Katherine A Bessette’s research while affiliated with White River Junction VA Medical Center and other places

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Publications (4)


25-hydroxyvitamin D levels in the four treatment groups at the end of the experimental period. Values shown reflect means ± SEM of 19–23 mice per group. Levels of 25-hydroxyvitamin D in mice fed control diets were significantly different than mice fed a vitamin D deficient diet (p = 0.001).
Table 2 | Histological review of mouse lungs.
Normal and emphysema-like features in hematoxylin and eosin (H&E) stained sections of lung representative of lung sections from each treatment group. All images are 40× enlargements.
Mean Linear Intercept (LM) in experimental groups. Levels shown reflect means ± SEM. LM is significantly longer in VDD-CSE mice compared to all other treatment groups and is consistent with emphysema. Data shown are based on analyses of 10 images from each lung section of each of eleven mice in each of the four treatment groups (440 total images analyzed).
Total lung capacity (TLC) in experimental groups. Over the course of three separate experiments, total lung capacity was determined by flexiVent™ in 63 mice. Each point represents the data from one mouse with 14 to 17 mice per treatment group. Horizontal bars mark medians. A Two-Way ANOVA indicated that the mean TLC in the VDD-NS group and the CD-CSE group was significantly greater than the mean TLC in the control group (CD-NS) (indicated by *** in the figure; p = 0.001).

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Modeling the influence of vitamin D deficiency on cigarette smoke-induced emphysema
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June 2013

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1,011 Reads

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24 Citations

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Candice C. Black

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Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. While the primary risk factor for COPD is cigarette smoke exposure, vitamin D deficiency has been epidemiologically implicated as a factor in the progressive development of COPD-associated emphysema. Because of difficulties inherent to studies involving multiple risk factors in the progression of COPD in humans, we developed a murine model in which to study the separate and combined effects of vitamin D deficiency and cigarette smoke exposure. During a 16-week period, mice were exposed to one of four conditions, control diet breathing room air (CD-NS), control diet with cigarette smoke exposure (CD-CSE), vitamin D deficient diet breathing room air (VDD-NS) or vitamin D deficient diet with cigarette smoke exposure (VDD-CSE). At the end of the exposure period, the lungs were examined by a pathologist and separately by morphometric analysis. In parallel experiments, mice were anesthetized for pulmonary function testing followed by sacrifice and analysis. Emphysema (determined by an increase in alveolar mean linear intercept length) was more severe in the VDD-CSE mice compared to control animals and animals exposed to VDD or CSE alone. The VDD-CSE and the CD-CSE mice had increased total lung capacity and increased static lung compliance. There was also a significant increase in the matrix metalloproteinase-9: tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio in VDD-CSE mice compared with all controls. Alpha-1 antitrypsin (A1AT) expression was reduced in VDD-CSE mice as well. In summary, vitamin D deficiency, when combined with cigarette smoke exposure, seemed to accelerate the appearance of emphysemas, perhaps by virtue of an increased protease-antiprotease ratio in the combined VDD-CSE animals. These results support the value of our mouse model in the study of COPD.

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MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood

September 2011

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99 Reads

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26 Citations

International Immunology

Increasing the pool of cells at early T-cell developmental stages enhances thymopoiesis and is especially beneficial when T-cell production is compromised by radiation or aging. Within the immature double-negative (DN; CD4(-)CD8(-)) thymocyte subpopulation, the DN1 subset contains the most primitive cells including the rare early T-cell progenitors (ETPs). In the present study, a human MCL1 transgene, under the control of its endogenous promoter, resulted in enlargement of an undistorted thymus in C57/BL6 mice. Enlargement occurred in females but not males, being seen at 1 month of age and maintained during progression into adulthood as the thymus underwent involution. The small DN1 subset was expanded disproportionally (ETPs increasing from ∼0.016 to 0.03% of thymocytes), while more mature thymocytes were increased proportionally (1.5-fold) along with the stroma. DN1 cells from transgenic females exhibited increased viability with maintained proliferation, and their survival in primary culture was extended. Exposure of transgenic females to γ-irradiation also revealed an expanded pool of radioresistant DN1 cells exhibiting increased viability. While the viability of DN1 cells from transgenic males was equivalent to that of their non-transgenic counterparts directly after harvest, it was enhanced in culture-suggesting that the effect of the transgene was suppressed in the in vivo environment of the male. Viability was increased in ETPs from transgenic females, but unchanged in more mature thymocytes, indicating that primitive cells were affected selectively. The MCL1 transgene thus increases the viability and pool size of primitive ETP/DN1 cells, promoting thymopoiesis and radioresistance in peripubescent females and into adulthood.


Figure 1 Decreased lesion formation in the aortic root or innominate artery in FcgRIII 2/2 Â LDLR 2/2 double knockouts. (A) Lesion formation in the aortic root determined by Oil Red-O staining at 14 weeks (for LDLR 2/2 n ¼ 20 males and 23 females; for FcgRIII 2/2 Â LDLR 2/2 n ¼ 12 males and 18 females, P ¼ 0.007). (B) Lesion formation in the aortic root after 24 weeks of high-fat diet (for LDLR 2/2 n ¼ 6 males and 5 females; for FcgRIII 2/2 Â LDLR 2/2 n ¼ 6 males and 5 females, P , 0.0001). (C) Lesion formation in the innominate artery after 24 weeks of high-fat diet for the same mice as in (B) (P , 0.0008).  
Figure 2 Decreased lesion formation in FcgRIII 2/2 Â LDLR 2/2 double knockout mice. Representative illustrations of the distribution of neutral lipid (A and B) or of CD68þ macrophages (C and D) in the aortic root of the indicated strains after 24 weeks of high-fat diet. Sections taken through the valve leaflets are shown in each case. All of the material extending into the lumen stained with Oil Red-O, but gaps indicative of cholesterol clefts are present in regions largely devoid of cells in each case.  
Table 2 Selected endpoints from LDLR 2/2 and FcgRIII 2/2 double knockouts after 24 weeks of high-fat diet 
Figure 3 T-cell content of arterial lesions in the aortic root of FcgRIII double knockouts after 6 months of high-fat diet. Sections were fixed in acetone and stained with APC-anti-CD3 (A) or APC-anti-CD3 plus FITC-anti-B220 (B) as described in Methods. (A) A typical example of clusters of T-cells (red) is shown in the plaque from a section taken through the aortic root; (B) an ectopic follicle with a core of T-cells surrounded by numerous B-cells (green) in a section adjacent to the aortic root. The upper arrow denotes the aorta while the lower arrow is opposite a layer of heart muscle.  
Inhibition of arterial lesion progression in CD16-deficient mice: Evidence for altered immunity and the role of IL-10

September 2009

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74 Reads

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43 Citations

Cardiovascular Research

Given the importance of IgG Fc receptors in immune regulation, we hypothesized that Fcg receptor type III (FcgRIII, CD16) plays an important role in atherogenesis. We therefore analysed the formation of arterial lesions in LDL receptor-deficient (LDLR(-/-)) and FcgRIII(-/-)xLDLR(-/-) double knockout mice at three different points up to 24 weeks of exposure to a high-fat diet. Analysis of Oil Red-O-stained sections revealed no difference in lesion formation between strains after 6 weeks of a high-fat diet, and a modest decrease after 14 weeks in double knockouts relative to LDLR(-/-) controls. After 24 weeks, lesion formation was decreased in the aortic root (30%) and innominate artery (50%) in FcgRIII double knockouts relative to LDLR(-/-) controls. Analysis of peripheral CD4+ T-cells by intracellular flow cytometry from double knockouts after 24 weeks of a high-fat diet revealed statistically significant increases in the percentages of cells producing interferon-gamma, interleukin (IL)-10, and IL-4 relative to controls, differences that were also observed by analyses of whole aortas for cytokine mRNA levels. As determined by flow cytometry, FcgRIII deficiency resulted in an expansion of CD4+ cells and an increase in the CD4 to CD8 ratio. Analysis of plasma anti-oxidized LDL (OxLDL) antibodies by chemiluminescent assay revealed that IgG1 and IgG2c titers to OxLDL were increased in FcgRIII (-/-)xLDLR(-/-) double knockouts relative to LDLR(-/-) controls, while total IgG levels were similar. These results reveal altered immunity in FcgRIII(-/-)xLDLR(-/-) mice and a reduction in lesion formation associated with increased production of IL-10 by an expansion of CD4+ T-cells. The reduction in lesion formation was manifest well after evidence of an immune response to OxLDL, suggesting that FcgRIII contributes to lesion progression in murine atherosclerosis.


Table 1 0-10 Weeks 10-20 Weeks 
Table 2 
A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling

February 2008

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80 Reads

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12 Citations

Blood

Stat5 proteins are critical signaling molecules activated by many cytokines. Within the immune system, Stat5 plays important roles related to the development of thymocytes and proliferation of T cells. Stat5 has been implicated in malignant transformation, and moreover, the activated tyrosine phosphorylated form of Stat5 is frequently observed in human lymphomas. We previously demonstrated the oncogenic potential of Stat5, with thymic lymphoblastic lymphomas developing in a significant proportion of transgenic (TG) mice overexpressing Stat5a or Stat5b in lymphocytes. In addition, immunization or expression of a T-cell receptor (TCR) transgene augmented the rate of tumor formation. Here, we investigate the mechanism of Stat5-mediated lymphomagenesis by exploring the contributions of major histocompatibility complex (MHC)/TCR and pre-TCR signals. We present data demonstrating that Stat5b TG mice unexpectedly develop CD8(+) lymphoma even in the absence of either pre-TCR signaling or normal thymic selection. Indeed, acceleration of Stat5b transgene-mediated lymphoma occurred on TCRalpha(-/-) and pre-TCRalpha(-/-) backgrounds. In light of these data, we propose a model in which alterations in T-cell development at the double-negative/double-positive (DN/DP) stages cooperate with cytokine-mediated pathways in immature thymocytes to give rise to lymphoblastic T-cell lymphomas in Stat5b TG mice.

Citations (4)


... It reduced inflammation via ERK and JAK-STAT pathways, elevated antioxidant activity in the lung, and decreased protease-antiprotease imbalance in BALF. Recently, there has been an increasing interest in vitamin D supplementation since its deficiency in serum was associated with emphysema progression in men [111] and mice [112]. Ghosh et al. also found a correlation between vitamin D deficiency and decreased lung function in smokers; controversially, there was no significant correlation with CT measures of emphysema [113]. ...

Reference:

Impaired Alveolar Re-Epithelialization in Pulmonary Emphysema
Modeling the influence of vitamin D deficiency on cigarette smoke-induced emphysema

... The thymus rapidly atrophies after puberty where it is then replaced by adipose tissue by adulthood (Li et al., 2021). It has been reported that thymocyte number decreased to less than 50% at 7-month-old (Gui, Morales, et al., 2011;Gui, Mustachio, et al., 2012). ...

MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood

International Immunology

... For instance, in T2D patients, although there was no alteration in the proportion of monocyte subsets, a higher CD16 expression was detected on all three monocyte subsets [20]. Additionally, deletion of CD16 in mice can significantly inhibit the progression of atherosclerosis [23]. CD16 is involved in the pathogenesis of atherosclerosis, and increased CD16 expression may provide additional information for assessing the risk of atherosclerosis. ...

Inhibition of arterial lesion progression in CD16-deficient mice: Evidence for altered immunity and the role of IL-10

Cardiovascular Research

... Like STAT3, experimental evidence implicates STAT5B as a driver of tumorigenesis, as it can drive EMT and increased invasiveness in hepatocellular carcinoma (HCC) [233]. Moreover, in mammary epithelial cells, thymocytes, and epithelial prostate cancer cells, persistent activation of STAT5 is sufficient to drive transformation [234][235][236]. Furthermore, the function of STAT5 in solid tumors extends beyond oncogenesis as evidence has emerged that STAT5 signaling can induce a metastatic cascade. ...

A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling

Blood