New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity.

Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8+ T cells (specifically CD44+ memory/activated phenotype) and NK cells. Intracellular IFN-γ and TNF-α secretion by CD8+ T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8+ T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells.We then evaluated IL-15SA\u27s effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL-15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy

The Use of Infliximab to Control Recurrent Cytokine Storms in EBV-Associated Angioimmunoblastic Lymphoma and Hemophagocytic Syndrome

Introduction: Chronic active Epstein-Barr virus infection (CAEBV) has been implicated in several diseases including hemophagocytic lymphohistiocytosis (EBV-HLH) and lymphomas including Angioimmunoblastic T cell lymphoma. The exact mechanism by which EBV infection causes these complications is currently not well understood. EBV-HLH is a syndrome in which T-cells, NK cells and macrophages are aberrantly activated. Cytokine storms play a major role in cellular damage and organ dysfunction. In the event that the body is unable to clear the EBV viremia, dysregulated T, NK cells and macrophages continue to release cytokines leading to the accumulation of lymphohistiocytic infiltrates into organs and organ damage. Cytokine storms can lead to death from multi-organ failure. During a cytokine storm, levels of several cytokines are elevated including TNF-a, IFN-g, sCD25, IL-12, IL-1, IL-10 and IL-18.1–3 Current lines of therapy of EBV-HLH include steroids, etoposide, cyclosporine, ATG and hematopoietic stem cell transplantation. We report successfully controlling frequent cytokine storms in a patient with EBV induced angioimmunoblastic lymphoma and HLH with weekly infliximab after failure to do so with chemotherapy (CHOP-E; cyclophosphamide, daunorubicin, vincristine, prednisone, etoposide), rituximab and bortezomib

Much ado about shear correction factors in Timoshenko beam theory

AbstractMany shear correction factors have appeared since the inception of Timoshenko beam theory in 1921. While rational bases for them have been offered, there continues to be some reluctance to their full acceptance because the explanations are not totally convincing and their efficacies have not been comprehensively evaluated over a range of application. Herein, three-dimensional static and dynamic information and results for a beam of general (both symmetric and non-symmetric) cross-section are brought to bear on these issues. Only homogeneous, isotropic beams are considered. Semi-analytical finite element (SAFE) computer codes provide static and dynamic response data for our purposes. Greater clarification of issues relating to the bases for shear correction factors can be seen. Also, comparisons of numerical results with Timoshenko beam data will show the effectiveness of these factors beyond the range of application of elementary (Bernoulli–Euler) theory.An issue concerning principal shear axes arose in the definition of shear correction factors for non-symmetric cross-sections. In this method, expressions for the shear energies of two transverse forces applied on the cross-section by beam and three-dimensional elasticity theories are equated to determine the shear correction factors. This led to the necessity for principal shear axes. We will argue against this concept and show that when two forces are applied simultaneously to a cross-section, it leads to an inconsistency. Only one force should be used at a time, and two sets of calculations are needed to establish the shear correction factors for a non-symmetrical cross-section

The Effect of Carfilzomib and Bortezomib Based Regimes on Cardiotoxicity in Multiple Myeloma Patients at Cooper University Hospital

Introduction Multiple myeloma (MM) is a cancer of plasma cells, which is a white blood cell that normally produces antibodies Treatment in patients younger than 65 years old is typically high dose chemotherapy, usually with bortezomib based regimens or lenalidomide dexamethasone, followed by a stem cell transplant For patients with relapsed myeloma, carfilzomib is usually the treatment of choice Carfilzomib is a highly selective, irreversible proteasome inhibitor that binds to the 20 S proteasome. Several studies have illustrated that carfilzomib has been associated with cardiovascular adverse events (CVAE). Current literature on the role and effect of bortezomib on cardiotoxicity is contradictory Past studies have shown benefits of using carfilzomib in MM patients, leading to improved response rates and overall survival There is scarce research on the risk factors associated with the development of cardiotoxicity with carfilzomib Objective To determine the incidence of cardiovascular adverse events (CVAE) associated with carfilzomib and bortezomib utilization and to assess risk factors for carfilzomib related cardiotoxicit

Application of computer-aided image reconstruction and image guide in parasagittal meningioma resection

Background In recent years, smaller-sized (diameter < 2.5 cm) meningiomas are diagnosed due to increased cranial imaging. Symptomatic meningiomas need to be removed surgically. Therefore, it is extremely important to locate the lesion exactly to tailor the craniotomy especially if the neuro-navigation system is not available. Many hospitals located in the underdeveloped countries cannot afford the high costs of neuro-navigation equipment. Hence, it is relevant to discover low-cost associated and effective methods for lesion localization for surgery. Methods The use of localization markers in advance can help to acquire preoperative CT images of the patients to create and calculate a three-dimensional (3D) virtual graph using a computer. With the 3D graph, spatial distance of the tumor from the markers is calculated and the tumor location projected on the scalp by the Triangle Pythagorean theorem. This enables precise localization of intracranial microlesions preoperatively. Results The location of the tumor was consistent with that of the pre-operative virtual image, and the craniotomy was exact. The patient was discharged 3 days later without any neurological deficits. Conclusions This method is simple and reliable, inexpensive, and accurate in the location of small-sized lesions, which can partially compensate for the lack of neuro-navigation and is suitable for widespread application in hospitals in developing countries.Peer reviewe

Extreme Peripheral Blood Plasmacytosis Mimicking Plasma Cell Leukemia as a Presenting Feature of Angioimmunoblastic T-Cell Lymphoma (AITL).

Angioimmunoblastic T-cell lymphoma (AITL) is one of four major subtypes of nodal peripheral T cell lymphoma, characterized by its cell of origin, the follicular helper T-cell (TFH). Patients typically present with prominent constitutional (B) symptoms, generalized lymphadenopathy, hepatosplenomegaly, cytopenias, and rash. Here we present a case of a 62-year-old male with progressive cervical adenopathy, fevers and weight loss presenting with extreme polyclonal plasmacytosis and high plasma EBV viral load. While the initial presentation appeared to mimic plasma cell leukemia or severe infection, lymph node biopsy and bone marrow biopsy confirmed a diagnosis of AITL. This case highlights the heterogeneity of the clinical presentation of AITL to enable physicians to more promptly recognize, diagnose and initiate treatment

Intracerebroventrikuläre Injektionen von Zink Ionen und Histidin als Carrier modulieren die Anfallsaktivität nach experimentell induzierter Epileptogenese unterschiedlich in Cav2.3-defizienten Mäusen und Kontrolltieren

Hintergrund: Epilepsie ist eine neurologische Erkrankung, an der weltweit über 50 Millionen Menschen aus allen Altersgruppen erkrankt sind. Die Erkrankung hat viele Formen und unterschiedliche Symptome. Die genauen Mechanismen für die Entstehung von epileptischen Anfällen sind sehr vielfältig. Zum einen ist der Cav2.3 Calcium-Kanal an der Generierung von epileptischen Anfällen beteiligt. Zusätzlich verdichteten sich in den letzten Jahren vermehrt Hinweise, dass die Homöostase von bestimmten Spurenmetall-Ionen, insbesondere von Zink, eine Rolle in der Epileptogenese einnehmen. Ziele: In dieser Arbeit soll die Funktion von Zink und seine Bedeutung in der Kainat induzierten Epileptogenese über den Cav2.3 Calcium-Kanal untersucht werden. Methoden: In dieser Arbeit wird daher die Zinkhomöostase manipuliert, um den Einfluss von Zink bei der Kainat induzierten Epilepsie in Mäusen mit und ohne Cav2.3 Calcium-Kanal zu untersuchen. Mäusen wird entweder 1 mM Histidin (His) allein oder in Kombination mit 10 µM Zinkchlorid (ZnCl2) zusätzlich zur intraperitonealen Injektion von 15 mg / kg Kainat (KA) zur Anfallsinduktion injiziert. Es wurde eine Methode zur intracerebroventrikulären (i.c.v.) Injektion von Histidin allein oder in Kombination mit Zink bei Mäusen entwickelt, um eine direkte Anreicherung von Zink Ionen im Gehirn zu erreichen. Wildtyp-Mäuse und Mäuse mit deletiertem Cav2.3 Ca2+-Kanal wurden in je 3 Hauptgruppen eingeteilt: A. Mäuse ohne i.c.v. Injektion (ohne Kanüle), B. mit i.c.v. Histidin Injektion (mit Kanüle) und C. mit i.c.v. Injektion von Zink mit Histidin (mit Kanüle). Jede Hauptgruppe enthielt eine Kontrollgruppe und einer Gruppe von Mäusen bei denen konvulsive Anfälle durch ein intraperitoneal (i.p.) injiziertes chemisches Läsionswerkzeug, dem Kainat (KA) ausgelöst wurden. Nach den Injektionen wurden telemetrische Messungen an der Hirnoberfläche von sich frei bewegenden Mäusen zur Erfassung von epileptischen Anfällen durchgeführt. Zusätzlich wurde für eine Gesamtbeobachtungszeit von 2 h nach Injektion der Schweregrad von Anfällen registriert und quantifiziert. Darüber hinaus wurde eine immunhistochemische Methode zum Nachweis von Schwermetall-Kationen im Gehirn angewendet, um die Ausbreitung von injiziertem Zink zu verfolgen oder den Verbleib von endogenem Zink darzustellen. Ergebnisse: Nach Kainat Injektion wurde in Cav2.3-kompetenten Mäusen schwerere Anfälle und eine höhere Sterblichkeitsrate festgestellt verglichen mit Cav2.3 KO-Mäusen. Nach zusätzlicher intracerebroventrikulärer Gabe von Histidin reduzierten sich die Sterberaten drastisch in beiden Genotypen. Jedoch zeigte sich nur in Wildtyp-Mäusen eine signifikante Verbesserung in der Anfallsintensität. Zusätzlich wurde dabei eine Abnahme der Färbeintensität nach der Methode von Timm registriert. Die zusätzliche Applikation von Zink in Verbindung mit Histidin sorgte hingegen erneut für einen Anstieg der Sterblichkeitsrate jedoch nur in Cav2.3(+|+) Wildtyp-Mäusen und zu einer intensiveren Färbung im Gehirn. Schlussfolgernd liegt es nahe, dass Zink durch die modulierenden Effekte am Cav2.3 Ca2+-Kanal Einfluss auf die Epileptogenese hat

Oral Inflammatory Diseases and Systemic Inflammation: Role of the Macrophage

Inflammation is a complex reaction to injurious agents and includes vascular responses, migration, and activation of leukocytes. Inflammation starts with an acute reaction, which evolves into a chronic phase if allowed to persist unresolved. Acute inflammation is a rapid process characterized by fluid exudation and emigration of leukocytes, primarily neutrophils, whereas chronic inflammation extends over a longer time and is associated with lymphocyte and macrophage infiltration, blood vessel proliferation, and fibrosis. Inflammation is terminated when the invader is eliminated, and the secreted mediators are removed; however, many factors modify the course and morphologic appearance as well as the termination pattern and duration of inflammation. Chronic inflammatory illnesses such as diabetes, arthritis, and heart disease are now seen as problems that might have an impact on the periodontium. Reciprocal effects of periodontal diseases are potential factors modifying severity in the progression of systemic inflammatory diseases. Macrophages are key cells for the inflammatory processes as regulators directing inflammation to chronic pathological changes or resolution with no damage or scar tissue formation. As such, macrophages are involved in a remarkably diverse array of homeostatic processes of vital importance to the host. In addition to their critical role in immunity, macrophages are also widely recognized as ubiquitous mediators of cellular turnover and maintenance of extracellular matrix homeostasis. In this review, our objective is to identify macrophage-mediated events central to the inflammatory basis of chronic diseases, with an emphasis on how control of macrophage function can be used to prevent or treat harmful outcomes linked to uncontrolled inflammation

Extracción en fase sólida de β-sitosterol y α-tocoferol de destilados de aceite de girasol desodorizado utilizando zeolita desilicada

In this study, the efficiency of using zeolite-based adsorbents in a solid phase extraction (SPE) procedure of α-tocopherol and β-sitosterol isolation from Sunflower Oil Deodorizer Distillate (SuDOD) with­out pre-treatment was investigated. The results showed that 99.2% α-tocopherol and 97.3% β-sitosterol were suc­cessfully isolated as pure fractions from SuDOD, when desilicated ZSM-5-type zeolite (DSiZSM-5) was used as adsorbent on a SPE. A simple and rapid HPLC method for simultaneous α-tocopherol and β-sitosterol analysis was developed and validated according to AOAC guidelines. It was found that the inclusion of a DSiZSM-5 SPE step increased the precision of the α-tocopherol and β-sitosterol analysis. In conclusion, DSiZSM-5 zeo­lite was proven to be an efficient adsorbent which can be used not only for the recovery of α-tocopherol and β-sitosterol from SuDOD in industrial scale, but also in a laboratory scale clean-up method prior to the analysis of α-tocopherol and β-sitosterol.En este estudio, se investigó la eficacia del uso de adsorbentes a base de zeolita en el procedimiento de extracción en fase sólida (EFS) para el aislamiento de α-tocoferol y β-sitosterol a partir de destilados de aceites de girasol desodorizados (SuDOD) sin ningún tratamiento previo. Los resultados mostraron que el 99,2% de α-tocoferol y el 97,3% de β-sitosterol se aislaron con éxito como fracciones puras de SuDOD, cuando se usó zeolita de tipo ZSM-5 desilicado (DSiZSM-5) como adsorbente en una EFS. Se desarrolló y validó un método HPLC simple y rápido para el análisis simultáneo de α-tocoferol y β-sitosterol de acuerdo con las directrices de la AOAC. Se encontró que la inclusión del paso DSiZSM-5 EFS aumentó la precisión del análisis de α-tocoferol y β-sitosterol. En conclusión, se demostró que la zeolita DSiZSM-5 es un adsorbente eficiente que puede usarse, no solo para la recuperación de α-tocoferol y β-sitosterol de SuDOD a escala industrial, sino también en un método de limpieza a escala de laboratorio antes del análisis de α-tocoferol y β-sitosterol