The Organophosphate Chlorpyrifos Interferes with the Responses to 17β-Estradiol in the Digestive Gland of the Marine Mussel Mytilus galloprovincialis

BACKGROUND: Many pesticides have been shown to act as endocrine disrupters. Although the potencies of currently used pesticides as hormone agonists/antagonists are low compared with those of natural ligands, their ability to act via multiple mechanisms might enhance the biological effect. The organophosphate Chlorpyrifos (CHP) has been shown to be weakly estrogenic and cause adverse neurodevelopmental effects in mammals. However, no information is available on the endocrine effects of CHP in aquatic organisms. In the digestive gland of the bivalve Mytilus galloprovincialis, a target tissue of both estrogens and pesticides, the possible effects of CHP on the responses to the natural estrogen 17β-estradiol (E(2)) were investigated. METHODOLOGY/PRINCIPAL FINDINGS: Mussels were exposed to CHP (4.5 mg/l, 72 hrs) and subsequently injected with E(2) (6.75 ng/g dw). Responses were evaluated in CHP, E(2) and CHP/E(2) treatment groups at 24 h p.i. by a biomarker/transcriptomic approach. CHP and E(2) induced additive, synergistic, and antagonistic effects on lysosomal biomarkers (lysosomal membrane stability, lysosome/cytoplasm volume ratio, lipofuscin and neutral lipid accumulation). Additive and synergistic effects were also observed on the expression of estrogen-responsive genes (GSTπ, catalase, 5-HTR) evaluated by RT-Q-PCR. The use of a 1.7K cDNA Mytilus microarray showed that CHP, E(2) and CHP/E(2), induced 81, 44, and 65 Differentially Expressed Genes (DEGs), respectively. 24 genes were exclusively shared between CHP and CHP/E(2), only 2 genes between E(2) and CHP/E(2). Moreover, 36 genes were uniquely modulated by CHP/E(2). Gene ontology annotation was used to elucidate the putative mechanisms involved in the responses elicited by different treatments. CONCLUSIONS: The results show complex interactions between CHP and E(2) in the digestive gland, indicating that the combination of certain pesticides and hormones may give rise to unexpected effects at the molecular/cellular level. Overall, these data demonstrate that CHP can interfere with the mussel responses to natural estrogens

One-Year Outcomes of Orbital Atherectomy of Long, Diffusely Calcified Coronary Artery Lesions

© 2018 HMP Communications. All rights reserved. Objectives: The aim of this study was to determine the clinical outcomes of patients with long, diffusely calcified coronary artery lesions who underwent orbital atherectomy. Background: The presence of severe coronary artery calcification increases the complexity of percutaneous coronary intervention. Orbital atherectomy of long, diffusely calcified lesions may increase the risk of periprocedural angiographic complications. Furthermore, the rate of ischemic complications, including target-vessel revascularization (TVR), in these long, calcified lesions is historically high. Methods: In this retrospective multicenter registry, which included 458 real-world patients who underwent orbital atherectomy, a total of 154 patients (33.6%) required a total stent length of ≥50 mm (long-stent group). The primary endpoint was the 1-year major adverse cardiac and cerebrovascular event (MACCE) rate, defined as the composite of death, myocardial infarction, TVR, and stroke. Results: The long stent group had a higher rate of perforation (1.9% vs 0.0%; P≤.01) and dissection (2.6% vs 0.0%; P.90). The stent thrombosis rate was similar in both groups (1.3% vs 1.3%; P\u3e.90). Conclusions: Despite the higher angiographic complication rates, orbital atherectomy of long, diffusely calcified lesions was associated with acceptable rates of ischemic complications in this challenging lesion subset at 1-year follow-up

Impact of the Use of Intravascular Imaging on Patients Who Underwent Orbital Atherectomy

OBJECTIVES: We assessed the impact of intravascular ultrasound (IVUS)/optical coherence tomography (OCT) on outcomes of patients who underwent orbital atherectomy. BACKGROUND: Intravascular imaging provides enhanced lesion morphology assessment and optimization of percutaneous coronary intervention (PCI) outcomes. Severe coronary artery calcification increases the complexity of PCI and is associated with worse clinical outcomes. Orbital atherectomy modifies calcified plaque, facilitating stent delivery and optimizing stent expansion. The impact of IVUS/OCT on clinical outcomes after orbital atherectomy is unknown. METHODS: Of the 458 consecutive real-world patients in our retrospective multicenter registry, a total of 138 patients (30.1%) underwent orbital atherectomy with IVUS/OCT. The primary safety endpoint was the rate of 30-day major adverse cardiac and cerebrovascular events, comprised of death, myocardial infarction (MI), target-vessel revascularization (TVR), and stroke. RESULTS: The IVUS/OCT group and no-imaging group had similar rates of the primary endpoint (1.5% vs 2.5%; P≤.48) as well as death (1.5% vs 1.3%; P≤.86), MI (1.5% vs 0.9%; P≤.63), TVR (0% vs 0%; P≤NS), and stroke (0% vs 0.3%; P≤.51). The 30-day stent thrombosis rates were low in both groups (0.7% vs 0.9%; P≤.82). Emergent coronary artery bypass graft surgery was uncommonly performed in both groups (0.0% vs 0.9%; P≤.25). CONCLUSION: Orbital atherectomy guided by intravascular imaging is feasible and safe. A large prospective randomized trial is needed to determine the clinical benefit of IVUS/OCT during PCI with orbital atherectomy

Comprehensive adipocytic and neurogenic tissue microarray analysis of NY-ESO-1 expression - a promising immunotherapy target in malignant peripheral nerve sheath tumor and liposarcoma.

BackgroundImmunotherapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors with poor response to chemoradiation. Malignant peripheral nerve sheath tumors (MPNSTs) and liposarcomas (LPS) are chemoresistant and have few effective treatment options. Materials Methods: Using a comprehensive tissue microarray (TMA) of both benign and malignant tumors in primary, recurrent, and metastatic samples, we examined NY-ESO-1 expression in peripheral nerve sheath tumor (PNST) and adipocytic tumors. The PNST TMA included 42 MPNSTs (spontaneous n = 26, NF1-associated n = 16), 35 neurofibromas (spontaneous n = 22, NF-1 associated n = 13), 11 schwannomas, and 18 normal nerves. The LPS TMA included 48 well-differentiated/dedifferentiated (WD/DD) LPS, 13 myxoid/round cell LPS, 3 pleomorphic LPS, 8 lipomas, 1 myelolipoma, and 3 normal adipocytic tissue samples. Stained in triplicate, NY-ESO-1 intensity and density were scored.ResultsNY-ESO-1 expression was exclusive to malignant tumors. 100% of myxoid/round cell LPS demonstrated NY-ESO-1 expression, while only 6% of WD/DD LPS showed protein expression, one of which was WD LPS. Of MPNST, 4/26 (15%) spontaneous and 2/16 (12%) NF1-associated MPNSTs demonstrated NY-ESO-1 expression. Strong NY-ESO-1 expression was observed in myxoid/round cell and dedifferentiated LPS, and MPNST in primary, neoadjuvant, and metastatic settings.ConclusionsWe found higher prevalence of NY-ESO-1 expression in MPNSTs than previously reported, highlighting a subset of MPNST patients who may benefit from immunotherapy. This study expands our understanding of NY-ESO-1 in WD/DD LPS and is the first demonstration of staining in a WD LPS and metastatic/recurrent myxoid/round cell LPS. These results suggest immunotherapy targeting NY-ESO-1 may benefit patients with aggressive tumors resistant to conventional therapy

PKCθ signaling is required for myoblast fusion by regulating the expression of caveolin-3 and β1D integrin upstream focal adhesion kinase

Using both in vivo and in vitro protein kinase C (PKC) θ mutant models, we found that PKCθ, the PKC isoform predominantly expressed in skeletal muscle, is required for myoblast fusion and myofiber growth, by regulating focal adhesion kinase activity and, in turn, the expression of the pro-fusion genes caveolin-3 and β1D-integrin

Sexually Dimorphic Diet-Induced Insulin Resistance in Obese Tissue Inhibitor of Metalloproteinase-2 (TIMP-2)-Deficient Mice

We report an MMP/TIMP-deficient mouse in which both sexes develop obesity when fed a standard chow diet