tbuckley/cabot-search huggingface dataset:
Live cell imaging of signaling and metabolic activities
Authors: Maria R. Depaoli, Helmut Bischof, Emrah Eroglu, Sandra Burgstaller, Jeta Ramadani-Muja, Thomas Rauter, Maximilian Schinagl, Markus Waldeck-Weiermair, Jesse C. Hay, Wolfgang F. Graier, Roland Malli
Journal: Pharmacology & Therapeutics (2019)

The interplay of metabolic and signaling processes is prerequisite for the functionality of cells. Any disturbances may have severe consequences, resulting in the development of diseases. However, the complex coordination of metabolism and signaling events makes it difficult to decipher the link between molecular irregularities and pathogenesis. An excellent way to provide more clarity is to see into the living cell and watch cellular processes in real-time, with the add-on of being able to manipulate certain processes. Live cell imaging enables us to do exactly that, with steadily improving spatial and temporal resolution. Modern genetically encoded fluorescent probes in combination with state-of-the-art high-resolution imaging devices have proven themselves as a valuable approach for monitoring, manipulating and ultimately understanding the interaction of cell metabolism and signaling. These probes also represent powerful tools for detecting biomarkers of disease, identifying new drug targets and elucidating drug actions at the cellular to the molecular level.
Sonoprinting of nanoparticle-loaded microbubbles: Unraveling the multi-timescale mechanism
Authors: Silke Roovers, Guillaume Lajoinie, Ine De Cock, Toon Brans, Heleen Dewitte, Kevin Braeckmans, Michel Versluis, Stefaan C. De Smedt, Ine Lentacker
Journal: Biomaterials (2019)
Лечение хеликобактер-ассоциированных заболеваний в Украине, место препарата коллоидного висмута субцитрата в комплексной терапии таких больных
Authors: A.E. Dorofeiev, M.M. Rudenko, S.M. Tkach, A.V. Sybiliov
Journal: GASTROENTEROLOGY (2020)

В статье рассматривается один из актуальных вопросов современной гастроэнтерологии — лечение хеликобактерной инфекции (Нр). Подчеркнуто, что эрадикационная терапия в настоящее время определяется рекомендациями IV Маастрихтского консенсуса и, согласно современным стандартам, первая линия лечения должна основываться на национальных или региональных особенностях чувствительности возбудителя к основным антибактериальным препаратам. В случае множественной резистентности Нр во многих странах на первой ступени используются схемы, содержащие фторхинолоны. В странах с широкой распространенностью туберкулезной инфекции, к которым относится и Украина, с целью замедления формирования резистентности микобактерий целесообразно максимально сократить применение фторхинолонов для лечения других инфекций. Поэтому схемы эрадикации Нр с включением фторхинолонов в нашей стране следует использовать только при неэффективности стартовой терапии на второй ступени. В настоящее время чаще всего используются висмутсодержащие четырехкомпонентные схемы. Преимущества применения препаратов висмута в схемах антихеликобактерной терапии активно изучаются и доказываются клиническими исследованиями. В Украине висмутсодержащие схемы с применением коллоидного висмута субцитрата используют в качестве терапии второй линии. В данной статье представлены результаты исследования эффективности модифицированной четырехкомпонентной схемы лечения (ингибиторы протонной помпы в сочетании с фуразолидоном, амоксициллином и коллоидным субцитратом висмута (препарат Де-Нол)) при сохранении Нр-инфекции после стандартной трехкомпонентной терапии. Уделено внимание различиям схем терапии с учетом региональных особенностей резистентности Нр.
Abstract 4698: Development of a CRISPR-Cas9D10A targetable, high-complexity, single-cell barcoding approach for capture of treatment resistant subclones from heterogeneous cancers
Authors: Ze-yan Zhang, Ravesanker Ezhilarasan, Yingwen Ding, Qianghu Wang, Jie Yang, Lihong Long, Roel G. Verhaak, Erik P. Sulman
Journal: Cancer Research (2019)

Abstract Cancers are composed of heterogeneous cell populations and the clonal evolution of these cells is one of the key reasons for treatment resistance and tumor recurrence. A fundamental challenge in studying clonal evolution in these tumors is the difficulty in capturing the phenotype-associated (e.g. treatment resistant) sub-populations from the heterogeneous population. We developed an approach to individually barcode and isolate specific cell subpopulations by constructing a Cas9D10A and paired-gRNA targetable unique reporter (CAPTURE) barcoding library with up to 36 million unique barcodes. This approach enabled us to uniquely barcode &amp;gt; 1 million cells, track barcode distribution following treatment and then isolate the resistant subpopulation using the subpopulation-specific barcode. Proof of principle studies showed that specific barcoding cells, even at as low as 0.1%, could be efficiently isolated using barcode targeting and cell sorting. Applied our barcoding approach, we found that A375 cell acquired BRAF inhibitor resistance both from pre-exiting and late-emerging mechanisms. Colony formation experiments showed that the isolated subpopulations were indeed resistant clones. Whole exome, transcriptome and methylome analysis were applied to study the captured subpopulations. Our CAPTURE barcoding approach will enable the identification of the both pre-exiting and late-emerging genetic or epigenetic changes driving treatment resistance. Citation Format: Ze-yan Zhang, Ravesanker Ezhilarasan, Yingwen Ding, Qianghu Wang, Jie Yang, Lihong Long, Roel G. Verhaak, Erik P. Sulman. Development of a CRISPR-Cas9D10A targetable, high-complexity, single-cell barcoding approach for capture of treatment resistant subclones from heterogeneous cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4698.
Abstract 4587: The N-terminal domain of HARS is a novel NRP2 ligand and can regulate NRP2-dependent macrophage function
Authors: Navatha Shree Sharma, Samikshan Dutta, Steve Crampton, Sanna Rosengren, Kaustubh Datta
Journal: Cancer Research (2019)

Abstract Tumor-associated macrophages (TAM) are associated with regulation of antitumor immune responses, and neuropilin-2 (NRP2), a pleiotropic receptor with an emerging role in immune responses, has recently been demonstrated to be important for this activity (Roy et al, Cancer Res. 2018). Deletion of NRP2 results in impaired clearance of apoptotic tumor cells through reduced efferocytosis, which plays a role in tumor promotion. We now show that the N-terminal domain of the histidyl-tRNA synthetase (HARS) is a specific binding partner of NRP2, and can regulate the phagocytic function of NRP2 in macrophages. The HARS N-terminal domain, which is found only in higher eukaryotes, is conserved among splice variants of HARS and has evolved to regulate immune cell engagement. Incubation of macrophages with recombinant HARS N-terminal domain, had no effect on phagocytic uptake, but significantly impaired the maturation of phagosomes in a dose dependent manner. This phenotype mimics that of the NRP2 knockout, suggesting pharmacological intervention with this agent to modulate NRP2 driven biology may be possible. Citation Format: Navatha Shree Sharma, Samikshan Dutta, Steve Crampton, Sanna Rosengren, Kaustubh Datta. The N-terminal domain of HARS is a novel NRP2 ligand and can regulate NRP2-dependent macrophage function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4587.
Abstract 4741: Re-evaluating the role of P-glycoprotein in the resistance of high-risk neuroblastoma to standard-of-care chemotherapies
Authors: Caroline Atkinson, Carole M. Tactacan, Alvin Kamili, Federica Saletta, Christine Gana, Georgina L. Eden, Chelsea Mayoh, Richard B. Lock, Murray D. Norris, Michelle Haber, Andrew J. Gifford, Toby N. Trahair, Jamie I. Fletcher
Journal: Cancer Research (2019)

Abstract Background: Neuroblastoma is the most common extracranial solid malignancy in children, comprising 15% of cancer related deaths. Despite intensive treatment, patients with high-risk neuroblastoma (HR-NB) have a survival rate of ~50%, largely due to intrinsic or acquired drug resistance. The multidrug transporter P-glycoprotein (P-gp; ABCB1) effluxes several conventional agents used in HR-NB induction therapy, including doxorubicin, vincristine and etoposide, as well as the ALK inhibitor crizotinib. We observed high P-gp expression in HR-NB cell lines and patient-derived xenograft (PDX) models, so sought to assess the prevalence of P-gp expression and its role in resistance to standard-of-care chemotherapies and relevant targeted agents. Methods and Results: Using RNA-sequencing, immunohistochemistry and western blot on panels of neuroblastoma tumour samples, PDX models and cell lines, we demonstrated that high ABCB1/P-gp expression is frequent in HR-NB. Analysis of ABCB1 levels in large patient tumor datasets suggests that high expression is attributable to the sympathoadrenal lineage of the disease, that high expression is more common in HR-NB than in most other cancers, and that high relative expression of ABCB1 in HR-NB tumours is associated with poorer outcome, consistent with its multidrug transporter function. We demonstrated that the P-gp inhibitor tariquidar and P-gp knockdown (shRNA) both strongly sensitize cultured high P-gp expressing neuroblastoma cells to vincristine, doxorubicin and etoposide but not to ALK inhibitors. Further, P-gp knockdown sensitized human neuroblastoma xenografts to vincristine, substantially extending survival. Conclusions: Elevated P-gp expression is common in HR-NB and can be sufficient to confer resistance to standard-of-care chemotherapies in model systems. Our findings suggest that tumour P-gp levels might be used to guide treatment options for individual patients, and to avoid ineffective treatments. The potential of P-gp inhibitors as adjuncts to conventional chemotherapy for HR-NB should be further investigated. Citation Format: Caroline Atkinson, Carole M. Tactacan, Alvin Kamili, Federica Saletta, Christine Gana, Georgina L. Eden, Chelsea Mayoh, Richard B. Lock, Murray D. Norris, Michelle Haber, Andrew J. Gifford, Toby N. Trahair, Jamie I. Fletcher. Re-evaluating the role of P-glycoprotein in the resistance of high-risk neuroblastoma to standard-of-care chemotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4741.
Abstract 4129: Novel small molecule TLR7/8 agonists for enhancing NK cell-mediated ADCC
Authors: Vidhi Khanna, Hyunjoon Kim, Wenqui Zhang, Peter Larson, David Ferguson, Jayanth Panyam
Journal: Cancer Research (2019)

Abstract Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key mechanism of action for some therapeutic antibodies. ADCC involves killing of an antibody-coated target cell by an effector cell through the release of cytotoxic or cell death-inducing molecules. ADCC is triggered through interaction of Fcγ receptors present on the effector cell surface with the Fc region of the target-bound antibody. Natural killer (NK) cells are one of the primary effector cells that mediate ADCC. There is significant interest in designing therapeutic agents that can enhance ADCC because this can result in improved clinical responses with approved antibodies. We have developed a suite of highly substituted imidazoquinolines, which activate TLR 7 and/or 8 and induce significantly higher levels of cytokines compared to the FDA-approved TLR7 agonist imiquimod. In the current study, we evaluated our series of TLR7-specific, 8-specific and 7/8 dual selective agonists for their ability to improve ADCC with Cetuximab. We investigated NK cell activation in the presence of these compounds, as well as NK cell mediated ADCC against an EGFR expressing lung cancer cell line, A549. In addition, we also measured cytokine induction in human peripheral blood mononuclear cells in response to these compounds. Our studies show dual TLR 7/8 and 8-specific agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. however, mixed agonists also induce greater immunosuppressive cytokines compared to TLR8-specific agonists. Further, these agonists also significantly enhanced Cetuximab mediated ADCC in vitro. In vivo studies examining the anticancer efficacy of the combination of selected TLR7/8 agonists and Cetuximab are ongoing. Citation Format: Vidhi Khanna, Hyunjoon Kim, Wenqui Zhang, Peter Larson, David Ferguson, Jayanth Panyam. Novel small molecule TLR7/8 agonists for enhancing NK cell-mediated ADCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4129.
Abstract 123: Evaluating cellular cytotoxicity and potency of antibody-drug conjugates within 3-dimensional tumor models
Authors: Bhaskar S. Mandavilli, Chris Langsdorf, Aimei Chen, Yi-Zhen Hu, Marcy Wickett, Scott T. Clark
Journal: Cancer Research (2019)

Abstract 3-dimensional tumor spheroids provide biochemical conditions that closely resemble the tumor microenvironment in an intact organism. Noninvasive approaches such as fluorescence microscopy and high content analysis are highly advantageous as they allow for the study of these 3-dimensional systems. Here we investigate the penetration and potency of natural killer cells, cytotoxic T cells, and antibody-drug conjugates in three-dimensional models of breast and lung cancer. Unstimulated T cells produced minimal cytotoxicity, similar to untreated spheroids. Activated T cells penetrated and produced significant cytotoxicity throughout cancer spheroids. SKBR3 breast cancer cells form a compact, viable spheroid. Addition of NK cells leads to moderate cytotoxicity, while addition of NK cells and trastuzumab results in substantial cytotoxicity and degradation of spheroid structure. Trastuzumab labeled with iFL pHrodo Red becomes brightly fluorescent following specific endosomal internalization into breast cancer cells, but minimal toxicity is observed. Trastuzumab conjugated with both iFL pHrodo Red and MMAE internalizes into cells and results in cell killing. Fluorescence microscopy combined with novel cell and antibody labeling methods permits investigation of the penetration and potency of natural killer cells, cytotoxic T cells, and antibody-drug conjugates in three-dimensional solid tumor models. Citation Format: Bhaskar S. Mandavilli, Chris Langsdorf, Aimei Chen, Yi-Zhen Hu, Marcy Wickett, Scott T. Clark. Evaluating cellular cytotoxicity and potency of antibody-drug conjugates within 3-dimensional tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 123.
Abstract 10369: Safety of Anatomic versus Functional Diagnostic Testing: Insights From the PROMISE Trial (PROspective Multicenter Imaging Study for Evaluation of Chest Pain)
Authors: Michael T Lu, Pamela S Douglas, James E Udelson, Elizabeth C Adami, Brian B Ghoshhajra, Michael H Picard, Rhonda Roberts, Kerry L Lee, Andrew J Einstein, Daniel B Mark, Eric J Velazquez, William Carter, Michael Ridner, Hussein R Al-Khalidi, Udo Hoffmann
Journal: Circulation (2015)

Introduction: Suspected coronary artery disease (CAD) is a common indication for diagnostic testing. However, a comprehensive, randomized comparison of test safety, including radiation dose, incidental findings, and test complications, of coronary computed tomography angiography (CTA) and functional tests has not been performed. Methods: All PROMISE patients completing a diagnostic test were analyzed as tested for differences between CTA vs functional tests in A) 90 day cumulative radiation dose in milliSieverts (mSv), B) index test and cumulative dose for those whose physicians intended referral for nuclear stress before randomization, C) incidental findings (all and prespecified as potentially clinically significant) and D) index test complications. Results: Of 9470 eligible patients (mean age 61, 53% women), 4633 had CTA and 4837 had functional testing (3263 nuclear stress, 1083 stress echo and 491 exercise ECG). As a strategy comparison, CTA had lower median but higher mean cumulative radiation dose than functional testing (median: 10.3 vs 11.5 mSv, p&lt;0.001, mean: 12.5 vs 10.6, p&lt;0.001). In a test to test comparison in 6349 intended for nuclear stress before randomization, CTA had lower index test (mean: 10.5 vs 14.1, p&lt;0.001) and cumulative (mean: 12.4 vs 15.2, p&lt;0.001) dose than nuclear stress. Incidental findings were more common on CTA than functional tests (43% vs 2%, p&lt;0.001). CTA found more potentially clinically significant incidentals (19% vs 0.7%, p&lt;0.001), including valvular disease (echo), breast uptake (nuclear), and lung nodules, pneumonia or pulmonary embolism (CT). There were no major index test complications. Minor complications occurred in 0.8% of CTAs and 0.4% of functional tests (p&lt;0.01). In those intended for nuclear stress, complications occurred in 0.8% of CTAs and 0.5% of nuclear stress tests (p=0.17), including hypotension (nuclear) and mild contrast reaction or extravasation (CT). No CTA and 5 functional test complications led to hospitalization. Conclusions: CTA had lower median but higher mean radiation dose compared to all functional testing, but lower dose than nuclear stress. CTA had more potentially clinically meaningful incidental findings, and despite very low overall rates, more minor complications.
Abstract 18957: Dedifferentiation and Proliferation of Pre-Existing Cardiomyocytes Contribute to Endogenous Cardiomyocyte Renewal in Post-Infarct Hearts
Authors: Yiqiang Zhang, Nuria Gago-Lopez, Yonggang Liu, Ning Li, Amy M Martinson, W. R MacLellan
Journal: Circulation (2017)

Background: Albeit the evident renewal of adult cardiomyocytes (CMs), studying cellular mechanisms of endogenous myogenesis in adult hearts is challenging due to the scarcity of new CM formation an...
Phase 1 study of elotuzumab in combination with autologous stem cell transplantation and lenalidomide maintenance for multiple myeloma.
Authors: Keren Osman, Hearn J. Cho, Ajai Chari, Samir S. Parekh
Journal: Journal of Clinical Oncology (2019)

8021 Background: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. Methods: This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must be eligible for auto-SCT, and meet inclusion/exclusion criteria. Fifteen subjects participated in this study. The treatment plan is: In addition to PBSC harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily begins with cycle 4 of elotuzumab. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: 15 subjects have been enrolled in the study. All of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 15 subjects have completed 4 of the first 5 planned elotuzumab infusions.. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. There were no delays in hematopoietic reconstitution. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy appears to be safe and feasible. The trial is ongoing and has completed accrual. The clinical results will be updated for presentation.
Tumor Treating Fields (150 kHz) combined with FOLFOX inhibits gastric cancer in vitro
Authors: E. Zeevi, K. Gotlib, R. Shnaiderman, M. Munster, Y. Porat, T. Voloshin, S. Davidi, A. Shteingauz, N. Kaynan, M. Giladi, E. Kirson, U. Weinberg, A. Kinzel, Y. Palti
Journal: Annals of Oncology (2019)