Enhancing Chemotherapy Response with Bmi-1 Silencing in Ovarian Cancer

Undoubtedly ovarian cancer is a vexing, incurable disease for patients with recurrent cancer and therapeutic options are limited. Although the polycomb group gene, Bmi-1 that regulates the self-renewal of normal stem and progenitor cells has been implicated in the pathogenesis of many human malignancies, yet a role for Bmi-1 in influencing chemotherapy response has not been addressed before. Here we demonstrate that silencing Bmi-1 reduces intracellular GSH levels and thereby sensitizes chemoresistant ovarian cancer cells to chemotherapeutics such as cisplatin. By exacerbating ROS production in response to cisplatin, Bmi-1 silencing activates the DNA damage response pathway, caspases and cleaves PARP resulting in the induction apoptosis in ovarian cancer cells. In an in vivo orthotopic mouse model of chemoresistant ovarian cancer, knockdown of Bmi-1 by nanoliposomal delivery significantly inhibits tumor growth. While cisplatin monotherapy was inactive, combination of Bmi-1 silencing along with cisplatin almost completely abrogated ovarian tumor growth. Collectively these findings establish Bmi-1 as an important new target for therapy in chemoresistant ovarian cancer

Time-Dependent Subcellular Distribution and Effects of Carbon Nanotubes in Lungs of Mice

BACKGROUND AND METHODS:Pulmonary deposited carbon nanotubes (CNTs) are cleared very slowly from the lung, but there is limited information on how CNTs interact with the lung tissue over time. To address this, three different multiwalled CNTs were intratracheally instilled into female C57BL/6 mice: one short (850 nm) and tangled, and two longer (4 μm and 5.7 μm) and thicker. We assessed the cellular interaction with these CNTs using transmission electron microscopy (TEM) 1, 3 and 28 days after instillation. RESULTS:TEM analysis revealed that the three CNTs followed the same overall progression pattern over time. Initially, CNTs were taken up either by a diffusion mechanism or via endocytosis. Then CNTs were agglomerated in vesicles in macrophages. Lastly, at 28 days post-exposure, evidence suggesting CNT escape from vesicle enclosures were found. The longer and thicker CNTs more often perturbed and escaped vesicular enclosures in macrophages compared to the smaller CNTs. Bronchoalveolar lavage (BAL) showed that the CNT exposure induced both an eosinophil influx and also eosinophilic crystalline pneumonia. CONCLUSION:Two very different types of multiwalled CNTs had very similar pattern of cellular interactions in lung tissue, with the longer and thicker CNTs resulting in more severe effects in terms of eosinophil influx and incidence of eosinophilic crystalline pneumonia (ECP)

Unlocking the power of cross-species genomic analyses: identification of evolutionarily conserved breast cancer networks and validation of preclinical models

The application of high-throughput genomic technologies has revealed that individual breast tumors display a variety of molecular features that require more personalized approaches to treatment. Several recent studies have demonstrated that a cross-species analytic approach provides a powerful means to filter through genetic complexity by identifying evolutionarily conserved genetic networks that are fundamental to the oncogenic process. Mouse-human tumor comparisons will provide insights into cellular origins of tumor subtypes, define interactive oncogenetic networks, identify potential novel therapeutic targets, and further validate as well as guide the selection of genetically engineered mouse models for preclinical testing

Inflammasome activation is required for human rhinovirus-induced airway inflammation in naive and allergen-sensitized mice.

http://deepblue.lib.umich.edu/bitstream/2027.42/192082/2/1-s2.0-S1933021922002744-main.pdfDescription of 1-s2.0-S1933021922002744-main.pdf : Published versio

Inflammasome Activation is Required for Human Rhinovirus-Induced Airway Inflammation in Naïve and Allergen-Sensitized Mice.

Activation of the inflammasome is a key function of the innate immune response that regulates inflammation in response to microbial substances. Inflammasome activation by human rhinovirus (RV), a major cause of asthma exacerbations, has not been well studied. We examined whether RV induces inflammasome activation in vivo, molecular mechanisms underlying RV-stimulated inflammasome priming and activation, and the contribution of inflammasome activation to RV-induced airway inflammation and exacerbation. RV infection triggered lung mRNA and protein expression of pro-IL-1β and NLRP3, indicative of inflammasome priming, as well as cleavage of caspase-1 and pro-IL-1β, completing inflammasome activation. Immunofluorescence staining showed IL-1β in lung macrophages. Depletion with clodronate liposomes and adoptive transfer experiments showed macrophages to be required and sufficient for RV-induced inflammasome activation. TLR2 was required for RV-induced inflammasome priming in vivo. UV irradiation blocked inflammasome activation and RV genome was sufficient for inflammasome activation in primed cells. Naive and house dust mite-treated NLRP3−/− and IL-1β−/− mice, as well as IL-1 receptor antagonist-treated mice, showed attenuated airway inflammation and responsiveness following RV infection. We conclude that RV-induced inflammasome activation is required for maximal airway inflammation and hyperresponsiveness in naive and allergic mice. The inflammasome represents a molecular target for RV-induced asthma exacerbations.http://deepblue.lib.umich.edu/bitstream/2027.42/192080/2/1-s2.0-S1933021922002744-main.pdfPublished versionDescription of 1-s2.0-S1933021922002744-main.pdf : Published versio

Characterization of mouse mediastinal fat-associated lymphoid clusters

The association between adipose tissue and immunity has been established and fat-associated lymphoid clusters (FALCs) are considered as a source of immune cells. We discovered lymphoid clusters (LCs) in mouse mediastinal fat tissues (MFTs). In Th1-biased C57BL/6N (B6), Th2-biased DBA/2Cr (DBA) and autoimmune-prone MRL/MpJ (MRL) mice strains, LCs without a fibrous capsule and germinal center were observed in white-colored MFTs extending from the diaphragm to the heart. The number and size of the LCs were larger in 12-month-old mice than in 3-month-old mice in all of the examined strains. Moreover, B6 had an especially large number of LCs compared with DBA and MRL. The immune cells in the LCs consisted of mainly T-cells and some B-cells. The majority of T-cells were CD4+ helper T (Th) cells, rather than CD8+ cytotoxic T-cells and no obvious immune cell population difference was present among the strains. Furthermore, high endothelial venules and lymphatic vessels in the LCs were better developed in B6 mice than in the other strains. Interestingly, some CD133+ hematopoietic progenitor cells and some c-Kit+/CD127+ natural helper cells were detected in the LCs. BrdU+ proliferating cells were more abundant in the LCs of B6 mice than in the LCs of the other strains and the number of BrdU+ cells increased with age. This is the first report of LCs in mouse MFTs. We suggest that the mouse genetic background affects LC size and number. We term the LCs "mediastinal fat-associated lymphoid clusters". These clusters can be considered as niches for Th cell production