Background
Distinct monocyte subsets predict cardiovascular risk and contribute to heart failure progression in murine models but have not been examined in clinical acute decompensated heart failure (ADHF).
Methods and Results
Blood samples were obtained from 11 healthy controls (HC) and at admission and discharge in 19 ADHF patients. Serological markers of inflammation were assessed on admission and discharge. Monocyte populations were defined using flow cytometry for cell-surface expression of CD14 and CD16: CD14++CD16− (classical), CD14++CD16+ (intermediate), and CD14+CD16++ (non-classical). In ADHF patients, C-reactive protein (CRP) and IL-6 were higher compared with HC (both p<0.001), and decreased from admission to discharge (CRP: 12.1±10.1 to 8.6±8.4 mg/L, p=0.005; IL-6: 19.8±34.5 to 7.1±4.7 pg/ml, p=0.08). In ADHF patients, the admission proportion of CD14++CD16-monocytes was lower (68% vs. 85%, p< 0.001) and CD14++CD16+ (15% vs. 8%, p=0.002) and CD14+CD16++ (17% vs. 7%, p=0.07) monocytes higher compared with HC. Additionally, the proportion of CD14++CD16− monocytes increased (68% to 79%, p=0.04) and the CD14+CD16++ monocytes decreased (17% to 7%, p=0.049) between admission and discharge.
Conclusions
Following standard treatment of ADHF, the monocyte profile and circulating inflammatory markers shifts to more closely resemble those of HC, suggesting a resolving acute inflammatory state. Functional studies are warranted to understand how specific monocyte subsets and systemic inflammation may contribute to ADHF pathophysiology.
Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer–HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer–HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer–HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer.
Gastric cancer is a heterogeneous and prevalent disease. The traditional environmental exposures associated with an elevated risk of gastric cancer are less prevalent in the United States today. Genetic risks and risks associated with inflammation remain. Most cases are sporadic and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases. Here we review the genetic and environmental risk factors associated with the disease.
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