Stem Cells

Teach Me in 10

In advanced therapy medicinal products (ATMP) manufacturing, the quality and safety of the product need to be ensured from the first stages of development. 

In this episode, we are joined by Kris Wronski, Cell Culture Applications Scientist from Thermo Fisher Scientific. He will discuss how to design an effective contamination prevention strategy that will minimize risks to cell therapy products and allow you to implement appropriate control measures.

By watching this episode you will learn:
•	Why contamination prevention strategy is so important
•	About the types and sources of particulates in the cell therapy production environment and their impact on product quality and safety 
•	The role of laboratory equipment in contamination prevention and what to look for when sourcing suitable equipment

Contamination Prevention in Cell Therapy Environments With Kris Wronski

Oncotarget

Oncotarget published this trending research paper in Volume 13, entitled, "HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs" by researchers from the Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada.

DOI - https://doi.org/10.18632/oncotarget.28278

Correspondence to - Benigno C. Valdez - bvaldez@mdanderson.org 

Abstract

The therapeutic efficacy of histone deacetylase inhibitors (HDACi) for hematologic malignancies and solid tumors is attributed to their ability to remodel chromatin, normalize dysregulated gene expression, and inhibit repair of damaged DNA. Studies on the interactions of HDACi with PARP inhibitors in hematologic cancers are limited, especially when combined with chemotherapeutic agents. Exposure of hematologic cancer cell lines and patient-derived cell samples to various HDACi resulted in a significant caspase-independent inhibition of protein PARylation, mainly catalyzed by PARP1. HDACi affected the expression of PARP1 at the transcription and/or post-translation levels in a cell line-dependent manner. HDACi-mediated inhibition of PARylation correlated with decreased levels and phosphorylation of major proteins involved in DNA repair. Combination of HDAC and PARP1 inhibitors provided synergistic cytotoxicity, which was further enhanced when combined with a chemotherapeutic regimen containing gemcitabine, busulfan and melphalan as observed in lymphoma cell lines. Our results indicate that the anti-tumor efficacy of HDACi is partly due to down-regulation of PARylation, which negatively affects the status of DNA repair proteins. This repair inhibition, combined with the high levels of oxidative and DNA replication stress characteristic of cancer cells, could have conferred these hematologic cancer cells not only with a high sensitivity to HDACi but also with a heightened dependence on PARP and therefore with extreme sensitivity to combined HDACi/PARPi treatment and, by extension, to their combination with conventional DNA-damaging chemotherapeutic agents. The observed synergism of these drugs could have a major significance in improving treatment of these cancers.

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Keywords - poly(ADP-ribosyl)ation, HDAC inhibitors, PARP inhibitors, chemotherapy, hematologic malignancy

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us:

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Paper Spotlight: Combination of HDACi, PARPi and Chemotherapeutic Agents Treat Hematologic Cancer

It's easy to see why organoids have become popular over the years. These 3D cell cultures can self-organize into "mini-organs" capable of recapitulating their respective organ-specific functions. Organoids have been developed for several types of human organs, including the brain, breast, colon, liver, pancreas, stomach, esophagus, small intestine, ovary, uterus, fallopian tubes, prostate and retina.

However, organoids are more complex compared to traditional 2D cultures and even 3D spheroids. Fortunately, products such as the Corning Matrigel® matrix –  the most widely used and cited extracellular matrix (ECM) –  can help streamline workflows for more efficient culturing, storing and handling.

This Teach Me in 10 will cover best practices to consider for organoid work, as well as how to use Corning Matrigel matrix and other products to support organoid models in research.

Organoid Culture Made Easy With Hilary Sherman

In this Teach Me In 10 episode we are joined by Michiel Fokkelman, head of high throughput screening at Crown Bioscience.
We will discuss the concept and definitions of high content imaging, both for 2D and 3D cell culture systems. These rich and extensive morphological readouts provide phenotypic data showing the cellular response(s) to a compound or new potential drug. Michiel then explores the use of 3D-cultured organoids and how these are utilized in drug discovery and pre-clinical drug development using high content approaches. Finally, we will then look at the role of lab automation, essential in enabling high throughput and HCI-based phenotypic screening, and how you can benefit from these technologies.

High-Throughput and High-Content Screening in Organoids and 3D Models With Michiel Fokkelman

3D cell culture systems are gaining interest in the scientific community as they provide more physiologically relevant information and more predictive in vivo data. For more than 25 years, Corning Life Sciences has delivered innovative educational tools and protocols that have advanced the science of 3D cell culture and supported the widespread adoption of these models.

In this Teach Me In 10 episode one of Corning’s customers, Dr. Joseph Regan, shares information from a recently published protocol for the isolation and functional validation of label-retaining quiescent colorectal cancer stem cells from patient-derived organoids for RNA-seq.

Isolation and Functional Validation of Quiescent Colorectal Cancer Stem Cells With Joseph Regan

Oncotarget published this trending research paper on May 11, 2022 in Volume 13, entitled, "Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation" by researchers from the Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA; Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA; UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA.

DOI - https://doi.org/10.18632/oncotarget.28228

Correspondence to - Daniel J. Donoghue - ddonoghue@ucsd.edu

Abstract

Translocation of Fibroblast Growth Factor Receptors (FGFRs) often leads to aberrant cell proliferation and cancer. The BCR-FGFR1 fusion protein, created by chromosomal translocation t(8;22)(p11;q11), contains Breakpoint Cluster Region (BCR) joined to Fibroblast Growth Factor Receptor 1 (FGFR1). BCR-FGFR1 represents a significant driver of 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma, which progresses to acute myeloid leukemia or T-cell lymphoblastic leukemia/lymphoma. Mutations were introduced at Y177F, the binding site for adapter protein Grb2 within BCR; and at Y766F, the binding site for the membrane associated enzyme PLCγ1 within FGFR1. We examined anchorage-independent cell growth, overall cell proliferation using hematopoietic cells, and activation of downstream signaling pathways. BCR-FGFR1-induced changes in protein phosphorylation, binding partners, and signaling pathways were dissected using quantitative proteomics to interrogate the protein interactome, the phosphoproteome, and the interactome of BCR-FGFR1. The effects on BCR-FGFR1-stimulated cell proliferation were examined using the PLCγ1 inhibitor U73122, and the irreversible FGFR inhibitor futibatinib (TAS-120), both of which demonstrated efficacy. An absolute requirement is demonstrated for the dual binding partners Grb2 and PLCγ1 in BCR-FGFR1-driven cell proliferation, and new proteins such as ECSIT, USP15, GPR89, GAB1, and PTPN11 are identified as key effectors for hematopoietic transformation by BCR-FGFR1.

Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28228

Keywords - oncogenic fusion protein, chromosomal translocation, protein interactome, phosphoproteome, stem cell leukemia/lymphoma

About Oncotarget

Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us:

SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
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Oncotarget is published by Impact Journals, LLC: https://www.ImpactJournals.com

Media Contact
MEDIA@IMPACTJOURNALS.COM
18009220957

Trending With Impact: Grb2 and PLCγ1 Required in BCR-FGFR1-Driven SCLL

Harvesting your cells is an important step in maintaining healthy cultures.  Good technique will lead to a healthy single-cell suspension.  There are many harvesting options depending on the cell line and application.  In this video, we will discuss some tips and tricks for harvesting cells.

Techniques for Harvesting Adherent Cells With Hilary Sherman

For this week's episode of Teach Me in 10, we're joined by Dr.  Leonardo Ferreira, assistant professor of microbiology and immunology at the Medical University of South Carolina and the Hollings Cancer Center.  Type 1 diabetes (T1D) is the most common form of diabetes in infants and adolescents. It occurs when the immune system targets the patient’s own insulin-producing pancreatic islet cells for destruction. Right now, the only cure for T1D is a pancreas or pancreatic islet transplant. Yet, this procedure requires life-long immunosuppression to prevent immune rejection and autoimmunity. What if we could instead re-educate the patient’s immune system to accept pancreatic islets? That's the current focus of Ferreira's research, in which he is exploring the use of regulatory T cells as living drugs to treat T1D. This approach is unique in that it focuses on the root cause of the disease, immune attack of pancreatic islets, by genetically engineering human regulatory T cells to induce tolerance to pancreatic islets. He believes this line of work will help realize the promise of immune therapy for T1D, and explains how in less than 10 minutes.

Engineering Regulatory T Cells As Living Drugs With Dr. Leonardo Ferreira

For this Teach Me in 10 episode, we are joined by [url][link]https://www.wrh.ox.ac.uk/team/mara-artibani[/link][name]Dr. Mara Artibani[/name][/url], senior postdoc at the Ahmed Laboratory, Weatherall Institute of Molecular Medicine at the University of Oxford. In just 10 minutes, Dr. Artibani provides you with everything you need to know about ovarian cancer, what it is and how science can work to beat it.

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