Expansion and Characterization of Human Melanoma Tumor-Infiltrating Lymphocytes (TILs)

Various immunotherapeutic strategies for cancer are aimed at augmenting the T cell response against tumor cells. Adoptive cell therapy (ACT), where T cells are manipulated ex vivo and subsequently re-infused in an autologous manner, has been performed using T cells from various sources. Some of the highest clinical response rates for metastatic melanoma have been reported in trials using tumor-infiltrating lymphocytes (TILs). These protocols still have room for improvement and furthermore are currently only performed at a limited number of institutions. The goal of this work was to develop TILs as a therapeutic product at our institution.TILs from 40 melanoma tissue specimens were expanded and characterized. Under optimized culture conditions, 72% of specimens yielded rapidly proliferating TILs as defined as at least one culture reaching ≥3×10(7) TILs within 4 weeks. Flow cytometric analyses showed that cultures were predominantly CD3+ T cells, with highly variable CD4+:CD8+ T cell ratios. In total, 148 independent bulk TIL cultures were assayed for tumor reactivity. Thirty-four percent (50/148) exhibited tumor reactivity based on IFN-γ production and/or cytotoxic activity. Thirteen percent (19/148) showed specific cytotoxic activity but not IFN-γ production and only 1% (2/148) showed specific IFN-γ production but not cytotoxic activity. Further expansion of TILs using a 14-day "rapid expansion protocol" (REP) is required to induce a 500- to 2000-fold expansion of TILs in order to generate sufficient numbers of cells for current ACT protocols. Thirty-eight consecutive test REPs were performed with an average 1865-fold expansion (+/- 1034-fold) after 14 days.TILs generally expanded efficiently and tumor reactivity could be detected in vitro. These preclinical data from melanoma TILs lay the groundwork for clinical trials of ACT

The use of implantable cardioverter defibrillators in Iceland: a retrospective population based study

BACKGROUND: Indications for implantable cardioverter defibrillator (ICD) implantation have expanded considerably in recent years, resulting in steadily growing numbers of ICD recipients worldwide. The aim of this study was to review the overall experience with ICDs in Iceland. METHODS: This was a retrospective single centre study set at the University Hospital in Iceland. Data on all ICD implantations in Iceland from the first implantation in 1992 till the end of 2002 was reviewed. RESULTS: Sixty-two patients (71% male) received an ICD during this period. There was an increase in the number of implants by year and the number of new implants in 2001 and 2002 amounted to 56 and 38 per million, respectively. The mean age at implantation was 58 (+/-14) years. Forty patients (65%) had coronary artery disease. The most common indications for ICD implantation were cardiac arrest, 32 (52%) and another 26 (42%) had experienced ventricular tachycardia without cardiac arrest. The most common adverse event was inappropriate shocks. Twenty-eight patients (45%) received therapy from their ICDs, with the majority receiving appropriate therapy. Of the thirteen patients deceased before or during the study period, no case of sudden arrhythmic death was observed. CONCLUSION: This study shows that the experience with ICDs in Iceland is in most respects similar to other Western countries

Long-Term Locoregional Vascular Morbidity After Isolated Limb Perfusion and External-Beam Radiotherapy for Soft Tissue Sarcoma of the Extremity

Background: Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha) and melphalan, followed by delayed surgical resection and adjuvant external-beam radiotherapy is a limb salvage treatment strategy for locally advanced soft tissue sarcomas. The long-term vascular side effects of this combined procedure were evaluated. Methods: Thirty-two patients were treated for a locally advanced sarcoma of the upper (n = 5) or lower limb (n = 27). All patients underwent a noninvasive vascular work-up. Results: Five patients underwent a leg amputation, in two cases due to critical leg ischemia 10 years after ILP. With a median follow-up of 88 (range, 17-159) months, none of the patients with a salvaged lower leg (n = 22) experienced peripheral arterial occlusive disease. Ankle-brachial index (ABI) measurements in the involved leg (median, 1.02; range, .50-1.20) showed a significant decrease compared with the contralateral leg (median, 1.09; range, .91-1.36, P = .001). Pulsatility index (PI) was decreased in the treated leg in 17 of 22 patients at the femoral level (median, 6.30; range, 2.1-23.9 vs. median, 7.35; range, 4.8-21.9; P = .011) and in 19 of 20 patients at popliteal level (median, 8.35; range, 0-21.4 vs. median, 10.95; range, 8.0-32.6; P <.0005). In patients with follow-up of > 5 years, there was more often a decrease in ABI (P = .024) and PI at femoral level (P = .011). Conclusions: ILP followed by resection and external-beam radiotherapy can lead to major late vascular morbidity that requires amputation. Objective measurements show a time-related decrease of ABI and femoral PI in the treated extremity

Radio & Optical Interferometry: Basic Observing Techniques and Data Analysis

Astronomers usually need the highest angular resolution possible, but the blurring effect of diffraction imposes a fundamental limit on the image quality from any single telescope. Interferometry allows light collected at widely-separated telescopes to be combined in order to synthesize an aperture much larger than an individual telescope thereby improving angular resolution by orders of magnitude. Radio and millimeter wave astronomers depend on interferometry to achieve image quality on par with conventional visible and infrared telescopes. Interferometers at visible and infrared wavelengths extend angular resolution below the milli-arcsecond level to open up unique research areas in imaging stellar surfaces and circumstellar environments. In this chapter the basic principles of interferometry are reviewed with an emphasis on the common features for radio and optical observing. While many techniques are common to interferometers of all wavelengths, crucial differences are identified that will help new practitioners avoid unnecessary confusion and common pitfalls. Concepts essential for writing observing proposals and for planning observations are described, depending on the science wavelength, angular resolution, and field of view required. Atmospheric and ionospheric turbulence degrades the longest-baseline observations by significantly reducing the stability of interference fringes. Such instabilities represent a persistent challenge, and the basic techniques of phase-referencing and phase closure have been developed to deal with them. Synthesis imaging with large observing datasets has become a routine and straightforward process at radio observatories, but remains challenging for optical facilities. In this context the commonly-used image reconstruction algorithms CLEAN and MEM are presented. Lastly, a concise overview of current facilities is included as an appendix.Comment: 45 pages, 14 Figures; an abridged version of a chapter to appear in Volume 2 of Planets, Stars and Stellar Systems, to be published in 2011 by Springe

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics