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Vascular calcification is associated with increased cardiovascular morbidity and mortality and has long been
associated with advanced atherosclerotic lesions. While vascular calcification is considered a surrogate marker for ather...
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Vascular calcification is associated with increased cardiovascular morbidity and mortality and has long been
associated with advanced atherosclerotic lesions. While vascular calcification is considered a surrogate marker for atherosclerosis,
the mechanisms that link the two are poorly understood. The consensus of recent research is that active regulatory
processes govern vascular calcification, and much focus has been placed on elucidating the phenomenon of atherosclerotic
calcification. Building upon extensive in vitro work and the previous development of atherosclerotic murine
models, several groups have developed murine models of atherosclerotic calcification. From imposing chronic renal failure
to developing double-knockout mice, this recent work has provided insight into the pathophysiology of mineralized
matrix formation in atherosclerotic lesions, as well as development of potential therapies to prevent or inhibit progression
of calcified plaque. The aim is to briefly review current understanding of the molecular basis for atherosclerotic calcification
and to discuss some murine models that may be useful in advancing knowledge of its mechanisms
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DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs ...
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DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.
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The innominate artery is a predilection site for atherosclerotic lesion formation in hyperlipidemic mice. The lesions
at this site in chow-fed apo E-/- mice progress from fatty streaks through stages that include atheroma with lar...
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The innominate artery is a predilection site for atherosclerotic lesion formation in hyperlipidemic mice. The lesions
at this site in chow-fed apo E-/- mice progress from fatty streaks through stages that include atheroma with large necrotic
areas, fibro-fatty nodules containing chondrocyte-like cells and highly calcified, acellular plaques. The advanced lesions
in the innominate arteries of the apo E-/- mice exhibit a reproducible frequency of intra-plaque hemorrhage that occurs
primarily as a result of fissures through lateral fatty streaks that form adjacent to or on top of the established plaques.
However, this plaque disruption is not equivalent to plaque rupture in human lesions where there is rupture of well formed
fibrous caps. The plaque disruption in the lesions of the chow-fed apo E-/- mice also do not lead to formation of occlusive
thrombi, the predominant marker of plaque rupture in humans. Thus, although the lesions in the innominate arteries of hyperlipidemic
mice progress to very advanced stages of the disease, they are not, in our opinion a model in which to study
the mechanisms of plaque rupture in humans. The advanced lesions in the innominate arteries of the apo E-/- mice may
however be adequate models for studying vascular fibrosis and calcification.
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Purpose. To establish a murine model for keratoprosthesis. Methods. A miniature keratoprosthesis (m-KPro) device was created consisting of a poly[methyl methacrylate] front part and a titanium back plate, designed after the Boston...
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Purpose. To establish a murine model for keratoprosthesis. Methods. A miniature keratoprosthesis (m-KPro) device was created consisting of a poly[methyl methacrylate] front part and a titanium back plate, designed after the Boston KPro, which is in widespread clinical use. BALB/c mice were used and a 2 mm in diameter donor cornea was punched out. After 2-mm trepanation of the syngeneic recipient cornea, extracapsular crystalline lens extraction was performed. The m-KPro was assembled onto the cornea button in a similar manner to human KPro implantation. The cornea-device complex was secured to the recipient bed with eight interrupted 11-0 sutures. All mice (n = 10) were followed up for 8 weeks postoperatively. Results. All m-KPros were successfully implanted and retained in all 10 animals. There were no critical complications such as endophthalmitis, corneal melting, device extrusions, leakage, extensive inflammation, or weight loss in the animals. We observed mild to moderate donor and host corneal neovascularization in all cases throughout the follow-up period. Conclusions. We have established a novel murine model of KPro implantation that we anticipate will serve as a good experimental system for evaluating host responses after KPro surgery.
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Current in vivo studies on basic immunological research employ primarily murine models, whereas less than 1% of published work addresses the immune system in other animal species, including those of veterinary importance. This is ...
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Current in vivo studies on basic immunological research employ primarily murine models, whereas less than 1% of published work addresses the immune system in other animal species, including those of veterinary importance. This is due to a number of economic and practical reasons, in particular the excellent tools available for murine immunology, including wellestablished methodologies for selective depletion of cell populations,adoptive transfer capacities and gene knock-out mice. As a consequence, our current knowledge of murine immune systemfunctionality is at a level far exceeding that of other animal species. For example almost 80% of the articles recently published in Nature Immunology and The Journal of Experimental Medicine were studies using mouse models only. Although many useful disease and therapeutic models have been established in the mouse, these can often have important limitations. Accordingly,there is a clear need for translational immunological research applying the knowledge acquired from murine research to both human and veterinary research. This is made all the more important when considering the numerous examples of significant species-dependent variations, for example in immunogenetics,anatomical organization and functioning of the immune system. In particular, research in the latter area has revealed significant variations in terms of leukocyte subsets and their functional characteristics, as well as the patterns of cytokine regulatory pathways in the control of immune responses. Moreover,basic immunological research in a veterinary species such as the pig is further justified by the economic value of the species,and the pig has an added value in terms of its application as a biomedical research model in specialized areas. These elements have undoubtedly influenced the relatively high rate of publication in the area of porcine immunology over recent years,which have led to the demand for the present Special Issue of Developmental and Comparative Immunology.
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Temperatures of mice were measured using an infrared high performance non-contact thermometer, after the device had been calibrated using implantable microchips containing temperature transponders. Mice were infected with three sp...
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Temperatures of mice were measured using an infrared high performance non-contact thermometer, after the device had been calibrated using implantable microchips containing temperature transponders. Mice were infected with three species of Candida (isolates) and the resultant disseminated infections monitored. Mouse temperatures could be reliably measured using the infrared device and this measurement caused little distress to the mice. We were further able to demonstrate that mice rarely recovered if their body temperature dropped below 33.3degreesC (sensitivity 68%, specificity 97%). Adoption of a 33.3degreesC endpoint in fungal sepsis experiments measured by infrared non-contact thermometer would significantly reduce the suffering in the terminal stages of this type of infection model.
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Urinary tract infections (UTIs) inflict extreme pain and discomfort to those affected and have profound medical and socioeconomic impact. Although acute UTIs are often treatable with antibiotics, a large proportion of patients suf...
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Urinary tract infections (UTIs) inflict extreme pain and discomfort to those affected and have profound medical and socioeconomic impact. Although acute UTIs are often treatable with antibiotics, a large proportion of patients suffer from multiple recurrent infections. Here, we describe and provide a protocol for a robust murine UTI model that allows for the study of uropathogens in an ideal setting. The infections in the urinary tract can be monitored quantitatively by determining the bacterial loads at different times post-infection. In addition, the simple bladder architecture allows observation of disease progression and the uropathogenic virulence cascade using a variety of microscopic techniques. This mouse UTI model is extremely flexible, allowing the study of different bacterial strains and species of uropathogens in a broad range of mouse genetic backgrounds. We have used this protocol to identify important aspects of the host-pathogen interaction that determine the outcome of infection. The time required to complete the entire procedure will depend on the number of bacterial strains and mice included in the study. Nevertheless, one should expect 4 h of hands-on time, including inoculum preparation on the day of infection, transurethral inoculation, tissue harvest and post-harvest processing for a small group of mice (e.g., 5 mice).
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Mutations in the HER2 (dnase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2~(YVMA)) in mouse lung epithelium causes invasive ...
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Mutations in the HER2 (dnase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2~(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2~(YVMA) is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2~(YVMA)transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.
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Pancreatic neuroendocrine tumors (PNETs) are usually low-grade neoplasms derived from the endocrine pancreas. PNETs can be functioning and cause well-described hormonal hypersecretion syndromes or non-functioning and cause only tu...
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Pancreatic neuroendocrine tumors (PNETs) are usually low-grade neoplasms derived from the endocrine pancreas. PNETs can be functioning and cause well-described hormonal hypersecretion syndromes or non-functioning and cause only tumor mass effect. PNETs appear to be more common recently likely due to incidental detection by imaging. Although the diagnosis and management of PNETs have been evolving rapidly, much remains to be studied in the areas of molecular pathogenesis, molecular markers of tumor behavior, early detection, and targeted drug therapy. Unique challenges facing PNETs studies are long disease course, the deep location of pancreas and difficult access to pancreatic tissue, and the variety of tumors, which make animal models valuable tools for PNETs studies. Existing animal models of PNETs have provided insights into the pathogenesis and natural history of human PNETs. Future studies on animal models of PNETs should address early tumor detection, molecular markers of tumor behavior, and novel targeted therapies. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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