scholarly journals Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 883 ◽  
Author(s):  
Daniel Massó-Vallés ◽  
Laura Soucek
Keyword(s):  
Genetically Engineered ◽  
Dominant Negative ◽  
The Past ◽  
Genetically Engineered Mice ◽  
Wide Range ◽  
Anti Cancer ◽  
Development Pipeline ◽  
Laboratory Tool ◽  
Tumor Types ◽  
Surprising Discovery

First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein—following the surprising discovery of its cell-penetrating capacity—constitutes a paradigm shift. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic.

Is the hypotensive effect of clonidine and related drugs due to imidazoline binding sites?

1997 ◽  
Vol 273 (5) ◽  
pp. R1580-R1584 ◽  
Author(s):  
Patrice G. Guyenet
Keyword(s):  
Binding Sites ◽  
Hypotensive Effect ◽  
Genetically Engineered ◽  
Therapeutic Effects ◽  
Genetically Engineered Mice ◽  
Wide Range ◽  
The Central Nervous System ◽  
Imidazoline Binding Sites ◽  
Cellular Components

Clonidine and related α2-adrenergic receptor (α2AR) agonists lower arterial pressure primarily by an action within the central nervous system. These drugs also have varying degrees of affinity for other cellular components called nonadrenergic imidazoline binding sites (NAIBS). For over 20 years, the α2AR agonist activity of clonidine-like drugs was thought to account for their therapeutic effects (α2 theory). However, several groups have recently proposed a competing “imidazoline theory” according to which the hypotensive effect of clonidine-like drugs would in fact owe more to their affinity for one type of NAIBS, called I1receptors. The α2-theory is strongly supported by four main types of congruent data. First, the hypotensive effect of systemically administered clonidine is blocked by α2AR antagonists that are without affinity for I1 NAIBs. Second, the hypotensive effect of intravenous clonidine is absent in genetically engineered mice in which a defective α2AAR has been substituted for the normal one. Third, the sympatholytic effect of clonidine is consistent with the presence of conventional inhibitory α2ARs on sympathetic preganglionic neurons and on their main excitatory inputs in the medulla oblongata. Fourth, the first I1 ligand without affinity for α2ARs was found to be biologically inactive. The imidazoline theory is supported by a limited repertoire of whole animal “in vivo” pharmacological experiments that remain open to a wide range of interpretations. In conclusion, the bulk of the evidence strongly supports a largely predominant role of α2AR mechanisms in the action of most clonidine-like agents at therapeutically relevant doses or concentrations. Even the small pharmacological differences between these agents cannot yet be linked with certainty to their relative affinity for I1 NAIBS.

scholarly journals Animal models of colorectal peritoneal metastasis

2016 ◽  
Vol 1 (1) ◽  
pp. 23-43 ◽  
Author(s):  
Félix Gremonprez ◽  
Wouter Willaert ◽  
Wim Ceelen
Keyword(s):  
Colorectal Cancer ◽  
Animal Models ◽  
Peritoneal Carcinomatosis ◽  
Peritoneal Metastasis ◽  
Treatment Options ◽  
Genetically Engineered ◽  
Preclinical Research ◽  
Novel Treatment ◽  
Genetically Engineered Mice ◽  
Wide Range

AbstractColorectal cancer remains an important cause of mortality worldwide. The presence of peritoneal carcinomatosis (PC) causes significant symptoms and is notoriously difficult to treat. Therefore, informative preclinical research into the mechanisms and possible novel treatment options of colorectal PC is essential in order to improve the prognostic outlook in these patients. Several syngeneic and xenograft animal models of colorectal PC were established, studying a wide range of experimental procedures and substances. Regrettably, more sophisticated models such as those giving rise to spontaneous PC or involving genetically engineered mice are lacking. Here, we provide an overview of all reported colorectal PC animal models and briefly discuss their use, strengths, and limitations.

Caveolin-1, tetraspanin CD81 and flotillins in lymphocyte cell membrane organization, signaling and immunopathology

2020 ◽  
Vol 48 (6) ◽  
pp. 2387-2397
Author(s):  
Anna-Maria Schaffer ◽  
Susana Minguet
Keyword(s):  
Immune System ◽  
Intracellular Signaling ◽  
Antigen Receptor ◽  
Lymphocyte Activation ◽  
Genetically Engineered ◽  
Future Research ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Genetically Engineered Mice ◽  
Wide Range

The adaptive immune system relies on B and T lymphocytes to ensure a specific and long-lasting protection of an individual from a wide range of potential pathogenic hits. Lymphocytes are highly potent and efficient in eliminating pathogens. However, lymphocyte activation must be tightly regulated to prevent incorrect activity that could result in immunopathologies, such as autoimmune disorders or cancers. Comprehensive insight into the molecular events underlying lymphocyte activation is of enormous importance to better understand the function of the immune system. It provides the basis to design therapeutics to regulate lymphocyte activation in pathological scenarios. Most reported defects in immunopathologies affect the regulation of intracellular signaling pathways. This highlights the importance of these molecules, which control lymphocyte activation and homeostasis impacting lymphocyte tolerance to self, cytokine production and responses to infections. Most evidence for these defects comes from studies of disease models in genetically engineered mice. There is an increasing number of studies focusing on lymphocytes derived from patients which supports these findings. Many indirectly involved proteins are emerging as unexpected regulators of the immune system. In this mini-review, we focus in proteins that regulate plasma membrane (PM) compartmentalization and thereby impact the steady state and the activation of immunoreceptors, namely the T cell antigen receptor (TCR) and the B cell antigen receptor (BCR). Some of these membrane proteins are shown to be involved in immune abnormalities; others, however, are not thoroughly investigated in the context of immune pathogenesis. We aim to highlight them and stimulate future research avenues.

Early Tumor Detection Using Platelet Uptake of Angiogenesis Regulators.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 839-839 ◽  
Author(s):  
Giannoula Klement ◽  
Lena Kikuchi ◽  
Mark Kieran ◽  
Nava Almog ◽  
Tai-Tung Yip ◽  
...  
Keyword(s):  
Human Tumor ◽  
Human Platelets ◽  
Cancer Therapies ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Platelet Surface ◽  
Wide Range ◽  
Anti Cancer ◽  
Early Tumor ◽  
Tumor Types

Abstract We report a new function for platelets: selective sequestration of tumor-derived angiogenesis regulatory proteins above the concentration of these molecules in plasma. Iodinated VEGF in a Matrigel pellet (from 100 to 600 ng/100 microl), implanted subcutaneously in mice, accumulates almost exclusively in platelets in a dose-dependent manner over a period as long as 2–3 weeks, without raising plasma levels of VEGF. Similarly, platelet VEGF increases in the presence of a single microscopic VEGF-secreting human tumor of up to only 1 mm3 in SCID mice without any increase of VEGF in plasma. In addition to VEGF, other factors such as bFGF, PDGF, BDNF, endostatin and other regulators of angiogenesis are taken up by platelets in a selective and quantifiable manner which is dependent on tumor generation of these molecules. Our data show that these proteins are not simply associated with the platelet surface, but are internalized. Furthermore, they are protected from degradation within the platelet, and are not released by classical degranulating agents, such as thrombin, ADP or epinephrine. Incubation of human platelets with endostatin at above physiological levels results in decrease of the majority of platelet-associated VEGF and bFGF in a concentration-dependent manner. Using SELDI-ToF mass spectroscopy of platelet extracts, we have found that this novel property of platelets enables the detection of microscopic tumors that undetectable by any presently available diagnostic method. The platelet angiogenic profile is more inclusive than a single biomarker because it can detect a wide range of tumor types and tumor sizes. Relative changes in the platelet angiogenic profile permit the tracking of a tumor throughout its development, beginning from an early in situ cancer. Conclusions: (i) While the half-life of mouse platelets is approximately 3 days, the platelet angiogenic profile persists for as long as the tumor (or Matrigel pellet) is present. This indicates that platelets may continuously scavenge proteins which regulate angiogenesis. (ii) The fact that the presence of a human tumor can now be detected at microscopic size, suggests that it may not be necessary to know the type and location of a tumor before initiating treatment, especially since it is feasible to use anti-cancer therapies of little or no toxicity. Figure Figure

scholarly journals Cysteine depletion induces pancreatic tumor ferroptosis in mice

Science ◽  
2020 ◽  
Vol 368 (6486) ◽  
pp. 85-89 ◽  
Author(s):  
Michael A. Badgley ◽  
Daniel M. Kremer ◽  
H. Carlo Maurer ◽  
Kathleen E. DelGiorno ◽  
Ho-Joon Lee ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pancreatic Tumor ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Ros Production ◽  
Oxygen Species ◽  
Oncogenic Signaling ◽  
Genetically Engineered Mice ◽  
Tumor Types ◽  
Tumor Selective

Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

scholarly journals Machine Learning: An Overview and Applications in Pharmacogenetics

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1511
Author(s):  
Giovanna Cilluffo ◽  
Salvatore Fasola ◽  
Giuliana Ferrante ◽  
Velia Malizia ◽  
Laura Montalbano ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Machine Learning ◽  
Narrative Review ◽  
The Other ◽  
Underlying Structure ◽  
The Past ◽  
Satisfactory Performance ◽  
Final Goal ◽  
Wide Range ◽  
Anti Cancer

This narrative review aims to provide an overview of the main Machine Learning (ML) techniques and their applications in pharmacogenetics (such as antidepressant, anti-cancer and warfarin drugs) over the past 10 years. ML deals with the study, the design and the development of algorithms that give computers capability to learn without being explicitly programmed. ML is a sub-field of artificial intelligence, and to date, it has demonstrated satisfactory performance on a wide range of tasks in biomedicine. According to the final goal, ML can be defined as Supervised (SML) or as Unsupervised (UML). SML techniques are applied when prediction is the focus of the research. On the other hand, UML techniques are used when the outcome is not known, and the goal of the research is unveiling the underlying structure of the data. The increasing use of sophisticated ML algorithms will likely be instrumental in improving knowledge in pharmacogenetics.

scholarly journals Evaluating the transcriptional fidelity of cancer models

2020 ◽  
Author(s):  
Da Peng ◽  
Rachel Gleyzer ◽  
Wen-Hsin Tai ◽  
Pavithra Kumar ◽  
Qin Bian ◽  
...  
Keyword(s):  
Cell Lines ◽  
Web Application ◽  
Rapid Assessment ◽  
Tumor Biology ◽  
Genetically Engineered ◽  
Tumor Type ◽  
Genetically Engineered Mouse Models ◽  
Cancer Models ◽  
Genetically Engineered Mice ◽  
Tumor Types

Background: Cancer researchers use cell lines, patient derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derives from the fidelity with which it represents the tumor type under investigation, however, the extent to which this is true is often unclear. The preponderance of models and the ability to readily generate new ones has created a demand for tools that can measure the extent and ways in which cancer models resemble or diverge from native tumors. Methods: We developed a machine learning based computational tool, CancerCellNet, that measures the similarity of cancer models to 22 naturally occurring tumor types and 36 subtypes, in a platform and species agnostic manner. We applied this tool to 657 cancer cell lines, 415 patient derived xenografts, 26 distinct genetically engineered mouse models, and 131 tumoroids. We validated CancerCellNet by application to independent data, and we tested several predictions with immunofluorescence. Results: We have documented the cancer models with the greatest transcriptional fidelity to natural tumors, we have identified cancers underserved by adequate models, and we have found models with annotations that do not match their classification. By comparing models across modalities, we report that, on average, genetically engineered mice and tumoroids have higher transcriptional fidelity than patient derived xenografts and cell lines in four out of five tumor types. However, several patient derived xenografts and tumoroids have classification scores that are on par with native tumors, highlighting both their potential as faithful model classes and their heterogeneity. Conclusions: CancerCellNet enables the rapid assessment of transcriptional fidelity of tumor models. We have made CancerCellNet available as freely downloadable software and as a web application that can be applied to new cancer models that allows for direct comparison to the cancer models evaluated here.

scholarly journals Evaluating the transcriptional fidelity of cancer models

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Da Peng ◽  
Rachel Gleyzer ◽  
Wen-Hsin Tai ◽  
Pavithra Kumar ◽  
Qin Bian ◽  
...  
Keyword(s):  
Cell Lines ◽  
Web Application ◽  
Rapid Assessment ◽  
Tumor Biology ◽  
Genetically Engineered ◽  
Tumor Type ◽  
Link Type ◽  
Cancer Models ◽  
Genetically Engineered Mice ◽  
Tumor Types

Abstract Background Cancer researchers use cell lines, patient-derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derive from the fidelity with which it represents the tumor type under investigation; however, the extent to which this is true is often unclear. The preponderance of models and the ability to readily generate new ones has created a demand for tools that can measure the extent and ways in which cancer models resemble or diverge from native tumors. Methods We developed a machine learning-based computational tool, CancerCellNet, that measures the similarity of cancer models to 22 naturally occurring tumor types and 36 subtypes, in a platform and species agnostic manner. We applied this tool to 657 cancer cell lines, 415 patient-derived xenografts, 26 distinct genetically engineered mouse models, and 131 tumoroids. We validated CancerCellNet by application to independent data, and we tested several predictions with immunofluorescence. Results We have documented the cancer models with the greatest transcriptional fidelity to natural tumors, we have identified cancers underserved by adequate models, and we have found models with annotations that do not match their classification. By comparing models across modalities, we report that, on average, genetically engineered mice and tumoroids have higher transcriptional fidelity than patient-derived xenografts and cell lines in four out of five tumor types. However, several patient-derived xenografts and tumoroids have classification scores that are on par with native tumors, highlighting both their potential as faithful model classes and their heterogeneity. Conclusions CancerCellNet enables the rapid assessment of transcriptional fidelity of tumor models. We have made CancerCellNet available as a freely downloadable R package (https://github.com/pcahan1/cancerCellNet) and as a web application (http://www.cahanlab.org/resources/cancerCellNet_web) that can be applied to new cancer models that allows for direct comparison to the cancer models evaluated here.

Optical Properties of HVEM Accelerators

1975 ◽  
Vol 33 ◽  
pp. 180-181
Author(s):  
A. Strojnik ◽  
J.W. Scholl ◽  
V. Bevc
Keyword(s):  
Optical Properties ◽  
Electron Accelerator ◽  
Systematic Investigation ◽  
Electron Source ◽  
High Brightness ◽  
The Past ◽  
Wide Range ◽  
Optical Behavior

The electron accelerator, as inserted between the electron source (injector) and the imaging column of the HVEM, is usually a strong lens and should be optimized in order to ensure high brightness over a wide range of accelerating voltages and illuminating conditions. This is especially true in the case of the STEM where the brightness directly determines the highest resolution attainable. In the past, the optical behavior of accelerators was usually determined for a particular configuration. During the development of the accelerator for the Arizona 1 MEV STEM, systematic investigation was made of the major optical properties for a variety of electrode configurations, number of stages N, accelerating voltages, 1 and 10 MEV, and a range of injection voltages ϕ0 = 1, 3, 10, 30, 100, 300 kV).

Pursuit of the Abscopal Effect

2020 ◽  
Vol 04 (04) ◽  
pp. 369-372
Author(s):  
Paul B. Romesser ◽  
Christopher H. Crane
Keyword(s):  
Tumor Immunology ◽  
Antitumor Immunity ◽  
Clinical Success ◽  
Immune Recognition ◽  
Immune Modulators ◽  
Cancer Subtypes ◽  
The Past ◽  
Tumor Irradiation ◽  
Wide Range ◽  
Tumor Recognition

AbstractEvasion of immune recognition is a hallmark of cancer that facilitates tumorigenesis, maintenance, and progression. Systemic immune activation can incite tumor recognition and stimulate potent antitumor responses. While the concept of antitumor immunity is not new, there is renewed interest in tumor immunology given the clinical success of immune modulators in a wide range of cancer subtypes over the past decade. One particularly interesting, yet exceedingly rare phenomenon, is the abscopal response, characterized by a potent systemic antitumor response following localized tumor irradiation presumably attributed to reactivation of antitumor immunity.

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