Guanylin ligand protects the intestinal immune barrier by activating the guanylate cyclase-C signaling pathway

xlomafota13 shared this article with you from Inoreader Guanylin ligand protects the intestinal immune barrier by activating the guanylate cyclase-C signaling pathway Via histochem Acta Histochem. 2021 Dec 14;124(1):151811. doi: 10.1016/j.acthis.2021.151811. Online ahead of print. ABSTRACT Inflammatory bowel disease (IBD) impacts patient quality of life significantly. The dysfunction of intestinal immune barrier is closely associated with IBD. The guanylate cyclase-C (GC-C) signaling pathway activated by the guanylin (Gn) ligand is involved in the occurrence and development of IBD. However, how it regulates the intestinal immune barrier is still unclea r. To investigate the effect of the GC-C pathway on intestinal mucosal immunity and provide experimental basis for seeking new therapeutic strategies for IBD, we focused on Caco-2 cells and intestinal intra-epithelial lymphocytes (IELs), which displayed inflammatory responses induced by lipopolysaccharide (LPS). GC-C activity was modulated by transfection with Gn overexpression or GC-C shRNA plasmid. Levels of Gn, GC-C, and CFTR; transepithelial electrical resistance (TER); paracellula r permeability; and levels of IL-2, IFN-γ, and secretory IgA (sIgA) were examined. The study found that after stimulation with LPS, Gn, GC-C, CFTR, TER, and sIgA levels were all significantly reduced, IL-2 and IFN-γ levels as well as paracellular permeability were significantly increased. These indicators changed inversely and significantly after transfection with the Gn overexpression vector. Compared to the vector controls, GC-C-silenced cells displayed significantly decreased levels of GC-C, CFTR , and TER and increased levels of IL-2, IFN-γ, and paracellular permeability stimulated by LPS. The results show that Gn ligand can protect the intestinal immune barrier by activating the GC-C signaling pathway, which may be helpful for the development of new treatments for IBD. DATA AVAILABILITY STATEMENT: The data used to support the findings of this study are available from the corresponding author upon request. PMID:34920371 | DOI:10.1016/j.acthis.2021.151811 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Bispecific antibodies targeting CD3 in oncology and hematology

xlomafota13 shared this article with you from Inoreader Bispecific antibodies targeting CD3 in oncology and hematology Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S181-S194. doi: 10.1016/j.bulcan.2021.06.003. ABSTRACT Bispecific therapies targeting CD3, so-called T-cell engagers (TCE), belong to the new spectrum of anti-tumor immunotherapies stimulating T-lymphocytes. TCE are unique constructs targeting the MHC-independent CD3 epsilon subunit (CD3e) and a tumor antigen. To date, only blinatumomab have reached market agreements in lymphoid malignancies with constructs targeting CD3exCD19. Other TCE are in advances development, with promising results targeting CD20 and BSMA in lymphoma and myeloma. These successes have relaunched the development of TCE in solid tumors, bringing mixed results so far (notably in terms of tolerance). Still, TCE pave the way to new immunotherapy in tumors considered to be refractory to inhibitors of immune checkpoints such as prostate cancer or colorectal cancer. PMID:34920802 | DOI:10.1016/j.bulcan.2021.06.003 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Bispecific antibodies in onco-hematology: Applications and perspectives

xlomafota13 shared this article with you from Inoreader Bispecific antibodies in onco-hematology: Applications and perspectives Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S195-S204. doi: 10.1016/j.bulcan.2021.10.002. ABSTRACT Bispecific antibodies are novel approaches of immunotherapy engaging immune cells to destroy tumor cells. Their structure is variable and underlies their pharmacocinetic properties. These coumpounds are now being evaluated across multiple hematological malignancies. The anti-CD3/CD19 antibody blinatumomab is the first in class and have been approved for the treatment of patients with Ph-negative B-cell acute lymphoblastic leukemia. Other emerging applications are lymphoma, multiple myeloma and acute myeloid leukemia. The safety profile of bispecific antibodies is acceptable while limited by neurotoxicity and cytokine-release syndrome. The present review aims to depict the landscape of emerging bispecific antibodies currently in development for hematological malignancies. PMID:34920803 | DOI:10.1016/j.bulcan.2021.10.002 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CAR-T cells in lymphomas: Current and evolving role

xlomafota13 shared this article with you from Inoreader CAR-T cells in lymphomas: Current and evolving role Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S28-S39. doi: 10.1016/j.bulcan.2021.04.022. ABSTRACT Three CD19 CAR-T cells (Yescarta®, Kymriah® and Breyanzi®), have been approved in relapsed or refractory diffuse large B cell lymphomas (DLBCL) after at least two previous lines of therapy. These immunotherapies have transformed the prognosis of these lymphomas, which can't be cured by conventional treatments. Long-term updates of registration studies as well as the first real-life data allow a better knowledge of the efficacy of these emerging therapies, their toxicity and their resistance mechanisms. These advances have also led to consider the earlier use of CAR-T cells in the therapeutic strategy and to extend it to other B lymphomas such as mantle cell and indolent lymphomas. Indeed, Yescarta® and Tecartus® have been recently approved in those malignancies, Furthermore, other strategies are being investigated to develop new CAR-T cells to targ et Hodgkin's lymphomas and T-cell lymphomas, although data in these settings still have to be completed. In this article, we review the latest data on the use of CAR-T cells in lymphomas. PMID:34920805 | DOI:10.1016/j.bulcan.2021.04.022 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CAR-T cells, from principle to clinical applications

xlomafota13 shared this article with you from Inoreader CAR-T cells, from principle to clinical applications Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S4-S17. doi: 10.1016/j.bulcan.2021.02.017. ABSTRACT Chimeric antigen receptors (CAR)-T cells are genetically engineered T-lymphocytes redirected with a predefined specificity to any target antigen, in a non-HLA restricted manner, therefore combining antibody-type specificity with effector T-cell function. This strategy was developed some thirty years ago, after extensive work established the key role of the immune system against cancer. The first-engineered T-cell with chimeric molecule was designed in 1993 by Israeli immunologist Zelig Eshhar. Since then, several modifications took place, including the addition of co-stimulatory domain, to further improve CAR-T cell anti-tumor potency. The first clinical application of CAR-T cell was done in Rotterdam in 2005 for metastatic renal cell carcinoma and simultaneously at the National Cancer Institute (NCI) for metastatic ovarian cancer. These pioneered studie s failed to demonstrate a therapeutic benefit, but warning emerged concerning their safety of use. The real clinical success came with anti-CD19 CAR-T cells, used since 2009 by Steven Rosenberg at the NCI in a patient with refractory follicular lymphoma and in 2011 by Carl June and David Porter from the University of Pennsylvania in patients with chronic lymphocytic leukemia and B-cell acute lymphoblastic leukemia. From that time, large centers in North America have embarked in several early phase and pivotal trials that have demonstrated unprecedent response rate in heavily pretreated chemo refractory patient with B-cell malignancies. Theses clinical success have led to the approval of three anti-CD19 CAR-T cells products for the management of B-cell malignancies in the United States and in Europe as of December 2020. PMID:34920806 | DOI:10.1016/j.bulcan.2021.02.017 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CAR T-cells in acute lymphoblastic leukemia: Current results

xlomafota13 shared this article with you from Inoreader CAR T-cells in acute lymphoblastic leukemia: Current results Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S40-S54. doi: 10.1016/j.bulcan.2021.08.001. ABSTRACT The marketing authorization of tisagenlecleucel, a 2nd generation of CD19-directed CAR T-cells, containing the 4-1 BB co-stimulatory domain, in 2017 in USA and in 2018 in EU, has revolutionized the therapeutic strategy in advanced B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents and young adults (AYAs) with relapsed or refractory disease. This innovative treatment, based on a "living drug", has shown very impressive short-term responses. However, safety profile and complex logistics require high expertise centers and tight collaborations between addressing and treating centers. Current research is exploring the possibility to move to first line ALL with high-risk features and/or first high-risk relapse. More efficient CAR T-cells products, are still lacking to counteract the escape mechanisms already described. Moreover, to define th e bridge-to-CAR time for each patient remains a challenge to obtain optimal disease burden allowing expansion and persistence of CAR T-cells. Also difficult is to identify patients who will benefit from further therapy after infusion, such as allogeneic HSCT or may be immuno-modulatory treatment. Finally, CAR T-cells directed against T-ALL are only in their beginning but require more complex engineering process to avoid T- cell immune-deficiency or fratricide. PMID:34920807 | DOI:10.1016/j.bulcan.2021.08.001 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CARTi: The French-speaking group for the harmonization of immune monitoring in patients treated with CAR-T cells

xlomafota13 shared this article with you from Inoreader CARTi: The French-speaking group for the harmonization of immune monitoring in patients treated with CAR-T cells Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S141-S142. doi: 10.1016/j.bulcan.2021.06.006. NO ABSTRACT PMID:34920796 | DOI:10.1016/j.bulcan.2021.06.006 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Bispecific antibodies: An old story with a bright future… with CAR-T cells!

xlomafota13 shared this article with you from Inoreader Bispecific antibodies: An old story with a bright future… with CAR-T cells! Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S168-S180. doi: 10.1016/j.bulcan.2021.02.016. ABSTRACT CAR-T cells originate from two different approaches, cellular immunotherapy based on tumor immunosurveillance by T lymphocytes, combined with molecular engineering of bispecific antibodies and antibody fragments. The latter makes it possible to retarget immune effector cytotoxic cells (such as NK cells and T lymphocytes) to tumor cells through the binding to tumor-associated antigens. We present herein the history of bispecific antibodies, highlighting how such antibodies played a major role in CAR-T cell development. We will first evoke how antibody engineering led to the construction of various bispecific formats, in particular using the single chain Fv fragment (scFv) which has been used as the initial building block to generate chimeric bi-, tri- or multifunctional molecules. We will also describe how bispecific antibodies, either full IgG or as s cFv or F(ab')2 format, directed against Fcγ receptors or CD3ɛ and against tumor-associated antigens, induce a potent anti-tumor cytotoxicity following the recruitment and activation of immune effector cells, including CD3+ T lymphocytes. These anti-tumor effects have been translated into the clinics, especially to treat malignant hemopathies. At last, recently generated bispecific CAR-T cells suggest that the embrace between cell therapy and bispecific antibodies is not over and that we are yet to witness further discoveries enabling these cells to be even more efficient. PMID:34920800 | DOI:10.1016/j.bulcan.2021.02.016 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CAR-T cell: Toxicities issues: Mechanisms and clinical management

xlomafota13 shared this article with you from Inoreader CAR-T cell: Toxicities issues: Mechanisms and clinical management Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S117-S127. doi: 10.1016/j.bulcan.2021.05.003. ABSTRACT CAR-T cells are modified T cells expressing a chimeric antigen receptor targeting a specific antigen. They have revolutionized the treatment of B cell malignancies (aggressive lymphomas, B-ALL), and this has raised hopes for application in many other pathologies (myeloma, AML, solid tumors, etc.). However, these therapies are associated with novel and specific toxicities (cytokine release syndrome and neurotoxicity). These complications, although mostly managed in a conventional hospitalization unit, can sometimes be life threatening, leading to admission of patients to the intensive care unit. Management relies mainly on anti-IL6R (tocilizumab) and corticosteroids. However, the optimal treatment regimen is still a matter of debate, and the management of the most severe forms is even less well codified. In addition to CRS and ICANS, infections, cytope nia and hypogammaglobulinemia are other frequent complications. This article reviews the mechanisms, risk factors, clinical presentation, and management of these toxicities. PMID:34920794 | DOI:10.1016/j.bulcan.2021.05.003 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

T cell-based immunotherapies in solid tumors

xlomafota13 shared this article with you from Inoreader T cell-based immunotherapies in solid tumors Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S96-S108. doi: 10.1016/j.bulcan.2021.06.004. ABSTRACT In solid tumors, adoptive T cell therapies based on ex vivo amplification of antitumor T cell are represented by three main complementary approaches : (i) tumor infiltrating lymphocytes (TILs) which are amplified in vitro before reinjection to the patient, (ii) chimeric antigen receptor (CAR) engineered T cells and (iii) T cell receptor (TCR) engineered T cells. Despite encouraging results, some obstacles remain, such as optimal target selection and tumor microenvironment. In this Review, we discuss pros and cons of these different therapeutic strategies that may open new perspectives in the treatment of solid tumors. PMID:34920813 | DOI:10.1016/j.bulcan.2021.06.004 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CAR-T CELLS: How does the EBMT registry monitor European activities, identify hurdles and prepare for changes in regulations

xlomafota13 shared this article with you from Inoreader CAR-T CELLS: How does the EBMT registry monitor European activities, identify hurdles and prepare for changes in regulations Via Association française pour l'étude du cancer Bull Cancer. 2021 Oct;108(10S):S155-S161. doi: 10.1016/j.bulcan.2021.08.004. ABSTRACT CAR-T Cells are gene therapy medicinal products, a subcategory of Advanced Therapy Medicinal Products as defined in the EC Regulation 1394/2007. They may represent the first example of such medicinal products that are industry-manufactured and commercialized on a large scale. Their very nature, their manufacturing processes, pricing and conditions upon which they were approved by regulatory agencies, all lead the latter to require long-term follow-up after marketing approval with a view for a better definition of CAR-T Cells safety profile and efficacy profile in real world conditions. Collection and analysis of data over a 15-year period of time represents a technical and political challenge. So does the a priori definition of data to be collected for a wealth of forthcoming analyses that focus on the interests of a variety of stakeholders. EBMT has been collecting and analyzing data on hematopoietic cell transplants for decades. EBMT currently works with many interested parties to collect data on patients treated with CAR-T Cells. PMID:34920798 | DOI:10.1016/j.bulcan.2021.08.004 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The Voice Problem Impact Scales (VPIS)

xlomafota13 shared this article with you from Inoreader The Voice Problem Impact Scales (VPIS) Via Journal of Voice Patient-reported outcome measures (PROMs) are important for systematically assessing a person's perspectives and experiences with disease to inform clinical decision-making. However, PROMs can occasionally fail to capture subtle differences amongst subgroups. In response to this problem, the aim of the current study was to examine the convergent validity of four patient-reported voice activity and participation scales to better reflect and describe the impact of a voice problem in a patient's work, home, social and overall life. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.