. Participants: Women were ages 18-24 y, full-time students who attended in-person university classes before COVID-19. Methods: They completed an online cross-sectional survey between July-September 2020 collecting demographic, university PA (via IPAQ), and perceived PA resource data. Results: Most participants reported metropolitan area high school (70.4%) and university (92.3%) attendance. Metropolitan participants did less job-related moderate PA during university (0.0 (0.0-360.0) MET-min) than rural (160.0 (0.0-1320.0) MET-min) participants. Metropolitan and micropolitan participants identified more high school community and natural resources than rural participants. Rural participants identified more university campus and community resources than metropolitan participants. Conclusions: University women reported similar levels of PA regardless of the rurality of their high school community.
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United States Army soldiers must meet physical fitness test standards. Criticisms of the Army Physical Fitness Test (APFT) include limited testing of only aerobic and muscular endurance activity domains; yet, it is unclear what levels of aerobic and muscle strengthening activity may help predict performance in aspects of the new Army Combat Fitness Test (ACFT). This study explored relationships between baseline self-reported aerobic and muscle strengthening activities and APFT- and ACFT-related performance. Baseline participant data (N = 123) were from a cluster-randomized clinical trial that recruited active-duty military personnel (mean age 33.7 ± 5.7 years, 72.4% White, 87.0% college-educated, 81.5% Officers). An online survey was used for self-report of socio-demographic characteristics and weekly aerobic and muscle-strengthening physical activity behaviors. Participants also completed the APFT (2 min push-ups, 2 min sit-ups, 2-mile run) and ACFT-related measures (1-repetition maximum deadlift, pull-up repetitions or timed flexed arm hang, horizontal jump, and dummy drag). Bivariate logistic regression found greater aerobic and muscle-strengthening activity predicted better APFT performance, while better ACFT-related performance was predicted by greater muscle-strengthening activity. Although our data are mostly from mid-career officers, command policies should emphasize the new Holistic Health and Fitness initiative that encourages regular aerobic and muscle-strengthening physical activity for soldiers.
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Caffeine improves short-to-moderate distance running performance, but the effect of caffeine on repeated sprints are equivocal. This research determined if caffeine improved exercise tolerance during repeated-sprint exercise. iCV is a running velocity that distinguishes intermittent running velocities (velocities ≤ iCV) that are sustainable from those resulting in a predictable time to exhaustion (velocities > iCV). Seven physically active men (age = 21.6 ± 1.5 years, body mass = 72.8 ± 5.1 kg, VO2max = 56.9 ± 9.8 mL/kg/min) ingested caffeine (5 mg/kg) or placebo (crossover design) 60 min prior to an intermittent critical velocity (iCV) test. The treadmill grade and velocity at VO2max (vVO2max) were used for iCV testing, and consisted of 3 bouts (10 sec running and 10 sec passive rest) at 130, 110 and 120% vVO2max. Each bout continued until volitional exhaustion and was separated by 20 min of passive rest. Total distance and duration were recorded to determine exercise tolerance using the iCV model. Caffeine ingestion increased running duration at 110% vVO2max (p = 0.02), but not at 120 (p = 0.93) and 130% vVO2max (p = 0.14). Caffeine did not improve iCV model parameters. A single dose of caffeine consumed 60 min before repeated-sprints can improve performance at 110% vVO2max, but not at higher velocities.
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While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin.
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Neoplasias de la Mama/genética , Eritropoyetina/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Ováricas/genética , Receptor EphB4/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Western Blotting , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Eritropoyetina/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Células MCF-7 , Ratones Endogámicos C57BL , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Unión Proteica/efectos de los fármacos , Receptor EphB4/metabolismo , Receptores de Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo , Proteínas Recombinantes/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Adulto JovenRESUMEN
UNLABELLED: Metastasis is a complex, multistep process that begins with the epithelial-mesenchymal transition (EMT). Circulating tumor cells (CTC) are believed to have undergone EMT and thus lack or express low levels of epithelial markers commonly used for enrichment and/or detection of such cells. However, most current CTC detection methods target only EpCAM and/or cytokeratin (CK) to enrich epithelial CTCs, resulting in failure to recognize other, perhaps more important, CTC phenotypes that lack expression of these markers. Here, we describe a population of complex aneuploid CTCs that do not express CK or CD45 antigen in patients with breast, ovarian, or colorectal cancer. These cells were not observed in healthy subjects. We show that the primary epithelial tumors were characterized by similar complex aneuploidy, indicating conversion to an EMT phenotype in the captured cells. Collectively, our study provides a new method for highly efficient capture of previously unrecognized populations of CTCs. SIGNIFICANCE: Current assays for CTC capture likely miss populations of cells that have undergone EMT. Capture and study of CTCs that have undergone EMT would allow a better understanding of the mechanisms driving metastasis.
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Neoplasias de la Mama/patología , Neoplasias Colorrectales/patología , Queratinas/sangre , Células Neoplásicas Circulantes/química , Neoplasias Ováricas/patología , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Queratinas/análisis , Queratinas/genética , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/patología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/genéticaRESUMEN
PURPOSE: Jagged1, a Notch ligand, is expressed on both tumor epithelial and endothelial cells and therefore may be amenable to dual targeting of the tumor stroma and malignant cell compartments of the tumor microenvironment. EXPERIMENTAL DESIGN: We describe in vitro effects of targeting of Jagged1 on ovarian cancer cells and in vivo effects of independent targeting of stromal and malignant cell Jagged1 using species-specific human or murine siRNA constructs incorporated into chitosan nanoparticles and delivered intravenously in an orthotopic mouse model. RESULTS: Jagged1 expression was prominent in SKOV3ip1 and IGROV-AF1, and significantly overexpressed in SKOV3TRip2, a taxane-resistant SKOV3 subclone. Jagged1 silencing with siRNA decreased cell viability and reversed taxane chemoresistance. In two different orthotopic ovarian cancer models, treatment with anti-human Jagged1 siRNA-CH reduced growth by 54.4% to 58.3% and with anti-murine Jagged1 siRNA-CH reduced growth by 41.7% to 48.8%. The combination of both species-specific constructs reduced tumor weight by 87.5% to 93.1% and sensitized SKOV3TRip2 tumors to docetaxel in vivo. Tumors showed reduced microvessel density with anti-murine Jagged1 constructs and decreased proliferation with anti-human Jagged1 siRNAs-CH. In addition, we show that Jagged1 downregulation does not sensitize cells to taxanes through a reduction in MDR1 expression, but at least in part by cross-talk with the GLI2 mediator of the Hedgehog pathway. CONCLUSIONS: Jagged1 plays dual roles in cancer progression through an angiogenic function in tumor endothelial cells and through proliferation and chemoresistance in tumor cells. Dual inhibition represents an attractive therapeutic strategy for ovarian and potentially other malignancies.
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Proteínas de Unión al Calcio/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Receptores Notch/metabolismo , Taxoides/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Hidrocarburos Aromáticos con Puentes/farmacología , Proteínas de Unión al Calcio/genética , Línea Celular Tumoral , Proliferación Celular , Docetaxel , Resistencia a Antineoplásicos , Células Endoteliales/metabolismo , Células Epiteliales/metabolismo , Femenino , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Proteína Jagged-1 , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Proteínas de la Membrana/genética , Ratones , Terapia Molecular Dirigida , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Interferencia de ARN , ARN Interferente Pequeño , Receptores Notch/genética , Proteínas Serrate-Jagged , Células del Estroma , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína con Dedos de Zinc GLI1 , Proteína Gli2 con Dedos de ZincRESUMEN
Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment.
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Proteínas de la Membrana/biosíntesis , Neoplasias Ováricas/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Animales , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Regulación hacia Abajo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Silenciador del Gen , Terapia Genética , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/terapia , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Factor A de Crecimiento Endotelial Vascular/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor-initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane- and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression in which the percentage of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 vs. 13.81 months; P < 0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor-initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared with chemotherapy alone (a 74%-90% reduction; P < 0.015). These data show that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity but do have differentiation capacity lacking in ALDH1A1-negative cells. This enzyme may be important for identification and targeting of chemoresistant cell populations in ovarian cancer.
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Aldehído Deshidrogenasa/metabolismo , Células Madre Neoplásicas/enzimología , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Aldehído Deshidrogenasa/genética , Familia de Aldehído Deshidrogenasa 1 , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genoma Humano/genética , Humanos , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Neoplasias Ováricas/genética , ARN Interferente Pequeño/metabolismo , Retinal-Deshidrogenasa , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach.