Faculty Bibliography

Current approaches for the treatment of skeletal defects are suboptimal, principally because the ability of bone to repair and regenerate is poor. Although the promise of effective cellular therapies for skeletal repair is encouraging, these approaches are limited by the risks of infection, cellular contamination, and tumorigenicity. Development of a pharmacological approach would therefore help avoid some of these potential risks. This study identifies transforming growth factor beta (TGFβ) signaling as a potential pathway for pharmacological modulation in vivo. We demonstrate that inhibition of TGFβ signaling by the small molecule SB431542 potentiates calvarial skeletal repair through activation of bone morphogenetic protein (BMP) signaling on osteoblasts and dura mater cells participating in healing of calvarial defects. Cells respond to inhibition of TGFβ signaling by producing higher levels of BMP2 that upregulates inhibitory Smad6 expression, thus providing a negative feedback loop to contain excessive BMP signaling. Importantly, study on human osteoblasts indicates that molecular mechanism(s) triggered by SB431542 are conserved. Collectively, these data provide insights into the use of small molecules to modulate key signaling pathways for repairing skeletal defects.

Improved prevention and treatment of cardiovascular diseases is one of the challenges in Western societies, where ischemic heart disease and stroke are the leading cause of death. Early epidemiological studies have shown an inverse correlation between circulating high-density lipoprotein-cholesterol (HDL-C) and cardiovascular diseases. The cardioprotective effect of HDL is because of its ability to remove cholesterol from plaques in the artery wall to the liver for excretion by a process known as reverse cholesterol transport. Numerous studies have reported the role that micro-RNAs (miRNA) play in the regulation of the different steps in reverse cholesterol transport, including HDL biogenesis, cholesterol efflux, and cholesterol uptake in the liver and bile acid synthesis and secretion. Because of their ability to control different aspects of HDL metabolism and function, miRNAs have emerged as potential therapeutic targets to combat cardiovascular diseases. In this review, we summarize the recent advances in the miRNA-mediated control of HDL metabolism. We also discuss how HDL particles serve as carriers of miRNAs and the potential use of HDL-containing miRNAs as cardiovascular diseases biomarkers.

BACKGROUND:Indications for nipple-sparing mastectomy (NSM) are expanding; however, high-risk patients have more ischemic complications. Surgical devascularization of the nipple-areolar complex (NAC) prior to NSM can reduce complications. This study reports perfusion patterns and complications in high-risk patients undergoing 2-stage NSM. METHODS:Surgical devascularization of the NAC was performed 3-6 weeks prior to NSM in 28 women. Risk factors included ptosis, obesity, smoking, prior breast surgery, and radiation. Using indocyanine green (ICG)-based fluorescence and an infrared camera, blood inflow was visualized intraoperatively. NAC perfusion patterns were classified as: V1, underlying breast; V2, surrounding skin; V3 = V1 + V2, or V4, capillary fill following devascularization. Ischemic complications were analyzed. RESULTS:Baseline perfusion for 54 breasts was 35 % V1, 32 % V2, and 33 % V3. Increasing ptosis was associated with V1 pattern: 86 % for grade 3, 31 % for grade 2, and 18 % for grade 1. Postdevascularization epidermolysis was observed in 63 % of V1 baseline, 41 % of V2, and 22 % of V3 (P = .042) and after NSM in 26 % for V1, 7 % for V2, and 6 % for V3 (P = .131). Ptosis was significantly associated with epidermolysis postdevascularization (P = .002) and NSM (P = .002). Smoking and BMI ≥30 were related to increased ischemic complications. Two or more risk factors were associated with postdevascularization ischemic changes (P = .026), but were not significant after NSM. Nipple loss was not observed, but 2 patients underwent partial areolar resection. CONCLUSION/CONCLUSIONS:Adaptive circulatory changes after devascularization allow tissues to tolerate the additional ischemic challenge of mastectomy. Our findings support extending 2-staged operations to high-risk women previously considered unsuitable for NSM.

Aging leads to a proinflammatory state within the vasculature without disease, yet whether this inflammatory state occurs during atherogenesis remains unclear. Here, we examined how aging impacts atherosclerosis using Ldlr(-/-) mice, an established murine model of atherosclerosis. We found that aged atherosclerotic Ldlr(-/-) mice exhibited enhanced atherogenesis within the aorta. Aging also led to increased LDL levels, elevated blood pressure on a low-fat diet, and insulin resistance after a high-fat diet (HFD). On a HFD, aging increased a monocytosis in the peripheral blood and enhanced macrophage accumulation within the aorta. When we conducted bone marrow transplant experiments, we found that stromal factors contributed to age-enhanced atherosclerosis. To delineate these stromal factors, we determined that the vasculature exhibited an age-enhanced inflammatory response consisting of elevated production of CCL-2, osteopontin, and IL-6 during atherogenesis. In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells. Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas. Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.

AIM/OBJECTIVE:We conducted a retrospective analysis of summary medical reports of children diagnosed with cerebral palsy (CP) to identify clinical features of antenatal onset of CP secondary to transient ischemia in utero. METHODS:The 658 brief summary reports available in the Japan Obstetric Compensation System for Cerebral Palsy were screened, and we identified cases of singleton pregnancy, delivered at gestational age ≥ 33 weeks and those with cord blood gas pH ≥ 7.20. Of the 137 cases identified, 84 were excluded for the following reasons: no evidence of ischemic brain lesion, clear post-natal causative factor of CP, presence of a congenital condition, and sentinel hypoxic event, such as uterine rupture. The demographic profiles of the 53 cases included in our analysis were compared to identify those with and without an abnormal variability in fetal heart rate. RESULTS:Between-group comparison identified an association between abnormal heart rate variability and a lower Apgar score at 1 min (2 vs 6; P < 0.001) and 5 min (5.5 vs 8; P = 0.002), and more frequent episodes of fetal movement loss (41% vs 10%; P = 0.027). An hypoxic event ≤ 1 week before delivery was more likely to be associated with abnormal heart rate variability (89%) and low Apgar score (82%), while events at > 1 week were associated with development of polyhydramnios (44%). CONCLUSION/CONCLUSIONS:In utero transient ischemic events can contribute to term or near-term CP. Careful follow-up is recommended for fetuses with a history of fetal movement loss, abnormal variability in heart rate, and polyhydramnios of unknown causes.

Upstream open reading frames (uORFs) are ubiquitous repressive genetic elements in vertebrate mRNAs. While much is known about the regulation of individual genes by their uORFs, the range of uORF-mediated translational repression in vertebrate genomes is largely unexplored. Moreover, it is unclear whether the repressive effects of uORFs are conserved across species. To address these questions, we analyse transcript sequences and ribosome profiling data from human, mouse and zebrafish. We find that uORFs are depleted near coding sequences (CDSes) and have initiation contexts that diminish their translation. Linear modelling reveals that sequence features at both uORFs and CDSes modulate the translation of CDSes. Moreover, the ratio of translation over 5' leaders and CDSes is conserved between human and mouse, and correlates with the number of uORFs. These observations suggest that the prevalence of vertebrate uORFs may be explained by their conserved role in repressing CDS translation.

Abnormal remodeling of atherosclerotic plaques can lead to rupture, acute myocardial infarction, and death. Enhancement of plaque extracellular matrix (ECM) may improve plaque morphology and stabilize lesions. Here, we demonstrate that chronic administration of LNA-miR-29 into an atherosclerotic mouse model improves indices of plaque morphology. This occurs due to upregulation of miR-29 target genes of the ECM (col1A and col3A) resulting in reduced lesion size, enhanced fibrous cap thickness, and reduced necrotic zones. Sustained LNA-miR-29 treatment did not affect circulating lipids, blood chemistry, or ECM of solid organs including liver, lung, kidney, spleen, or heart. Collectively, these data support the idea that antagonizing miR-29 may promote beneficial plaque remodeling as an independent approach to stabilize vulnerable atherosclerotic lesions.