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Sinonasal-inverted papilloma (SNIP) is a rare, benign tumor of the sinonasal tract. Although these tumors are inherently benign, they are prone to malignant transformation and are associated with an unusually high rate of recurrence, even after complete surgical resection. As such, these patients must be followed long-term to monitor for recurrence or the presence of cancer. Unfortunately, there are currently no standards for long-term surveillance, and protocols usually require routine radiography and/or nasal endoscopy, which are not highly sensitive or specific, are time consuming, expensive, and confer morbidity to the patient. There is evidence that suggests that SNIP is associated with a uniquely detectable volatile metabolite signature. This study investigates the ability of four privately owned dogs to learn to identify the presence of SNIP in patients based on blood plasma samples. This type of medical detection is currently being used to create early diagnostic tools for other disease processes, which suggests promising results for the outcome of this study. Blood/plasma and nasal secretions were collected from both patients with SNIP, and healthy age-, sex-, and smoking-status-matched controls. Training was conducted twice weekly using errorless learning techniques that allowed the dogs to utilize odor concentration to guide their understanding of the target odor. After further training, a subsequent double-blind testing phase was conducted, in which the dogs' ability to expand recognition of the target odor from blood plasma samples to nasal secretion samples was assessed. Analysis of recorded training sessions revealed that the dogs exhibited successful odor discrimination between SNIP-positive plasma samples and SNIP-negative controls. Their pattern of behavior change also suggested similarity between SNIP odor in plasma and nasal secretions. [Display omitted] • Trained detection dogs can differentiate between blood plasma from people with sinonasal inverted papillomas (SNIP) and healthy blood plasma. • Dogs differentiated positive and negative SNIP odor in blood plasma, even though they were trained on a very small sample set. • These trained detection dogs demonstrate that there is similarity between the SNIP-positive odor from the medium of blood plasma to the SNIP-positive odor in the medium of nasal secretions, suggesting that may be a common SNIP odor biomarker between the two sample types. [ABSTRACT FROM AUTHOR]

Ovarian cancer is known as a "silent killer" because of its nonspecific symptoms and generally late diagnosis due to the lack of reliable early detection tools. Medical detection canines have been shown to recognize the odor profile of malignant tumors of many types, including ovarian cancer, and may be utilized to help produce a much-needed early detection system for ovarian cancer. One significant drawback, however, is that to train detection canines on the odor signature of ovarian cancer, different samples or sets of samples must be used in every training session so that the canines do not begin to recognize an individual patient's odor signature or attune to patient-specific noncancerous olfactory cues. Therefore, numerous patient-derived samples must be obtained and stored for use in the training process. Ovarian cancer cell lines may be able to solve this obstacle, as they have low sample-to-sample variability and do not present patient-specific confounding olfactory cues. In this study, we attempted to train three medical detection dogs to alert to an ovarian cancer cell line (OVKATE) but not the culture media or nonmalignant cultured fallopian tube cells. Only one dog was able to discriminate between OVKATE and culture media and was able to be tested on other ovarian cancer cell lines (OVCAR-4, OVCAR-8, and SK-OV-3). The dog's responses suggest a common or related olfactory signature of malignant ovarian cancer cell lines. We then tested whether an OVKATE-trained dog recognized the blood plasma of patients with confirmed ovarian cancer. We did not find strong evidence that the dog recognized the blood plasma of a patient with confirmed ovarian cancer within three testing trials, with the dog only hesitating at the target odor, suggesting that while training on the cell lines may prepare medical dedication canines to recognize the blood plasma of patient with ovarian cancer, it is not a spontaneous switch to blood plasma. Despite this outcome, the behavior of the dog led us to believe that this method could help further the use of medical detection canines to inform the production of early detection tools for ovarian cancer, which would lead to earlier diagnoses and more favorable outcomes from therapy. [ABSTRACT FROM AUTHOR]

Abstract: Inducible nitric oxide synthase (iNOS) catalyzes the reaction that converts the substrates O2 and l-arginine to the products nitric oxide (NO) and l-citrulline. Macrophages, and many other cell types, upregulate and express iNOS primarily in response to inflammatory stimuli. Physiological and pathophysiological oxygen tension can regulate NO production by iNOS at multiple levels, including transcriptional, translational, posttranslational, enzyme dimerization, cofactor availability, and substrate dependence. Cell culture techniques that emphasize control of cellular PO2, and measurement of NO or its stable products, have been used by several investigators for in vitro study of the O2 dependence of NO production at one or more of these levels. In most cell types, prior or concurrent exposure to cytokines or other inflammatory stimuli is required for the upregulation of iNOS mRNA and protein by hypoxia. Important transcription factors that target the iNOS promoter in hypoxia include hypoxia-inducible factor 1 and/or nuclear factor κB. In contrast to the upregulation of iNOS by hypoxia, in most cell types NO production is reduced by hypoxia. Recent work suggests a prominent role for O2 substrate dependence in the short-term regulation of iNOS-mediated NO production. [Copyright &y& Elsevier]

Abstract: Stimulated macrophages produce nitric oxide (NO) via inducible nitric oxide synthase (iNOS) using molecular O2, L-arginine, and NADPH. Exposure of macrophages to hypoxia decreases NO production within seconds, suggesting substrate limitation as the mechanism. Conflicting data exist regarding the effect of pO2 on NADPH production via the oxidative pentose phosphate cycle (OPPC). Therefore, the present studies were developed to determine whether NADPH could be limiting for NO production under hypoxia. Production of NO metabolites (NOx) and OPPC activity by RAW 264.7 cells was significantly increased by stimulation with lipopolysaccharide (LPS) and interferon γ (IFNγ) at pO2 ranging from 0.07 to 50%. OPPC activity correlated linearly with NOx production at pO2 >0.13%. Increased OPPC activity by stimulated RAW 264.7 cells was significantly reduced by 1400 W, an iNOS inhibitor. OPPC activity was significantly increased by concomitant treatment of stimulated RAW 264.7 cells with chemical oxidants such as hydroxyethyldisulfide or pimonidazole, at 0.07 and 50% O2, without decreasing NOx production. These results are the first to investigate the effect of pO2 on the relationship between NO production and OPPC activity, and to rule out limitations in OPPC activity as a mechanism by which NO production is decreased under hypoxia. [Copyright &y& Elsevier]