tbuckley/cabot-search huggingface dataset:
Improving T Cell Receptor On-Target Specificity via Structure-Guided Design
Authors: Lance M. Hellman, Kendra C. Foley, Nishant K. Singh, Jesus A. Alonso, Timothy P. Riley, Jason R. Devlin, Cory M. Ayres, Grant L.J. Keller, Yuting Zhang, Craig W. Vander Kooi, Michael I. Nishimura, Brian M. Baker
Journal: Molecular Therapy (2018)

T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use. T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use.
Abstract 225: Sudden Cardiac Arrest Messaging Study. The Public’s Motivation to Learn CPR/AED Skills and to Act in an Emergency Increases With a Clear Understanding of SCA and the Impact These Skills Have on Increasing Survival
Authors: Mary M Newman, Jennifer Chap, Karen Ba, Youssou Ba, Rick Chap, Kelly N Sawyer
Journal: Circulation (2018)

Introduction: Survival from sudden cardiac arrest (SCA) outside hospitals depends largely on immediate bystander intervention. We measured the impact a layperson-friendly definition of SCA has on increasing perceived importance of CPR/AED (automated external defibrillator) skills and the likelihood to act, plus messages that drive action. Hypothesis: Low public awareness of SCA contributes to low survival rates; a layperson-friendly definition of SCA could improve perceived importance of CPR/AED training and likelihood to act in emergencies; identifying messages that motivate action could help reveal an effective communications strategy. Methods: We conducted a quantitative/qualitative study with an online survey of a representative national sample of adults (n=2,232) and in-depth interviews (n=20). Online respondents were exposed to framing questions, then split into two matched panels. One panel was exposed to a layperson-friendly definition of SCA (n=1,128); the other was exposed to 11 discrete messages (n=1,104). Questions pre- and post-exposure to the definition measured lift in importance to learn skills and likelihood to give CPR/use an AED. Messages were tested on relative strength in motivating action and grabbing attention. Results: The public is confused/unfamiliar with SCA and the need for immediate intervention. Barriers to bystander intervention include lack of confidence (39%), concerns about hurting the victim (38%), belief another is more competent (37%), and liability (28%); notably, 18% of respondents indicate no barriers (n=2,232). A friendly definition of SCA increases the belief that learning CPR/AED skills is “extremely important.” Those “very likely” to give CPR/use AED jump 26% and 38% respectively (n=1,128). Including “sudden” in the definition proves important, conveying urgency. The messages that drive motivation to act and grab attention address doubling or tripling the chance of survival and saving the life of a loved one. Conclusions: Lack of awareness/understanding of SCA contributes to public apathy. A layperson-friendly definition of SCA significantly increases likelihood to give CPR and use an AED. Including “sudden” in the definition signals urgency. Two key messages show strength in driving action.
Abstract 16541: Abnormal Brain Connectivity and Poor Neurodevelopmental Outcome in Congenital Heart Disease Patients With Subtle Brain Dysplasia
Authors: Ashok Panigrahy, Jodie Votava-Smith, Vincent Lee, George Gabriel, Nikolai Klena, Brian Gibbs, William T Reynolds, Giulio Zuccoli, Sharon O'Neil, Vincent J Schmithorst, Lisa Paquette, Cecilia W Lo
Journal: Circulation (2015)

Introduction: Mutant mouse models with congenital heart disease (CHD) were observed to have distinct brain dysplasia, prompting an assessment for brain anomalies in CHD patients. CHD infants with brain magnetic resonance imaging (MRI) assessments were recruited and scored using a novel brain dysplasia index. Validation was conducted with parallel brain connectome analysis and neurodevelopment outcome assessments. Methods: The Ohia mutant mouse line and others were analyzed for brain defects using 3D episcopic confocal histopathology. In parallel, we recruited 220 CHD neonates with MRI scans from two large centers. This included pre and postoperative conventional MRI sequences and diffusion tensor imaging (DTI). Brain connectivity measurements with DTI-graph analysis and neurodevelopmental testing at 18 months of age (Battelle Developmental Inventory) were obtained. Results: The CHD mouse mutant analysis revealed high prevalence of brain dysplasia involving the olfactory bulb, cerebellum, hippocampus, corpus callosum and choroid plexus. Based on these findings, a brain dysplasia index (BDI) was developed for clinical assessment of CHD patients, with one point for abnormality in any of these structures right or left and for presence of extra-axial cerebral spinal fluid. Analysis of 220 CHD neonates yielded BDI scores ranging from 1 to 17, with average score of 4.1. An elevated BDI score was seen across a spectrum of cardiac lesions, and was similar pre-op and post-op. DTI graph connectivity measurements (reduced nodal efficiency) correlated with high BDI score (p&lt;0.05), but not to specific heart lesions or white matter injury. Neurodevelopmental assessment of 20 patients at 18 months showed higher BDI score correlated with reduction in Total Developmental Quotient (p &lt;0.05) and Adaptive Developmental Quotient (p&lt;0.009). Conclusion: A brain dysplasia index was developed based on brain anomalies seen in CHD mutant mouse models. Infants with CHD of a broad spectrum with high BDI score showed abnormal brain connectivity and poor neurodevelopmental outcome. These findings suggest the poor neurodevelopmental outcome associated with CHD may involve subtle brain dysplasia with a shared developmental etiology with the structural heart disease.
Corporal Punishment and Children’s Report Cards—Failing Our Children
Authors: Antoinette L. Laskey
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Pelvic Complications After Prostate Cancer Radiation Therapy and Their Management: An International Collaborative Narrative Review
Authors: Rano Matta, Christopher R. Chapple, Margit Fisch, Axel Heidenreich, Sender Herschorn, Ronald T. Kodama, Bridget F. Koontz, Declan G. Murphy, Paul L. Nguyen, Robert K. Nam
Journal: European Urology (2018)
Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma
Authors: Atish Mohanty, Natalie Sandoval, An Phan, Thang V. Nguyen, Robert W. Chen, Elizabeth Budde, Matthew Mei, Leslie Popplewell, Lan V. Pham, Larry W. Kwak, Dennis D. Weisenburger, Steven T. Rosen, Wing C. Chan, Markus Müschen, Vu N. Ngo
Journal: Blood (2018)
Multimodal and Multiscale Analysis Reveals Distinct Vascular, Metabolic and Inflammatory Components of the Tissue Response to Limb Ischemia
Authors: Tamar Kapanadze, Jens P. Bankstahl, Alexander Wittneben, Wolfgang Koestner, Matthias Ballmaier, Jaba Gamrekelashvili, Kashyap Krishnasamy, Anne Limbourg, Tobias L. Ross, Geerd-Jürgen Meyer, Hermann Haller, Frank M. Bengel, Florian P. Limbourg
Journal: Theranostics (2018)

Ischemia triggers a complex tissue response involving vascular, metabolic and inflammatory changes.Methods: We combined hybrid SPECT/CT or PET/CT nuclear imaging studies of perfusion, metabolism and inflammation with multicolor flow cytometry-based cell population analysis to comprehensively analyze the ischemic tissue response and to elucidate the cellular substrate of noninvasive molecular imaging techniques in a mouse model of hind limb ischemia.Results: Comparative analysis of tissue perfusion with [ 99m Tc]-Sestamibi and arterial influx with [ 99m Tc]-labeled albumin microspheres by SPECT/CT revealed a distinct pattern of response to vascular occlusion: an early ischemic period of matched suppression of tissue perfusion and arterial influx, a subacute ischemic period of normalized arterial influx but impaired tissue perfusion, and a protracted post-ischemic period of hyperdynamic arterial and normalized tissue perfusion, indicating coordination of macrovascular and microvascular responses.In addition, the subacute period showed increased glucose uptake by [ 18 F]-FDG PET/CT scanning as the metabolic response of viable tissue to hypoperfusion.This was associated with robust macrophage infiltration by flow cytometry, and glucose uptake studies identified macrophages as major contributors to glucose utilization in ischemic tissue.Furthermore, imaging with the TSPO ligand [ 18 F]-GE180 showed a peaked response during the subacute phase due to preferential labeling of monocytes and macrophages, while imaging with [ 68 Ga]-RGD, an integrin ligand, showed prolonged post-ischemic upregulation, which was attributed to labeling of macrophages and endothelial cells by flow cytometry.Conclusion: Combined nuclear imaging and cell population analysis reveals distinct components of the ischemic tissue response and associated cell subsets, which could be targeted for therapeutic interventions.
Microhexagon gradient array directs spatial diversification of spinal motor neurons
Authors: Geok Soon Lim, Jin Hui Hor, Nicholas R Y Ho, Chi Yan Wong, Shi Yan Ng, Boon Seng Soh, Huilin Shao
Journal: Theranostics (2018)

Motor neuron diversification and regionalization are important hallmarks of spinal cord development and rely on fine spatiotemporal release of molecular cues. Here, we present a dedicated platform to engineer complex molecular profiles for directed neuronal differentiation. Methods: The technology, termed microhexagon interlace for generation of versatile and fine gradients (microHIVE), leverages on an interlocking honeycomb lattice of microstructures to dynamically pattern molecular profiles at a high spatial resolution. By packing the microhexagons as a divergent, mirrored array, the platform not only enables maximal mixing efficiency but also maintains a small device footprint. Results: Employing the microHIVE platform, we developed optimized profiles of growth factors to induce rostral-caudal patterning of spinal motor neurons, and directed stem cell differentiation in situ into a spatial continuum of different motor neuron subtypes. Conclusions: The differentiated cells showed progressive RNA and protein signatures, consistent with that of representative brachial, thoracic and lumbar regions of the human spinal cord. The microHIVE platform can thus be utilized to develop advanced biomimetic systems for the study of diseases in vitro.
A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Malignancies
Authors: Naval G. Daver, Harry P. Erba, Nikolaos Papadantonakis, Daniel J. DeAngelo, Eunice S. Wang, Marina Y. Konopleva, Callum M. Sloss, Kerry Culm-Merdek, Patrick A. Zweidler-McKay, Hagop M. Kantarjian
Journal: Blood (2018)
Abstract 15969: A Novel Proteomic Predictor of Cholesterol Efflux Capacity Demonstrates Inverse Association With Cardiovascular Disease
Authors: Timothy Collier, Zhicheng Jin, Marc Penn, Cory Bystrom
Journal: Circulation (2018)

Introduction: Cholesterol efflux capacity (CEC) is a cell-based measure of HDL function. Low CEC has been shown to be associated with cardiovascular disease. However, cell-based CEC assay is comple...
Arylsulfonamide 64B Inhibits Hypoxia/HIF-Induced Expression of c-Met and CXCR4 and Reduces Primary Tumor Growth and Metastasis of Uveal Melanoma
Authors: Lei Dong, Shuo You, Qing Zhang, Satoru Osuka, Narra S. Devi, Stefan Kaluz, Jalisa H. Ferguson, Hua Yang, Guoliang Chen, Binghe Wang, Hans E. Grossniklaus, Erwin G. Van Meir
Journal: Clinical Cancer Research (2018)

Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the antitumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms.UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver, and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal-epithelial transition factor (c-Met) were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex.Systemic administration of 64B had potent antitumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (∼70% reduction) and spontaneous liver metastasis (∼50% reduction), and extending mice survival (P < 0.001) while being well tolerated. 64B inhibited hypoxia-induced expression of CXCR4 and c-Met, 2 key drivers of tumor invasion and metastasis. 64B disrupted the HIF-1 complex by interfering with HIF-1α binding to p300/CBP co-factors, thus reducing p300 recruitment to the MET and CXCR4 gene promoters. 64B could thermostabilize p300, supporting direct 64B binding to p300.Our preclinical efficacy studies support the further optimization of the 64B chemical scaffold toward a clinical candidate for the treatment of UM.
Abstract IA04: Opportunities for translational and discovery research: Next-Gen genomics
Authors: William C. Hahn
Journal: Clinical Cancer Research (2018)

Abstract Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. These approaches will yield critical information regarding the identification, number, and types of alterations found in human tumors and are increasingly being applied prospectively to patient samples in the clinic. We have deployed an enterprise level cancer genotyping test, PROFILE, for all cancer patients at the Brigham and Women's Hospital and the Dana-Farber Cancer Institute. This initial approach has already provided insight into how to integrate such efforts into clinical care. New technologies now also allow the interrogation of tumors from circulating nucleic acids. At the same time, complementary efforts to identify new targets and therapeutics are being used to increase the repertoire of agents to operationalize precision cancer medicine. Citation Format: William C. Hahn. Opportunities for translational and discovery research: Next-Gen genomics [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA04.
Pharmacodynamic modelling of β-lactam/β-lactamase inhibitor checkerboard data: illustration with aztreonam–avibactam
Authors: A. Chauzy, J. Buyck, B.L.M. de Jonge, S. Marchand, N. Grégoire, W. Couet
Journal: Clinical Microbiology and Infection (2018)

Checkerboard experiments followed by fractional inhibitory concentration (FIC) index determinations are commonly used to assess in vitro pharmacodynamic interactions between combined antibiotics, but FIC index cannot be determined in case of antibiotic/non-active compound combinations. The aim of this study was to use a simple modelling approach to quantify the in vitro activity of aztreonam-avibactam, a new β-lactam-β-lactamase inhibitor combination.MIC checkerboard experiments were performed with 12 Enterobacteriaceae with diverse β-lactamases profiles. Aztreonam MICs in the absence and presence of avibactam at different concentrations (ranging from 0.0625 to 4 mg/L) were determined. Aztreonam MIC versus avibactam concentrations were fitted by an inhibitory Emax model with a baseline effect parameter.A concentration-dependent relationship was observed with a steep initial reduction of aztreonam MIC at low avibactam concentrations and reaching a maximum at higher avibactam concentrations that was adequately fitted by the model. Maximum avibactam effect was characterized by the ratio of aztreonam MICs in the absence of avibactam (MIC0) and when avibactam concentration tends toward infinity (MIC∞), and this ratio ranged between 90 and 10 068 depending on the strain. Avibactam potency was characterized by avibactam concentrations corresponding to 50% of the maximum effect (IC50 values between 0.00022 and 0.053 mg/L).An inhibitory Emax model with a baseline effect could quantify maximum avibactam effect and potency among various strains. This simple modelling approach can be used to compare the activity of other combinations of antibiotics with non-antibiotic drugs when FIC index is inappropriate.
<b>T</b> <sub> <b>RM</b> </sub> <b>maintenance is regulated by tissue damage via P2RX7</b>
Authors: Regina Stark, Thomas H. Wesselink, Felix M. Behr, Natasja A. M. Kragten, Ramon Arens, Friedrich Koch-Nolte, Klaas P. J. M. van Gisbergen, René A. W. van Lier
Journal: Science Immunology (2018)

The recognition of tissue damage via P2RX7 reduces the persistence of tissue-resident memory T cells (T RM ).
The <scp>FACE</scp> ‐Q Skin Cancer Module addresses post‐resection aesthetic and quality of life outcomes
Authors: E.H. Lee, A.L. Pusic, S.J. Cano, A.F. Klassen
Journal: British Journal of Dermatology (2018)

Linked Article: Dobbs et al. Br J Dermatol 2019; DOI: 10.1111/bjd.17342
Poly(β‐Amino Esters): Synthesis, Formulations, and Their Biomedical Applications
Authors: Yong Liu, Yuanfeng Li, Damla Keskin, Linqi Shi
Journal: Advanced Healthcare Materials (2018)

Abstract Poly(β‐amino ester) (abbreviated as PBAE or PAE) refers to a polymer synthesized from an acrylate and an amine by Michael addition and has properties inherent to tertiary amines and esters, such as pH responsiveness and biodegradability. The versatility of building blocks provides a library of polymers with miscellaneous physicochemical and mechanical properties. When used alone or together with other materials, PBAEs can be fabricated into different formulations in order to fulfill various requirements in drug delivery (for instance, gene, anticancer drugs, and antimicrobials delivery) and natural complex mimicry (nanochaperones). This progress report discusses the recent developments in design, synthesis, formulations, and applications of PBAEs in biomedical fields and provides a perspective view for the future of the PBAEs.