Citations

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.

Abstract Biomarkers are lacking for identifying the switch of transforming growth factor-beta (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Further, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling, but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Since TGF-β is known to activate MAPK/ERK pathway through direct phosphorylation of adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of TGF-β's role during carcinogenesis. We found that mp53 expression led to decrease of phosphorylated p52ShcA/ERK levels and increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines, and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we show that TGF-β's role in regulating anchorage-dependent and -independent growth, and migration, can be shifted between growth suppression and migration promotion. Thus, our results, for the first time, suggest that mp53 disrupts ShcA's role in balancing Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1069. doi:1538-7445.AM2012-1069

OBJECTIVE Stroke symptoms among individuals reporting no physician diagnosis of stroke are associated with an increased risk of future stroke. Few studies have assessed whether individuals with diabetes or prediabetes, but no physician diagnosis of stroke, have an increased prevalence of stroke symptoms. RESEARCH DESIGN AND METHODS This study included 25,696 individuals aged ≥45 years from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who reported no history of stroke or transient ischemic attack at baseline (2003–2007). Glucose measurements, medication use, and self-reported physician diagnosis were used to categorize participants into diabetes, prediabetes, or normal glycemia groups. The presence of six stroke symptoms was assessed using a validated questionnaire. RESULTS The prevalence of any stroke symptom was higher among participants with diabetes (22.7%) compared with those with prediabetes (15.6%) or normal glycemia (14.9%). In multivariable models, diabetes was associated with any stroke symptom (prevalence odds ratio [POR] 1.28 [95% CI 1.18–1.39]) and two or more stroke symptoms (1.26 [1.12–1.43]) compared with normal glycemia. In analyses of individual stroke symptoms, diabetes was associated with numbness (1.15 [1.03–1.29]), vision loss (1.52 [1.31–1.76]), half-vision loss (1.54 [1.30–1.84]), and lost ability to understand people (1.34 [1.12–1.61]) after multivariable adjustment. No association was present between prediabetes and stroke symptoms. CONCLUSIONS In this population-based study, almost one in four individuals with diabetes reported stroke symptoms, which suggests that screening for stroke symptoms in diabetes may be warranted.

Background There are few data comparing clinical outcome and potential indications for routine post–myocardial infarction cardiac catheterization and revascularization of patients who sustain a non–Q-wave versus Q-wave infarct after thrombolytic therapy. Methods and Results A secondary analysis of 2634 patients enrolled in the TIMI II trial with a first myocardial infarction was performed to determine 6-week and 1-year cardiac event rates and identify clinical and angiographic differences between the 1867 patients (70.9%) who evolved a Q-wave infarct and the 767 patients (29.1%) who sustained a non–Q-wave infarct after treatment with intravenous thrombolytic therapy. Male sex (85.3% versus 75.6%; P <.001) and anterior wall infarcts (53.8% versus 43.7%; P <.001) were more frequent in the Q-wave versus the non–Q-wave group. During recombinant tissue-type plasminogen activator (rTPA) infusion, a greater percentage of non–Q-wave patients (37.3% versus 23.5%; P =.001) had normalization of initial ST-segment elevation. Infarct-related artery patency (TIMI flow grade 2 or 3) ( P =.02), complete infarct-related artery reperfusion (TIMI 3 flow grade) ( P <.001), and the percentage of patients with a predischarge resting left ventricular ejection fraction >55% ( P <.001) were greater in the non–Q-wave group. New congestive heart failure during hospitalization developed more frequently in Q-wave patients (18.9% versus 11.6%; P <.001). After 42 days, the occurrences of reinfarction ( P =.76), death ( P =.76), and combined death or reinfarction ( P =.43) were similar in patients assigned to the invasive or conservative postlytic management strategy, regardless of infarct type. One-year mortality was 3.4% versus 4.4% for non–Q-wave versus Q-wave infarct type, respectively ( P =.25). Conclusions Angiographic and clinical differences were observed between patients who present with initial ST-segment elevation and evolve early non–Q-wave versus Q-wave myocardial infarcts after treatment with rTPA, heparin, and aspirin. Early mortality and adverse clinical cardiac events in these patients are not significantly different after a conservative compared with an invasive treatment strategy, regardless of whether the infarct type is non–Q wave or Q wave.

Abstract —The present study was performed to determine whether physiologically relevant doses of angiotensin II (Ang II), which do not affect renal hemodynamics but do cause slow response hypertension, result in oxidative stress as measured by production of vasoconstrictor F 2 -isoprostane, a prostaglandin-like non–cyclooxygenase-produced arachidonic acid metabolite that is the end product of lipid peroxidation. Rats were instrumented with abdominal aortic and left femoral venous catheters, and before and throughout Ang II (or saline) infusion, all rats received enalapril (250 mg/L). Four days after the initiation of enalapril, rats were infused with Ang II (10 ng · kg −1 · min −1 , n=6) or saline (n=6) for 14 days. Mean arterial pressure was measured 24 hours per day, and on day 12, glomerular filtration rate and renal plasma flow were measured. Mean arterial pressure in control rats averaged 85±1 mm Hg, and with Ang II infusion, mean arterial pressure increased slowly and reached a plateau on day 3, averaging 117±2 mm Hg ( P <0.0001 compared with enalapril alone). Glomerular filtration rate and renal plasma flow were not affected by Ang II. Free F 2 -isoprostanes in plasma increased by 54% with Ang II ( P <0.01), and the production of F 2 -isoprostanes esterified in plasma lipids tended to be higher with Ang II also but did not reach significance ( P =0.1). These studies suggest that low doses of Ang II are capable of producing oxidative stress in animals. Whether oxidative stress plays a causative role in Ang II–mediated slow-response hypertension or is secondary to the hypertension is not clear from these data and will require further study.

AbstractBackgroundAmpullary and extensive periampullary lesions can be difficult to treat and often require pancreaticoduodenectomy (PD) for complete removal, even if benign. However, PD may be overtreatment for noninvasive lesions, and pancreas‐sparing total duodenectomy (PSTD) is an emerging valid surgical option for selected cases.MethodsWe reviewed patients undergoing PSTD at our institution over 16 months and a comparison group who had undergone PD for benign duodenal disease over the past 15 years. We also reviewed cases in the English‐language literature and performed a meta‐analysis of those patients who had undergone PSTD.ResultsPSTD had been performed in four patients, who had an average hospital length of stay (LOS) of 13 days; two of them experienced complications. None required conversion to PD, experienced a postoperative fistula or endocrine or exocrine insufficiency, or required intensive care. Two of the PSTDs were performed laparoscopically. Open PD for benign duodenal disease was performed in 22 patients, with overall morbidity and pancreas fistula rates of 82 and 27 %, respectively. The meta‐analysis found 128 unique cases of PSTD with morbidity and mortality rates of 46.4 and 2.3 %, respectively. Pancreaticobiliary leak was seen in 20 %, with an average LOS of 17 days.ConclusionsAlthough PSTD can be used to avoid PD and can be performed laparoscopically, it is technically challenging and still associated with morbidity.