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Drug screening immune response cancer

Susmita Ghosh, Manu Prasad, Kiran Kundu, Limor Cohen, Ksenia M Yegodayev, Jonathan Zorea, Ben-Zion Joshua, Batel Lasry, Orr Dimitstein, Anat Bahat-Dinur, Aviram Mizrachi, Vladimir Lazar, Moshe Elkabets, Angel Porgador
Despite of remarkable progress made in the head and neck cancer (HNC) therapy, the survival rate of this metastatic disease remain low. Tailoring the appropriate therapy to patients is a major challenge and highlights the unmet need to have a good preclinical model that will predict clinical response. Hence, we developed an accurate and time efficient drug screening method of tumor ex vivo analysis (TEVA) system, which can predict patient-specific drug responses. In this study, we generated six patient derived xenografts (PDXs) which were utilized for TEVA...
2019: Frontiers in Oncology
Jian Cai, Lei Wang
Colorectal cancer is one of the most common malignant tumors, and its incidence and mortality are increasing year by year in China. In 2018, for the first time, the FIT-DNA test was written into the expert consensus as the recommended screening technology in China. As the core technology of colorectal cancer screening, colonoscopy for right colon cancer is further supported. With the application of artificial intelligence technology in colonoscopy, the efficiency and accuracy of screening will be greatly improved...
January 25, 2019: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
Peter H Liu, Richa B Shah, Yuanyuan Li, Arshi Arora, Peter Man-Un Ung, Renuka Raman, Andrej Gorbatenko, Shingo Kozono, Xiao Zhen Zhou, Vincent Brechin, John M Barbaro, Ruth Thompson, Richard M White, Julio A Aguirre-Ghiso, John V Heymach, Kun Ping Lu, Jose M Silva, Katherine S Panageas, Avner Schlessinger, Robert G Maki, Heath D Skinner, Elisa de Stanchina, Samuel Sidi
Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, platinums) and a lack of targeted alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic oxfendazole. Surprisingly, oxfendazole acts via the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) immune responses...
January 21, 2019: Nature Cell Biology
Zhen Xiang, Yingyan Yu
Immune checkpoint inhibitors are a promising strategy in the treatment of cancer, especially advanced types. However, not all patients are responsive to immune checkpoint inhibitors. The response rate depends on the immune microenvironment, tumor mutational burden (TMB), expression level of immune checkpoint proteins, and molecular subtypes of cancers. Along with the Cancer Genome Project, various open access databases, including The Cancer Genome Atlas and Gene Expression Omnibus, provide large volumes of data, which allow researchers to explore responsive or resistant biomarkers of immune checkpoint inhibitors...
January 18, 2019: Frontiers of Medicine
A V Kanygina, E I Sharova, R I Sultanov, Y A Schelygin, Y V Doludin, E S Kostryukova, E V Generozov
Cancer immunotherapy represents a promising and rapidly developing approach for the treatment of oncological diseases. Among the methods of personalized adjuvant immunotherapy, neoantigenic peptide-based drugs have demonstrated substantial efficiency. These drugs are designed to target mutant proteins arising from somatic alterations in the genome of tumor cells and thus stimulate immune response against tumor tissues. The methods of individual screening for potentially immunogenic mutations are mostly based on next-generation exome sequencing of tumor samples, which is a complex and costly procedure for clinical application...
November 2018: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
Wassim Abida, Michael L Cheng, Joshua Armenia, Sumit Middha, Karen A Autio, Hebert Alberto Vargas, Dana Rathkopf, Michael J Morris, Daniel C Danila, Susan F Slovin, Emily Carbone, Ethan S Barnett, Melanie Hullings, Jaclyn F Hechtman, Ahmet Zehir, Jinru Shia, Philip Jonsson, Zsofia K Stadler, Preethi Srinivasan, Vincent P Laudone, Victor Reuter, Jedd D Wolchok, Nicholas D Socci, Barry S Taylor, Michael F Berger, Philip W Kantoff, Charles L Sawyers, Nikolaus Schultz, David B Solit, Anuradha Gopalan, Howard I Scher
Importance: The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. Objective: To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population...
December 27, 2018: JAMA Oncology
Kritika Sinha, Manisha Majhi, Garima Thakur, Khushboo Patidar, Jajoriya Sweta, Anuraj Nayarisseri, Sanjeev Kumar Singh
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a B-lineage lymphoid malignancy of self-reactive cells that are focused to produce polyreactive natural auto antibodies. Its surface protein marker CD20 plays an important role in the humoral immune response, targeting which have emerged as an attractive therapeutic option for the treatment of CLL. The present study explains the interaction of the CD20 with its established inhibitors and to discover the compound having high binding affinity against the target protein receptor...
December 10, 2018: Current Topics in Medicinal Chemistry
Eric Shifrut, Julia Carnevale, Victoria Tobin, Theodore L Roth, Jonathan M Woo, Christina T Bui, P Jonathan Li, Morgan E Diolaiti, Alan Ashworth, Alexander Marson
Human T cells are central effectors of immunity and cancer immunotherapy. CRISPR-based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, single guide RNA (sgRNA) lentiviral infection with Cas9 protein electroporation (SLICE), to identify regulators of stimulation responses in primary human T cells...
November 13, 2018: Cell
Olha Nazarko, Amanuel Kibrom, Jana Winkler, Katherine Leon, Hannah Stoveken, Gabriel Salzman, Katarzyna Merdas, Yue Lu, Pradnya Narkhede, Gregory Tall, Simone Prömel, Demet Araç
Adhesion G-protein-coupled receptors (aGPCRs) play critical roles in diverse cellular processes in neurobiology, development, immunity, and numerous diseases. The lack of molecular understanding of their activation mechanisms, especially with regard to the transmembrane domains, hampers further studies to facilitate aGPCR-targeted drug development. Latrophilin-1/ADGRL1 is a model aGPCR that regulates synapse formation and embryogenesis, and its mutations are associated with cancer and attention-deficit/hyperactivity disorder...
May 25, 2018: iScience
Wan He, Xiangmei Zhang, Wenwen Li, Cheng Kong, Yuanyang Wang, Lianyu Zhu, Ruilian Xu, Guofang Deng, Peize Zhang
Background: PD-1 checkpoint inhibitors have shown a robust tumor response in the treatment of various cancers. Pembrolizumab is an anti-PD-1 checkpoint antibody approved for the treatment of unresectable or metastatic melanoma in more than 40 countries. Although autoimmune pneumonitis is considered a common immune-related adverse event of PD-1 inhibitors, only limited studies have assessed the development of opportunistic infections such as pulmonary tuberculosis (TB). Case presentation: A patient with metastatic melanoma whose pulmonary TB was activated after administration of pembrolizumab for melanoma is reported...
2018: OncoTargets and Therapy
Henry H Chung, Sean D Bellefeuille, Hayley N Miller, Thomas R Gaborski
Cell migration is essential to many life processes, including immune response, tissue repair, and cancer progression. A reliable quantitative characterization of the cell migration can therefore aid in the high throughput screening of drug efficacy in wound healing and cancer treatments. In this work, we report what we believe is the first use of SiR-Hoechst for extended live tracking and automated analysis of cell migration and wound healing. We showed through rigorous statistical comparisons that this far-red label does not affect migratory behavior...
November 3, 2018: Experimental Cell Research
E Albini, A Coletti, F Greco, M T Pallotta, G Mondanelli, M Gargaro, M L Belladonna, C Volpi, R Bianchi, U Grohmann, A Macchiarulo, C Orabona
Indoleamine 2,3 dioxygenase 1 (IDO1) is a metabolic enzyme that catalyzes the conversion of the essential amino acid tryptophan (Trp) into a series of immunoactive catabolites, collectively known as kynurenines. Through the depletion of Trp and the generation of kynurenines, IDO1 represents a key regulator of the immune responses involved in physiologic homeostasis as well as in neoplastic and autoimmune pathologies. The IDO1 enzyme has been described as an important immune checkpoint to be targeted by catalytic inhibitors in the treatment of cancer...
November 1, 2018: Biochemical Pharmacology
Christopher B Rodell, Sean P Arlauckas, Michael F Cuccarese, Christopher S Garris, Ran Li, Maaz S Ahmed, Rainer H Kohler, Mikael J Pittet, Ralph Weissleder
Tumour-associated macrophages (TAMs) are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet macrophages are highly plastic and can also acquire an anti-tumourigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors (TLRs) TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNPs) lead to efficient drug delivery to TAMs in vivo...
2018: Nature Biomedical Engineering
Jane Harper, Katherine J Adams, Giovanna Bossi, Debbie E Wright, Andrea R Stacey, Nicole Bedke, Ruth Martinez-Hague, Dan Blat, Laure Humbert, Hazel Buchanan, Gabrielle S Le Provost, Zoe Donnellan, Ricardo J Carreira, Samantha J Paston, Luise U Weigand, Martina Canestraro, Joseph P Sanderson, Sophie Botta Gordon-Smith, Kate L Lowe, Karolina A Rygiel, Alex S Powlesland, Annelise Vuidepot, Namir J Hassan, Brian J Cameron, Bent K Jakobsen, Joseph Dukes
Robust preclinical testing is essential to predict clinical safety and efficacy and provide data to determine safe dose for first-in-man studies. There are a growing number of examples where the preclinical development of drugs failed to adequately predict clinical adverse events in part due to their assessment with inappropriate preclinical models. Preclinical investigations of T cell receptor (TCR)-based immunotherapies prove particularly challenging as these biologics are human-specific and thus the conventional testing in animal models is inadequate...
2018: PloS One
Lesley Mathews Griner, Kalyani Gampa, Toan Do, Huyen Nguyen, David Farley, Christopher J Hogan, Douglas S Auld, Serena J Silver
Cancer cells have routinely been cultured in two dimensions (2D) on a plastic surface. This technique, however, lacks the true environment a tumor mass is exposed to in vivo. Solid tumors grow not as a sheet attached to plastic, but instead as a collection of clonal cells in a three-dimensional (3D) space interacting with their neighbors, and with distinct spatial properties such as the disruption of normal cellular polarity. These interactions cause 3D-cultured cells to acquire morphological and cellular characteristics which are more relevant to in vivo tumors...
September 5, 2018: Journal of Visualized Experiments: JoVE
Adrien Costantini, Catherine Julie, Coraline Dumenil, Zofia Hélias-Rodzewicz, Julie Tisserand, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Thierry Chinet, Jean-François Emile, Etienne Giroux Leprieur
Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA...
2018: Oncoimmunology
Simon Hayek, Nassima Bekaddour, Laurie Besson, Rodolphe Alves de Sousa, Nicolas Pietrancosta, Sébastien Viel, Nikaia Smith, Yves Jacob, Sébastien Nisole, Rupasri Mandal, David S Wishart, Thierry Walzer, Jean-Philippe Herbeuval, Pierre-Olivier Vidalain
Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings...
September 5, 2018: SLAS Discovery
Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf Huang
In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death...
August 28, 2018: ACS Nano
Wenxia Xu, Qi Wei, Mengjiao Han, Bingluo Zhou, Hanying Wang, Jianbing Zhang, Qiang Wang, Jie Sun, Lifeng Feng, Shouyu Wang, Yang Ye, Xian Wang, Jianwei Zhou, Hongchuan Jin
Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells...
2018: International Journal of Biological Sciences
Serena Varesano, Maria Raffaella Zocchi, Alessandro Poggi
New successful anti-cancer strategies are based on the stimulation of immune reaction against tumors: however, preclinical testing of such treatments is still a challenge. To improve the screening of anti-cancer drugs, three-dimensional (3D) culture systems, including spheroids, have been validated as preclinical models. We propose the spheroid 3D system to test anti-tumor drug-induced immune responses. We show that colorectal carcinoma (CRC) spheroids, generated with the epithelial growth factor (EGF), can be co-cultured with Vδ2 T cells to evaluate the anti-tumor activity of these effector lymphocytes...
2018: Frontiers in Immunology
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