Despite the success of current therapies for acute myocardial infarction (MI), many patients still develop adverse cardiac remodeling and heart failure. With the growing prevalence of heart failure, a new therapy is needed that can prevent remodeling and support tissue repair. Herein, we report on injectable recombinant human collagen type I (rHCI) and type III (rHCIII) matrices for treating MI. Injecting rHCI or rHCIII matrices in mice during the late proliferative phase post-MI restores the myocardium’s mechanical properties and reduces scar size, but only the rHCI matrix maintains remote wall thickness and prevents heart enlargement. rHCI treatment increases cardiomyocyte and capillary numbers in the border zone and the presence of pro-wound healing macrophages in the ischemic area, while reducing the overall recruitment of bone marrow monocytes. Our findings show functional recovery post-MI using rHCI by promoting a healing environment, cardiomyocyte survival, and less pathological remodeling of the myocardium.

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The aim of this study was to develop an MRI fluorocarbon oximetry technique using snapshot inversion recovery and compare it with fluorescence quenching fiber-optic probe oximetry (OxyLite) performed simultaneously in experimental mouse tumors. The oxygen reporter probe hexafluorobenzene (HFB) was injected directly into the tumors, along with the insertion of the OxyLite probe. Tumor oxygenation (pO 2 ) was modified using carbogen or lethal doses of the anesthetic gas. MRI pO 2 maps were generated in 1.

Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death from abdominal cancers. Immunotherapies have been effective for selected solid malignancies, but their potential in PC has been little explored. Here, we report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex vivo with an oncolytic Maraba MG1 virus expressing IL12, promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of IFNγ-induced protein-10 (IP-10) from dendritic cells. The recruitment of cytotoxic, IFNγ-secreting NK cells was associated with reduced tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors > 8 mm), a complete radiologic response was demonstrated within 8 to14 weeks, associated with 100% long-term survival. The impact of MG1-IL12-ICV upon NK-cell recruitment and function observed in the murine system was recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. These findings suggest that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. Cancer Immunol Res; 5(3); 211–21. ©2017 AACR.

Both benign and malignant breast lesions may exhibit intense contrast enhancement when imaged using gadolinium-enhanced MRI. We propose a quantitative approach for fitting dynamic signal intensity (SI) data that may distinguish benign from malignant lesions. We studied 78 lesions in 75 women (18 malignancies, 16 fibroadenomas, and 44 other benign breast lesions) to determine the potential of this model for decreasing false-positive MR results. Twenty-eight lesions showed no enhancement; all were benign. One lesion showed a complex pattern not amenable to region-of-interest analysis and was considered a false positive. SI versus time data for the remaining 49 lesions were fit to the proposed model. We found that one parameter, M, the normalized slope of the SI enhancement profile evaluated at half the maximal signal intensity, seemed to be highly correlated with malignancy and offered improved discrimination between malignant and benign lesions compared to a previously published two-point slope method.

Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and is generally believed to be caused by tumor blood flow instabilities. It was recently demonstrated that T2*-weighted (T2*w) gradient echo (GRE) MRI is a powerful non-invasive method for investigating periodic changes in tumor pO2 and blood flow associated with acute hypoxia. Here, the possible correlation between tumor vessel immaturity, vessel functionality and T2*w GRE signal fluctuations was investigated. Intramuscularly implanted FSa II fibrosarcoma-bearing mice were imaged at 4.7 T. Maps of spontaneous fluctuations of MR signal intensity in tumor tissue during air breathing were obtained using a T2*w GRE sequence. This same sequence was also employed during air-5% CO2 breathing (hypercapnia) and carbogen breathing (hypercapnic hyperoxia) to obtain parametric maps representing vessel maturation and vessel function, respectively. Vascular density, vessel maturation and vessel perfusion were also assessed histologically by using CD31 labeling, alpha-smooth muscle actin immunoreactivity and Hoechst 33242 labeling, respectively. About 50% of the tumor fluctuations occurred in functional tumor regions (responsive to carbogen) and 80% occurred in tumor regions with immature vessels (lack of response to hypercapnia). The proportion of hypercapnia-responsive voxels were found to be twice as great in fluctuating than in non-fluctuating tumor areas (P: 0.22 vs 0.13). Similarly, the proportion of functional voxels was somewhat greater in fluctuating tumor areas (P: 0.54 vs 0.43). The mean values of MR signal changes during hypercapnia (VD) and during carbogen breathing (VF) (significant voxels only) were also larger in fluctuating than in non-fluctuating tumor areas (P < 0.05). This study demonstrated that adequate vessel functionality and advanced vessel maturation could explain at least in part the occurrence of spontaneous T2*w GRE signal fluctuations. Functionality and maturation are not required for signal fluctuations, however, because a large fraction of fluctuations could still occur in non-perfused and/or immature vessels.

Type 2 diabetes, hepatic steatosis, and gut dysbiosis are pathophysiological consequences of obesity. Sirtuin (SIRT)-1 is a protein deacetylase implicated in the regulation of metabolic activity. We set out to determine whether the catalytic activity of SIRT1 plays a role in the development of metabolic syndrome, hepatic steatosis, and the distribution of gut microbiota. We challenged with a high-fat diet (HFD) a strain of mice homozygous for a Sirt1 allele carrying a point mutation that ablates the deacetylase activity of SIRT1. When compared to wild-type animals, mice lacking SIRT1 catalytic activity rapidly accumulated excessive hepatic lipid while fed the HFD, an effect evident within 2 wk of HFD feeding. Both white and brown adipose depots became hypertrophic, and the animals developed insulin resistance. The ratio of the major phyla of gut microbiota (Firmicutes and Bacteroidetes) increased rapidly in the SIRT1-deficient mice after HFD challenge. We conclude that the deacetylase activity of SIRT1 plays an important role in regulating glucose and hepatic lipid homeostasis. In addition, the composition of gut microbiota is influenced by both the animals' Sirt1 genotype and diet composition.

We used the dual capability of hyperpolarized 129 Xe for spectroscopy and imaging to develop new measures of xenon diffusing capacity in the rat lung that (analogously to the diffusing capacity of carbon monoxide or D LCO ) are calculated as a product of total lung volume and gas transfer rate constants divided by the pressure gradient. Under conditions of known constant pressure breath-hold, the volume is measured by hyperpolarized 129 Xe MRI, and the transfer rate is measured by dynamic spectroscopy. The new quantities (xenon diffusing capacity in lung parenchyma (D LXeLP )), xenon diffusing capacity in RBCs (D LXeRBC ), and total lung xenon diffusing capacity (D LXe )) were measured in six normal rats and six rats with lung inflammation induced by instillation of fungal spores of Stachybotrys chartarum. D LXeLP , D LXeRBC , and D LXe were 56 ؎ 10 ml/min/mmHg, 64 ؎ 35 ml/min/mmHg, and 29 ؎ 9 ml/min/mmHg, respectively, for normal rats, and 27 ؎ 9 ml/min/mmHg, 42 ؎ 27 ml/min/ mmHg, and 16 ؎ 7 ml/min/mmHg, respectively, for diseased rats. Lung volumes and gas transfer times for LP (T trLP ) were 16 ؎ 2 ml and 22 ؎ 3 ms, respectively, for normal rats and 12 ؎ 2 ml and 35 ؎ 8 ms, respectively, for diseased rats. Xenon diffusing capacities may be useful for measuring changes in gas exchange associated with inflammation and other lung diseases. Anatomical and functional imaging of small animals has become important in the study of lung biology (1). The use of genetically altered mice has also increased the demand for methods to establish physiological phenotypes, including those corresponding to lung disease (2). Xe) for lung applications has been illustrated by the use of 3 He in rats and guinea pigs, including in vivo determination of regional ventilation (3-5), ventilation/perfusion ratio (6), and diffusion (7). The production of high-quality images in human subjects has also been demonstrated (8). Although hyperpolarized 129 Xe (hereafter referred to simply as "xenon") suffers from lower polarizations and gyromagnetic ratios relative to 3 He, it has several advantages due to its high lipid solubility and sensitivity of chemical shift to the molecular environment. In particular, dynamic xenon spectroscopy is capable of identifying the gas exchange properties of the lung. Wagshul et al. (9) were the first to report xenon spectra and images of the mouse lung consisting of three dissolved phase peaks at 190 ppm, 196 ppm, and 198 ppm with respect to the gas resonance, which were tentatively assigned to thoracic tissue, lung parenchyma (LP), and blood, respectively. Subsequent work identified three dissolved-phase resonances in tracheostomized Sprague Dawley rats at 191 ppm, 199 ppm, and 213 ppm, which were attributed to plasma/adipose tissue, LP, and red blood cells (RBCs), respectively (10). To confirm the compartmental assignment of these three peaks, Swanson et al. (11) correlated xenon spectroscopy with 1D chemical shift imaging in Sprague Dawley rats. They observed the in vivo dynamics of xenon in rats that breat...