Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Congenital anomalies in low- and middle-income countries: the unborn child of global surgery.

Surgically correctable congenital anomalies cause a substantial burden of global morbidity and mortality. These anomalies disproportionately affect children in low- and middle-income countries (LMICs) due to sociocultural, economic, and structural factors that limit the accessibility and quality of pediatric surgery. While data from LMICs are sparse, available evidence suggests that the true human and financial cost of congenital anomalies is grossly underestimated and that pediatric surgery is a cost-effective intervention with the potential to avert significant premature mortality and lifelong disability

Force and Motion Generation of Molecular Motors: A Generic Description

We review the properties of biological motor proteins which move along linear filaments that are polar and periodic. The physics of the operation of such motors can be described by simple stochastic models which are coupled to a chemical reaction. We analyze the essential features of force and motion generation and discuss the general properties of single motors in the framework of two-state models. Systems which contain large numbers of motors such as muscles and flagella motivate the study of many interacting motors within the framework of simple models. In this case, collective effects can lead to new types of behaviors such as dynamic instabilities of the steady states and oscillatory motion.Comment: 29 pages, 9 figure

Microblogging, constituency service and impression management – UK MPs and the use of Twitter

Twitter, a microblogging site which allows users to deliver statements, thoughts and links in 140 characters to followers as well as a wider Internet audience, is the latest online communications technology adopted by MPs. Assessing the use of early adopters, this article considers which MPs are most likely to use Twitter (e.g. tweeting), and how. Content analysis of tweeting MPs was conducted, and identified personal and political characteristics which may influence use. The data suggested that of the six characteristics tested, gender, party and seniority had most impact on adoption. Applying Jones and Pittman’s (1982) typology there is clear evidence that MPs use Twitter as a tool of impression management. Constituency service is a secondary function of the use of Twitter by MPs. Where MPs use Twitter as part of their constituency role it is to promote their local activity. We note that a small group of MPs use Twitter as a regular communication channel, but most are only occasionally dipping their toe into the microbloggersphere

The Role of Demography in the Transition to Sustainable Societies

Currently, although the global population has surpassed 7.5 billion and continues to increase in about 80 million each year, attention to demography is almost absent in most of the studies and publications related to the current situation of planetary emergency and the necessary transition to sustainable societies. For this reason, our first aim in this paper has been to discuss if this current lack of attention to demography is justified or not. With this purpose, we begin considering the scientific meaning of Sustainability, in order to overlay distorted and impoverish views of this concept that may hinder our study. Then, we analyse the reasons given by experts for and against the incidence of demographic growth in the current unsustainable situation of planetary emergency. Finally, we present proposals to face the ensemble of interconnected socio-environmental problems (including demographic evolution), to make possible an appropriate transition to sustainable societies. Aunque la población mundial ha sobrepasado los 7500 millones y continúa aumentando anualmente en alrededor de 80 millones, la atención a la demografía está hoy prácticamente ausente en la mayoría de los estudios y publicaciones acerca de la actual situación de emergencia planetaria y la necesidad de una transición a sociedades sostenibles. Con el propósito de analizar si esta falta de atención a la demografía está o no justificada, en esta contribución comenzamos discutiendo el significado científico de Sostenibilidad socioambiental, para evitar concepciones distorsionadas y empobrecidas de este concepto que pueden dificultar dicho análisis. A continuación estudiaremos las razones dadas por distintos expertos a favor y en contra de la incidencia del crecimiento demográfico en la insostenible situación actual de emergencia planetaria. Finalmente presentamos propuestas para hacer frente al conjunto de problemas estrechamente interconectados - incluido el problema demográfico - que caracterizan dicha situación, para hacer así posible una adecuada transición a sociedades sostenibles

Single-molecule experiments in biological physics: methods and applications

I review single-molecule experiments (SME) in biological physics. Recent technological developments have provided the tools to design and build scientific instruments of high enough sensitivity and precision to manipulate and visualize individual molecules and measure microscopic forces. Using SME it is possible to: manipulate molecules one at a time and measure distributions describing molecular properties; characterize the kinetics of biomolecular reactions and; detect molecular intermediates. SME provide the additional information about thermodynamics and kinetics of biomolecular processes. This complements information obtained in traditional bulk assays. In SME it is also possible to measure small energies and detect large Brownian deviations in biomolecular reactions, thereby offering new methods and systems to scrutinize the basic foundations of statistical mechanics. This review is written at a very introductory level emphasizing the importance of SME to scientists interested in knowing the common playground of ideas and the interdisciplinary topics accessible by these techniques. The review discusses SME from an experimental perspective, first exposing the most common experimental methodologies and later presenting various molecular systems where such techniques have been applied. I briefly discuss experimental techniques such as atomic-force microscopy (AFM), laser optical tweezers (LOT), magnetic tweezers (MT), biomembrane force probe (BFP) and single-molecule fluorescence (SMF). I then present several applications of SME to the study of nucleic acids (DNA, RNA and DNA condensation), proteins (protein-protein interactions, protein folding and molecular motors). Finally, I discuss applications of SME to the study of the nonequilibrium thermodynamics of small systems and the experimental verification of fluctuation theorems. I conclude with a discussion of open questions and future perspectives.Comment: Latex, 60 pages, 12 figures, Topical Review for J. Phys. C (Cond. Matt