Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient ...responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
Selective activation of the Group II metabotropic glutamate receptors 2/3 (mGlu2/3) by either full agonists or positive allosteric modulators (PAMs) show anxiolytic activity. In the present study the ...anxiolytic profile of mGlu2/3 receptor agonists LY-354740 and LY-404039 and the mGlu2 receptor PAM 1-methyl-2-((cis-3-methyl-4-(4-trifluoromethyl-2-methoxy)-phenyl)piperidin-1-yl)-1H-imidazo4,5-bpyridine (MTFIP) were evaluated using neurophysiology-based assays. Activation of mGlu2/3 receptors by these compounds, as well as the positive control diazepam, significantly decreased the frequency of hippocampal theta oscillation elicited by stimulation of the brainstem nucleus pontis oralis (nPO), a characteristic action of anxiolytic compounds. Since the nPO is a critical region involved in regulation of rapid eye movement sleep, mGlu2/3 receptor activators were also tested on sleep parameters, as well as on cortical and hippocampal encephalography (EEG) activity. Both mGlu2/3 agonists and the mGlu2 PAM significantly prolonged REM sleep latency and reduced total REM sleep duration while during the active awake state all compounds lowered hippocampal peak theta frequency. However, diazepam and mGlu2/3 agonists/PAM elicited opposite changes in cortical EEG delta and beta bands. Delta power significantly increased after any of the mGlu2/3 compounds but decreased after diazepam. In the beta band, mGlu2/3 receptor agonists dose-dependently decreased beta power in contrast to the well-known beta activation by diazepam. These effects lasted 3–4h and could not be explained by modest, transient changes (<1h) in waking and slow wave sleep. The current observations support the role of mGlu2/3 receptor activators as potential anxiolytic compounds, but indicate a distinct action on cortical EEG activity which is different from the effects of GABAA PAMs.
This article is part of a Special Issue entitled ‘Anxiety and Depression’.
► Hippocampal theta is modulated similarly by diazepam and mGlu2/3 activators. ► mGlu2/3 receptor activators decrease the frequency of stimulated theta in rats. ► In freely moving rats mGlu2/3 activation decreases REM sleep. ► mGlu2/3 activators elicit EEG changes in freely moving rats opposite to diazepam.
Abstract
Cyclorotors employ cyclically pitched axial rotor blades to create an extremely maneuverable propulsion system. The pitch angle throughout one rotation is defined so that the resulting blade ...angle of attack follows a prescribed function that generates lift. The lift and drag produced is also affected by curvilinear flow, dynamic stall, and induced velocities, all of which affect the resulting angle of attack. These factors form complex relationships that are difficult to model analytically, making it hard to predict a cyclorotor’s performance. Here, a numerical model is presented which can be used to predict thrust and power draw of different cyclorotor configurations. Parameters include airfoil, number of rotor blades, rotational velocity, pivot function, fluid properties and Reynold’s number. The numerical model builds on previously implemented approximations but focuses on time-efficient calculations so that many configurations may be calculated in an iterative process. In each iteration the parameters can be adjusted according to machine learning or other metaheuristic optimization algorithms to determine an optimal configuration.
The rise of China has shifted the balance of power in the Indo-Pacific region. China has tried to influence small island states that were previously under the spheres of influence of Australia and ...India by offering lucrative offers under its Belt and Road Initiative (BRI). Small states remain in a quandary about how to approach the evolving regional security paradigm. Using a realism-based perspective, this paper explores small state options through two case studies: Sri Lanka and Fiji and contributes to the scholarly literature by analysing and drawing conclusions about small state options and whether they can opt to return to their traditional relationships and partnerships. The paper draws some conclusions that contrast with some realist assumptions, including a defiance on the part of small island states, who under the right circumstances can upend the status quo in the pursuit of greater economic benefits.
Here we describe a suite of experiments probing the ability of ESI propulsion sources to serve as TOF-MS ionization stages in pure vacuum operation. The goals of the study are to assess the ...operational parameter space which may result in biomolecules entrained in an ion spray, detectable by traditional mass spectrometry techniques. The variables explored in this work include the ionic liquid solvents EMI-BF4 and EMI-Am, and biomolecules arginine and cellulose. A laboratory ESI source is coupled with a TOF-MS capable of providing a mass resolution (m/dm) between 200 and 1000 for the ion range of interest (100-500 amu), The ion spray is characterized with the solvent alone and with the biomolecules mixed in. Initial experiments indicate that cellulose may be detectable at high concentrations in EMI-BF 4 while operation with EMI-Am may require heating above room temperature.
Multiple myeloma has a continued need for more effective and durable therapies. B cell maturation antigen (BCMA), a plasma cell surface antigen and member of the tumor necrosis factor (TNF) receptor ...superfamily, is an attractive target for immunotherapy of multiple myeloma due to its high prevalence on malignant plasma cells. The current work details the pre-clinical evaluation of BCMA expression and development of a chimeric antigen receptor (CAR) targeting this antigen using a fully human single chain variable fragment (scFv). We demonstrate that BCMA is prevalently, but variably expressed by all MM with expression on 25-100% of malignant plasma cells. Extensive Immunohistochemical analysis of normal tissue expression using commercially available polyclonal antibodies demonstrated expression within B-lineage cells across a number of tissues as expected. Based upon the highly restricted expression of BCMA within normal tissues, we generated a set of novel, fully human scFv binding domains to BCMA by screening a naïve B-cell derived phage display library. Using a series of
and pre-clinical
studies, we identified a scFv with high specificity for BCMA and robust anti-myeloma activity when used as the binding domain of a second-generation CAR bearing a CD137 costimulatory domain. This BCMA-specific CAR is currently being evaluated in a Phase 1b clinical study in relapsed and refractory MM patients (NCT02546167).
India–Thailand Security Cooperation Cogan, Mark Shawn; Mishra, Vivek
Journal of Asian security and international affairs,
04/2020, Letnik:
7, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In the past, India’s resolve to connect with countries further to its east centred on its relationship with ASEAN as a group and lacked a holistic outlook as it emphasised on a lopsided approach that ...left out the security dimension. The bilateral relationship between Bangkok and New Delhi marks an emerging departure from this past trend. In the recent past, Thailand has emerged as a bright spot in India’s vast array of security relationships, with growing focus on maritime security, counterinsurgency and counterterrorism operations, joint patrols and exchange of personnel in training. Besides boosting interoperability, increasing joint actions seek to marry India’s Act East policy with Thailand’s Look West policy, both of which emerged in the past decade of the twentieth century. Both countries look to strengthening their resolve in the Indo-Pacific, even as the region’s stability gets further complicated by sharpening Great Power politics. This article scrutinises the India–Thailand relationship from a security perspective and tests the compatibility of this emerging bilateral relationship with a regional security architecture conceptualisation in the Indo-Pacific. As such, this article seeks to fulfil two important goals: fill the literature deficit in India–Thailand relations that has often been eclipsed and subsequently neglected by the overarching canvass of India–ASEAN relations and analyse India–Thailand bilateral relations from the perspective of an emerging security partnership in the complex labyrinth of relationships in the Indo-Pacific.
Although there have been compelling advances in the cancer immunotherapy space recently in the form of chimeric antigen receptor (CAR) modified T-cells and checkpoint inhibitors, advanced tools to ...explore the therapeutic mechanisms of their combination are not adequately developed or widely available. To address this growing need, we developed a robust quantitative fluorescent immunohistochemistry platform using multiplex AQUA (Automated Quantitative Analysis) technology to evaluate checkpoint inhibitor expression, enumerate CAR T cells and determine the interaction between tumor cells and immune cells via novel co-localization algorithms. We explored utility of this method both in preclinical- and clinical model systems. In an immunodeficient mouse model of B-cell lymphoma, we evaluated homing of CAR T cells to malignant B-cells in primary lymphoid organs. We determined the phenotype and functional status of the CAR T cells via multiplex analyses of CD4, CD8, PD1 and FOXP3 expression. Additionally, to enable combination immunotherapies in Diffuse Large B-Cell Lymphoma (DLBCL) setting, we explored prevalence of adaptive immune resistance mechanisms in the form of PD1 and PD-L1 expression in immune- and tumor cell compartments via landmarks created by cytoplasmic and nuclear stains in both primary and secondary biopsies from DLBCL patients (n = 63). To support patient selection for CAR T trials, we quantified expression and prevalence of relevant tumor antigens that could not be scored reproducibly by traditional methods to yield objective cut points. We anticipate utilization of these quantitative multiplexed IHC methods for optimal selection of patients into upcoming novel combination immunotherapy trials
Tran:Genoptix: Employment. Scott:Genoptix: Employment. Lee:Genoptix: Employment. Singh:Novartis: Employment. Cogan:Novartis: Employment. Bordeaux:Genoptix: Employment. Jennifer:Genoptix: Employment. Lameh:Genoptix: Employment. Tribouley:Novartis: Employment. Kassim:Novartis: Employment. Tangri:Genoptix Inc., a Novartis company: Employment. Dakappagari:Genoptix Inc., a Novartis company: Employment.
Abstract Introduction Multiple myeloma (MM) is the second most prevalent hematopoietic malignancy with an overall 5-year survival rate of 58%. B cell maturation antigen (BCMA) is selectively ...expressed on normal and malignant plasma cells, making it an attractive MM target. Anti-BCMA chimeric antigen receptor (CAR) T cell therapy and T cell engagers have shown promise as treatment options for certain MM patients; however, potential toxicities associated with these anti-BCMA therapies, such as cytokine release syndrome (CRS), have limited broader utilization. Much like T cells, natural killer (NK) cells are cytolytic and have demonstrated an innate capacity to reduce tumor burden while exhibiting a more favorable safety profile in clinical testing. To that end, we developed a cryopreserved allogeneic cell therapy comprised of genetically modified human umbilical cord blood-derived (CB) NK cells transduced with a gammaretroviral vector, which incorporates genes for an anti-BCMA CAR and soluble human interleukin-15 (sIL-15). Referred to hereafter as anti-BCMA CAR-NK, it exhibits both innate NK- and CAR-mediated killing in vitro and robust in vivo activity against established MM tumors. Methods CBNK cells were isolated from donor cord blood units, propagated using feeder cells, transduced with a gammaretroviral vector to express an anti-BCMA CAR and soluble human IL-15, and propagated further before harvest and cryopreservation. Donor-equivalent untransduced (UTD) NK cells were generated via the same process but without the transduction step. Cryopreserved anti-BCMA CAR-NK and UTD NK cells were used for in vitro studies, including short-term killing, as well as for evaluation of activity against established MM tumors in vivo using the MM.1S-Luc4 model. Results The anti-BCMA CAR was successfully expressed across all batches of anti-BCMA CAR-NK generated. Results from an in vitro cytotoxicity assay indicated that anti-BCMA CAR-NK kills BCMA expressing MM.1S-Luc4 tumor cells and secretes IFNγ, TNFα, and granzyme B at greater amounts compared to donor-equivalent UTD NK. Anti-BCMA CAR-NK and UTD NK cells also demonstrated equivalent cytotoxicity towards BCMA non-expressing cell lines, JJN3-Luc BCMA KO and NCI-H520, in an effector:target cancer cell dependent manner, highlighting the potential for treatment with anti-BCMA CAR-NK post-prior BCMA therapy. In in vivo studies, anti-BCMA CAR-NK exhibited robust anti-tumor activity in an MM.1S-Luc4 NSG mouse xenograft model, with no signs of anti-BCMA CAR-NK related body weight loss. Conclusion A cryopreserved allogeneic anti-BCMA CAR-NK cellular therapy exhibits both innate and CAR-mediated killing in vitro and robust in vivo activity in MM tumor models. Preclinical data supports future clinical evaluation in relapsed/refractory MM patients who have received prior BCMA therapy and IND enabling studies are ongoing. Citation Format: LeeAnn Talarico, Christina Wong, Chunyan Pang, Taylor Hickman, Chenqi Hu, Amy Shaw, Emily Wisniewski, Shao-Chiang (Michael) Lai, Pranjal Sharma, Shaun Moore, Luan Nguyen, Kayla Rhuda, Saurin Patel, Paul Lin, Rafet Basar, Shawn Cogan, Kat Sofjan, Arun Ramamurthy, Aaron Handler, Kathryn Fraser, Yana Wang, Katayoun Rezvani, Michael D. Curley. A cryopreserved allogeneic anti-BCMA CAR-NK cellular therapy exhibits both innate and CAR-mediated MM cell killing in vitro and in vivo abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1322.
Abstract
Metastatic melanoma is a highly lethal type of cancer and is often refractory to all traditional chemotherapeutic agents. Melanoma is associated with a high burden of genetic alteration, ...e.g. BRAF, NRAS or NF1 mutation. In the clinic, BRAF inhibitors are used as a targeted therapy to treat melanoma patients, but thus far a single-agent approach is not capable of achieving a durable response for this lethal disease. Very often, patients rapidly develop resistance to BRAF inhibitors. In the current study, we propose a large scale in vivo screening using patient-derived xenograft models (PDXs) for compound profiling. Since these PDX melanoma models are derived from individual patient tumors and therefore represent the genetic heterogeneity of patient tumors, we propose a “one animal per model per compound” approach (mouse clinical trial) to understand the genetic factors that contribute to drug response. In addition, we use this approach to model drug resistance after long-term compound treatment. We find that the mouse clinical trial approach accurately predicts response of both cytotoxic chemotherapeutics as well as targeted therapies. In addition, this approach successfully recapitulates the resistance profile of a novel BRAF inhibitor LGX818 in melanoma. We also find that combination of LGX818 with other targeted therapy agents including PI3K and MEK inhibitors significantly increases the response rates and delays the development of resistance. Taken together, our findings suggest that the mouse clinical trial is a valid approach to model drug response and resistance, and can be used to predict patient response in the clinic.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A11.
Citation Format: Guizhi Yang, John Green, Colleen Kowal, Shawn Cogan, Roberto Velazquez, John Monahan, Joshua Korn, Nicholas Keen, Juliet Williams, Hui Gao. Modeling drug response and resistance using patient-derived xenograft models. abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A11.
PDF
