Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Interrogation of genomic datasets identified increased PIM1 copy number-driven expression in TNBC. RNA interference in breast cancer and non-malignant mammary epithelial cell models revealed a PIM1 dependency in TNBC cells for proliferation and apoptotic protection, absent in non-malignant cells. PIM1 knockdown reduced BCL2 expression, and dynamic BH3 profiling analysis revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. PIM1 expression associates with several MYC-transcriptional signatures and promotes cell population growth through regulation of c-MYC and transcription of MYC-targets, including MCL1. The pan-PIM kinase inhibitor AZD1208 inhibited growth and sensitized TNBC cell lines, xenografts and patient-derived xenografts to standard of care chemotherapy. We identify PIM1 as a malignant cell-selective target in TNBC, illustrating relationships with MYC activation, regulation of anti-apoptotic BCL2 and MCL1, established TNBC oncogenic proteins SHP2 and EPHA2 and cell cycle inhibitor p27. Finally we identify a potential use of PIM1 inhibitors to abrogate TNBC's high threshold to TNBC standard of care chemotherapy induced apoptotic cell death.
Drug-coated sutures are widely used as delivery depots for antibiotics and anti-inflammatory drugs at surgical wound sites. Although drug-laden coating provides good localized drug concentration, variable loading efficiency and release kinetics limits its use. Alternatively, drug incorporation within suture matrices is hampered by the harsh fabrication conditions required for suture-strength enhancement. To circumvent these limitations, we fabricated mechanically robust electrospun core-sheath yarns as sutures, with a central poly-l-lactic acid core, and a drug-eluting poly-lactic-co-glycolic acid sheath. The electrospun sheath was incorporated with aceclofenac or insulin to demonstrate versatility of the suture in loading both chemical and biological class of drugs. Aceclofenac and insulin incorporated sutures exhibited 15% and 4% loading, and release for 10 and 7 days, respectively. Aceclofenac sutures demonstrated reduced epidermal hyperplasia and cellularity in skin-inflammation animal model, while insulin loaded sutures showed enhanced cellular migration in wound healing assay. In conclusion, we demonstrate an innovative strategy of producing mechanically strong, prolonged drug-release sutures loaded with different classes of drugs.
Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes. Further analysis reveals a cluster of 13 TNBC addiction genes frequently co-upregulated that includes genes regulating cell cycle checkpoints, DNA damage response, and malignant cell selective mitotic genes. We validate the mechanism of addiction to a potential drug target: the mitotic kinesin family member C1 (KIFC1/HSET), essential for successful bipolar division of centrosome-amplified malignant cells and develop a potential selection biomarker to identify patients with tumors exhibiting centrosome amplification.
The purpose of this work was to develop and evaluate the accuracy of a breath-hold IR-TrueFISP acquisition capable of monitoring gadolinium (Gd) concentrations through T 1 measurements in the left ventricular blood pool and segments of the myocardium over an extended duration. Measurements using a phantom were performed to assess the accuracy of the technique. Accurate T 1 measurements in the expected range after contrast agent administration were obtained with several theoretical formulations. Accurate T 1 values before the administration of the contrast agent were obtained only when the incomplete recovery of magnetization during the delay time (TD) between imaging segments was incorporated into the observed signal intensity calculations. T 1 measurements over a 1-hr time period were performed in four subjects with known myocardial infarctions. In this small study, Gd differences between recent and old myocardial infarctions were observed. Studies have shown that MR imaging (MRI) after the administration of contrast material (delayed gadolinium (Gd)-enhanced T 1 -sensitive MRI) can be used to accurately distinguish between reversible and irreversible myocardial ischemic injury (1,2). Irreversibly injured regions of the myocardium have a slightly higher concentration of intravenously injected Gd contrast agents compared to normal myocardium. Typically, inversion recovery (IR) gradient-echo pulse sequences (3) are used to identify regions of injured myocardium. Since optimal imaging parameters are subject-and time-dependent, either inversion delay times (TDs) are iteratively adjusted or a phasesensitive reconstruction (4) is used to provide optimal contrast.It was recently shown that T 1 quantification can be robustly performed with the use of an IR-TrueFISP acquisition (5,6). Following an inversion pulse, k-space data are repetitively acquired with refocused gradient waveforms. This results in a series of images with consecutive inversion TDs. T 1 values can be calculated from images acquired during the recovery of longitudinal magnetization using analytical expressions for image-based signal intensities.Several small studies (7-9) using delayed enhancement imaging at different time points after contrast agent administration have provided insights into the kinetics of delayed enhancement for optimizing imaging parameters, measuring infarct size, and assessing the severity of myocardial injury. However, since several breath-holds were required for quantitative in vivo measurements, it was difficult to measure Gd concentrations at multiple time points. Therefore, these studies provided only a limited number of time points. Other studies (10) that attempted to show either a change or no change in infarct size were also performed with a limited number of time points. Parameter optimization proved to be important, and although it is widely believed that measured chronic infarct size is not a function of imaging time after injection (11), this has not yet been shown over a 1-hr time period.The purpose of this work wa...
Congestive heart failure in the elderly is recognized as a national public health priority; however, clinical diagnosis can be problematic in elderly persons, many of whom have a history of heart failure in the presence of normal or only minimally decreased ejection fraction. Findings of the Cardiovascular Health Study have underscored the common substrate and predictors underlying heart failure both with decreased ejection fraction and with normal ejection fraction (i.e., diastolic heart failure). Coronary heart disease, systolic blood pressure, and C-reactive protein (a measure of inflammation) are predictive of heart failure independent of ejection fraction. Left atrial size, arguably a marker of the effects of impaired diastolic filling over time, is increased in both systolic and diastolic heart failure of the elderly, as is atrial natriuretic peptide. The outcome of heart failure in elderly persons is poor both for systolic and diastolic heart failure. Moreover, many community-dwelling elderly persons have decreased ejection fraction without heart failure. In these persons the chance of death is similar to that of participants with diastolic heart failure. Since most clinical trials have studied younger patients with predominantly systolic heart failure, the appropriate therapy for heart failure in elderly persons remains to be determined.
Despite its aggressive nature, triple-negative breast cancer (TNBC) often exhibits leucocyte infiltrations that correlate with favorable prognosis. In this study, we offer an explanation for this apparent conundrum by defining TNBC cell subsets that overexpress the IL15 immune receptor IL15RA. This receptor usually forms a heterotrimer with the IL2 receptors IL2RB and IL2RG, which regulates the proliferation and differentiation of cytotoxic T cells and NK cells. However, unlike IL15RA, the IL2RB and IL2RG receptors are not upregulated in basal-like TNBC breast cancer cells that express IL15RA. Mechanistic investigations indicated that IL15RA signaling activated JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 in the absence of IL2RB and IL2RG, whereas neither STAT5 nor JAK2 were activated. RNAi-mediated attenuation of IL15RA established its role in cell growth, apoptosis, and migration, whereas expression of the IL15 cytokine in IL15RA-expressing cells stimulated an autocrine signaling cascade that promoted cell proliferation and migration and blocked apoptosis. Notably, coexpression of IL15RA and IL15 was also sufficient to activate peripheral blood mononuclear cells upon coculture in a paracrine signaling manner. Overall, our findings offer a mechanistic explanation for the paradoxical association of some high-grade breast tumors with better survival outcomes, due to engagement of the immune stroma. Cancer Res; 74(17); 4908-21. Ó2014 AACR.
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