Citations

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus‐induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine‐activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus‐loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand‐off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL‐12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune‐mediated tumor cell killing.

IntroductionMuscle sympathetic nerve activity (MSNA) is an independent prognostic marker in patients with heart failure (HF). Therefore, its relevance to the treatment of HF patients is unquestionable.ObjectivesIn this study, we investigated the effects of cardiac resynchronization therapy (CRT) on MSNA response at rest and during exercise in patients with advanced HF.MethodsWe assessed 11 HF patients (51 ± 3.4 years; New York Heart Association class III–IV; left ventricular ejection fraction 27.8 ± 2.2%; optimal medical therapy) submitted to CRT. Evaluations were made prior to and 3 months after CRT. MSNA was performed at rest and during moderate static exercise (handgrip). Peak oxygen consumption (VO2) was evaluated by means of cardiopulmonary exercise test. HF patients with advanced NYHA class without CRT and healthy individuals were also studied.ResultsCRT reduced MSNA at rest (48.9 ± 11.1 bursts/min vs 33.7 ± 15.3 bursts/min, P < 0.05) and during handgrip exercise (MSNA 62.3 ± 13.1 bursts/min vs 46.9 ± 14.3 bursts/min, P < 0.05). Among HF patients submitted to CRT, the peak VO2 increased (12.9 ± 2.8 mL/kg/min vs 16.5 ± 3.9 mL/kg/min, P < 0.05) and an inverse correlation between peak VO2 and resting MSNA (r = –0.74, P = 0.01) was observed.ConclusionsIn patients with advanced HF and severe systolic dysfunction: (1) a significant reduction of MSNA (at rest and during handgrip) occurred after CRT, and this behavior was significantly superior to HF patients receiving only medical therapy; (2) MSNA reduction after CRT had an inverse correlation with O2 consumption outcomes.

AbstractThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β‐amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151–3) and tau‐mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [18F]‐fluorodeoxyglucose‐PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β‐amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI‐like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease‐modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2‐year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI‐2) in October 2010 through to 2016, with enrollment of an additional 550 participants.

Meniscal attachments serve to anchor and transfer loads from menisci to the tibia. These ligamentous tissues are composed of collagen fibers, elastin, ground substance and water. Ligaments have a time- and history-dependent viscoelastic behavior due in part to the interaction of the water and the ground substance [1]. The movement of water within ligamentous tissue is limited because of charged proteoglycan molecules. It has been shown that some exudation of water is present during cyclic loading of ligamentous tissue [2]. The movement and its inhibition could lead to changes of pressure within the meniscal attachments. Therefore, the purpose of this study was to quantify the internal pressure in human meniscal attachments subjected to physiological loading. Since it is thought that the posterior attachment is subjected to both tension and compression, while the anterior attachment is primarily subjected to tension [3–5], we hypothesized that the attachments mechanical environment is dictated by the external loads, and hence, the posterior attachment would elicit higher pressures.

Mechanical circulatory support emerged for the pediatric population in the late 1980s as a bridge to cardiac transplantation. The Total Artificial Heart (TAH-t) (SynCardia Systems Inc., Tuscon, AZ) has been approved for compassionate use by the Food and Drug Administration for patients with end-stage biventricular heart failure as a bridge to heart transplantation since 1985 and has had FDA approval since 2004. However, of the 1,061 patients placed on the TAH-t, only 21 (2%) were under the age 18. SynCardia Systems, Inc. recommends a minimum patient body surface area (BSA) of 1.7 m 2 , thus, limiting pediatric application of this device. This unique case report shares this pediatric institution’s first experience with the TAH-t. A 14-year-old male was admitted with dilated cardiomyopathy and severe biventricular heart failure. The patient rapidly decompensated, requiring extracorporeal life support. An echocardiogram revealed severe biventricular dysfunction and diffuse clot formation in the left ventricle and outflow tract. The decision was made to transition to biventricular assist device. The biventricular failure and clot formation helped guide the team to the TAH-t, in spite of a BSA (1.5 m 2 ) below the recommendation of 1.7m 2 . A computed tomography (CT) scan of the thorax, in conjunction with a novel three-dimensional (3D) modeling system and team, assisted in determining appropriate fit. Chest CT and 3D modeling following implantation were utilized to determine all major vascular structures were unobstructed and the bronchi were open. The virtual 3D model confirmed appropriate device fit with no evidence of compression to the left pulmonary veins. The postoperative course was complicated by a left lung opacification. The left lung anomalies proved to be atelectasis and improved with aggressive recruitment maneuvers. The patient was supported for 11 days prior to transplantation. Chest CT and 3D modeling were crucial in assessing whether the device would fit, as well as postoperative complications in this smaller pediatric patient.

Key Points miR-155 levels are significantly and increasingly overexpressed as normal B cells progress to MBL and to CLL. Plasma levels of miR-155 before treatment were significantly lower in patients with CLL who experienced complete response than in all others.

ABSTRACTThis study investigated the internal fluid pressure of human cadaver meniscal root attachments. A pressure micro‐sensor was implanted inside each attachment site. Tibiofemoral joints were compressed to 2× body weight at various flexion angles and pressure recorded for 20 min. The anterior cruciate ligament (ACL) was then transected and joints retested. Lastly, a longitudinal incision of the lateral posterior (LP) horn was made and the joint retested. Ramp pressure was defined as the pressure when 2× body weight was reached, and equilibrium pressure was recorded at the end of the hold period. The medial posterior (MP) attachment was subjected to greater ramp pressure than the medial anterior (p = 0.002) and greater equilibrium pressure than all other root attachment sites (p < 0.001). Flexion angle had a significant effect on pressure as full extension was greatest at ramp (p = 0.040). Transection of the ACL decreased ramp pressure in the LP attachment (p = 0.025) and increased equilibrium pressure (p = 0.031) in the MP attachment. The results suggest that repair strategies should be developed which reconstruct the MP attachments to be sufficient to withstand large pressures. Furthermore, since meniscal pressure is highest at full extension, this fact should be considered when prescribing rehabilitation following repair of an attachment. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1507–1513, 2013

Background and Aims . EUS-FNA is an accurate and safe technique to biopsy mediastinal lymph nodes. However, there are few data pertaining to the role of EUS-FNA to biopsy central lung masses. The aim of the study was to assess the diagnostic yield and safety of EUS-FNA of indeterminate central mediastinal lung masses. Methods . Design: Retrospective review of a prospectively maintained database; noncomparative. Setting: Tertiary referral center. From 10/2004 to 12/2010, all patients with a lung mass located within proximity to the esophagus were referred for EUS-FNA. Main Outcome Measurement: EUS-FNA diagnostic accuracy and safety. Results . 73 consecutive patients were included. EUS allowed detection in 62 (85%) patients with lack of visualization prohibiting FNA in 11 patients. Among sampled lesions, one patient (1/62 = 1.6%) had a benign lung mass (hamartoma), while the remaining 61 patients (61/62 = 98.4%) had a malignant mass (primary lung cancer: 55/61 = 90%; lung metastasis: 6/61 = 10%). The sensitivity, specificity, and accuracy of EUS-FNA were 96.7%, 100%, and 96.7%, respectively. The sensitivity was 80.8% when considering nonvisualized masses. One patient developed a pneumothorax (1/62 = 1.6%). Conclusions . EUS-FNA appears to be an accurate and safe technique for tissue diagnosis of central mediastinal lung masses.