The ability to genetically manipulate mice has led to rapid progress in our understanding of the roles of different gene products in human disease. Transgenic mice have often been created in the FVB/NJ (FVB) strain due to its high fecundity, while gene-targeted mice have been developed in the 129/SvJ-C57Bl/6J strains due to the capacity of 129/SvJ embryonic stem cells to facilitate germline transmission. Genetargeted mice are commonly backcrossed into the C57Bl/6J (B6) background for comparison with existing data. Genetic modifiers have been shown to modulate mammary tumor latency in mouse models of breast cancer and it is commonly known that the FVB strain is susceptible to mammary tumors while the B6 strain is more resistant. Since gene-targeted mice in the B6 background are frequently bred into the polyomavirus middle T (PyMT) mouse model of breast cancer in the FVB strain, we have sought to understand the impact of the different genetic backgrounds on the resulting phenotype. We bred mice deficient in the inducible nitric oxide synthase (iNOS) until they were congenic in the PyMT model in the FVB and B6 strains. Our results reveal that the large difference in mean tumor latencies in the two backgrounds of 53 and 92 days respectively affect the ability to discern smaller differences in latency due to the Nos2 genetic mutation. Furthermore, the longer latency in the B6 strain enables a more detailed analysis of tumor formation indicating that individual tumor development is not stoichastic, but is initiated in the #1 glands and proceeds in early and late phases. NO production affects tumors that develop early suggesting an association of iNOS-induced NO with a more aggressive tumor phenotype, consistent with human clinical data positively correlating iNOS expression with breast cancer progression. An examination of lung metastases, which are significantly reduced in PyMT/iNOS -/-mice compared with PyMT/ iNOS +/+ mice only in the B6 background, is concordant with these findings. Our data suggest that PyMT in the B6 background provides a useful model for the study of inflammationinduced breast cancer.Keywords FVB/NJ Á C57Bl/6J Á Strain Á iNOS Á Breast Á Cancer Á Polyomavirus middle T antigen Á Mouse

Posttraumatic stress disorder (PTSD) is associated with fear response system dysregulation. Research has shown that the anterior cingulate cortex (ACC) may modulate the fear response and that individuals with PTSD have abnormalities in ACC structure and functioning. Our objective was to assess whether ACC volume moderates the relationship between PTSD and fear-potentiated psychophysiological response in a sample of Gulf War Veterans. 142 Veteran participants who were associated with a larger study associated with Gulf War Illness were exposed to no threat, ambiguous threat, and high threat conditions in a fear conditioned startle response paradigm and also provided MRI imaging data. PTSD was assessed using the Clinician Administered PTSD Scale (CAPS). Decreased caudal ACC volume predicted greater psychophysiological responses with a slower habituation of psychophysiological magnitudes across trials (p < 0.001). PTSD diagnosis interacted significantly with both caudal and rostral ACC volumes on psychophysiological response magnitudes, where participants with PTSD and smaller rostral and caudal ACC volumes had greater psychophysiological magnitudes across trials (p < 0.05 and p < 0.001, respectively) and threat conditions (p < 0.05 and p < 0.005). Our results suggest that ACC volume may moderate both threat sensitivity and threat response via impaired habituation in individuals who have been exposed to traumatic events. More research is needed to assess whether ACC size and these associated response patterns are due to neurological processes resulting from trauma exposure or if they are indicative of a premorbid risk for PTSD subsequent to trauma exposure.

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