mTOR Signaling and Endoplasmic Reticulum Stress in Mixed Glial Cultures

Oligodendrocytes are the myelinating cells of the central nervous system. The extraordinary protein and lipid synthesis that myelin production entails makes oligodendrocytes especially prone to endoplasmic reticulum (ER) stress. In this experiment, we set out to investigate the dynamics of ER stress in mixed glial cultures, and how the consequences of that stress vary based on the activity of the anabolic PI3K/AKT/mTOR pathway. Previous experiments in isolated oligodendrocyte cultures demonstrated a negative correlation between AKT/mTOR signaling and oligodendrocyte cell viability in the presence of ER stressors. Because ER stress leads to a buildup of improperly processed proteins, decreases in mTOR pathway activity are thought to moderate the excess of misfolded polypeptides. We hypothesized that administration of rapamycin, an inhibitor of mTOR, would ameliorate the effects of ER stress by preventing protein buildup caused by mTOR pathway activity. To test this hypothesis, mixed cultures of oligodendrocytes and astrocytes were isolated from neonatal rat brains and exposed to tunicamycin (TU), an inhibitor of n-linked glycosylation, to induce ER stress. TU was administered alone and after pre-treatment with rapamycin, to investigate how the effects of ER stress change when the activity of that pathway was limited. By assaying cell survival and protein expression, we were able to determine how ER stress, with and without mTOR inhibition, affected cell populations in mixed glial cultures. We found that chronic TU exposure in the absence of rapamycin failed to decrease the percentage of oligodendrocyte-lineage cells, which we attribute to the protective effects of astrocytes. Acute exposure, however, did decrease the percentage of oligodendrocyte-lineage cells in culture. These two trends lead us to speculate that the protective effects astrocytes offer to oligodendrocytes consist of relatively slow-acting growth-factor production and secretion by astrocytes. Adding strength to this contention, we found that the mTOR inhibitor rapamycin did not increase the percentage of oligodendrocyte-lineage cells in cultures exposed to TU. Because mTOR is involved in the function of many growth factors, its inhibition may have hampered the protective functions of astrocytes. While other experiments have investigated the effects of ER toxins on activity of the mTOR pathway, this experiment is more faithful to in vivo conditions because it incorporates meaningful astrocyte-oligodendrocyte interactions. As observed in this experiment, these effects are powerful and serve to improve our understanding of the dynamics of ER stress and mTOR inhibitors in organismal glial cells

Management Perception: Phase I The Concept of Event-Structure as a Perceptual Aid to the Manager

Industrial Engineering and Managemen

The comparative safety and effectiveness of bivalirudin versus heparin monotherapy in patients on dialysis undergoing percutaneous coronary intervention: Insights from the Blue Cross Blue Shield of Michigan cardiovascular consortium

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139064/1/ccd27001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139064/2/ccd27001_am.pd

A Review of the Impella Devices

The use of mechanical circulatory support (MCS) to provide acute haemodynamic support for cardiogenic shock or to support high-risk percutaneous coronary intervention (HRPCI) has grown over the past decade. There is currently no consensus on best practice regarding its use in these two distinct indications. Impella heart pumps (Abiomed) are intravascular microaxial blood pumps that provide temporary MCS during HRPCI or in the treatment of cardiogenic shock. The authors outline technical specifications of the individual Impella heart pumps and their accompanying technology, the Automated Impella Controller and SmartAssist, their indications for use and patient selection, implantation techniques, device weaning and escalation, closure strategies, anticoagulation regimens, complications, future directions and upcoming trials

Comparative results of transluminal extraction coronary atherectomy in saphenous vein graft lesions with and without thrombus

AbstractObjectives. The purpose of this retrospective study was to compare the results of transluminal extraction coronary atherectomy in saphenous vein graft lesions with and without angiographic thrombus.Background. Percutaneous interventions in lesions with thrombus are associated with reduced procedural success and increased risk of complications. Use of the transluminal extraction catheter, which cuts and aspirates atheroma and thrombus, has been advocated as a potential revascularization strategy for lesions with thrombus.Methods. Baseline patient characteristics, lesion morphology, immediate angiographic results, in-hospital complications and follow-up were prospectively entered into an interventional cardiology data base. The results of transluminal extraction coronary atherectomy in saphenous vein bypass grafts with angiographic thrombus were compared with results in similar grafts without angiographic thrombus.Results. Transluminal extraction coronary atherectomy was performed in 175 patients with 183 vein graft lesions, including 59 lesions (32%) with thrombus (Group 1) and 124 (68%) without thrombus (Group 2). Compared with lesions in Group 2, lesions in Group 1 were associated with a higher incidence of baseline total occlusion, diffuse disease and abnormal Thrombolysis in Myocardial Infarction (TIMI) grade flow (p < 0.05); more severe diameter stenosis at baseline, after atherectomy and after final angiography (p < 0.05); a lower rate of clinical success (69% vs, 88%, p < 0.01); and more angiographic and clinical complications, including no reflow (p < 0.05), vascular repair (p < 0.05) and Q wave myocardial infarction (p = 0.09).Conclusions. In transluminal extraction coronary atherectomy of saphenous vein bypass grafts, the presence of thrombus is associated with more baseline lesion complexity, reduced clinical success and increased risk of no reflow, Q wave myocardial infarction and vascular repair

Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

AbstractIn order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells

Sex‐related difference in the use of percutaneous left ventricular assist device in patients undergoing complex high‐risk percutaneous coronary intervention: Insight from the cVAD registry

ObjectiveTo assess the in‐hospital and short‐term outcome differences between males and females who underwent high‐risk PCI with mechanical circulatory support (MCS).BackgroundSex differences have been noted in several percutaneous coronary intervention (PCI) series with females less likely to be referred for PCI due increased risk of adverse events. However, data on sex differences in utilization and outcomes of high‐risk PCI with MCS is scarce.MethodsUsing the cVAD Registry, we identified 1,053 high‐risk patients who underwent PCI with MCS using Impella 2.5 or Impella CP. Patients with cardiogenic shock were excluded. A total of 792 (75.21%) males and 261 (24.79%) females were included in the analysis with median follow‐up of 81.5 days.ResultsFemales were more likely to be African American, older (72.05 ± 11.66 vs. 68.87 ± 11.17, p < .001), have a higher prevalence of diabetes (59.30 vs. 49.04%, p = .005), renal insufficiency (35.41 vs. 27.39%, p = .018), and peripheral vascular disease (31.89 vs. 25.39%, p of .05). Women had a higher mean STS score (8.21 ± 8.21 vs. 5.04 ± 5.97, p < .001) and lower cardiac output on presentation (3.64 ± 1.30 vs. 4.63 ± 1.49, p < .001). Although women had more comorbidities, there was no difference in in‐hospital mortality, stroke, MI or need for recurrent revascularization compared to males. Females were more likely to have multivessel revascularization than males. Ejection fraction improved in both males and females at the time of discharge (26.59 to 31.40% and 30.75 to 36.05%, respectively, p < .0001). However, females had higher rate of bleeding requiring transfusion compared with males (9.58 vs. 5.30%, p = .019).ConclusionFemale patients undergoing high PCI were older and had more comorbidities but had similar outcomes compared to males.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162726/2/ccd28509_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162726/1/ccd28509.pd

A CD3-Specific Antibody Reduces Cytokine Production and Alters Phosphoprotein Profiles in Intestinal Tissues From Patients With Inflammatory Bowel Disease

NOTICE: this is the author’s version of a work that was accepted for publication in Gastroenterology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in GASTROENTEROLOGY, 10.1053/j.gastro.2014.03.04