Successful translation and future prospects of TALEN editing for leukemia patients

n recent years chimeric antigen receptor (CAR) T cell therapies have emerged as powerful targeted immunotherapies [1]. They have had impressive success in the treatment of different types of B cell leukemias, with early phase trials of CAR T cell therapy against the B cell antigen CD19 (CAR19) accomplishing disease remission in a significant proportion of treated patients [2]. The process for the generation of these autologous CAR T cells requires leukapheresis for the isolation of the T cells, followed by genetic engineering to express the desired CAR against one or more B cell antigens (e.g. CD19, CD22) on their surface. Finally, these CAR T cells are expanded and, after the patient has been lymphodepleted using combination chemotherapy, they are reinfused. Because these are patient-specific therapies, the manufacturing of these cells has proven to be expensive, time-consuming, and in some cases technically difficult, especially in patients that have been extensively treated and rendered lymphopenic. Due to these difficulties, there has been marked interest in generating an ‘off-the-shelf’, universal CAR T cell that could be derived from unrelated donors. There are two major barriers in this regard. The first involves the recognition of the patient’s human leucocyte antigens (HLA) by the native T cell receptor (TCR) of the CAR T cells, potentially causing transfusional graft-versus-host disease (GvHD), which often manifests with cytopenias and is potentially life threatening. The second involves the foreign HLA expressed by the CAR T cells being recognized by the immune system of the patient (hence rejection of the CAR T cells)

Power grip, pinch grip, manual muscle testing or thenar atrophy - which should be assessed as a motor outcome after carpal tunnel decompression? A systematic review

<p>Abstract</p> <p>Background</p> <p>Objective assessment of motor function is frequently used to evaluate outcome after surgical treatment of carpal tunnel syndrome (CTS). However a range of outcome measures are used and there appears to be no consensus on which measure of motor function effectively captures change. The purpose of this systematic review was to identify the methods used to assess motor function in randomized controlled trials of surgical interventions for CTS. A secondary aim was to evaluate which instruments reflect clinical change and are psychometrically robust.</p> <p>Methods</p> <p>The bibliographic databases Medline, AMED and CINAHL were searched for randomized controlled trials of surgical interventions for CTS. Data on instruments used, methods of assessment and results of tests of motor function was extracted by two independent reviewers.</p> <p>Results</p> <p>Twenty-two studies were retrieved which included performance based assessments of motor function. Nineteen studies assessed power grip dynamometry, fourteen studies used both power and pinch grip dynamometry, eight used manual muscle testing and five assessed the presence or absence of thenar atrophy. Several studies used multiple tests of motor function. Two studies included both power and pinch strength and reported descriptive statistics enabling calculation of effect sizes to compare the relative responsiveness of grip and pinch strength within study samples. The study findings suggest that tip pinch is more responsive than lateral pinch or power grip up to 12 weeks following surgery for CTS.</p> <p>Conclusion</p> <p>Although used most frequently and known to be reliable, power and key pinch dynamometry are not the most valid or responsive tools for assessing motor outcome up to 12 weeks following surgery for CTS. Tip pinch dynamometry more specifically targets the thenar musculature and appears to be more responsive. Manual muscle testing, which in theory is most specific to the thenar musculature, may be more sensitive if assessed using a hand held dynamometer – the Rotterdam Intrinsic Handheld Myometer. However further research is needed to evaluate its reliability and responsiveness and establish the most efficient and psychometrically robust method of evaluating motor function following surgery for CTS.</p

CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity.

Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies

The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours and whether this affects patient outcomes is unknown. Here, we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets with strong phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states was associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action

Social media for health promotion and weight management: A critical debate

© 2018 The Author(s). Background: In 2016 an estimated 1.9 billion adults world-wide were either overweight or obese. The health consequences of obesity are responsible for 2.8 million preventable deaths per year. The WHO now considers obesity as a global epidemic and recommends population-wide health promotion strategies to address this issue. Weight gain is caused by increased energy intake and physical inactivity, so treatment should focus on changes to behaviour regarding diet and physical activity. Discussion: The WHO has also recognised the importance of social resources as a valuable agent for behaviour change in health promotion. Social resources are translated at the community level as support provided by significant others such as family, partners and peers, in the form of information, material aid and encouragement. Social support has been shown to improve health and well-being, whereas social isolation has been shown to have a negative impact on health outcomes. Social support provided by peers has been shown to be a useful strategy to employ in weight management programmes. The documented increased use of ICT and social media has presented health promoters with a potentially useful medium to increase social support for weight management. Conclusion: While the use of social media for health promotion is an emerging field of investigation, preliminary research suggests that it increases participant engagement, and may provide a cost-effective tool to provide social support for individuals participating in weight management programmes. With stringent privacy protocols in place, social media may be a useful, cost-effective accompaniment to multifactorial weight management programmes. However more research is needed to identify how to make the best use of social media as health promotion tool

Homeostatic regulation of the endoneurial microenvironment during development, aging and in response to trauma, disease and toxic insult

The endoneurial microenvironment, delimited by the endothelium of endoneurial vessels and a multi-layered ensheathing perineurium, is a specialized milieu intérieur within which axons, associated Schwann cells and other resident cells of peripheral nerves function. The endothelium and perineurium restricts as well as regulates exchange of material between the endoneurial microenvironment and the surrounding extracellular space and thus is more appropriately described as a blood–nerve interface (BNI) rather than a blood–nerve barrier (BNB). Input to and output from the endoneurial microenvironment occurs via blood–nerve exchange and convective endoneurial fluid flow driven by a proximo-distal hydrostatic pressure gradient. The independent regulation of the endothelial and perineurial components of the BNI during development, aging and in response to trauma is consistent with homeostatic regulation of the endoneurial microenvironment. Pathophysiological alterations of the endoneurium in experimental allergic neuritis (EAN), and diabetic and lead neuropathy are considered to be perturbations of endoneurial homeostasis. The interactions of Schwann cells, axons, macrophages, and mast cells via cell–cell and cell–matrix signaling regulate the permeability of this interface. A greater knowledge of the dynamic nature of tight junctions and the factors that induce and/or modulate these key elements of the BNI will increase our understanding of peripheral nerve disorders as well as stimulate the development of therapeutic strategies to treat these disorders

Valid and reliable instruments for arm-hand assessment at ICF activity level in persons with hemiplegia: a systematic review

Contains fulltext : 110141.pdf (publisher's version ) (Open Access)BACKGROUND: Loss of arm-hand performance due to a hemiparesis as a result of stroke or cerebral palsy (CP), leads to large problems in daily life of these patients. Assessment of arm-hand performance is important in both clinical practice and research. To gain more insight in e.g. effectiveness of common therapies for different patient populations with similar clinical characteristics, consensus regarding the choice and use of outcome measures is paramount. To guide this choice, an overview of available instruments is necessary. The aim of this systematic review is to identify, evaluate and categorize instruments, reported to be valid and reliable, assessing arm-hand performance at the ICF activity level in patients with stroke or cerebral palsy. METHODS: A systematic literature search was performed to identify articles containing instruments assessing arm-hand skilled performance in patients with stroke or cerebral palsy. Instruments were identified and divided into the categories capacity, perceived performance and actual performance. A second search was performed to obtain information on their content and psychometrics. RESULTS: Regarding capacity, perceived performance and actual performance, 18, 9 and 3 instruments were included respectively. Only 3 of all included instruments were used and tested in both patient populations. The content of the instruments differed widely regarding the ICF levels measured, assessment of the amount of use versus the quality of use, the inclusion of unimanual and/or bimanual tasks and the inclusion of basic and/or extended tasks. CONCLUSIONS: Although many instruments assess capacity and perceived performance, a dearth exists of instruments assessing actual performance. In addition, instruments appropriate for more than one patient population are sparse. For actual performance, new instruments have to be developed, with specific focus on the usability in different patient populations and the assessment of quality of use as well as amount of use. Also, consensus about the choice and use of instruments within and across populations is needed

Technology-assisted training of arm-hand skills in stroke: concepts on reacquisition of motor control and therapist guidelines for rehabilitation technology design

<p>Abstract</p> <p>Background</p> <p>It is the purpose of this article to identify and review criteria that rehabilitation technology should meet in order to offer arm-hand training to stroke patients, based on recent principles of motor learning.</p> <p>Methods</p> <p>A literature search was conducted in PubMed, MEDLINE, CINAHL, and EMBASE (1997–2007).</p> <p>Results</p> <p>One hundred and eighty seven scientific papers/book references were identified as being relevant. Rehabilitation approaches for upper limb training after stroke show to have shifted in the last decade from being analytical towards being focussed on environmentally contextual skill training (task-oriented training). Training programmes for enhancing motor skills use patient and goal-tailored exercise schedules and individual feedback on exercise performance. Therapist criteria for upper limb rehabilitation technology are suggested which are used to evaluate the strengths and weaknesses of a number of current technological systems.</p> <p>Conclusion</p> <p>This review shows that technology for supporting upper limb training after stroke needs to align with the evolution in rehabilitation training approaches of the last decade. A major challenge for related technological developments is to provide engaging patient-tailored task oriented arm-hand training in natural environments with patient-tailored feedback to support (re) learning of motor skills.</p

A Review on the Mechanical Modeling of Composite Manufacturing Processes

© 2016, The Author(s). The increased usage of fiber reinforced polymer composites in load bearing applications requires a detailed understanding of the process induced residual stresses and their effect on the shape distortions. This is utmost necessary in order to have more reliable composite manufacturing since the residual stresses alter the internal stress level of the composite part during the service life and the residual shape distortions may lead to not meeting the desired geometrical tolerances. The occurrence of residual stresses during the manufacturing process inherently contains diverse interactions between the involved physical phenomena mainly related to material flow, heat transfer and polymerization or crystallization. Development of numerical process models is required for virtual design and optimization of the composite manufacturing process which avoids the expensive trial-and-error based approaches. The process models as well as applications focusing on the prediction of residual stresses and shape distortions taking place in composite manufacturing are discussed in this study. The applications on both thermoset and thermoplastic based composites are reviewed in detail