Hematological Disorders and Pulmonary Hypertension

Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. Several hematological disorders such as sickle cell disease, thalassemia and myeloproliferative diseases develop PH which worsens the prognosis. Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction. Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity, activation of proliferative and antiapoptotic pathways leading to vascular remodeling, elevated pulmonary artery pressure, right ventricular hypertrophy and premature death. Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide (NO), limiting its bioavailability, and leading to endothelial dysfunction. In addition, hemolysis releases arginase into the circulation which converts L-arginine to ornithine, thus bypassing NO production. Furthermore, treatments for hematological disorders such as immunosuppressive therapy, splenectomy, bone marrow transplantation, and radiation have been shown to contribute to the development of PH. Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension (PAH). Several studies have reported low iron levels in patients with idiopathic PAH, and iron deficiency is an important risk factor. This article reviews PH associated with hematological disorders and its mechanism; and iron homeostasis and its relevance to PH

Relational grounding facilitates development of scientifically useful multiscale models

We review grounding issues that influence the scientific usefulness of any biomedical multiscale model (MSM). Groundings are the collection of units, dimensions, and/or objects to which a variable or model constituent refers. To date, models that primarily use continuous mathematics rely heavily on absolute grounding, whereas those that primarily use discrete software paradigms (e.g., object-oriented, agent-based, actor) typically employ relational grounding. We review grounding issues and identify strategies to address them. We maintain that grounding issues should be addressed at the start of any MSM project and should be reevaluated throughout the model development process. We make the following points. Grounding decisions influence model flexibility, adaptability, and thus reusability. Grounding choices should be influenced by measures, uncertainty, system information, and the nature of available validation data. Absolute grounding complicates the process of combining models to form larger models unless all are grounded absolutely. Relational grounding facilitates referent knowledge embodiment within computational mechanisms but requires separate model-to-referent mappings. Absolute grounding can simplify integration by forcing common units and, hence, a common integration target, but context change may require model reengineering. Relational grounding enables synthesis of large, composite (multi-module) models that can be robust to context changes. Because biological components have varying degrees of autonomy, corresponding components in MSMs need to do the same. Relational grounding facilitates achieving such autonomy. Biomimetic analogues designed to facilitate translational research and development must have long lifecycles. Exploring mechanisms of normal-to-disease transition requires model components that are grounded relationally. Multi-paradigm modeling requires both hyperspatial and relational grounding

Periodontal disease and atherosclerotic vascular disease: Does the evidence support an independent association?: A scientific statement from the American heart association

A link between oral health and cardiovascular disease has been proposed for more than a century. Recently, concern about possible links between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) has intensified and is driving an active field of investigation into possible association and causality. The 2 disorders share several common risk factors, including cigarette smoking, age, and diabetes mellitus. Patients and providers are increasingly presented with claims that PD treatment strategies offer ASVD protection; these claims are often endorsed by professional and industrial stakeholders. The focus of this review is to assess whether available data support an independent association between ASVD and PD and whether PD treatment might modify ASVD risks or outcomes. It also presents mechanistic details of both PD and ASVD relevant to this topic. The correlation of PD with ASVD outcomes and surrogate markers is discussed, as well as the correlation of response to PD therapy with ASVD event rates. Methodological issues that complicate studies of this association are outlined, with an emphasis on the terms and metrics that would be applicable in future studies. Observational studies to date support an association between PD and ASVD independent of known confounders. They do not, however, support a causative relationship. Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes

Uptake and metabolism of biogenic amines in the developing rabbit lung

Uptake and metabolism of biogenic amines in developing lung were studied in a total of 62 New Zealand White rabbits aged 28 days of gestation to 28 days postnatal. Lungs were perfused in vitro with 5-[14C]hydroxytryptamine (5-HT) or [14C]phenylethylamine (PEA) and coperfused with high-molecular-weight [3H]dextran to assess the vascular space perfused. Patterns of uptake and metabolism of PEA and 5-HT as functions of age were markedly different. PEA uptake and metabolism gradually increased with advancing age. No differences were observed in 5-HT uptake or metabolism within the postnatal age range studied, but the magnitude of each process for 5-HT was significantly lower in premature animals. Functional maturity for both uptake and metabolism of PEA was observed by 14-21 days of age. Inhibition of intrapulmonary monoamine oxidase by semicarbazide and pargyline showed that PEA metabolism was unaffected by the former and moderately reduced by the latter agent only in animals older than 1 wk. Thus the lung of the newborn rabbit effectively takes up and metabolizes PEA and 5-HT, but age-related differences are evident in the development of specific monoamine oxidase subtypes. Reduced 5-HT metabolism in lung of premature animals paralleled changes in the measured vascular space, possibly reflecting difficulty in perfusing premature lungs as well as immature functional status. This study emphasizes the importance of determining functional vascular perfusion (by coperfusion with intravascular markers) when studying the developing lung. </jats:p

Abstract 324: Cytoprotective versus nonprotective autophagy induced by radiation in head and neck cancer cells

Abstract The primary treatment options for head and neck cancer are radiation therapy or surgery, or both combined; chemotherapy is often used as an additional, or adjuvant, treatment. Patients treated with radiotherapy are exposed to a high dose of radiation for a long period of time and there is a 17-33% chance of recurrence. High doses of radiation, a long time course of treatment, side effects and the possibility of recurrence provide the rationale for developing approaches for radiation sensitization, which could be helpful to patients in decreasing the dose, duration of radiation, side effects,or the chance of recurrence. Radiation induces autophagy,which is a catabolic process involving the degradation of the cell's own components to generate energy under conditions of stress. Autophagy can be cytoprotective,helping the cell to survive during stress such as nutrient deprivation or it can be cytotoxic, leading the cell toward death.We investigated whether blocking autophagy by the use the antimalarial drug,chloroquine, could sensitize head and neck cancer cells to radiation. Studies were performed using the HN30 human head and neck cancer line (p53 wild type) derived from the pharynx as well as HN6 human cells (p53 mutant) derived from the base of the tongue.Cell viability was determined by cell counting Hemocytometer. and clonogenic survival assays, autophagy was monitored based on acridine orange staining accompanied by flowcytometry ,while western blotting, DAPI and TUNEL staining and PI/annexin/FACS were utilized for determination and quantification of apoptosis. Senescence was monitored by beta-galactosidase staining/ FACSanalysis. Radiation alone produced a transient growth arrest followed by proliferative recovery in both the HN30 and HN6 cancer cells. Radiation also promoted autophagy in both cell lines, although the extent of autophagy was only modestly increased over basal control levels in the HN30 cells. The combination of chloroquine with radiation inhibited autophagy and promoted apoptotic cell death and suppression of proliferative recovery for the HN30 cells, but had little effect on sensitivity to radiation and proliferative recovery in the HN6 cells. The data suggest that autophagy induced by radiation serves a protective function in the HN30 cells and that a blockade to autophagy by chloroquine drives the cell toward apoptosis and death. In contrast, autophagy in HN6 cells appears to be non-protective as a pharmacological blockade did not sensitize the HN6 cells to radiation. These studies support the premise that autophagy induction by radiation need not necessarily have a cytoprotective function and further indicates that caution should be exercised in efforts to sensitize head and neck cancer to radiation through the clinical suppression of autophagy. Citation Format: Duaa M. Bakhshwin, David Gewitz, Andrew Yeudall. Cytoprotective versus nonprotective autophagy induced by radiation in head and neck cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 324. doi:10.1158/1538-7445.AM2014-324</jats:p