Aisha Y. Abdool, Merry L. Lindsey, and Upendra Chalise
Myocardial Infarction (MI) results in a loss of cardiomyocytes, which stimulates a wound healing response to form scar tissue in the heart. Mapping inflammatory and extracellular matrix (ECM) gene changes after MI will help us to understand the temporal evolution in profiles. Using the Mouse Heart Attack Research Tool (mHART), a comprehensive database of previous MI studies in wild-type C57/BL6J mice, we retrospectively analyzed gene array data that included 84 inflammatory genes (n=91 mice) and 84 ECM genes (n=109 mice) at time 0 (no MI) and MI day (D)1, 3, 5, 7, and 28. Temporal evolution was assessed by ANOVA, and unpaired t-test was used to compare consecutive days. Ingenuity Pathway Analysis was used for data visualization and to identify pathways enriched at specific MI days. Overall, we saw three major shifts in wound healing after MI. The first was an early robust inflammation at D1 and D3, shifting to resolution of inflammation by D5 and D7, and leading to establishment of a neo-homeostasis by MI D28. The major genes represented at MI D1 were IL1b, IL1a, and IFNg; at D3 were inhibition of IL13, IL4, and C3; at D5 were activation of TGFb1, IFNg, and TNF; at D7 were inhibition of TNF, IL17Ra and IL36A; and at D28 inhibition of IFNg, CCR5, and CCR2. The transition from D0 to MI D1 showed maximum activation of the inflammatory response, with the primary pathways induced being activation and adhesion of neutrophils, cellular movement, and recruitment of antigen presenting cells. The signaling pathways induced during the shift from MI D5 to D7 included inhibition of cellular infiltration of myeloid cells and inhibition of chemotaxis of monocytes. Pathways induced from MI D7 to D28 indicated a shift to the new homeostasis indicated by further inhibition of cellular movement and inhibition of growth of blood vessels. In summary, our evaluation revealed a steady shift in signaling from early inflammation to resolution and repair over the course of MI.
Franchesca G. Fonseca, Srijanee Das, Denise Cobb, Mohammad U. Nayan, Howard E. Gendelman, and Benson Edagwa
Antiretroviral therapy (ART) has significantly improved the quality of life of Human Immunodeficiency Virus (HIV) patients; but adverse side effects and poor patient compliance to lifelong daily pills remain major challenges. To this end, the need for long acting (LA) therapies that can improve treatment adherence, positively affect drug resistance patterns in addition to limiting drug toxicities cannot be overstated. Tenofovir alafenamide (TAF), a nucleotide reverse transcriptase inhibitor of HIV infection and prodrug of tenofovir (TFV), is characterized by potent antiretroviral activities and high genetic barrier to viral resistance making it a suitable candidate for long-acting antiretroviral therapy. However, the inherent physicochemical features of TAF that includes high water solubility and susceptibility to degradation in aqueous buffers has limited its transformation into long-acting sustained release formulations. With these limitations in mind, this work sought to produce a stable TFV prodrug that would facilitate development of a long-acting formulation without compromising on TAF’s antiretroviral activity and safety profile. A lipophilic and hydrophobic prodrug of TFV (M1TFV) was therefore developed through chemical synthesis making it possible to formulate the drug as a stable aqueous nanosuspension to improve upon drug dissolution. The aqueous poloxamer stabilized TFV prodrug nanosuspension (NM1TFV) was characterized for physicochemical properties, chemical stability, cellular drug uptake and retention. The average particle size of the nanoparticles was 220-270 nm with a polydispersity index of
Radiogenomics is a fusion of two methods, radiomics, and genomics. Radiomics is the process in which features are extracted from medical images such as MRIs, CT scans, and PET scans. Genomics on the other hand is studying an organism's genome and, in this study, their respective gene mutations. By combining both methods, radiogenomics can help find biomarkers for various cancers to help diagnose and treat patients more efficiently. In this study, Radiogenomics was used to find an association between genomic profiles and imaging features of patients with pancreatic ductal adenocarcinoma (PDAC). Out of a total of 117 patients available, only 29 patients were selected for the study. The study required that the patients must have a complete genetic profile available, a preoperative CT scan, PDAC, and are participating in the Rapid Autopsy Program (RAP).
Kiersten M. Preuss
Radiomics is a process that mines quantitative data from imaging techniques, including MRIs, CTs, and PET scans. In this study, radiomics is used to find associations between clinical factors such as the number of metastases in pancreatic ductal adenocarcinoma (PDAC) patients from their preoperative CT scans. PDAC patients have a five-year survival rate only barely above 10%. By the time of diagnosis over half of pancreatic cancers are metastasized, and when that is the case the five-year survival rate is only 3%. It is hypothesized that radiomics can help predict clinical factors such as the number of metastases in pancreatic patients. These predictions can lead to improved treatment plans by risk stratification. Patients with a higher risk of metastases would adopt more aggressive treatment than patients with lower risk. This study included 87 patients diagnosed with PDAC who consented to a Rapid Autopsy Program. Although results have not yet been processed, future work would include finishing developing a model to use to predict PDAC metastases.
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