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Agarwala S.S.,St Lukes Cancer Center | Ribas A.,Jonsson Comprehensive Cancer Center
Journal of Immunotherapy | Year: 2010

Monoclonal antibodies (mAbs) specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA4) are a novel form of immunotherapy for treatment of patients with advanced cancers. These anti-CTLA4mAbs prevent normal downregulation of the immune system, thus prolonging and enhancing T-cell activation and potentially promoting an antitumor immune response. Clinical studies in patients with advanced cancers have indicated that CTLA4 blockade with mAbs is associated with antitumor activity in a small percentage of patients and has a manageable toxicity profile. The key limitations for broader applicability of this mode of therapy are better definition of the mechanism that leads to tumor rejection and the validation of favorable observations in single-arm studies into prospectively randomized clinical trials. Copyright © 2010 by Lippincott Williams & Wilkins.

O'Connell R.M.,University of Utah | Rao D.S.,Laboratory Medicine | Rao D.S.,Jonsson Comprehensive Cancer Center | Rao D.S.,University of California at Los Angeles | And 2 more authors.
Annual Review of Immunology | Year: 2012

The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases. © 2012 by Annual Reviews. All rights reserved.

Teng M.W.L.,QIMR Berghofer Medical Research Institute | Teng M.W.L.,University of Queensland | Ngiow S.F.,QIMR Berghofer Medical Research Institute | Ribas A.,University of California at Los Angeles | And 3 more authors.
Cancer Research | Year: 2015

Cancer immunotherapy may become a major treatment backbone in many cancers over the next decade. There are numerous immune cell types found in cancers and many components of an immune reaction to cancer. Thus, the tumor has many strategies to evade an immune response. It has been proposed that four different types of tumor microenvironment exist based on the presence or absence of tumor-infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression. We review this stratification and the latest in a series of results that shed light on new approaches for rationally designing ideal combination cancer therapies based on tumor immunology. © 2015 American Association for Cancer Research.

Cole S.W.,University of California at Los Angeles | Cole S.W.,Jonsson Comprehensive Cancer Center | Cole S.W.,Norman Cousins Center | Sood A.K.,University of Houston
Clinical Cancer Research | Year: 2012

Beta-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial-mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor-mediated activation of protein kinase A and exchange protein activated by adenylyl cyclase signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression, and now suggests a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and preclinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology. ©2011 AACR.

News Article
Site: www.biosciencetechnology.com

Scientists have previously established that many types of cancer cells are squishier and more pliable than normal, healthy cells. Now, researchers led by UCLA’s Amy Rowat have developed a screening method that utilizes this information to classify many more different types of cancer cells and that could ultimately lead to better treatments for cancer, diabetes, malaria and other diseases. Cancer cells are generally two to five times squishier than normal cells, with a pliability similar to that of a wobbly Jell-O, said Rowat, senior author of the research and an assistant professor of integrative biology and physiology. “We want to screen cells based on their squishiness or stiffness,” said Rowat, who is also a member of UCLA’s Jonsson Comprehensive Cancer Center. “We created a technology to probe the deformability of hundreds of cell samples at the same time, so we can identify compounds that make the cells stiffer. Our hope is that we can identify new compounds that can help to prevent the spread of cancer.” Rowat calls the approach the parallel microfiltration method, or PMF. Researchers place a mixture of cells and liquid on a porous membrane, and apply air pressure to force the mixture down through tiny pores that have a smaller circumference than the cells. Stiffer cells block the pores so that not much liquid can filter through; for squishier cells, more of the cell-and-liquid mixture passes through. Researchers can use parallel microfiltration to test many different small molecules at once by measuring the filtration of fluid into individual compartments. A study detailing the method is published today in the journal Scientific Reports. The team found that drug-resistant human ovarian cancer cells are softer than their drug-sensitive counterparts, and that more-invasive cancer cells are softer than less-invasive ones. In future research, Rowat hopes to establish whether squishier cancer cells are in fact more harmful than stiffer cancer cells, and whether their softness can be reversed. “It’s easy to imagine softer cells can spread more easily through the body to invade distant tissues, but this is still a hypothesis,” she said. Some chemotherapy drugs make cancer cells stiffer because they help to stop cells from dividing, Rowat added. But it isn’t clear whether this stiffening of the cells is a key mechanism for preventing the spread of cancer or simply a byproduct of the cells being blocked from dividing. Parallel microfiltration may also have broader applications, including the ability to screen molecules that can alter particular genes and protein levels inside a cell, which could be useful in treating a variety of other diseases, Rowat said. The research was funded by a National Science Foundation CAREER award, the Hellmann Foundation, a Jonsson Comprehensive Cancer Center Impact Grant and the California Translational Science Institute.

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