scholarly journals Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Warren Fiskus ◽  
Steffen Boettcher ◽  
Naval Daver ◽  
Christopher P. Mill ◽  
Koji Sasaki ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Cell Line ◽  
Cell Lines ◽  
Clinical Studies ◽  
Combined Therapy ◽  
Npm1 Mutation ◽  
In Vivo Efficacy ◽  
Clinical Responses ◽  
A Cell

AbstractTreatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

scholarly journals MUTANTS OF NONPRODUCER CELL LINES TRANSFORMED BY MURINE SARCOMA VIRUS

1973 ◽  
Vol 138 (2) ◽  
pp. 364-372 ◽  
Author(s):  
M. Hatanaka ◽  
R. Klein ◽  
C. W. Long ◽  
R. Gilden
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
In Vitro Cultivation ◽  
Murine Sarcoma Virus ◽  
Sarcoma Virus ◽  
A Cell ◽  
Phenotypic Reversion

Tumorigenic and nontumorigenic mutants induced by a single 5'-bromodeoxyuridine (BrdU) treatment of a nonproducer (NP) tumorigenic cell line were isolated and characterized. Among the cloned derivatives were examples of virus-free and sarcoma virus-producing cell lines. Oncogenicity did not correlate with production of virus or ease of rescue of the sarcoma genome. All lines, including nononcogenic derivatives, retained the sarcoma genome. Phenotypic reversion of some cell mutants was observed after in vivo inoculation or long term in vitro cultivation. The M-50T cell line, obtained from a tumor induced by M-50 cells, had a sarcoma genome rescuable by direct superinfection; this was only achieved with parental M-50 cells by a cell fusion rescue technique. The M-43-2T cell, obtained from a single small static tumor induced by otherwise nononcogenic M-43-2 cells, shed sarcoma virus and became tumorigenic. M-58-4-48 became tumorigenic after passage 48 of the M-58-4 line, which was originally nontumorigenic. These observations of phenotypic reversion demonstrate that the presence of the sarcoma gene in cells is an essential but not sufficient condition of tumorigenesis.

scholarly journals Human Astrovirus MLB Replication In Vitro: Persistence in Extraintestinal Cell Lines

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Diem-Lan Vu ◽  
Albert Bosch ◽  
Rosa M. Pintó ◽  
Enric Ribes ◽  
Susana Guix
Keyword(s):  
Cell Culture ◽  
Cell Line ◽  
Cell Lines ◽  
Culture System ◽  
Unknown Etiology ◽  
Cell Culture System ◽  
Persistent Infections ◽  
A Cell ◽  
Replicative Cycle

ABSTRACT MLB astroviruses were identified 10 years ago in feces from children with gastroenteritis of unknown etiology and have been unexpectedly detected in severe cases of meningitis/encephalitis, febrile illness of unknown etiology, and respiratory syndromes. The aim of this study was to establish a cell culture system supporting MLB astrovirus replication. We used two clinical strains to infect several cell lines, an MLB1 strain from a gastroenteritis case, and an MLB2 strain associated with a neurologic infection. Efforts to propagate the viruses in the Caco-2 cell line were unsuccessful. In contrast, we identified two human nonintestinal cell lines, Huh-7 and A549, permissive for both genotypes. After serial passages in the Huh-7.5 cell line, the adapted strains were able to establish persistent infections in the Huh-7.5, Huh-7AI, and A549 cell lines, with high viral loads (up to 10 log10 genome copies/ml) detected by quantitative reverse transcription-PCR (RT-qPCR) in the culture supernatant. Immunofluorescence assays demonstrated infection in about 10% of cells in persistently infected cultures. Electron microscopy revealed particles of 32 to 33 nm in diameter after negative staining of cell supernatants and capsid arrays in ultrathin sections with a particularly high production in Huh-7.5 cells. Interferon (IFN) expression by infected cells and effect of exogenous IFN varied depending on the type of infection and the cell line. The availability of a cell culture system to propagate MLB astroviruses represents a key step to better understand their replicative cycle, as well as a source of viruses to conduct a wide variety of basic virologic studies. IMPORTANCE MLB astroviruses are emerging viruses infecting humans. More studies are required to determine their exact epidemiology, but several reports have already identified them as the cause of unexpected clinical diseases, including severe neurologic diseases. Our study provides the first description of a cell culture system for the propagation of MLB astroviruses, enabling the study of their replicative cycle. Moreover, we demonstrated the unknown capacity of MLB astrovirus to establish persistent infections in cell culture. Whether these persistent infections are also established in vivo remains unknown, but the clinical consequences would be of high interest if persistence was confirmed in vivo. Finally, our analysis of IFN expression provides some trails to understand the mechanism by which MLB astroviruses can cause persistent infections in the assayed cultures.

The in vivo efficacy of docetaxel and cabazitaxel in a cell-line based xenograft of castration-resistant prostate cancer (CRPC) previously treated with enzalutamide.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 5046-5046 ◽  
Author(s):  
Robert J. van Soest ◽  
Ellen S. de Morrée ◽  
Corrina M.A. de Ridder ◽  
Herman Burger ◽  
Erik A.C. Wiemer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Castration Resistant Prostate Cancer ◽  
In Vivo Efficacy ◽  
Castration Resistant ◽  
A Cell ◽  
Previously Treated

scholarly journals The Anti-Tumor Activity of Igm-8444, an Agonistic Death Receptor 5 (DR5) IgM Antibody, Is Sensitized in Combination with Chemotherapy and Bcl-2 Inhibitors in NHL and AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Beatrice T. Wang ◽  
Thomas J. Matthew ◽  
Ling Wang ◽  
Tasnim Kothambawala ◽  
Susan E. Calhoun ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Single Agent ◽  
Mouse Tumor ◽  
Targeted Agents ◽  
Publicly Traded ◽  
Tumor Models ◽  
In Vivo Efficacy

Background: Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF) receptor superfamily that multimerizes when bound to its ligand, TNF-related apoptosis inducing ligand (TRAIL), to activate the extrinsic apoptotic pathway. DR5 is broadly expressed on solid and hematologic cancers and has been targeted with both recombinant TRAIL and agonistic antibodies in the clinic. However, these therapeutics have been unsuccessful due to lack of efficacy or hepatotoxicity. We have developed IGM-8444, a pentameric IgM with 10 binding sites specific for DR5, that multimerizes DR5 to selectively and potently induce tumor cell apoptosis while maintaining tolerability. We have previously presented the in vitro and in vivo efficacy of IGM-8444 in solid tumor models, demonstrating low picomolar potency across multiple tumor cell lines, strong tumor regressions in cell line and patient derived xenograft mouse tumor models, and dose-dependent increases in apoptotic biomarkers. Here, we evaluate the activity of IGM-8444 in hematologic malignancies in combination with chemotherapy or targeted agents including Bcl-2 inhibitors targeting the intrinsic apoptotic pathway. Methods: Human hematologic cancer cell lines and primary human hepatocytes were evaluated in vitro for dose-dependent IGM-8444-induced cytotoxicity. Cell lines were further evaluated using IGM-8444 in combination with chemotherapy or targeted agents including Bcl-2 inhibitor ABT-199. In vivo efficacy was evaluated using IGM-8444 in combination with ABT-199 in cell line-derived xenograft mouse tumor models. Results: In a previous cancer cell line screen profiling single agent IGM-8444 cytotoxicity across 190 solid and hematologic cell lines, 25 (13%) were classified as highly responsive and 75 (39%) as moderately responsive to IGM-8444 induced cell death. Here the in vitro activity of IGM-8444 was evaluated across a subset of 32 NHL and AML cell lines. 5/21 (24%) of NHL cell lines and 5/11 (45%) of AML cell lines tested were classified as highly responsive or moderately responsive to IGM-8444-induced cytotoxicity. The DOHH-2 and JEKO1 NHL cell lines were amongst the most sensitive, with growth-normalized EC50 values as low as 0.03 ng/mL (0.03 pM) for JEKO1. Combinations with chemotherapy including cytarabine and doxorubicin or targeted agents such as Bcl-2 inhibitor ABT-199 resulted in synergistic in vitro cytotoxicity in multiple cell lines, as determined by Bliss synergy scores. IGM-8444 demonstrated minimal to no in vitro cytotoxicity to primary human hepatocytes at doses several log-fold higher than efficacious doses, and this favorable in vitro safety profile was maintained in combination with chemotherapeutic agents and ABT-199. Combination of IGM-8444 with ABT-199 also resulted in synergistic in vivo efficacy. In a DOHH-2 NHL model, IGM-8444 and ABT-199 showed modest tumor growth inhibition as single agents. However the combined treatment regimen led to tumor regressions during the first 2 weeks of treatment, with 3 of 10 animals showing a partial response and 2 of 10 animals achieving a complete response. The combined treatment also extended median overall survival compared to the control group, which was a significant improvement compared to either agent alone. Collectively, these results provide a strong rationale for simultaneously targeting the extrinsic and intrinsic apoptotic pathways to achieve enhanced efficacy. Conclusions: These data support the clinical development of IGM-8444 in hematological malignancies as a single agent, in combination with standard of care chemotherapy, and in combination with targeted agents that impact the intrinsic signaling pathway such as Bcl-2 inhibitor ABT-199. Initiation of a Phase I clinical study evaluating the safety of IGM-8444 is anticipated in 2020. Disclosures Wang: IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Matthew:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Wang:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Kothambawala:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Calhoun:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Humke:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Sinclair:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Keyt:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company.

Cytotoxicity of chitosan ultrafine nanoshuttles on MCF-7 cell line as surrogate model for breast cancer

2020 ◽  
Vol 17 ◽  
Author(s):  
Tarek Faris ◽  
Gamaleldin I. Harisa ◽  
Fars K. Alanazi ◽  
Mohamed M. Badran ◽  
Afraa Mohammad Alotaibi ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Factorial Design ◽  
Cell Line ◽  
Cell Lines ◽  
Blood Cells ◽  
Sodium Tripolyphosphate ◽  
Physicochemical Characterization ◽  
Spherical Shape ◽  
Mcf 7

Aim: This study aimed to explore an affordable technique for the fabrication of Chitosan Nanoshuttles (CSNS) at the ultrafine nanoscale less than 100 nm with improved physicochemical properties, and cytotoxicity on the MCF-7 cell line. Background: Despite several studies reported that the antitumor effect of CS and CSNS could achieve intracellular compartment target ability, no enough available about this issue and further studies are required to address this assumption. Objectives: The objective of the current study was to investigate the potential processing variables for the production of ultrafine CSNS (> 100 nm) using Box-Benhken Design factorial design (BBD). This was achieved through a study of the effects of processing factors, such as CS concentration, CS/TPP ratio, and pH of the CS solution, on PS, PDI, and ZP. Moreover, the obtained CSNS was evaluated for physicochemical characteristics, morphology Also, hemocompatibility, and cytotoxicity using Red Blood Cells (RBCs) and MCF-7 cell lines were investigated. Methods: Box-Benhken Design factorial design (BBD) was used in the analysis of different selected variables. The effects of CS concentration, sodium tripolyphosphate (TPP) ratio, and pH on particle size, Polydispersity Index (PDI), and Zeta Potential (ZP) were measured. Subsequently, the prepared CS nanoshuttles were exposed to stability studies, physicochemical characterization, hemocompatibility, and cytotoxicity using red blood cells and MCF-7 cell lines as surrogate models for in vivo study. Result: The present results revealed that the optimized CSNS have ultrafine nanosize, (78.3±0.22 nm), homogenous with PDI (0.131±0.11), and ZP (31.9±0.25 mV). Moreover, CSNS have a spherical shape, amorphous in structure, and physically stable. Also, CSNS has biological safety as indicated by a gentle effect on red blood cell hemolysis, besides, the obtained nanoshuttles decrease MCF-7 viability. Conclusion: The present findings concluded that the developed ultrafine CSNS has unique properties with enhanced cytotoxicity. thus promising for use in intracellular organelles drug delivery.

scholarly journals Transformation-associated alterations in interactions between pre-B cells and fibronectin

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2311-2320 ◽  
Author(s):  
FM Lemoine ◽  
S Dedhar ◽  
GM Lima ◽  
CJ Eaves
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cell Attachment ◽  
Attachment Site ◽  
Receptor Antibodies

Abstract Marrow stromal elements produce as yet uncharacterized soluble growth factors that can stimulate the proliferation of murine pre-B cells, although close contact between these two cell types appears to ensure a better pre-B cell response. We have now shown that freshly isolated normal pre-B cells (ie, the B220+, surface mu- fraction of adult mouse bone marrow) adhere to fibronectin (FN) via an RGD cell-attachment site, as shown in a serum-free adherence assay, and they lose this functional ability on differentiation in vivo into B cells (ie, the B220+, surface mu+ fraction). Similarly, cells from an immortalized but stromal cell-dependent and nontumorigenic murine pre-B cell line originally derived from a Whitlock-Witte culture were also found to adhere to fibronectin (FN) via an RGD cell-attachment site. Moreover, in the presence of anti-FN receptor antibodies, the ability of this immortalized pre-B cell line to proliferate when co-cultured with a supportive stromal cell line (M2–10B4 cells) was markedly reduced (down to 30% of control). This suggests that pre-B cell attachment to FN on stromal cells may be an important component of the mechanism by which stromal cells stimulate normal pre-B cell proliferation and one that is no longer operative to control their more differentiated progeny. Two differently transformed pre-B cell lines, both of which are autocrine, stromal-independent, tumorigenic in vivo, and partially or completely differentiation-arrested at a very early stage of pre-B cell development, did not bind to FN. In addition, anti-FN receptor antibodies were much less effective in diminishing the ability of these tumorigenic pre-B cells to respond to M2–10B4 cell stimulation, which could still be demonstrated when the tumorigenic pre-B cells were co- cultured with M2–10B4 cells at a sufficiently low cell density. Analysis of cell surface molecules immunoprecipitated from both the nontumorigenic and tumorigenic pre-B cell lines by an anti-FN receptor antibody showed an increase in very late antigen (VLA) alpha chain(s) in both tumorigenic pre-B cell lines and a decrease in the beta 1 chain in one. Interestingly, all of the pre-B cell lines expressed similar amounts of messenger RNA for the beta 1 chain of the FN receptor. These results suggest that alteration of FN receptor expression on pre-B cells may represent a mechanism contributing to the outgrowth of leukemic pre-B cells with an autocrine phenotype and capable of stromal cell-independent, autonomous growth.

scholarly journals Probing the Intracellular Bio-Nano Interface in Different Cell Lines with Gold Nanostars

Nanomaterials ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1183
Author(s):  
Cecilia Spedalieri ◽  
Gergo Péter Szekeres ◽  
Stephan Werner ◽  
Peter Guttmann ◽  
Janina Kneipp
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Early Stage ◽  
Protein Corona ◽  
Fibroblast Cell ◽  
Ultrastructural Level ◽  
Epithelial Cell Line ◽  
Animal Cells ◽  
Gold Nanostars

Gold nanostars are a versatile plasmonic nanomaterial with many applications in bioanalysis. Their interactions with animal cells of three different cell lines are studied here at the molecular and ultrastructural level at an early stage of endolysosomal processing. Using the gold nanostars themselves as substrate for surface-enhanced Raman scattering, their protein corona and the molecules in the endolysosomal environment were characterized. Localization, morphology, and size of the nanostar aggregates in the endolysosomal compartment of the cells were probed by cryo soft-X-ray nanotomography. The processing of the nanostars by macrophages of cell line J774 differed greatly from that in the fibroblast cell line 3T3 and in the epithelial cell line HCT-116, and the structure and composition of the biomolecular corona was found to resemble that of spherical gold nanoparticles in the same cells. Data obtained with gold nanostars of varied morphology indicate that the biomolecular interactions at the surface in vivo are influenced by the spike length, with increased interaction with hydrophobic groups of proteins and lipids for longer spike lengths, and independent of the cell line. The results will support optimized nanostar synthesis and delivery for sensing, imaging, and theranostics.

lncLocator 2.0: a cell-line-specific subcellular localization predictor for long non-coding RNAs with interpretable deep learning

2021 ◽  
Author(s):  
Yang Lin ◽  
Xiaoyong Pan ◽  
Hong-Bin Shen
Keyword(s):  
Subcellular Localization ◽  
Cell Line ◽  
Cell Lines ◽  
Short Term Memory ◽  
Computational Method ◽  
Language Models ◽  
Supplementary Information ◽  
Deep Model ◽  
A Cell ◽  
Non Coding Rnas

Abstract Motivation Long non-coding RNAs (lncRNAs) are generally expressed in a tissue-specific way, and subcellular localizations of lncRNAs depend on the tissues or cell lines that they are expressed. Previous computational methods for predicting subcellular localizations of lncRNAs do not take this characteristic into account, they train a unified machine learning model for pooled lncRNAs from all available cell lines. It is of importance to develop a cell-line-specific computational method to predict lncRNA locations in different cell lines. Results In this study, we present an updated cell-line-specific predictor lncLocator 2.0, which trains an end-to-end deep model per cell line, for predicting lncRNA subcellular localization from sequences.We first construct benchmark datasets of lncRNA subcellular localizations for 15 cell lines. Then we learn word embeddings using natural language models, and these learned embeddings are fed into convolutional neural network, long short-term memory and multilayer perceptron to classify subcellular localizations. lncLocator 2.0 achieves varying effectiveness for different cell lines and demonstrates the necessity of training cell-line-specific models. Furthermore, we adopt Integrated Gradients to explain the proposed model in lncLocator 2.0, and find some potential patterns that determine the subcellular localizations of lncRNAs, suggesting that the subcellular localization of lncRNAs is linked to some specific nucleotides. Availability The lncLocator 2.0 is available at www.csbio.sjtu.edu.cn/bioinf/lncLocator2 and the source code can be found at https://github.com/Yang-J-LIN/lncLocator2. Supplementary information Supplementary data are available at Bioinformatics online.

Quantitative cell fusion: the fusion sensitivity (FS) potential

1981 ◽  
Vol 49 (1) ◽  
pp. 87-97
Author(s):  
D. Rohme
Keyword(s):  
Cell Line ◽  
Cell Fusion ◽  
Cell Lines ◽  
Dose Response ◽  
Sendai Virus ◽  
Biological Significance ◽  
Diploid Cell ◽  
Mammalian Cell Lines ◽  
Virus Dose ◽  
A Cell

The dose response of Sendai virus-induced cell fusion was studied in 10 mammalian cell lines, comprising 5 continuous and 5 diploid cell lines originating from 5 species. The extent of fusion was calculated using a parameter directly proportional to the number of fusion events (t-parameter). At lower levels of fusion the dose response was found to be based on the same simple kinetic rules in all cell lines and was defined by the formula: t = FS. FAU/(I + FS. FAU), where FS (fusion sensitivity) is a cell-specific constant of the fusion rate and FAU (fusion activity units) is the virus dose. The FS potential of a cell line was determined as the linear regression coefficient of the fusion index (t/(I - t)) on the virus dose. At higher levels of fusion, when the fusion extent reached cell-line-specific maximal levels, the dose response was not as uniform. In general, and particularly in the cases of the diploid cell lines, these maximal levels were directly proportional to the FS potentials. Thus, it was concluded that the FS potential is the basic quantitative feature, which expresses the cellular fusion efficiency. The fact that FS varied extensively between cell lines, but at the same time apparently followed certain patterns (being higher in continuous compared to diploid cell lines and being related to the species of origin of the cells), emphasizes it biological significance as well as its possible usefulness in studies of the efficiency of various molecular interactions in the cell membrane/cytoskeleton system.

Vitamin D as Radiosensitizer: A Review in Cell Line -

2020 ◽  
Vol 10 (6) ◽  
pp. 315-324
Author(s):  
Fahmi Radityamurti ◽  
Fauzan Herdian ◽  
Tiara Bunga Mayang Permata ◽  
Handoko Handoko ◽  
Henry Kodrat ◽  
...  
Keyword(s):  
Vitamin D ◽  
Cell Differentiation ◽  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agent ◽  
Medical Literature ◽  
In Vitro Studies ◽  
Anti Cancer

Introduction: Vitamin D has been shown to have anti-cancer properties such as antioxidants, anti-proliferative, and cell differentiation. The property of vitamin D as an anticancer agent triggers researchers to find out whether vitamin D is useful as a radiosensitizer. Multiple studies have been carried out on cell lines in various types of cancer, but the benefits of vitamin D as a radiosensitizer still controversial. This paperwork aims to investigate the utilization of Vitamin D3 (Calcitriol) as radiosensitizer in various cell line through literature review.Methods: A systematic search of available medical literature databases was performed on in-vitro studies with Vitamin D as a radiosensitizer in all types of cell lines. A total of 11 in-vitro studies were evaluated.Results: Nine studies in this review showed a significant effect of Vitamin D as a radiosensitizer agent by promoting cytotoxic autophagy, increasing apoptosis, inhibiting of cell survival and proliferation, promoting gene in ReIB inhibition, inducing senescene and necrosis. The two remaining studies showed no significant effect in the radiosensitizing mechanism of Vitamin D due to lack of evidence in-vitro settings.Conclusion: Vitamin D have anticancer property and can be used as a radiosensitizer by imploring various mechanism pathways in various cell lines. Further research especially in-vivo settings need to be evaluated.

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