Novel Therapies for Managing Cholestasis.
Ontology highlight
ABSTRACT:
SUBMITTER: Santiago P
PROVIDER: S-EPMC7128034 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Publications
Novel Therapies for Managing Cholestasis.
Santiago Priscila P Levy Cynthia C
Clinical liver disease 20200301 3
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-santiago a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-interview-levy an interview with the author https://www.wileyhealthlearning.com/Activity/7058605/disclaimerspopup.aspx quertions and earn CME. ...[more]
Similar Datasets
Project description:Chimeric antigen receptor (CAR)-modified T cells and bispecific T cell-engaging antibodies have demonstrated dramatic clinical responses in recent clinical trials. The hallmark of these novel highly active immunotherapies is nonphysiologic T cell activation, which has correlated not only with greatly increased efficacy but also with notable toxicity in some cases. We and others have observed a cytokine release syndrome (CRS), which correlates with both toxicity and efficacy in patients receiving T cell-engaging therapies. In addition to elevations in effector cytokines, such as interferon-?, cytokines associated with hemophagocytic lymphohistiocytosis or macrophage activation syndrome, such as interleukin (IL)-10 and IL-6, may also be markedly elevated. Whereas corticosteroids may control some of these toxicities, their potential to block T cell activation and abrogate clinical benefit is a concern. Detailed studies of T cell proliferation and the resultant immune activation produced by these novel therapies have led to more targeted approaches that have the potential to provide superior toxicity control without compromising efficacy. One approach we have developed targets IL-6, a prominent cytokine in CRS, using the IL-6R antagonist tocilizumab. We will review the pathophysiology and management options for CRS associated with T cell-engaging therapies.
| S-EPMC4119809 | biostudies-literature
Project description:Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.
| S-EPMC8392259 | biostudies-literature
Project description: Not available
| S-EPMC8611182 | biostudies-literature
Project description:microRNA array profiling by comparing the isolated cholangiocytes from Bile Duct Ligated and Normal mouse liver
2014-12-31 | E-MTAB-2267 | biostudies-arrayexpress
Project description:Many measures can control lipid risk factors for atherosclerosis. Yet, even with excellent control of dyslipidemia, other sources of risk remain. Hence, we must look beyond lipids to address residual risk. Lifestyle measures should form the foundation of cardiovascular risk control. Many pharmacological interventions targeting oxidation have proven disappointing. A large program tested inhibition of a LpPLA2 (lipoprotein-associated phospholipase A2), culminating in 2 large-scale clinical trials that did not meet their primary end points. A variety of antioxidants have not shown benefit in clinical trials. Numerous laboratory and clinical studies have inculpated inflammatory pathways in the pathogenesis of atherosclerotic events. The p38 MAPK (mitogen-activated protein kinase) inhibitor losmapimod and an inhibitor of a leukocyte adhesion molecule, P-selectin, did not alter adverse events in trials. Low-dose methotrexate, despite the promising observational studies, did not lower biomarkers of inflammation or alter cardiovascular outcomes in the CIRT (cardiovascular inflammation reduction trial). Four large-scale investigations underway will determine colchicine's ability to reduce recurrent events in secondary prevention. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an antibody that neutralizes IL (interleukin)-1β can reduce recurrent cardiovascular events in secondary prevention. The success of CANTOS points to the pathway that leads from the NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome through IL-1β to IL-6 as an attractive target for further study and clinical development beyond lipid therapies to address the unacceptable burden of risk that remains despite our best current care in secondary prevention.
| S-EPMC6436984 | biostudies-literature
Project description:Conventional treatment of glioblastoma has advanced only incrementally in the last 30 years and still yields poor outcomes. The current strategy of surgery, radiation, and chemotherapy has increased median survival to approximately 15 months. With the advent of molecular biology and consequent improved understanding of basic tumor biology, targeted therapies have become cornerstones for cancer treatment. Many pathways (RTKs, PI3K/AKT/mTOR, angiogenesis, etc.) have been identified in GBM as playing major roles in tumorigenesis, treatment resistance, or natural history of disease. Despite the growing understanding of the complex networks regulating GBM tumors, many targeted therapies have fallen short of expectations. In this paper, we will discuss novel therapies and the successes and failures that have occurred. One clear message is that monotherapies yield minor results, likely due to functionally redundant pathways. A better understanding of underlying tumor biology may yield insights into optimal targeting strategies which could improve the overall therapeutic ratio of conventional treatments.
| S-EPMC3316989 | biostudies-other
Project description:Purpose of reviewPatients diagnosed with CLL have an increased susceptibility to infections. Over the years, there has been a shift of the treatment arsenal to an increasing use of chemotherapy-free regimens, particularly small molecule inhibitors. These therapies have proven to be effective and have a favorable toxicity profile. Infections continue to represent a significant complication in the era of novel therapies.Recent findingsRecent studies continue to bring new insights into the effects of modern therapies on the immune system. Evidence supporting infection prevention strategies is scarce. We will review the available recommendations to prevent infections in patients with CLL treated with novel therapies. New CLL therapies are broadly adopted in routine practice, requiring optimization of their side effects. Timely prevention, recognition, and treatment of infections should remain an important aspect of the standard management of a patient with CLL.
| S-EPMC8976213 | biostudies-literature
Project description:Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis-related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed.
| S-EPMC5449464 | biostudies-literature
Project description:Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2(V617F) mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e. mammalian target of rapamycin/AKT/phosphoinositide 3-kinase) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies.
| S-EPMC5008691 | biostudies-literature
Project description:The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era.Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.
| S-EPMC5808510 | biostudies-literature