While there has been an explosion of mobile device applications (apps) promoting healthful behaviors, including physical activity and sedentary patterns, surprisingly few have been based explicitly ...on strategies drawn from behavioral theory and evidence.
This study provided an initial 8-week evaluation of three different customized physical activity-sedentary behavior apps drawn from conceptually distinct motivational frames in comparison with a commercially available control app.
Ninety-five underactive adults ages 45 years and older with no prior smartphone experience were randomized to use an analytically framed app, a socially framed app, an affectively framed app, or a diet-tracker control app. Daily physical activity and sedentary behavior were measured using the smartphone's built-in accelerometer and daily self-report measures.
Mixed-effects models indicated that, over the 8-week period, the social app users showed significantly greater overall increases in weekly accelerometry-derived moderate to vigorous physical activity relative to the other three arms (P values for between-arm differences = .04-.005; Social vs. Control app: d = 1.05, CI = 0.44,1.67; Social vs. Affect app: d = 0.89, CI = 0.27,1.51; Social vs. Analytic app: d = 0.89, CI = 0.27,1.51), while more variable responses were observed among users of the other two motivationally framed apps. Social app users also had significantly lower overall amounts of accelerometry-derived sedentary behavior relative to the other three arms (P values for between-arm differences = .02-.001; Social vs. Control app: d = 1.10,CI = 0.48,1.72; Social vs. Affect app: d = 0.94, CI = 0.32,1.56; Social vs. Analytic app: d = 1.24, CI = 0.59,1.89). Additionally, Social and Affect app users reported lower overall sitting time compared to the other two arms (P values for between-arm differences < .001; Social vs. Control app: d = 1.59,CI = 0.92, 2.25; Social vs. Analytic app: d = 1.89,CI = 1.17, 2.61; Affect vs. Control app: d = 1.19,CI = 0.56, 1.81; Affect vs. Analytic app: d = 1.41,CI = 0.74, 2.07).
The results provide initial support for the use of a smartphone-delivered social frame in the early induction of both physical activity and sedentary behavior changes. The information obtained also sets the stage for further investigation of subgroups that might particularly benefit from different motivationally framed apps in these two key health promotion areas.
ClinicalTrials.gov NCT01516411.
Mobile devices are a promising channel for delivering just-in-time guidance and support for improving key daily health behaviors. Despite an explosion of mobile phone applications aimed at physical ...activity and other health behaviors, few have been based on theoretically derived constructs and empirical evidence. Eighty adults ages 45 years and older who were insufficiently physically active, engaged in prolonged daily sitting, and were new to smartphone technology, participated in iterative design development and feasibility testing of three daily activity smartphone applications based on motivational frames drawn from behavioral science theory and evidence. An "analytically" framed custom application focused on personalized goal setting, self-monitoring, and active problem solving around barriers to behavior change. A "socially" framed custom application focused on social comparisons, norms, and support. An "affectively" framed custom application focused on operant conditioning principles of reinforcement scheduling and emotional transference to an avatar, whose movements and behaviors reflected the physical activity and sedentary levels of the user. To explore the applications' initial efficacy in changing regular physical activity and leisure-time sitting, behavioral changes were assessed across eight weeks in 68 participants using the CHAMPS physical activity questionnaire and the Australian sedentary behavior questionnaire. User acceptability of and satisfaction with the applications was explored via a post-intervention user survey. The results indicated that the three applications were sufficiently robust to significantly improve regular moderate-to-vigorous intensity physical activity and decrease leisure-time sitting during the 8-week behavioral adoption period. Acceptability of the applications was confirmed in the post-intervention surveys for this sample of midlife and older adults new to smartphone technology. Preliminary data exploring sustained use of the applications across a longer time period yielded promising results. The results support further systematic investigation of the efficacy of the applications for changing these key health-promoting behaviors.
The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with ...CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL.
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•T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma•Cxcl12 deletion in vascular endothelial, but not perivascular, cells suppresses disease•Cxcr4 deletion in T-ALL cells after disease onset inhibits leukemia progression•CXCR4 antagonism suppresses human T-ALL in a primary xenograft model
Pitt et al. identify a T cell acute lymphoblastic leukemia (T-ALL) niche and show that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Importantly, targeting CXCL12 or its receptor CXCR4 expressed in T-ALL cells reduces tumor growth in murine T-ALL and xenograft models.
Mounting evidence suggests that the immune landscape within prostate tumors influences progression, metastasis, treatment response, and patient outcomes. In this study, we investigated the spatial ...density of innate immune cell populations within NOD.SCID orthotopic prostate cancer xenografts following microinjection of human DU145 prostate cancer cells. Our laboratory has previously developed nanoscale liposomes that attach to leukocytes via conjugated E-selectin (ES) and kill cancer cells via TNF-related apoptosis inducing ligand (TRAIL). Immunohistochemistry (IHC) staining was performed on tumor samples to identify and quantify leukocyte infiltration for different periods of tumor growth and E-selectin/TRAIL (EST) liposome treatments. We examined the spatial-temporal dynamics of three different immune cell types infiltrating tumors using QuPath image analysis software. IHC staining revealed that F4/80+ tumor-associated macrophages (TAMs) were the most abundant immune cells in all groups, irrespective of time or treatment. The density of TAMs decreased over the course of tumor growth and decreased in response to EST liposome treatments. Intratumoral versus marginal analysis showed a greater presence of TAMs in the marginal regions at 3 weeks of tumor growth which became more evenly distributed over time and in tumors treated with EST liposomes. TUNEL staining indicated that EST liposomes significantly increased cell apoptosis in treated tumors. Additionally, confocal microscopy identified liposome-coated TAMs in both the core and periphery of tumors, highlighting the ability of liposomes to infiltrate tumors by "piggybacking" on macrophages. The results of this study indicate that TAMs represent the majority of innate immune cells within NOD.SCID orthotopic prostate tumors, and spatial density varies widely as a function of tumor size, duration of tumor growth, and treatment of EST liposomes.
While considerable progress has been made in studying genetic and cellular aspects of metastasis with in vitro cell culture and in vivo animal models, the driving mechanisms of each step of ...metastasis are still relatively unclear due to their complexity. Moreover, little progress has been made in understanding how cellular fitness in one step of the metastatic cascade correlates with ability to survive other subsequent steps. Engineered models incorporate tools such as tailored biomaterials and microfabrication to mimic human disease progression, which when coupled with advanced quantification methods permit comparisons to human patient samples and in vivo studies. Here, we review novel tools and techniques that have been recently developed to dissect key features of the metastatic cascade using primary patient samples and highly representative microenvironments for the purposes of advancing personalized medicine and precision oncology. Although improvements are needed to increase tractability and accessibility while faithfully simulating the in vivo microenvironment, these models are powerful experimental platforms for understanding cancer biology, furthering drug screening, and facilitating development of therapeutics.
Abstract
Background
Intratumor heterogeneity is a well-established hallmark of cancer that impedes cancer research, diagnosis, and treatment. Previously, we phenotypically sorted human breast cancer ...cells based on migratory potential. When injected into mice, highly migratory cells were weakly metastatic and weakly migratory cells were highly metastatic. The purpose of this study was to determine whether these weakly and highly migratory cells interact with each other in vitro or in vivo
.
Methods
To assess the relationship between heterogeneity in cancer cell migration and metastatic fitness, MDA-MB-231 and SUM159PT triple negative breast cancer cells were phenotypically sorted into highly migratory and weakly migratory subpopulations and assayed separately and in a 1:1 mixture in vitro and in vivo for metastatic behaviors. Unpaired, two-tailed Student’s
t
-tests, Mann–Whitney tests, ordinary, one-way ANOVAs, and Kruskal–Wallis
H
tests were performed as appropriate with
p
< 0.05 as the cutoff for statistical significance.
Results
When highly and weakly migratory cells are co-seeded in mixed spheroids, the weakly migratory cells migrated farther than weakly migratory only spheroids. In mixed spheroids, leader–follower behavior occurred with highly migratory cells leading the weakly migratory cells in migration strands. When cell suspensions of highly migratory, weakly migratory, or a 1:1 mixture of both subpopulations were injected orthotopically into mice, both the mixed cell suspensions and weakly migratory cells showed significant distal metastasis, but the highly migratory cells did not metastasize significantly to any location. Notably, significantly more distal metastasis was observed in mice injected with the 1:1 mixture compared to either subpopulation alone.
Conclusions
This study suggests that weakly migratory cells interact with highly migratory cells in a commensal fashion resulting in increased migration and metastasis. Together, these findings indicate that cancer cell subpopulation migration ability does not correlate with metastatic potential and that cooperation between highly migratory and weakly migratory subpopulations can enhance overall metastatic fitness.
Purpose
Since the 1960s, increasing oral contraceptive (OC) use has mirrored decreasing ovarian cancer incidence. The impact of intrauterine devices (IUDs) on cancer risk is less well established. ...With improved access and increased options, we must consider how changing usage can affect cancer risks.
Methods
Nationally representative data from the National Health and Nutrition Examination Survey (NHANES, 1999–2016) and the National Survey for Family Growth (NSFG, 2006–2017) were used to evaluate contraceptive use over time in premenopausal women (NHANES
n
= 13,179; NSFG
n
= 26,262). Trends were assessed overall and by race, age, pregnancy history, education, and body mass index.
Results
The average annual absolute increase in self-reported IUD use was 0.81% (NSFG), while OC use decreased 0.49% in NSFG and 0.47% in NHANES. This represents a significant decrease in OC use in NSFG annual percent change (APC) − 2.2% (95% CI − 3.4, − 1.0%),
p
< 0.01. Trends in OC use varied somewhat by pregnancy history in NHANES (
p-
interaction = 0.054). In contrast, IUD use increased 6.2% annually (1.4, 11.2%),
p
= 0.03 and varied significantly by pregnancy history (
p-
interaction < 0.01). Nulligravid women increased IUD use 11.0% annually (2.6, 20.1%),
p
= 0.02 compared to women with prior pregnancy at 5.2% (0.4, 10.2%),
p
= 0.04. In 2015–2017, IUD use was 76.5% hormonal (71.1, 81.8%) and 22.9% copper (17.4, 28.3%) with greater hormonal IUD use in obese women 89.4%, (82.9, 95.9%).
Conclusion
Increasing IUD use outpaced declining OC use in premenopausal US women. There may be a resulting decreased gynecologic cancer risk as more women gain access to potentially risk-reducing contraceptives.
Per- and polyfluoroalkyl substances (PFAS) are a class of toxic manufactured chemicals in commercial and consumer products. They are resistant to environmental degradation and mobile in soil, air, ...and water. This study used the introduced bivalve Corbicula fluminea as a passive biomonitor at sampling locations in a primary drinking water source in Virginia, USA. Many potential PFAS sources were identified in the region. Perfluorohexane sulfonate (PFHxS) and 6:2 fluorotelomer sulfonic acid (6:2 FTS) levels were highest downstream of an airport. The highest levels of short-chain carboxylic acids were in locations downstream of a wastewater treatment plant. Measured PFAS concentrations varied by location in C. fluminea, sediment, and surface water samples. Two compounds were detected across all three mediums. Calculated partitioning coefficients confirm bioaccumulation of PFAS in C. fluminea and sorption to sediment. C. fluminea bioaccumulated two PFAS not found in the other mediums. Perfluoroalkyl carboxylic acids and short-chain compounds dominated in clam tissue, which contrasts with findings of accumulation of longer-chain and perfluorosulfonic acids in fish. These findings suggest the potential for using bivalves to complement other organisms to better understand the bioaccumulation of PFAS and their fate and transport in a freshwater ecosystem.
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•Twelve species of PFAS were quantified across sediment, water, and C. fluminea.•Two short chain PFAS, PFHxA and PFHpA, were identified in all three mediums.•C. fluminea had highest bioaccumulation of short-chain PFSAs and FTS.•BSAF values were detected for 8:2 FTS, suggesting bioaccumulative properties.
Although intratumoral genomic heterogeneity can impede cancer research and treatment, less is known about the effects of phenotypic heterogeneities. To investigate the role of cell migration ...heterogeneities in metastasis, we phenotypically sorted metastatic breast cancer cells into two subpopulations based on migration ability. Although migration is typically considered to be associated with metastasis, when injected orthotopically
, the weakly migratory subpopulation metastasized significantly more than the highly migratory subpopulation. To investigate the mechanism behind this observation, both subpopulations were assessed at each stage of the metastatic cascade, including dissemination from the primary tumor, survival in the circulation, extravasation, and colonization. Although both subpopulations performed each step successfully, weakly migratory cells presented as circulating tumor cell (CTC) clusters in the circulation, suggesting clustering as one potential mechanism behind the increased metastasis of weakly migratory cells. RNA sequencing revealed weakly migratory subpopulations to be more epithelial and highly migratory subpopulations to be more mesenchymal. Depletion of E-cadherin expression from weakly migratory cells abrogated metastasis. Conversely, induction of E-cadherin expression in highly migratory cells increased metastasis. Clinical patient data and blood samples showed that CTC clustering and E-cadherin expression are both associated with worsened patient outcome. This study demonstrates that deconvolving phenotypic heterogeneities can reveal fundamental insights into metastatic progression. More specifically, these results indicate that migratory ability does not necessarily correlate with metastatic potential and that E-cadherin promotes metastasis in phenotypically sorted breast cancer cell subpopulations by enabling CTC clustering. SIGNIFICANCE: This study employs phenotypic cell sorting for migration to reveal a weakly migratory, highly metastatic breast cancer cell subpopulation regulated by E-cadherin, highlighting the dichotomy between cancer cell migration and metastasis.
Associations between benign gynecologic pathologies and circulating inflammatory markers are unknown. Our goal was to evaluate self-reported history of benign gynecologic pathology and subsequent ...alterations in systemic inflammation.
Using nested case-control studies from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, study-specific associations between self-reported history of benign ovarian cysts, uterine fibroids, and endometriosis with inflammatory marker concentrations were evaluated using logistic regression and combined using meta-analysis. Inflammatory markers associated with individual benign pathologies were mutually adjusted for one another to evaluate independent associations.
Compared to women without a self-reported history of the pathology evaluated, benign ovarian cysts were associated with increased PAI-1 (OR 95% CI 6.24 2.53–15.39, P <.001) and TGF-β1 (3.79 1.62–8.86, P =.002) and decreased BCA-1 (0.38 0.19–0.73, P =.004). Uterine fibroids were associated with decreased CXCL11 (0.37 0.22–0.63, P <.001) and VEGFR3 (0.40 0.24–0.65, P <.001). Endometriosis was associated with increased SIL-4R (4.75 1.84–12.26, P =.001).
Self-reported history of benign gynecologic pathologies were associated with alterations in inflammatory markers that have been previously linked to cancer risk. Understanding interactions between benign gynecologic pathologies and the systemic immune system may help inform disease risk later in life.
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