Готові списки джерел за темами / Anti-tumor agent

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Добірка наукової літератури з теми "Anti-tumor agent"

Автор: Grafiati
Опубліковано: 3 червня 2025
Оновлено: 31 липня 2025

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Статті в журналах з теми "Anti-tumor agent"

1

Chen, Weicui, Bo Liu, Jun Chen, Guoqing Liu, and Xian Liu. "Targeted tumor MRI with gadobutrol-loaded anti-HER2 immunoliposomes." Acta Radiologica 58, no. 5 (2016): 573–80. http://dx.doi.org/10.1177/0284185116664225.

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Background Immunoliposomes have been used to deliver MR contrast agents to cancer tissue by targeting tumor associated antigens, thus enabling the visualization of biological processes at the cellular level. Purpose To develop and evaluate the feasibility of specific HER2 targeted liposomal MR contrast agent. Material and Methods Gd-loaded anti-HER2 immunolipomes (Gd-ILs) and non-targeted PEGylated liposomes (Gd-NTLs) were prepared and characterized. Tumor bearing animals were randomized into three groups: Gd- ILs, Gd- NTLs and gadobutrol. Animals were imaged prior and 5, 15, 60, 120 and 180 m
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2

Fareed, Jawed, Angel Gray, Daniel Kahn, et al. "The effect of tissue factor pathway inhibitor release and interactions with growth factors on the antitumor effects of ultra low molecular weight heparin semuloparin." Journal of Clinical Oncology 30, no. 15_suppl (2012): e13117-e13117. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13117.

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e13117 Background: Heparins are known to produce anti-tumor effects beside other pharmacologic actions. More recently an ultra LMWH has been developed for the prevention of thrombosis in cancer patients. Initial studies demonstrated that this agent also exhibits anti-tumor effects in animal models. To understand the mechanism of anti-tumor effects of this agent studies were designed to fractionate this ULMWH in to various AT affinity fractions. Methods: An ULMWH (semuloparin, Sanofi-aventis) and its high (HAF) and low (LAF) affinity fractions were prepare by AT affinity chromatography. These a
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3

Yamamoto, Satoshi, Eriko Aizu, Hong Jiang, et al. "The potent anti-tumor-promoting agent isoliquiritigenin." Carcinogenesis 12, no. 2 (1991): 317–23. http://dx.doi.org/10.1093/carcin/12.2.317.

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4

Wang, X. L., B. Q. Fu, S. J. Yang, et al. "Trichinella spiralis—A potential anti-tumor agent." Veterinary Parasitology 159, no. 3-4 (2009): 249–52. http://dx.doi.org/10.1016/j.vetpar.2008.10.052.

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OBATA, Rika, and Takeshi OHNUMA. "Electrochemical Oxidation of Anti-tumor Agent, Etoposide." CHEMICAL & PHARMACEUTICAL BULLETIN 41, no. 10 (1993): 1846–47. http://dx.doi.org/10.1248/cpb.41.1846.

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6

Rajabi, Mehdi, Mary Adeyeye, and Shaker A. Mousa. "Peptide-Conjugated Nanoparticles as Targeted Anti-angiogenesis Therapeutic and Diagnostic in Cancer." Current Medicinal Chemistry 26, no. 30 (2019): 5664–83. http://dx.doi.org/10.2174/0929867326666190620100800.

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:Targeting angiogenesis in the microenvironment of a tumor can enable suppression of tumor angiogenesis and delivery of anticancer drugs into the tumor. Anti-angiogenesis targeted delivery systems utilizing passive targeting such as Enhanced Permeability and Retention (EPR) and specific receptor-mediated targeting (active targeting) should result in tumor-specific targeting. One targeted anti-angiogenesis approach uses peptides conjugated to nanoparticles, which can be loaded with anticancer agents. Anti-angiogenesis agents can suppress tumor angiogenesis and thereby affect tumor growth progre
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7

Villegas-Vázquez, Edgar Yebrán, Laura Itzel Quintas-Granados, Hernán Cortés, et al. "Lithium: A Promising Anticancer Agent." Life 13, no. 2 (2023): 537. http://dx.doi.org/10.3390/life13020537.

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Lithium is a therapeutic cation used to treat bipolar disorders but also has some important features as an anti-cancer agent. In this review, we provide a general overview of lithium, from its transport into cells, to its innovative administration forms, and based on genomic, transcriptomic, and proteomic data. Lithium formulations such as lithium acetoacetate (LiAcAc), lithium chloride (LiCl), lithium citrate (Li3C6H5O7), and lithium carbonate (Li2CO3) induce apoptosis, autophagy, and inhibition of tumor growth and also participate in the regulation of tumor proliferation, tumor invasion, and
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Kakodkar, Nisha C., Radhika Peddinti, Morris Kletzel, et al. "The quinoxaline anti-tumor agent (R+)XK469 inhibits neuroblastoma tumor growth." Pediatric Blood & Cancer 56, no. 1 (2010): 164–67. http://dx.doi.org/10.1002/pbc.22639.

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Linot, Camille, Jasmeen Saini, and Prasad S. Adusumilli. "Sustained, cell-intrinsic versus intermittent, cell-extrinsic checkpoint blockade in solid tumor CAR T-cell therapy." Journal of Clinical Oncology 38, no. 5_suppl (2020): 16. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.16.

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16 Background: We and others have published that antigen-stress induced functional exhaustion of chimeric antigen receptor (CAR) T cells can be rescued by addition of anti-PD1 agents. To avoid the need for multiple administrations of anti-PD1 agent, we developed CAR T-cell intrinsic PD1 dominant negative receptor (PD1 DNR). Herein, we investigated the anti-tumor efficacy of cell-extrinsic versus intrinsic anti-PD1 strategies. Methods: Human T cells transduced with CD28 costimulated mesothelin-targeted CAR T cells (M28z) with or without anti-PD1 agent, and M28zPD1DNR CAR T cells were investigat
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Samuel, Samson, Elizabeth Varghese, Peter Kubatka, Chris Triggle, and Dietrich Büsselberg. "Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer." Biomolecules 9, no. 12 (2019): 846. http://dx.doi.org/10.3390/biom9120846.

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Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incid
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Дисертації з теми "Anti-tumor agent"

1

Jain, Neera. "Preformulation and formulation studies of RH1: A new investigational anti-tumor agent." Diss., The University of Arizona, 2001. http://hdl.handle.net/10150/290568.

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Currently, the National Cancer Institute is investigating RH1 for its potential use as an anti-tumor agent. A parenteral formulation is desired but the drug is highly unstable in aqueous solutions. Various effects on the stability of RH1 are investigated. All the reactions of RH1 follow first-order kinetics. The maximum shelf-life, obtained in neutral conditions, is about one week. The pH-rate profile shows slopes of approximately -1 in acidic conditions and +1 in basic conditions indicating that the degradation of RH1 is specific acid-base catalyzed. The energies of activation at pH's 6.0 and
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2

Fedeleş, Bogdan I. "The androgen receptor independent mechanism of toxicity of the novel anti-tumor agent 11[beta]-dichloro." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/61222.

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Анотація:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2009.<br>In title on title-page "[beta]" appears as the lower-case Greek letter. Vita. Page 284 blank. Cataloged from PDF version of thesis.<br>Includes bibliographical references.<br>Inspired by the toxicity mechanism of cisplatin in testicular cancer, a series of bi-functional genotoxicants has been designed that supplement their DNA damaging properties with the ability to interact with tumor specific proteins. One such compound, 11[beta] -dichloro links an aniline mustard moiety to a steroid ligand for
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LOPEZ, RIVAS PAULA. "SYNTHESIS OF INTEGRIN-TARGETING PRO-DRUGS FOR THE SELECTIVE RELEASE OF ANTI-TUMOR AGENTS." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/584099.

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In this PhD work, a variety of new SMDCs were designed and synthesized featuring different types of linkers and cytotoxic payloads. All of them were characterized and conjugated to peptidomimetic ligands bearing the RGD sequence (namely, the cyclo[DKP-RGD] and cyclo[RDGfK] compounds) aimed at targeting αVβ3 integrin receptor, which is overexpressed in many human cancers. Firstly, six new conjugates containing peptide linkers prone to cleavage in intracellular vesicles (such as the lysosomes) were synthesized and evaluated in vitro. The loss of potency generally displayed by these SMDCs in ant
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Wiesmann, Nadine [Verfasser]. "Analysis of the toxicity mechanism of zinc oxide nanoparticles aiming at their application as innovative anti-tumor agent / Nadine Wiesmann." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1186315172/34.

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5

BAN, NOBUTARO, YUKITOSHI TAKAHASHI, GEN SOBUE, et al. "LIMBIC ENCEPHALITIS ASSOCIATED WITH RELAPSING POLYCHONDRITIS RESPONDED TO INFLIXIMAB AND MAINTAINED ITS CONDITION WITHOUT RECURRENCE AFTER DISCONTINUATION : A CASE REPORT AND REVIEW OF THE LITERATURE." Nagoya University School of Medicine, 2014. http://hdl.handle.net/2237/20556.

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McCray, Andrea Nicole. "Electrogenetherapy of established B16 murine melanoma by using an expression plasmid for HIV-1 viral protein R." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001758.

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7

Lee, Yee Man. "Anti-tumor mechanisms of 2-methoxyestradiol in nasopharyngeal carcinoma." HKBU Institutional Repository, 2007. http://repository.hkbu.edu.hk/etd_ra/866.

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Southerland, Marie R. "SYNTHESIS AND BIOLOGICAL EVALUATION OF IMIDAZOLIUM SALTS AS ANTI-CANCER AGENTS." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1524075623735265.

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Zhu, Eric F. (Eric Franklin). "Synergistic anti-tumor immune response to combination immunotherapy consisting of anti-tumor antibodies, extended half-life Interleukin-2, and other immunomodulatory agents." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/107872.

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Анотація:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (pages 109-123).<br>Cancer immunotherapies under development have generally focused on either stimulating T-cell immunity or driving antibody-directed effector functions of the innate immune system such as antibody-dependent cell-mediated cytotoxicity (ADCC). However, as our understanding of antitumor immune responses grows, it has become increasingly apparent that single agent therapies may be insufficient to effective
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Lu, Qiang. "Potent short-chain fatty acid-based histone deacetylase inhibitors as anti-tumor agents." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117541292.

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Thesis (Ph. D.)--Ohio State University, 2005.<br>Title from first page of PDF file. Document formatted into pages; contains xix, 116 p.; also includes graphics. Includes bibliographical references (p. 106-116). Available online via OhioLINK's ETD Center
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Книги з теми "Anti-tumor agent"

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Reznik, Samuel Kaye. Methodological Innovations in Polyketide Synthesis and their Application toward the Scalable Synthesis of Anti-Tumor Agent Spongistatin 1. [publisher not identified], 2012.

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2

M, Muggia Franco, and Rozencweig Marcel, eds. Clinical evaluation of anti-tumor therapy. Nijhoff, 1987.

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3

Altmann, K. H., G. Höfle, R. Müller, J. Mulzer, and K. Prantz. The Epothilones: An Outstanding Family of Anti-Tumor Agents. Springer Vienna, 2009. http://dx.doi.org/10.1007/978-3-211-78207-1.

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4

Li, Shiyou. Camptotheca acuminata decaisne, Xi shu [Hsi shu] (Chinese Happytree): A promising anti-tumor and anti-viral tree for the 21st century. Tucker Center, College of Forestry, Stephen F. Austin State University, 1994.

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5

Mulzer, Johann H. The Epothilones: An Outstanding Family of Anti-Tumor Agents. Springer, 2009.

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6

J, Smith Paul, and Eddy W. Yue. Inhibitors of Cyclin-Dependent Kinases As Anti-tumor Agents. Taylor & Francis Group, 2006.

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7

J, Smith Paul, and Eddy W. Yue. Inhibitors of Cyclin-Dependent Kinases As Anti-Tumor Agents. Taylor & Francis Group, 2010.

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8

Adair, Kent T., and Shiyou Li. Camptotheca Acuminata Decaisne, XI Shu, a Promising Anti-Tumor and Anti-Viral Tree for the Twenty-First Century (Chinese Happytree : a Promising Anti-Tumor and Anti-Viral Tree for the 21st Century). Stephen F. Austin State University, School of, 1997.

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9

Smith, Paul J. Inhibitors of Cyclin-Dependent Kinases as Anti-Tumor Agents (Enzyme Inhibitors). CRC Press, 2006.

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10

(Editor), Franco M. Muggia, and Marcel Rozencweig (Editor), eds. Clinical Evaluation of Anti-Tumor Therapy (Developments in Oncology). Springer, 1986.

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Частини книг з теми "Anti-tumor agent"

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Borcoman, Edith, and Christophe Le Tourneau. "Novel Immune Oncology Targets Beyond PD-1/PD-L1 in Head and Neck Cancer." In Critical Issues in Head and Neck Oncology. Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-23175-9_5.

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AbstractAnti-PD-1 immune checkpoint inhibitors have recently revolutionized the treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) patients, both in the first and second recurrent and metastatic settings. However, not all patients respond to PD-1 blockade, nor derive prolonged benefit from these immunotherapies, requiring further development of immune-oncology strategies beyond PD-1/PD-L1 inhibitors. There has been an important therapeutic development with the evaluation of many new immune checkpoints molecules and other type of immunomodulatory molecules, a
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2

MacLaughlin, David T., James Epstein, and Patricia K. Donahoe. "Mullerian Inhibiting Substance: Studies on its Mechanism of Action and Activity as an Anti-Tumor Agent." In Autocrine and Paracrine Mechanisms in Reproductive Endocrinology. Springer US, 1989. http://dx.doi.org/10.1007/978-1-4684-5751-3_7.

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Sakaguchi, Masakiyo, Nam-ho Huh, and Masayoshi Namba. "A Novel Tumor Suppressor, REIC/Dkk-3 Gene Identified by Our In Vitro Transformation Model of Normal Human Fibroblasts Works as a Potent Therapeutic Anti-tumor Agent." In Advances in Experimental Medicine and Biology. Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4614-0254-1_17.

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4

Matsumoto, Alan K., and Joan M. Bathon. "Anti-Tumor Necrosis Factor Agents." In Modern Therapeutics in Rheumatic Diseases. Humana Press, 2002. https://doi.org/10.1007/978-1-59259-239-5_6.

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Dubler, Erich. "22Ti Anti-Tumor Titanium Drugs." In Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. John Wiley & Sons, Ltd, 2005. http://dx.doi.org/10.1002/0470864052.ch7.

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Chua, Joel V., and John W. Baddley. "Anti-tumor Necrosis Factor-Alpha Agents." In Infectious Complications in Biologic and Targeted Therapies. Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-11363-5_5.

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Lapis, Károly, József Timár, Katalin Pál, András Jeney, Ferenc Timár, and László Kopper. "Membrane Properties of Lewis Lung Tumor Cells with “Low” and “High” Metastatic Capacity: Anti-Metastatic Effect of a Glycosaminoglycan Biosynthesis Blocking Agent 5-Hexyl-2′-Deoxyuridine (HUdR)." In Cancer Biology and Therapeutics. Springer US, 1987. http://dx.doi.org/10.1007/978-1-4757-9564-6_5.

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Höfle, Gerhard. "General Aspects." In The Epothilones: An Outstanding Family of Anti-Tumor Agents. Springer Vienna, 2009. http://dx.doi.org/10.1007/978-3-211-78207-1_1.

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Müller, Rolf. "Biosynthesis and Heterologous Production of Epothilones." In The Epothilones: An Outstanding Family of Anti-Tumor Agents. Springer Vienna, 2009. http://dx.doi.org/10.1007/978-3-211-78207-1_2.

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10

Mulzer, Johann, and Kathrin Prantz. "Total Synthesis of Epothilones A-F." In The Epothilones: An Outstanding Family of Anti-Tumor Agents. Springer Vienna, 2009. http://dx.doi.org/10.1007/978-3-211-78207-1_3.

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Тези доповідей конференцій з теми "Anti-tumor agent"

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Pishko, Gregory L., Morad Nasseri, Seymur Gahramanov, Leslie L. Muldoon, and Edward A. Neuwelt. "Blood-Tumor Barrier Normalization Effects on Cytotoxic Drug Delivery to Brain Tumors." In ASME 2013 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/sbc2013-14648.

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The blood-brain barrier (BBB) restricts delivery of anti-cancer drugs to brain tumors, but the leaky neovasculature of the blood-tumor barrier (BTB) permits systemically delivered cytotoxic agents to reach the tumor. Anti-angiogenic therapies such as bevacizumab (BEV) have been shown to “normalize” brain tumor vasculature,1 but the impact on chemotherapy delivery remains unclear.2 The goal of this study was to use magnetic resonance imaging (MRI) to investigate the consequences of BTB normalization, via BEV, on temozolomide (TMZ) chemotherapy. Non-invasive MRI techniques were used to track the
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2

Li, Yiwen, Yuxiang Hu, Welson Wang, and Wei Wu. "Abstract 1879: CIT-801: a bifunctional anti-PD1xIL15 agent demonstrated synergy and enhanced in vivo anti-tumor efficacy." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1879.

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Mroz, Pawel, and Michael R. Hamblin. "Combination of PDT and a DNA demethylating agent produces anti-tumor immune response in a mouse tumor model." In 12th World Congress of the International Photodynamic Association, edited by David H. Kessel. SPIE, 2009. http://dx.doi.org/10.1117/12.823005.

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Chen, C., M. De Gasperi, R. Salcedo, D. Cavazos, and L. deGraffenried. "Evaluation of the Phytochemical Anethole as an Anti-Tumor Agent in MCF-7 Cells." In Abstracts: Thirty-Second Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 10‐13, 2009; San Antonio, TX. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/0008-5472.sabcs-09-3100.

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Gieffers, Christian, David Richards, Jaromir Sykora, et al. "Abstract 4690: Hexavalent CD27 agonists show single agent anti-tumor activity and enhanced memory formation in mouse syngeneic tumor models." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4690.

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Guillaudeux, Thierry, Kurt Lustig, Emily Frazier, et al. "425 KVA12.1: an anti-VISTA monoclonal antibody with strong single agent anti-tumor activity and no evidence of cytokine mediated toxicity." In SITC 37th Annual Meeting (SITC 2022) Abstracts. BMJ Publishing Group Ltd, 2022. http://dx.doi.org/10.1136/jitc-2022-sitc2022.0425.

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Das, Anusuya, Harry Asada, Doug Lauffenburger, and Roger Kamm. "A Stochastic Field/Agent Model of Angiogenesis." In ASME 2009 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2009. http://dx.doi.org/10.1115/sbc2009-204115.

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Анотація:
Angiogenesis is the formation of blood vessels from an existing vessel or a monolayer of endothelial cells. It is crucial during the processes of tissue and organ maintenance, wound healing, and development and also plays a crucial role in tumor growth. An understanding of this process is also critical from a tissue engineering perspective. Several biochemical factors such as VEGF, Angiopoietin I (Ang I), Angiopoietin II (Ang II), PLGF, PDGF, TNF α, TGF β, α-FGF, β-FGF, ENA/VASP [1] and biomechanical factors such as extracellular matrix (ECM) stiffness, interstitial flow, shear stress affect t
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Weiss, Julia M., Marion Guerin, Fabienne Regnier, et al. "Abstract A05: Biphasic anti-tumoral effect of a vascular-disrupting agent triggering STING and tumor regression." In Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; October 20-23, 2016; Boston, MA. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/2326-6074.tumimm16-a05.

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Bennett, Kaila M., Alex G. Batrouni, Jacob P. Matson, et al. "1284 BRG399, a novel oral microtubule-binding agent, exhibits immune-modulatory properties enhancing anti-tumor responses." In SITC 39th Annual Meeting (SITC 2024) Abstracts. BMJ Publishing Group Ltd, 2024. http://dx.doi.org/10.1136/jitc-2024-sitc2024.1284.

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Kamerkar, Sushrut, Dalia Burzyn, Olga Burenkova, et al. "Abstract 5696: Genetic reprogramming of TAMs by engineered exosomes results in potent single agent anti-tumor activity." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5696.

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Звіти організацій з теми "Anti-tumor agent"

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Chanprateep Napathorn, Suchada, and Tanapat Palaga. Expression of novel fusion proteins IL2/FU-MK-1-scFv in microorganism-host cells and its potential anti-tumor activities as a cytotoxic immunotherapy agent for FU-MK-1 expressing tumors. Chulalongkorn University, 2012. https://doi.org/10.58837/chula.res.2012.25.

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Анотація:
MK-1, the target molecule of FU-MK-1, is encoded by the GA733-2 gene, which is currently being used as a target in clinical trials for gastric, intestinal, and biliary cancer treatment with monoclonal antibodies. Here, two different arrangement of heavy-chain and K light-chain variable fusion gene, IL2/FUscFv(VK-VH) or IL2/FUscFv(VWVK), were constructed. The efficiency of protein expression in prokaryotic host expression system, Escherichia coli strains BL21(DE3)pLysS and Rosetta-gami B was compared with eukaryotic host expression system, Pichia pastoris strains GS115 and KM71H, for their abil
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2

Inoue, Takashi, and Mamoru Narukawa. Anti-tumor efficacy of anti-PD-1/PD-L1 antibodies in combination with other anticancer drugs in solid tumors: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, 2022. http://dx.doi.org/10.37766/inplasy2022.10.0004.

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Review question / Objective: The aim of this systematic review is to compare the combination of PD-1/PD-L1 inhibitors plus other anticancer drugs and monotherapies of PD-1/PD-L1 inhibitors in terms of antitumor efficacy in the solid tumors to better inform clinical practice. To this end, the proposed systematic review will address the following question: Which is the best choice to enhance response rate in subjects with solid tumors, PD-1/PD-L1 inhibitors plus cytotoxic agents or PD-1/PD-L1 inhibitors plus other targeted anticancer drugs? Condition being studied: Cancer is the leading cause of
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