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Objective: Clinical evidence suggests an association between oxidative stress and vascular disease, and in vitro studies have demonstrated that reactive oxygen species can have prothrombotic effects on vascular and blood cells. It remains unclear, however, whether elevated levels of reactive oxygen species accelerate susceptibility to experimental thrombosis in vivo., Approach and Results: Using a murine model with genetic deficiency in superoxide dismutase-1 (SOD1), we measured susceptibility to carotid artery thrombosis in response to photochemical injury. We found that SOD1-deficient (Sod1(-/-)) mice formed stable arterial occlusions significantly faster than wild-type (Sod1(+/+)) mice (P<0.05). Sod1(-/-) mice also developed significantly larger venous thrombi than Sod1(+/+) mice after inferior vena cava ligation (P<0.05). Activation of protein C by thrombin in lung was diminished in Sod1(-/-) mice (P<0.05 versus Sod1(+/+) mice), and generation of activated protein C in response to infusion of thrombin in vivo was decreased in Sod1(-/-) mice (P<0.05 versus Sod1(+/+) mice). SOD1 deficiency had no effect on the expression of thrombomodulin, endothelial protein C receptor, or tissue factor in lung or levels of protein C in plasma. Exposure of human thrombomodulin to superoxide in vitro caused oxidation of multiple methionine residues, including critical methionine 388, and a 40% decrease in thrombomodulin-dependent activation of protein C (P<0.05). SOD and catalase protected against superoxide-induced methionine oxidation and restored protein C activation in vitro (P<0.05)., Conclusions: SOD prevents thrombomodulin methionine oxidation, promotes protein C activation, and protects against arterial and venous thrombosis in mice., (© 2015 American Heart Association, Inc.)

Members of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) recently completed the process of updating the MASCC/ISOO Clinical Practice Guidelines for the prevention and treatment of mucositis. These guidelines, originally published in 2004, and last updated in 2007, provide clinicians with objective, evidence-based recommendations for the management of mucositis secondary to cancer therapy. This brief paper describes the methodology used to conduct the most recent systematic review in 2011, and develop new guidelines, providing the basis for the update. The overriding aims of the process were to assess evidence of effectiveness of interventions for the prevention and treatment of mucositis and to produce clinical practice guidelines for the management of mucositis using best available evidence.

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.

Considerable progress in research and clinical application has been made since the original guidelines for managing mucositis in cancer patients were published in 2004, and the first active drug for the prevention and treatment of this condition has been approved by the United States Food and Drug Administration and other regulatory agencies in Europe and Australia. These changes necessitate an updated review of the literature and guidelines. Panel members reviewed the biomedical literature on mucositis published in English between January 2002 and May 2005 and reached a consensus based on the criteria of the American Society of Clinical Oncology. Changes in the guidelines included recommendations for the use of palifermin for oral mucositis associated with stem cell transplantation, amifostine for radiation proctitis, and cryotherapy for mucositis associated with high-dose melphalan. Recommendations against specific practices were introduced: Systemic glutamine was not recommended for the prevention of gastrointestinal mucositis, and sucralfate and antimicrobial lozenges were not recommended for radiation-induced oral mucositis. Furthermore, new guidelines suggested that granulocyte-macrophage-colony stimulating factor mouthwashes not be used for oral mucositis prevention in the transplantation population. Advances in mucositis treatment and research have been complemented by an increased rate of publication on mucosal injury in cancer. However, additional and sustained efforts will be required to gain a fuller understanding of the pathobiology, impact on overall patient status, optimal therapeutic strategies, and improved educational programs for health professionals, patients, and caregivers. These efforts are likely to have significant clinical and economic impact on the treatment of cancer patients. Cancer 2007;109:820-31. (c) 2007 American Cancer Society.

Background and Significance: The field of terminology and assessment of oral and gastrointestinal mucosal injury caused by high-dose cancer therapies in cancer patients has undergone important evolution in recent years. The advances are important for several clinical and research reasons. These reasons include improved patient management and design and conduct of clinical trials based on molecularly targeted therapies. For several decades leading up to the 1980s, terminology was characterized by varying use of "mucositis" and "stomatitis" to describe oral mucosal inflammatory changes and ulceration caused by cancer treatments. In addition, oral mucositis was viewed principally as an epithelial event and one that likely did not intersect with causative mechanisms associated with gastrointestinal mucositis. The term "stomatitis" was directed to oral toxicities and seemed to isolate these conditions from parallel events occurring throughout the alimentary tract and potentially other tissues as well. These perspectives and varying use of these terms resulted in several dilemmas, including (1) difficulty in accurately reporting incidence and severity of oral mucositis and, (2) an under-appreciation of potential significance of alimentary tract mucosal toxicity relative to overall course of therapy, patient quality of life, and in some cases, survivorship. These and related components of the model relative to mucositis have undergone strategic shifts over the past 15 years. A 1989 National Institutes of Health Consensus Development Conference targeted oral mucositis research as one of the key areas for investigation relative to causation, clinical impact, and potential links with other complications in cancer patients. Research in this area over the past 15 years has evolved such that oral and gastrointestinal mucositis are now appropriately framed as a continuum of pathobiologic changes over time, with clinical impact that may well contribute to overall symptom clustering in selected patient cohorts., Objectives: This paper will review history, current status, and new research directions associated with terminology and assessment of mucosal injury in cancer patients in the context described above.