Hypoxia Inducible Factors in Cancer and Inflammation

Hypoxia-inducible factors (HIFs) mediate adaptation to low O2, or hypoxia, are important at every stage of tumor initiation, and impact the progression of a variety of diseases, including colorectal cancer. This body of work investigates the role of hypoxia and HIF-mediated signaling in both tumor cells and macrophages across the natural history of inflammation-induced cancers. First, the effect of HIF inhibition in tumor parenchyma and stroma in extant colitis-associated colon carcinomas (CAC) is investigated using acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity. Pharmacologic HIF inhibition represents a novel therapeutic strategy for cancer treatment and data indicates ACF treatment halts the progression of an autochthonous model of established CAC in immunocompetent mice and does so largely through HIF-dependent means. These results suggest pharmacologic HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression. Second, myeloid specific deletion (LysMCre) of the HIF constitutive binding partner ARNT is studied in the setting of acute and chronic inflammatory responses that eventually result in inflammation-associated cancer development. Data indicates loss of ARNT results in severe macrophage defects including decreased edema and inflammatory infiltrate in an acute model of skin inflammation and lower stage disease and decreased tumor inflammation in a model of CAC. Collectively, these data suggest the hypoxic response is necessary for sustained inflammation and tumor progression and may provide a link between chronic inflammatory conditions and cancer development

Rural Community Development as a Teaching Environment for Cross-Professional Training in Macro Social Work and Community and Regional Planning

A rural community development project combined faculty and students from two courses (community and regional planning, and social work practice in groups, communities, and organizations) housed in different colleges (Arts and Sciences, and Health Sciences, respectively) at a medium-sized public university in a small Appalachian community. The project required students from two different courses to cooperate on data collection, and collaborate on analysis and recommendations, in an exploratory effort at cross-professional training focusing on social work and community development in a rural region

Cultural Competence: A Content Analysis of a Public Health Curriculum for a Community Health Training Program in Haiti

Foreign public health practitioners, medical doctors, and humanitarian workers, are often the providers of global health interventions. As a result, there are cultural challenges that arise when outsiders provide health education for individuals from distinctly different sociocultural realities. This study, guided by the principles of cultural competence, examined a community health worker training program in Haiti, led by non-Haitian trainers. The training program provided public health information to 126 Haitian participants. The study specifically examined the application of the principle of culture competence in the training textbook used during this training program. Three criteria filtered and identified the degree of cultural competence demonstrated in the training textbook: language, resources, and racial representation. A qualitative content analysis approach determined the frequency of mismatched areas and inferred concepts for analysis of the text. The author\u27s personal field observations provided contextual information according to the three areas of analysis, which provided a triangulated research perspective. Overall, based on the reported demographic statistics of the trainees and supporting cultural competence literature, the textbook content data analysis showed mismatches, or inconsistencies of culturally competent uses of cross-cultural curriculum, in the program content based on language, resources, and racial representation. These mismatches were identified in the textbook in the areas of analysis according to the principle of cultural competence in that program design must tailor its information to the individuals and communities\u27 unique cultural and linguistic needs. Overall, mismatches in the textbook were most apparent in the language category with resources and racial representation showing fewer inconsistencies

Review and Refinement of a Database for Environmental Management Systems

This paper describes a research project that employs an Microsoft Access database to track the environmental management systems (EMS) at participating industrial and municipal facilities. Two existing databases, which record the pre-EMS state of a facility and the EMS plan each facility proposes, were reviewed critically. A prototype database demonstrates the integration of the two existing databases into a single database, to improve public access and promote data consistency. Recommendations to the project leaders relate to database design and data management

Homes, autos, and travel: household decision chains

Transportation planners have long recognized a role for the environment in travel behavior, although the most effective techniques for incorporating the environment into travel research remain an open and active area of inquiry. A clearer understanding of the link between the physical environment and travel may inform planning and policy that has the potential to influence household travel behavior and reap tangible benefits in air quality, congestion management, fuel conservation, and other areas. The objectives of this research are 1) Understand how auto ownership and travel behavior vary across physical environments 2) Understand direct and indirect associations between environment and travel behavior, mediated by auto ownership 3) Model and describe differences in environmental representations in travel models This work models household decisions relating to auto ownership and travel, specifically auto ownership, trip generation, and mode choice. Three different representations of the environment inform the models. These include 1) a neighborhood typology (transect) describing a range of development types from the intensely urban city center to rural greenfields; 2) factors used to generate clusters in the transect: walkability, access, agglomeration, industry, and property values; and 3) direct environmental measures: residential density, and distance to transit, commerce, and central business district. Auto ownership relates primarily to household factors. Trips are more sensitive than is the number of autos to the environment, and less sensitive to some household measures. Mode choice is sensitive to environmental measures; specifically, choice of the walk mode is associated with walkable and accessible environments, and with clusters on the more urban end of the transect. Trips differ by purpose, with home-based work trips sensitive to the environment but not socio-demographic variables, but the more discretionary other homebased trips showing the reverse. Comparing across environmental representations, factors prove to be more informative than clusters about autos and travel. The four direct measures generally are not statistically significant. Walk trips differ from drive trips in being sensitive to walkability and accessibility but not to socio-demographic variables. Path analysis shows that indirect effects mediated through autos are swamped by much larger direct associations of the environment with trips and mode choice

Use of Dog Parks and the Contribution to Physical Activity for Their Owners

This study described the use of dog parks in several diverse locations and explored the contribution dog parks made to physical activity of the dog owners

Comparing objective measures of environmental supports for pedestrian travel in adults

Background: Evidence is growing that the built environment has the potential to influence walking--both positively and negatively. However, uncertainty remains on the best approaches to representing the pedestrian environment in order to discern associations between walking and the environment. Research into the relationship between environment and walking is complex; challenges include choice of measures (objective and subjective), quality and availability of data, and methods for managing quantitative data through aggregation and weighting. In particular, little research has examined how to aggregate built environment data to best represent the neighborhood environments expected to influence residents' behavior. This study examined associations between walking and local pedestrian supports (as measured with an environmental audit), comparing the results of models using three different methods to aggregate and weight pedestrian features. Methods: Using data collected in 2005-2006 for a sample of 251 adult residents of Montgomery County, MD, we examined associations between pedestrian facilities and walking behaviors (pedestrian trips and average daily steps). Adjusted negative binomial and ordinary least-squares regression models were used to compare three different data aggregation techniques (raw averages, length weighting, distance weighting) for measures of pedestrian facilities that included presence, condition, width and connectivity of sidewalks, and presence of crossing aids and crosswalks. Results: Participants averaged 8.9 walk trips during the week; daily step counts averaged 7042. The three aggregation techniques revealed different associations between walk trips and the various pedestrian facilities. Crossing aids and good sidewalk conditions were associated with walk trips more than were other pedestrian facilities, while sidewalk facilities and features showed associations with steps not observed for crossing aids and crosswalks. Conclusion: Among three methods of aggregation examined, the method that accounted for distance from participant's home to the pedestrian facility (distance weighting) is promising; at the same time, it requires the most time and effort to calculate. This finding is consistent with the behavioral assumption that travelers may respond to environmental features closer to their residence more strongly than to more distant environmental qualities.close0

Ectopic expression of snail and twist in Ph+ leukemia cells upregulates CD44 expression and alters their differentiation potential

Philadelphia chromosome-positive (Ph+) leukemia is characterized by reciprocal translocation between chromosomes 9 and 22. The resultant BCR/ABL fusion protein displays constitutive tyrosine kinase activity, leading to the induction of aberrant proliferation and neoplastic transformation. The bone marrow (BM) microenvironment is tumor-promoting, and contributes to disease recurrence in Ph+ leukemia. Activity in the BM microenvironment is mediated by several cellular compartments, extracellular matrix, various soluble factors including transforming growth factor beta 1 (TGF-β1), and the hypoxic conditions in the BM niche. TGF-β1 is released during bone remodeling and plays a role in maintaining leukemic stem cells, as well as being implicated in the epithelial-mesenchymal transition (EMT) process in most solid tumors. Although EMT is largely implicated in epithelial tumors, recent findings argue for an EMT-like process in leukemia as well. The surface receptor CD44 is involved in cell adhesion, cell migration, and homing of normal and malignant hematopoietic stem cells. Elevation of CD44 expression is considered a marker for a worse prognosis in most hematological malignancies. We explored the functions of Snail and Twist1 in Ph+ leukemia. We showed that ectopic expression of Snail and, to a lesser extent, Twist1, upregulates CD44 expression that is β-catenin-dependent. Moreover, the presence of Snail or Twist1 partially blocked phorbol 12-myristate 13-acetate-induced megakaryocyte differentiation, while that of Twist significantly altered imatinib-induced erythroid differentiation. Thus EMT modulators affected proliferation, CD44 gene expression and differentiation ability of Ph+ leukemia cells

Sleep Apnea and Fetal Growth Restriction (SAFER) study: Protocol for a pragmatic randomised clinical trial of positive airway pressure as an antenatal therapy for fetal growth restriction in maternal obstructive sleep apnoea

INTRODUCTION: Fetal growth restriction (FGR) is a major contributor to fetal and neonatal morbidity and mortality with intrauterine, neonatal and lifelong complications. This study explores maternal obstructive sleep apnoea (OSA) as a potentially modifiable risk factor for FGR. We hypothesise that, in pregnancies complicated by FGR, treating mothers who have OSA using positive airway pressure (PAP) will improve birth weight and neonatal outcomes. METHODS AND ANALYSIS: The Sleep Apnea and Fetal Growth Restriction study is a prospective, block-randomised, single-blinded, multicentre, pragmatic controlled trial. We enrol pregnant women aged 18-50, between 22 and 31 weeks of gestation, with established FGR based on second trimester ultrasound, who do not have other prespecified known causes of FGR (such as congenital anomalies or intrauterine infection). In stage 1, participants are screened by questionnaire for OSA risk. If OSA risk is identified, participants proceed to stage 2, where they undergo home sleep apnoea testing. Participants are determined to have OSA if they have an apnoea-hypopnoea index (AHI) ≥5 (if the oxygen desaturation index (ODI) is also ≥5) or if they have an AHI ≥10 (even if the ODI is \u3c5). These participants proceed to stage 3, where they are randomised to nightly treatment with PAP or no PAP (standard care control), which is maintained until delivery. The primary outcome is unadjusted birth weight; secondary outcomes include fetal growth velocity on ultrasound, enrolment-to-delivery interval, gestational age at delivery, birth weight corrected for gestational age, stillbirth, Apgar score, rate of admission to higher levels of care (neonatal intensive care unit or special care nursery) and length of neonatal stay. These outcomes are compared between PAP and control using intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Boards at Washington University in St Louis, Missouri; Hadassah Hebrew University Medical Center, Jerusalem; and the University of Rochester, New York. Recruitment began in Washington University in November 2019 but stopped from March to November 2020 due to COVID-19. Recruitment began in Hadassah Hebrew University in March 2021, and in the University of Rochester in May 2021. Dissemination plans include presentations at scientific conferences and scientific publications. TRIAL REGISTRATION NUMBER: NCT04084990

Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration

Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal tha