bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design and development of therapies using chimeric antigen receptor‐expressing T cells
Authors: Dotti Gianpietro , Gottschalk Stephen , Savoldo Barbara , Brenner Malcolm K. 
Published: December 2013

SummaryInvestigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non‐protein antigens) with the persistence, trafficking, and effector functions of a T cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CAR‐T cells. Our review then describes our own and other investigators' work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR‐T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained.
Exploiting the curative potential of adoptive T‐cell therapy for cancer
Authors: Hinrichs Christian S. , Rosenberg Steven A. 
Published: December 2013

SummaryAdoptive T‐cell therapy (ACT) is a potent and flexible cancer treatment modality that can induce complete, durable regression of certain human malignancies. Long‐term follow‐up of patients receiving tumor‐infiltrating lymphocytes (TILs) for metastatic melanoma reveals a substantial subset that experienced complete, lasting tumor regression – and may be cured. Increasing evidence points to mutated gene products as the primary immunological targets of TILs from melanomas. Recent technological advances permit rapid identification of the neoepitopes resulting from these somatic gene mutations and of T cells with reactivity against these targets. Isolation and adoptive transfer of these T cells may improve TIL therapy for melanoma and permit its broader application to non‐melanoma tumors. Extension of ACT to other malignancies may also be possible through antigen receptor gene engineering. Tumor regression has been observed following transfer of T cells engineered to express chimeric antigen receptors against CD19 in B‐cell malignancies or a T‐cell receptor against NY‐ESO‐1 in synovial cell sarcoma and melanoma. Herein, we review recent clinical trials of TILs and antigen receptor gene therapy for advanced cancers. We discuss lessons from this experience and consider how they might be applied to realize the full curative potential of ACT.
Uncoupling T‐cell expansion from effector differentiation in cell‐based immunotherapy
Authors: Crompton Joseph G. , Sukumar Madhusudhanan , Restifo Nicholas P. 
Published: December 2013

SummaryAdoptive cellular immunotherapy (ACT) is a potentially curative therapy for patients with advanced cancer. Eradication of tumor in mouse models and humans correlates with both a high dose of adoptively transferred cells and cells with a minimally differentiated phenotype that maintain replicative capacity and multipotency. We speculate that response to ACT not only requires transfer of cells with immediate cytolytic effector function to kill the bulk of fast‐growing tumor but also transfer of tumor‐specific cells that maintain an ability for self‐renewal and the capacity to produce a continual supply of cytolytic effector progeny until all malignant cells are eliminated. Current in vitro methods to expand cells to sufficient numbers and still maintain a minimally differentiated phenotype are hindered by the biological coupling of clonal expansion and effector differentiation. Therefore, a better understanding of the physiologic mechanism that couples cell expansion and differentiation in CD8+ T cells may improve the efficacy of ACT.
Adoptive immunotherapy for cancer
Authors: Ruella Marco , Kalos Michael 
Published: December 2013

SummaryRecent clinical success has underscored the potential for immunotherapy based on the adoptive cell transfer (ACT) of engineered T lymphocytes to mediate dramatic, potent, and durable clinical responses. This success has led to the broader evaluation of engineered T‐lymphocyte‐based adoptive cell therapy to treat a broad range of malignancies. In this review, we summarize concepts, successes, and challenges for the broader development of this promising field, focusing principally on lessons gleaned from immunological principles and clinical thought. We present ACT in the context of integrating T‐cell and tumor biology and the broader systemic immune response.
A new approach to gene therapy using Sleeping Beauty to genetically modify clinical‐grade T cells to target CD19
Authors: Singh Harjeet , Huls Helen , Kebriaei Partow , Cooper Laurence J. N. 
Published: December 2013

SummaryThe advent of efficient approaches to the genetic modification of T cells has provided investigators with clinically appealing methods to improve the potency of tumor‐specific clinical grade T cells. For example, gene therapy has been successfully used to enforce expression of chimeric antigen receptors (CARs) that provide T cells with ability to directly recognize tumor‐associated antigens without the need for presentation by human leukocyte antigen. Gene transfer of CARs can be undertaken using viral‐based and non‐viral approaches. We have advanced DNA vectors derived from the Sleeping Beauty (SB) system to avoid the expense and manufacturing difficulty associated with transducing T cells with recombinant viral vectors. After electroporation, the transposon/transposase improves the efficiency of integration of plasmids used to express CAR and other transgenes in T cells. The SB system combined with artificial antigen‐presenting cells (aAPC) can selectively propagate and thus retrieve CAR+ T cells suitable for human application. This review describes the translation of the SB system and aAPC for use in clinical trials and highlights how a nimble and cost‐effective approach to developing genetically modified T cells can be used to implement clinical trials infusing next‐generation T cells with improved therapeutic potential.
Genetically engineered donor T cells to optimize graft‐versus‐tumor effects across MHC barriers
Authors: Ghosh Arnab , Holland Amanda M. , van den Brink Marcel R. M. 
Published: December 2013

SummaryHematopoietic stem cell transplantation has been used for more than 50 years to combat hematologic malignancies. In addition to being the first stem cell therapy, transplantation has provided evidence for the potent anti‐tumor effects of T cells. Facilitating T‐cell‐based immunity against malignancies requires a careful balancing act between generating a robust response and avoiding off‐target killing of healthy tissues, which is difficult to accomplish using bulk donor T cells. To address these issues, several approaches have been developed, drawing on basic T‐cell biology, to potentiate graft‐versus‐tumor activity while avoiding graft‐versus‐host disease. Current strategies for anti‐tumor cell therapies include: (i) selecting optimal T cells for transfer; (ii) engineering T cells to possess enhanced effector functions; and (iii) generating T‐cell precursors that complete development after adoptive transfer. In this review, we assess the current state of the art in T‐lineage cell therapy to treat malignancies in the context of allogeneic hematopoietic stem cell transplantation.
Zivilgesellschaft und sozialer Basisschutz
Authors: van Ginneken Wouter 
Published: December 2013

AuszugDie Zivilgesellschaft unterstützt voll und ganz das Konzept sozialer Basisschutzniveaus und insbesondere die Annahme der IAO‐Empfehlung (Nr. 202) betreffend den innerstaatlichen sozialen Basisschutz, 2012. Die Verwirklichung sozialer Basisschutzniveaus wird einen großen Schritt nach vorne bei der Verringerung von Armut und Ungleichheit bedeuten und weltweit zur Stärkung der Rechte von Menschen beitragen. Die zivilgesellschaftliche Bewegung ist überzeugt, dass der auf Rechten basierende Ansatz der wirksamste Weg ist zur Ausarbeitung und Verwirklichung sozialer Basisschutzniveaus, die zu mehr Autonomie verhelfen und nachhaltig sind. Bei den menschenrechtlichen Sozialschutzgarantien widmet sie ihre Aufmerksamkeit vier konkreten Punkten: i) der Achtung der Rechte und der Würde von Menschen mit Ansprüchen auf soziale Sicherheit; ii) der umfassenden Beteiligung der Zivilgesellschaft; iii) der allgemeinen Deckung auf der lokalen, nationalen und internationalen Ebene; iv) der besonderen Berücksichtigung schutzbedürftiger Gruppen. Im Anschluss an die 101. Internationale Arbeitskonferenz im Jahr 2012 gründeten 59 Organisationen der Zivilgesellschaft die „Koalition für einen sozialen Basisschutz“, deren zwei Hauptaufgaben folgende sind: die allgemeine Verwirklichung sozialer Basisschutzniveaus auf der lokalen und nationalen Ebene zu überwachen und dazu beizutragen; und das Konzept des sozialen Basisschutzes in der globalen Politikgestaltung zu fördern, beispielsweise in Diskussionen über die Entwicklungsagenda für die Zeit nach 2015.
Überprüfung der Methoden zum Erzielen eines Fortschritts hin zu einer universellen Krankenversicherungsdeckung in Ländern mit Niedrigeinkommen: Erfolg des staatlichen sozialen Basisschutzes
Authors: Scheil‐Adlung Xenia 
Published: December 2013

AuszugTrotz Fortschritten in der Ausweitung der Sozialschutzdeckung sind die meisten Länder mit Niedrigeinkommen immer noch weit entfernt von einer universellen Krankenversicherungsdeckung. Daher werden bis 2015 viele der Verbesserungen im Gesundheitsbereich und wesentliche Millenniumsentwicklungsziele (MDGs) mit grö
ßter Sicherheit nicht erreicht werden. In erster Linie sind die schwächsten Gruppen betroffen: die Armen in Stadt und Land sowie die Arbeitnehmer in der informellen Wirtschaft und deren Familien. Es ist von besonderem Belang, dass der Fortschritt nicht nur beschränkt bleiben, sondern gar ins Gegenteil umgekehrt werden könnte, wenn die Politik weiterhin darin scheitert, die eigentlichen Ursachen der Lücken und Mängel in der Krankenversicherungsdeckung anzugehen. Der Artikel liefert Belege dafür, dass diese Ursachen sowohl innerhalb als auch außerhalb des Gesundheitssektors liegen und eng verbunden sind mit Armut und anderen Formen von Gefährdung. Er vertritt die Ansicht, dass ein nachhaltiger Fortschritt hin zu einer universellen Krankenversicherungsdeckung innerhalb eines geeigneten Zeitrahmens nur erreichbar ist, wenn man sich gleichzeitig auf die folgenden Punkte konzentriert: i) Ausweitung der Krankenversicherungsdeckung und Verbesserung des Zugangs zur benötigten Gesundheitsversorgung, ii) Bereitstellung sicheren Einkommens durch Einkommensbeihilfen für Bedürftige, iii) Lösungen bei Einschränkungen in der Einkommensgenerierung oder Unfähigkeit zur Teilnahme an derselben durch Arbeit und iv) kohärente Maßnahmen im Sozial‐, Wirtschafts‐ und Gesundheitssektor und darüber hinaus zur Linderung der Armut. Solche Maßnahmen können am besten im Kontext des staatlichen sozialen Basisschutzes (SPF – social protection floor) eingeführt werden, die eine minimale Gesundheitsversorgung garantiert und allen Bedürftigen wenigstens eine elementare, lebenslange Einkommenssicherheit bietet. Eine SPF kann dazu beitragen, die Wechselwirkungen zwischen mangelnder Gesundheit, Armut und anderen Gefährdungen und Fortschritten bei der universellen Krankenversicherungsdeckung und weiteren Zielen des Sozialschutzes zu stoppen.
Eine Definition der Angemessenheit mit mehreren Variablen: Herausforderungen und Chancen
Authors: Brimblecombe Simon 
Published: December 2013

AuszugDie Verabschiedung der Empfehlung der Internationalen Arbeitsorganisation über sozialen Basisschutz, 2012 (Nr. 202), zeigt, wie wichtig die Ausweitung der Deckung der sozialen Sicherheit weltweit genommen wird. Damit die positiven Auswirkungen einer Deckungsausweitung maximal genutzt werden können, müssen nicht nur möglichst viele Menschen Leistungen und Dienstleistungen erhalten, die so viele Risiken wie möglich abdecken, sondern die Leistungen müssen auch angemessen sein. Wenn auch nicht ganz ohne Aufwand, so kann doch ein Deckungsniveau definiert und gemessen werden. Die Definition einer angemessene Leistung gestaltet sich hingegen oft schwieriger und beruhte bislang meist auf dem Mass relativer Angemessenheit der Geldleistungen: der Ersatzquote. Angesichts der vielfältigen Ziele, welche die Systeme der sozialen Sicherheit anstreben, erscheint allerdings die Verwendung einer umfassender angesetzten Angemessenheit, die nicht nur die Höhe der Geldleistungen betrachtet, nicht nur viel angebrachter, sondern auch notwendig. In einem Kontext, in dem die finanziellen Zwänge nachweislich stärker sind denn je, untersucht dieser Artikel die Bedeutung des Konzepts der Angemessenheit sowie die Frage, warum eine allgemeinere Betrachtung dieser Art notwendig scheint, damit auch andere Aspekte der Leistungs‐ und Dienstleistungserbringung berücksichtigt werden können. Der Artikel beschreibt, wie eine solche Analyse anhand mehrerer Variablen durchgeführt werden könnte und welches ihre Herausforderungen sind. Durch die Mitberücksichtigung weiterer Ziele der Leistungserbringung – wie etwa die Dienstleistungsqualität, die Sicherheit der Leistungen und die Interaktion mit anderen Akteuren – versucht der Artikel dazu beizutragen, die Debatte weiter zu führen.
Biomechanical comparison of two implants for the stabilization of incomplete ossification of the humeral condyle lesions in dogs
Authors: Coggeshall Jason D. , Lewis Daniel D. , Fitzpatrick Noel , Conrad Bryan P. , Swanson Katy R. , Kim Stanley E. , Palm Lindsey S. , Tremolada Giovanni , Pozzi Antonio 
Published: December 2013

ObjectiveTo compare biomechanical properties of (1) 4.5 mm cortical screws and Fitz Fenestrated Tubular Transcondylar (F2T2) screws; (2) normal humeri and humeri with an intracondylar osteotomy; and (3) humeri with an intracondylar osteotomy stabilized with either a 4.5 mm cortical screw or a F2T2 screw.Study DesignCadaveric biomechanical assessment.Sample Population4.5 mm cortical screws (n = 10), 5.85 mm F2T2 screws (n = 10), and paired dog humeri (n = 40).MethodsCortical and F2T2 screws were loaded to failure in 3‐point bending. Ten pairs of humeri with or without an intracondylar osteotomy were axially loaded to failure. Ten additional pairs of humeri with an intracondylar osteotomy were alternately stabilized with a positional cortical or F2T2 screw and axially loaded to failure.ResultsMean stiffness, yield load, and failure load was significantly greater (P < .001) for the F2T2 screws compared with cortical screws as well as for intact humeri compared with humeri with an intracondylar osteotomy (P < .001). There were no significant differences in mean stiffness (P = .59), yield load (P = .31), or failure load (P = .24) between humeri with stabilized intracondylar osteotomy.ConclusionIsolated F2T2 screws have superior mechanical properties to 4.5 mm cortical screws when loaded in 3‐point bending. Intracondylar osteotomy adversely affected humeral mechanical integrity. Osteotomized humeri stabilized by either screw had comparable mechanical properties.
Catalyst‐Assisted Growth of Single‐Crystalline Hafnium Carbide Nanotubes by Chemical Vapor Deposition
Authors: Tian Song , Li Hejun , Zhang Yulei , Ren Jincui , Qiang Xinfa , Wang Jie 
Published: December 2013

Single‐crystalline hafnium carbide (HfC) nanotubes were synthesized by a one‐step catalyst‐assisted chemical vapor deposition (CVD) method. The typical nanotubes had uniform diameters of ~60 nm and wall thicknesses of ~15 nm and preferentially grew along [201]. From HRTEM/EELS analysis, the growth mechanism based on carbon nanotubes (CNT) tip growth and CNT‐templated reaction was proposed for explaining the formation of HfC nanotubes. According to the mechanism, CNTs were first formed by diffusion of C atoms on the surface of solid Ni catalyst particles. Then, gaseous Hf species reacted with C atoms from CNTs to form HfC nanotubes. During the entire growth process, Hf atoms did not participate in the catalytic reaction. Thus, this process was distinguished from the conventional vapor–liquid–solid process.
Rapid Synthesis of DDR Zeolite at Room Temperature
Authors: Sen Mitali , Bose Ankita , Pal Pameli , Das Jugal K. , Das Nandini 
Published: December 2013

In this work, DDR zeolites were synthesized by sonochemical method without the application of any heat energy at room temperature. The synthesized zeolites were characterized by X‐ray diffraction (XRD), infrared (IR) spectral analysis, and field‐emission scanning electron microscopy (FESEM). XRD and IR results showed that phase pure DDR zeolite was started to form at room temperature after 24 h of aging and completed the formation after 5 d of aging. The Brunauer–Emmett–Teller (BET) surface area of the powder was found to be 202 m2/g. The FESEM micrograph and elemental analysis showed that desired atomic ratio of the DDR zeolite was obtained after 5 days of synthesis.
Coloration and Nonlinear Optical Properties of ZnTe Quantum Dots in ZnO–TeO2–P2O5 Glasses
Authors: Du Xi , Zhang Liaolin , Dong Guoping , Sharafudeen Kaniyarakkal , Wen Jian , Chen Dongdan , Qian Qi , Qiu Jianrong 
Published: December 2013

ZnO–TeO2–P2O5 glasses were prepared by melt‐quenching method. The color of the glass samples changed from colorless to pale red and dark red with increasing TeO2 content. Coloration mechanism and nonlinear optical properties of ZnO–TeO2–P2O5 glasses have been investigated. Raman spectra and transmission electron microscope measurements indicated the precipitation of ZnTe quantum dots in the glasses and ZnTe quantum dots are the origin of coloration. Z‐scan technique was used to examine the nonlinear optical properties of the glasses. The glass sample with 30 mol% TeO2 exhibits large third‐order nonlinear optical susceptibility of 10−11 esu.
Do Analysts Disclose Cash Flow Forecasts with Earnings Estimates when Earnings Quality is Low?
Authors: Bilinski Pawel 
Published: December 2013

AbstractCash flows are incrementally useful to earnings in security valuation mainly when earnings quality is low. This suggests that when earnings quality decreases, analysts will be more likely to supplement their earnings forecasts with cash flow estimates. Contrary to this prediction, we find that analysts do not disclose cash flow forecasts when the quality of earnings is low. This is because cash flow forecast accuracy depends on the accuracy of the accrual estimates and the precision of accrual forecasts decreases for firms with low quality earnings. Consequently, as earnings quality decreases, cash flow forecasts become increasingly inaccurate compared to earnings estimates. Cash flow estimates that lack reliability are not useful to investors and, consequently, unlikely to be reported by analysts. This result provides an explanation for why analysts are less likely to report cash flow estimates when earnings quality is low.
Cutaneous melanoma in patients treated with tumour necrosis factor inhibitors: a retrospective series of 15 patients
Authors: Chabbert C. , Adamski H. , Guillet G. , Sassolas B. , Misery L. , Perrinaud A. , Machet L. , Quereux G. , Esteve E. , Solau‐Gervais E. , Saraux A. , Polard E. , Lesimple T. , Le Gall F. , Dreno B. , Dupuy A. 
Published: December 2013

AbstractBackgroundSeveral case reports suggested that tumour necrosis factor‐α (TNF) inhibitors might increase the incidence and/or alter the natural course of melanoma towards a more aggressive behaviour.ObjectiveOur objective was to point if history of melanoma in patients exposed to TNF inhibitors could present with a particular pattern at diagnosis or during follow‐up.MethodsWe performed a retrospective multicentre study settled in the West part of France to collect and analyse all cases of patients with melanoma who received anti‐TNF therapy.ResultsFifteen cases were included. First, 10 patients (mean age: 55.6 years; sex ratio: 1) had a melanoma diagnosed after TNF inhibitors initiation. The mean duration between initiation of treatment and melanoma was 48.7 months. Two patients died of metastatic disease. Second, four patients had a past history of melanoma before anti‐TNF therapy (mean duration of treatment: 10.8 months). None experienced a progression of melanoma disease. Last, one woman had a past history of melanoma before and then developed a second melanoma when exposed to biotherapy.ConclusionOur case series does not reveal a distinct profile of melanoma in the patients exposed to TNF inhibitors. Additional prospective trials including larger number of patient are needed to demonstrate the possible link between biological therapy with TNF inhibitors and development of melanoma.
Prevention in primary care: facilitators and barriers to transform prevention from a random coincidence to a systematic approach
Authors: Vos Hedwig M. M. , Adan Iris M. A. , Schellevis François G. , Lagro‐Janssen Antoine L. M. 
Published: December 2013

AbstractRationale, aims and objectivesThe Dutch general practitioner (GP) plays a substantial role in prevention. At the same time, many GPs hesitate to incorporate large‐scale cardiovascular risk management (CVRM) programmes into their daily practice. By exploring facilitators and barriers occurring during the past three decades, we wish to find clues on how to motivate professionals to adopt and implement prevention programmes.MethodsA witness seminar was organized in September 2011, inviting key figures to discuss the decision‐making process of the implementation of systematic prevention programmes in the Netherlands in the past, thereby adding new perspectives on past events. The extensive discussion was fully audiotaped. The transcript was content‐analysed.ResultsWe came across four different transitional stages: (1) the conversion from GPs disputing prevention to the implementation of systematic influenza vaccination; (2) the transition from systematic influenza vaccination to planning CVRM programmes; (3) the transition from planning and piloting CVRM programmes to cancelling the large‐scale implementation of the CVRM programme; and (4) the reinforcement of prevention.ConclusionsThe GPs' fear to lose the domain of prevention to other health care professionals and financial and logistical support are the main facilitators for implementing prevention programmes in primary care. The main barriers for implementing prevention are the combination of insecurity about reimbursement and lack of scientific evidence. It appears that the ethical view of GPs that everyone should have the same right to obtain preventive care gradually takes over the inclination to hold on to evidence‐based prevention.