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S Kang, C Zhang, T Ohno, M Azuma
The PD-1/B7-H1 pathway regulates immune responses and maintains homeostasis. Here, we identified a unique expression of B7 homolog 1 (B7-H1) on masticatory mucosae in the oral cavity. B7-H1 was physiologically expressed on the dorsal surface of the tongue, gingiva, and hard palate. Other squamous epithelia and other structures of the epithelia did not express B7-H1 in the steady state. Physiological B7-H1 expression on masticatory mucosae was limited on prickle cells, and its expression on basal keratinocytes (KCs) was strictly regulated...
October 12, 2016: Mucosal Immunology
(no author information available yet)
Cotargeting CD73 and A2AR overcomes host-ablated A2AR-induced CD73 expression.
September 30, 2016: Cancer Discovery
Michael A Reid, Xazmin H Lowman, Min Pan, Thai Q Tran, Marc O Warmoes, Mari B Ishak Gabra, Ying Yang, Jason W Locasale, Mei Kong
Glutamine is an essential nutrient for cancer cell survival and proliferation. Enhanced utilization of glutamine often depletes its local supply, yet how cancer cells adapt to low glutamine conditions is largely unknown. Here, we report that IκB kinase β (IKKβ) is activated upon glutamine deprivation and is required for cell survival independently of NF-κB transcription. We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low...
August 15, 2016: Genes & Development
M A Zaimy, A Jebali, B Bazrafshan, S Mehrtashfar, S Shabani, A Tavakoli, S H Hekmatimoghaddam, A Sarli, H Azizi, P Izadi, B Kazemi, A Shojaei, A Abdalaian, J Tavakkoly-Bazzaz
The aim of this study was to evaluate an engineered nanostructure to silence five important oncogenes, including BAG1, MDM2, Bcl-2, BIRC5 (survivin) and XIAP, in acute myeloid leukemia subtype 2 (AML-M2). The smart nanostructures were functionalized gold nanoparticles (FGNs) containing five antisense oligonucleotides (AOs) and one anti-CD33(+)/CD34(+) aptamer. First, the best AO for each gene was selected with the OligoWalk online software, and then different arrangements of AOs were evaluated with the RNAstructure software...
September 2016: Cancer Gene Therapy
Lieyu Xu, Yicheng Qi, Yunze Xu, Jianpo Lian, Xiaojing Wang, Guang Ning, Weiqing Wang, Yu Zhu
PURPOSE: Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo. METHODS: The expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541...
April 18, 2016: Oncotarget
Sabrina Jutz, Judith Leitner, Klaus Schmetterer, Iago Doel-Perez, Otto Majdic, Katharina Grabmeier-Pfistershammer, Wolfgang Paster, Johannes B Huppa, Peter Steinberger
Engagement of the T cell receptor complex reprograms T cells for proliferation, cytokine production and differentiation towards effector cells. This process depends on activating costimulatory signals and is counteracted by coinhibitory molecules. Three transcription factors, namely NF-κB, NFAT and AP-1, have a major role in inducing the transcriptional program that is required for T cell activation and differentiation. Here we describe the generation of a triple parameter reporter based on the human Jurkat T cell line, where response elements for NF-κB, NFAT and AP-1 drive the expression of the fluorescent proteins CFP, eGFP and mCherry, respectively...
March 2016: Journal of Immunological Methods
Charles J Sherr, David Beach, Geoffrey I Shapiro
UNLABELLED: Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16(INK4)over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell-division cycle in a retinoblastoma protein-dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with coinhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy...
April 2016: Cancer Discovery
Xuegui Wang, Qiang Hao, Yiqu Chen, Surong Jiang, Qunfang Yang, Qing Li
The major chemical components of four essential oils (EOs) extracted from dry leaves of Citrus limonum, Cymbopogon citratus, Litsea cubeba, and Muristica fragrans were analyzed with gas chromatograph-mass spectrometer and their fumigant, contact, and repellent activities against 10th instar and adults of Tenebrio molitor were also assayed. The results indicated that the major constituents of C. limonum and Cy. citrates were D-limonene (38.22%) and 3,7-dimethyl-6-octenal (26.21%), while which of L. cubeba and M...
2015: Journal of Insect Science
Caitlin R Wagner, Jamie L Abaied
This research examined the moderating effect of the autonomic nervous system (ANS) on the associations between relational victimization and reactive and proactive relational aggression. Both branches of the ANS, the parasympathetic nervous system (indexed by respiratory sinus arrhythmia reactivity; RSA-Reactivity) and the sympathetic nervous system (indexed by skin conductance level reactivity; SCL-Reactivity), were examined. Emerging adults (N = 168) self-reported on relational victimization and proactive and reactive relational aggression; RSA-Reactivity and SCL-Reactivity were assessed in response to a laboratory stressor...
November 2015: Aggressive Behavior
Alice M Walsh, Gurpreet S Kapoor, Janine M Buonato, Lijoy K Mathew, Yingtao Bi, Ramana V Davuluri, Maria Martinez-Lage, M Celeste Simon, Donald M O'Rourke, Matthew J Lazzara
UNLABELLED: Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTK), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted cell death in response to coinhibition of the epidermal growth factor receptor (EGFR) and the c-MET receptor in GBM cells, an effect that involved regulation of the ability of the p38 mitogen-activated protein kinase (MAPK) to drive cell death in response to inhibitors...
August 2015: Molecular Cancer Research: MCR
Yanping Xiao, Gordon J Freeman
HHLA2 is a newly identified B7 family member that modulates T-cell functions through interaction with TMIGD2 and possibly a second receptor, with coinhibition in two studies and costimulation in one study. HHLA2 is expressed on a variety of human cancers, and its coinhibitory function makes it a candidate for cancer immunotherapy.
May 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Li Liu, Liang Liu, Lai-Han Leung, Austin J Cooney, Changyi Chen, Todd K Rosengart, Yupo Ma, Jianchang Yang
All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia. However, it has not been useful for other types of acute myeloid leukemia (AML). Here we explored the effect of SALL4, a stem cell factor, on ATRA-induced AML differentiation in both ATRA-sensitive and ATRA-resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases, whereas, in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells...
April 24, 2015: Journal of Biological Chemistry
Capucine Van Rechem, Joshua C Black, Myriam Boukhali, Martin J Aryee, Susanne Gräslund, Wilhelm Haas, Cyril H Benes, Johnathan R Whetstine
UNLABELLED: Chromatin-modifying enzymes are predominantly nuclear; however, these factors are also localized to the cytoplasm, and very little is known about their role in this compartment. In this report, we reveal a non-chromatin-linked role for the lysine-specific demethylase KDM4A. We demonstrate that KDM4A interacts with the translation initiation complex and affects the distribution of translation initiation factors within polysome fractions. Furthermore, KDM4A depletion reduced protein synthesis and enhanced the protein synthesis suppression observed with mTOR inhibitors, which paralleled an increased sensitivity to these drugs...
March 2015: Cancer Discovery
N Poirier, N Dilek, C Mary, S Ville, F Coulon, J Branchereau, X Tillou, V Charpy, S Pengam, V Nerriere-Daguin, J Hervouet, D Minault, S Le Bas-Bernardet, K Renaudin, B Vanhove, G Blancho
Selective targeting of CD28 might represent an effective immunomodulation strategy by preventing T cell costimulation, while favoring coinhibition since inhibitory signals transmitted through CTLA-4; PD-L1 and B7 would not be affected. We previously showed in vitro and in vivo that anti-CD28 antagonists suppress effector T cells while enhancing regulatory T cell (Treg) suppression and immune tolerance. Here, we evaluate FR104, a novel antagonist pegylated anti-CD28 Fab' antibody fragment, in nonhuman primate renal allotransplantation...
January 2015: American Journal of Transplantation
Kim C Ohaegbulam, Amer Assal, Eszter Lazar-Molnar, Yu Yao, Xingxing Zang
The programmed death 1 (PD-1) receptor and its ligands programmed death ligand 1 (PD-L1) and PD-L2, members of the CD28 and B7 families, play critical roles in T cell coinhibition and exhaustion. Overexpression of PD-L1 and PD-1 on tumor cells and tumor-infiltrating lymphocytes, respectively, correlates with poor disease outcome in some human cancers. Monoclonal antibodies (mAbs) blockading the PD-1/PD-L1 pathway have been developed for cancer immunotherapy via enhancing T cell functions. Clinical trials with mAbs to PD-1 and PD-L1 have shown impressive response rates in patients, particularly for melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), and bladder cancer...
January 2015: Trends in Molecular Medicine
Sarah L Buchan, Teresa Manzo, Barry Flutter, Anne Rogel, Noha Edwards, Lei Zhang, Shivajanani Sivakumaran, Sara Ghorashian, Ben Carpenter, Clare L Bennett, Gordon J Freeman, Megan Sykes, Michael Croft, Aymen Al-Shamkhani, Ronjon Chakraverty
Exhaustion of chronically stimulated CD8(+) T cells is a significant obstacle to immune control of chronic infections or tumors. Although coinhibitory checkpoint blockade with anti-programmed death ligand 1 (PD-L1) Ab can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bet(high) subset that expresses lower levels of PD-1. In a model in which unhelped, HY-specific CD8(+) T cells gradually lose function following transfer to male bone marrow transplantation recipients, we have explored the effect of shifting the balance away from coinhibition and toward costimulation by combining anti-PD-L1 with agonistic Abs to the TNFR superfamily members, OX40 and CD27...
January 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
S M Krummey, M L Ford
The coinhibitory receptor cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a master regulator of T cell responses and its function is critical in models of transplant tolerance. The CD28/CTLA-4 pathway is also an important therapeutic target, as the costimulation blocker belatacept was recently approved for use following renal transplantation. While the traditional model of CTLA-4 coinhibition focuses on its ability to directly counteract CD28 costimulation, recently this paradigm has significantly broadened. Recent work has uncovered the ability of CTLA-4 to act as a cell-extrinsic coinhibitory molecule on CD4(+) T cell effectors...
December 2014: American Journal of Transplantation
Olivia S Chao, Oscar B Goodman
UNLABELLED: Tumors with BRCA germline mutations are defective in repairing DNA double-strand breaks (DSB) through homologous recombination (HR) pathways, making them sensitive to PARP inhibitors (PARPi). However, BRCA germline mutations are rare in prostate cancer limiting the ability to therapeutically target these pathways. This study investigates whether histone deacetylase (HDAC) inhibitors (HDACi), reported to modulate DSB repair pathways in sporadic cancers, can downregulate DSB repair pathways and sensitize prostate cancer cells to PARPi...
December 2014: Molecular Cancer Research: MCR
Inge Verbrugge, Alessia Gasparini, Nicole M Haynes, Jim Hagekyriakou, Mara Galli, Trina J Stewart, Scott I Abrams, Hideo Yagita, Marcel Verheij, Ricky W Johnstone, Jannie Borst, Jacques Neefjes
Radiotherapy is a successful treatment modality for localized cancer. Our group has been exploring radiotherapy in combination with immunotherapy (radioimmunotherapy) to enhance systemic antitumor responses. Previously, we have shown that when local radiotherapy was combined with monoclonal antibodies (mAbs) (that enable T-cell responses by engaging costimulation [anti (α)-CD137] and blocking coinhibition [α-PD-1] [corrected], up to 100% of mice bearing established syngeneic AT-3 mammary tumors were cured, but single modality treatments were not curative...
August 2014: Radiation Research
Hao Li, Wouter A van der Linden, Martijn Verdoes, Bogdan I Florea, Fiona E McAllister, Kavitha Govindaswamy, Joshua E Elias, Purnima Bhanot, Herman S Overkleeft, Matthew Bogyo
The ubiquitin-proteasome system (UPS) is a potential pathway for therapeutic intervention for pathogens such as Plasmodium, the causative agent of malaria. However, due to the essential nature of this proteolytic pathway, proteasome inhibitors must avoid inhibition of the host enzyme complex to prevent toxic side effects. The Plasmodium proteasome is poorly characterized, making rational design of inhibitors that induce selective parasite killing difficult. In this study, we developed a chemical probe that labels all catalytic sites of the Plasmodium proteasome...
August 15, 2014: ACS Chemical Biology
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