Inducible nitric oxide (NO) synthase (iNOS) is a stress response protein upregulated in inflammatory conditions, and NO may suppress cellular proliferation. We hypothesized that preventing L-arginine (L-arg) uptake in endothelial cells would prevent lipopolysaccharide/tumor necrosis factor-α (LPS/TNF)-induced, NO-mediated suppression of cellular proliferation. Bovine pulmonary arterial endothelial cells (bPAEC) were treated with LPS/TNF or vehicle (control), and either 10 mM L-leucine [L-leu; a competitive inhibitor of L-arg uptake by the cationic amino acid transporter (CAT)] or its vehicle. In parallel experiments, iNOS or arginase II were overexpressed in bPAEC using an adenoviral vector (AdiNOS or AdArgII, respectively). LPS/TNF treatment increased the expression of iNOS, arginase II, CAT-1, and CAT-2 mRNA in bPAEC, resulting in greater NO and urea production than in control bPAEC, which was prevented by L-leu. LPS/TNF treatment resulted in fewer viable cells than in controls, and LPS/TNF-stimulated bPAEC treated with L-leu had more viable cells than LPS/TNF treatment alone. LPS/TNF treatment resulted in cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase expression, which was attenuated by L-leu. AdiNOS reduced viable cell number, and treatment of AdiNOS transfected bPAEC with L-leu preserved cell number. AdArgII increased viable cell number, and treatment of AdArgII transfected bPAEC with L-leu prevented the increase in cell number. These data demonstrate that iNOS expression in pulmonary endothelial cells leads to decreased cellular proliferation, which can be attenuated by preventing cellular L-arg uptake. We speculate that CAT activity may represent a novel therapeutic target in inflammatory lung diseases characterized by NO overproduction.
<p>Excel sheet showing mean signal intensities and p-values of SUP-B15 ALL cells cultured in media only or co-cultured with BMSC. Statistics were done as follows: Data were analyzed by first subtracting the background and then normalizing the signals using a LOWESS filter (Locally-weighted Regression) (2). For two color experiments, the ratio of the two sets of detected signals (log2 transformed, balanced) and p-values of the t-test were calculated; differentially detected signals were those with less than 0.01 p-values.</p>
The bone marrow niche has a significant impact on acute lymphoblastic leukemia (ALL) cell phenotype. Of clinical relevance is the frequency with which quiescent leukemic cells, in this niche, survive treatment and contribute to relapse. This study suggests that marrow microenvironment regulation of BCL6 in ALL is one factor that may be involved in the transition between proliferative and quiescent states of ALL cells. Utilizing ALL cell lines, and primary patient tumor cells we observed that tumor cell BCL6 protein abundance is decreased in the presence of primary human bone marrow stromal cells (BMSC) and osteoblasts (HOB). Chemical inhibition, or shRNA knockdown, of BCL6 in ALL cells resulted in diminished ALL proliferation. As many chemotherapy regimens require tumor cell proliferation for optimal efficacy, we investigated the consequences of constitutive BCL6 expression in leukemic cells during co-culture with BMSC or HOB. Forced chronic expression of BCL6 during co-culture with BMSC or HOB sensitized the tumor to chemotherapy induced cell death. Combination treatment of caffeine, which increases BCL6 expression in ALL cells, with chemotherapy extended the event free survival of mice. These data suggest that BCL6 is one factor, modulated by microenvironment derived cues that may contribute to regulation of ALL therapeutic response.
Photograph of Marc Cutright, an in-residence professor at UNT, walking into the main lobby of West Hall where he lives. Students are gathered behind him and Cutright is interacting with some students in front of him.
This work describes a method for estimating on-die and package jitter noise for standard-cell ASICs. This method uses extractions of the physical layouts, with current consumption behavioral model estimations of core cells, to estimate the core voltage noise at various die locations. The resulting voltage and ground noise waveforms are then used as the voltage rail inputs for simulations of extracted signal nets to estimate their jitter due to this core noise. These voltage noise waveforms are then used as the supply inputs for simulating jitter on critical nets.
As The Royal Australian College of General Practitioners (RACGP) introduces alternatives to the Objective Structured Clinical Examination, it is imperative that standards are continually set for a culturally safe general practice workforce. Assessments have many functions and should be continually reviewed to ensure that they require general practitioners (GPs) to demonstrate genuine cultural safety.
As part of the campus concern with retention, California State University at Long Beach developed several intervention strategies to work with students on academic probation. The Student Affirmative Action Program designed their program components based on an identification of key factors contributing to academic difficulties. Findings suggest that students who participated in this mandatory, long-term, comprehensive program made far more significant and steady progress compared with control populations who utilized other services or who did not participate in any campus program.
Abstract Introduction Australia's rapidly growing population of dentate, frail, care‐dependent older people require graduates skilled in managing the health needs of this patient group. The perceptions of academics teaching gerodontology may inform future dental curricula recommendations. This study explored the perceptions of gerodontology education amongst Australian dental school academics. Materials and Methods All nine Australian dental schools providing entry‐to‐practice dentistry programs were invited to participate in semi‐structured interviews. Academics from six dentistry programs took part, and the data were analysed using a thematic approach. Results The three main themes identified from interviews included ‘clinical exposure’, ‘organisational levers’, and ‘sociological barriers’. The attitudes of students, as well as society and health professionals, were seen as strongly influential in preparing the workforce for managing the oral health of older people. The themes inter‐linked with a knock‐on effect where societal attitudes and organisational levers impact on the ability to successfully support students' preparation for gerodontology practice. Limited resources were barriers to achieving ideal learning and teaching and continued upon graduation as oral health care for older people was perceived as undervalued and under‐resourced. Conclusion There has been a continued cycle of failure in healthcare schemes and advocacy for the improvement of oral health for older people which has contributed to the inadequate preparation of dental graduates for managing frail and care‐dependent older people. Organisational, societal, and political change is needed to support the education of dental students in this area to ensure graduate dentists are competent to manage the oral care needs of this growing population.
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