VE-Cadherin Expression and Regulation of Sensitivity to Apoptosis in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

The bone marrow microenvironment serves as the primary site for post-natal hematopoiesis allowing for HSC development and maturation. More specifically, B lineage cells rely on key signals from both the physical and soluble components of the marrow for their survival and maturation. In addition to normal hematopoiesis the bone marrow has been shown to be a sanctuary for leukemic cells, as well as other tumors, that can interact with cues from the microenvironment allowing for their protection during chemotherapy. The studies described in this dissertation focus on two supportive components of the bone marrow microenvironment, osteoblasts and bone marrow stromal cells (BMSC), in the settings of post high dose chemotherapy and survival of leukemic cells during chemotherapy, respectively.;In the first study we investigated the effects of high dose chemotherapy on human osteoblasts (HOB). Previous studies from our laboratory have shown that high dose chemotherapy causes increases in the amount of active TGF-beta released from BMSC and subsequently leads to diminished ability to support pro-B cells. Here we describe the novel observation that HOB treated with chemotherapy have increased levels of active TGF-beta as well as a diminished capacity to interact with, and support, human embryonic stem cells and pro-B cells. Additionally, we determined that HOB treatment with chemotherapy or rTGF-beta led to increased levels of active TGF-beta, as well as decreased CXCL12 mRNA and protein leading to a decreased adherence of pro-B cells to HOB. Chemotherapy or rTGF-beta treatment also lead to the diminished ability of HOB to support pluripotent OCT-4 positive stem cell colonies and microarray analysis of HOB treated with Melphlan, rTGF-beta or Conditioned Media from BMSC treated with Melphlan led to dramatic changes in the gene expression profiles of the HOB. This study elucidates the importance of osteoblasts in the marrow following ablative therapy and indicates how different components of the marrow are altered by chemotherapy.;Our laboratory and others have previously shown that BMSC are able to protect tumor cells from chemotherapy however the mechanisms by which the bone marrow microenvironment regulates tumor cell survival are diverse. This study describes the novel observation that in addition to Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cell lines, primary patient cells also express Vascular Endothelial Cadherin (VE-cadherin) which is regulated by Abl kinase and has been associated with aggressive phenotype and poor prognosis in other models. Targeted knockdown of VE-cadherin rendered ALL cells more susceptible to chemotherapy, even in the presence of BMSC derived survival cues. Pre-treatment of Ph+ ALL cells with ADH100191, a VE-cadherin antagonist, resulted in increased apoptosis during in vitro chemotherapy exposure. Consistent with a role for VE-cadherin in modulation of leukemia cell viability, lentiviral-mediated expression of VE-cadherin in Ph- ALL cells resulted in increased resistance to treatment-induced apoptosis. Collectively, these data contribute to our understanding of the alterations that occur to the different supportive components of the bone marrow microenvironment during chemotherapy and the mechanisms that alter their ability to support both normal and neoplastic cells

The Breathing Human Infrastructure: Integrating Air Quality, Traffic, And Social Media Indicators

Outdoor air pollution is a complex system that is responsible for the deaths of millions of people annually, yet the integration of interdisciplinary data necessary to assess air quality\u27s multiple metrics is still lacking. This case study integrates atmospheric indicators (concentrations of criteria pollutants including particulate matter and gaseous pollutants), traffic indicators (permanent traffic monitoring station data), and social indicators (community responses in Twitter archives) representing the interplay of the three critical pillars of the United Nations\u27 Triple Bottom Line: environment, economy, and society. During the watershed moment of the COVID-19 pandemic lockdowns in Florida, urban centers demonstrated the gaps and opportunities for understanding the relationships, through correlations rather than causations, between urban air quality, traffic emissions, and public perceptions. The relationship between the perception and the traffic variables were strongly correlated, however no correlation was observed between the perception and actual air quality indicators, except for NO2. These observations might consequently infer that traffic serves as people\u27s proxy for air quality, regardless of actual air quality, suggesting that social media messaging around asthma may be a way to monitor traffic patterns in areas where no infrastructure currently exists or is prohibited to build. It also indicates that people are less likely to be reliable sensors to accurately measure air quality due to bias in their observations of traffic volume and/or confirmation biases in broader social discourse. Results presented herein are of significance in demonstrating the capacity for interdisciplinary studies to consider the predictive capacities of social media and air pollution, its use as both lever and indicator of public support for air quality legislation and clean-air transitions, and its ability to overcome limitations of surface monitoring stations

Heavy maternal alcohol consumption and cerebral palsy in the offspring

AIM The aim of this study was to investigate the association between heavy maternal alcohol consumption and pre- peri- and postneonatally acquired cerebral palsy (CP). METHOD The records of all mothers with an International Classification of Diseases, revision 9 or 10 (ICD-9 ⁄ -10) alcohol-related diagnostic code, indicating heavy alcohol consumption, recorded on population-based health, mental health, and drug and alcohol data sets from 1983 to 2007, and their children were identified through the Western Australian Data-linkage System. This ‘exposed’ cohort was frequency matched with mothers without an alcohol-related diagnosis and their offspring (comparison group). Cases of CP were identified through linkage with the Western Australia CP Register. Analyses were undertaken using multivariate logistic regression. RESULTS There were 23 573 live births in the exposed group (58.6% non-Aboriginal; 41.4% Aboriginal) and 292 cases of CP. The odds of pre ⁄ perinatally acquired CP were elevated for children of non-Aboriginal mothers with an alcohol-related diagnosis recorded during pregnancy (adjusted odds ratio 3.32; 95% confidence interval [CI] 1.30–8.48) and for Aboriginal children when an alcohol-related diagnosis was recorded up to 12 months before the mother’s pregnancy (adjusted odds ratio 2.49; 95% CI 0.99–6.25). Increased odds of postneonatally acquired CP following any alcohol-related diagnosis were found for non-Aboriginal children (adjusted odds ratio 7.92; 95% CI 2.23–28.14). INTERPRETATION These results suggest that heavy maternal alcohol consumption is a direct cause of pre ⁄ perinatally acquired CP, and an indirect cause of postneonatally acquired CP, in non-Aboriginal children. The lack of an association for Aboriginal children requires further investigation but may be due to under ascertainment of alcohol use disorders during pregnancy and other aetiological pathways

Women\u27s Knowledge and Attitudes Regarding Alcohol Consumption in Pregnancy: A National Survey

Background: Alcohol exposure in pregnancy is a common and modifiable risk factor for poor pregnancy and child outcomes. Alcohol exposure in pregnancy can cause a range of physical and neurodevelopmental problems in the child including the Fetal Alcohol Spectrum Disorders (FASD). In order to improve prevention strategies, we sought to describe the knowledge and attitudes of women of childbearing age regarding alcohol consumption during pregnancy and its effects on the fetus. Methods: We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations with participants’ knowledge and attitudes. Results: Of women surveyed, 61.5% had heard about effects of alcohol on the fetus and 55.3% had heard of Fetal Alcohol Syndrome. Although 92.7% agreed alcohol can affect the unborn child, 16.2% did not agree that the disabilities could be lifelong. Most women agreed that pregnant women should not drink alcohol (80.2%) and 79.2% reported having negative feelings towards pregnant women drinking alcohol. Women with higher education levels were more likely to know the effects of alcohol consumption in pregnancy (adjusted OR 5.62; 95% CI 3.20 to 9.87) but education level and knowledge were not associated with attitude. Conclusions: There was a disjunction between knowledge and attitudes towards alcohol consumption in pregnancy. These findings will assist in developing effective health promotion campaigns to reduce fetal alcohol exposure and subsequent fetal damage

Attitudes and behaviour predict women\u27s intention to drink alcohol during pregnancy: The challenge for health professionals

Background: To explore women’s alcohol consumption in pregnancy, and potential predictors of alcohol consumption in pregnancy including: demographic characteristics; and women’s knowledge and attitudes regarding alcohol consumption in pregnancy and its effects on the fetus. Methods: We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations of alcohol consumption in pregnancy with participants’ characteristics, knowledge and attitudes. Results: The majority of women (89.4%) had consumed alcohol in the last 12 months. During their last pregnancy (n = 700), 34.1% drank alcohol. When asked what they would do if planning a pregnancy (n = 1103), 31.6% said they would consume alcohol and 4.8% would smoke. Intention to consume alcohol in a future pregnancy was associated with: alcohol use in the last pregnancy (adjusted OR (aOR) 43.9; 95% Confidence Interval (CI) 27.0 to 71.4); neutral or positive attitudes towards alcohol use in pregnancy (aOR 5.1; 95% CI 3.6 to 7.1); intention to smoke in a future pregnancy (aOR 4.7; 95% CI 2.5 to 9.0); and more frequent and higher current alcohol consumption. Conclusions: Women’s past pregnancy and current drinking behaviour, and attitudes to alcohol use in pregnancy were the strongest predictors of alcohol consumption in pregnancy. Targeted interventions for women at higher risk of alcohol consumption in pregnancy are needed to change women’s risk perception and behaviour

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead