1,720,985 research outputs found
ICOS-L as a Potential Therapeutic Target for Cancer Immunotherapy
Full text linkBACKGROUND:
The co-stimulatory B7 family members are cell-surface protein ligands, binding to receptors on lymphocytes to regulate immune responses. One of them is the inducible co-stimulatory molecule ligand (ICOS-L). This protein is expressed on professional antigen-presenting cells (APCs), including B cells, macrophages, and dendritic cells (DCs), but it can also be expressed by endothelial cells, lung epithelium and in tumour microenvironment cells. ICOS-L is important for memory and effector T cells during the specific humoral immune responses, but its role in cancer is not yet understood.
OBJECTIVE:
To discuss the role of ICOS/ICOS-L in cancer, given importance of identifying selective targets for cancer treatment, and knowing the mechanism of immune evasion by tumour.
MAIN FINDINGS:
ICOS/ICOS-L signal has opposite effects on the T-cell response. ICOS-L is activated in several types of cancers to maintain immunosuppressive CD4+ T cell subsets, such as regulatory T cells (Tregs). ICOS-L over-expression is associated with tumour progression and poor overall survival. In colon cancer, activation of this co-stimulatory signal is associated with improved survival suggesting a dualistic effect of the ICOS/ICOs-L signal pathway. Interestingly, following anti-cancer vaccine or anti- CTLA-4 treatment, ICOS+ T cells increased significantly in both the CD4+ and CD8+ population and the ratio Teff/Treg increased in tumour microenvironment. This suggests a potential role of ICOS/ICOS-L in improving effectiveness of cancer therapy.
CONCLUSION:
ICOS/ICOS-L signal pathway has the potential to improve cancer treatment. However, studies in other models are needed to understand whether inhibition of ICOS expression or the blockage of its co-stimulation could be a potential therapeutic target or adjuvant treatment for immunotherapy
Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells.
Full text linkCapsaicin (CPS) has been found to exhibit either tumor promoting or suppressing effects, many of which are mediated by the specific transient receptor potential vanilloid type-1 (TRPV1). Herein, we provide evidence that CPS treatment induced a more aggressive gene phenotype and invasiveness in 5637 cells-lacking TRPV1 receptor. CPS treatment of 5637 cells induced upregulation of pro-angiogenetic (angiopoietin 1, angiopoietin 2 and vascular endothelial growth factor), pro-invasive and pro-metastatic genes (MMP1, MMP9, TIMP1, TIMP3, granzyme A (GZMA), NM23A and S100A) with a downregulation of apoptotic genes (Fas/CD95 and tumor necrosis factor receptor superfamily member 1A). CPS increased the invasiveness of 5637 cells by triggering IGF (insulin-like growth factor)-1 release, GZMA and MMP9 activation, α-tubulin disassembly and cytoskeleton degradation. Finally, in order to evaluate the relationship between the lack of TRPV1 expression and increased CPS-induced invasiveness, we transfected 5637 cells with the TRPV1 complementary DNA (cDNA) sequence. We found that TRPV1-expressing cells show CPS-mediated calcium level increase, growth inhibition and apoptosis. Moreover, CPS-induced migration and MMP9 activation were reverted, suggesting an inhibitory role played by TRPV1 in urothelial cancer cell invasion and metastasis
Follicular fluid hormonal profile and cumulus cell gene expression in controlled ovarian hyperstimulation with recombinant FSH: effects of recombinant LH administration.
No full textPURPOSE: Down-regulation with gonadodropin-releasing agonist (GnRH-a) protocol
during IVF stimulation leads to a severe endogenous LH suppression, which may
affect the follicular development. The aim of the study was to evaluate the
effects of recombinant LH (r-LH) administration, during late follicular
development stages, in recombinant FSH (r-FSH) stimulated cycles on follicular
fluid (FF) parameters and on cumulus cell quality.
METHODS: Twenty patients undergoing IVF were stimulated in a long GnRH agonist
protocol with r-FSH alone or with r-LH supplementation when the leading follicle
reached diameter of 14 mm. FF was collected at the time of oocyte retrieval from
32 follicles ≥ 18 mm. Serum FSH, LH, estradiol (E(2)), and progesterone (P(4))
were evaluated on the day of hCG administration. Intra-follicular E(2), P(4), AMH
and TGF-β were assayed. Total RNA from 18 individual cumuli was isolated for gene
expression analyses.
RESULTS: R-LH increased FF P(4) levels. FF TGF-β levels and PTGS2 and HAS2
expression in cumulus cells (CCs) positively correlated with increased P(4)
levels observed in FFs, while a negative correlation was found between P(4) and
AMH levels.
CONCLUSIONS: FF positive correlation between P(4) and TGF-β levels and CC
expression of PTGS2 and HAS2 suggest an association with a better follicle
quality. In addition, our data suggest that late follicular phase r-LH
supplementation leads to a more advanced stage of follicular maturation
Essential role of Gli proteins in glioblastoma multiforme.
Full text linkGlioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Despite several advances, little is known about GBM-specific aberrant signalling processes. The hedgehog (Hh) signalling pathway plays a central role in GBM pathogenesis and tumor progression. Its activation is mediated by sonic hedgehog (Shh), which binds to its receptor patched, PTCH, promoting Gli1 activation. Gli1 is a member of the Kruppel family of zinc finger transcription factors. Hh/Gli1 axis controls glioma stem cells (GSCs) behaviour, which is essential to GBM chemoand radioresistance. Thus, Gli1 modulates the expression of stemness genes and the self-renewal of CD133(+) GSCs. The activation of Hh/Gli1 in GSCs seems to be dependent on the insulin-like growth factor (IGF) signaling, which also contributes to intrinsic and acquired resistance of GSCs to temozolomide (TMZ). Beyond Hh signals, Gli1 activity is also regulated by several elements, including Ras, Myc, Akt, p53 and PTEN. Recently, a truncated variant of Gli1 (tGli1) has been demonstrated to gain the ability to regulate expression of genes that are not modulated by Gli1, such as the migration/invasion-associated CD24 or the human vascular endothelial growth factor-A (VEGF-A), leading to their upregulation. This review will summarize the role of Gli proteins in GBM tumorigenesis and their potential impact on GBM therapy and treatment resistance
Capsaicin as new adjuvant in anti-cancer immunotherapy
No full textRed chili (Capsicum frutescens) is widely used as a spice for flavoring foods worldwide. Accumulating evidence has shown multiple pharmacological effects of Capsicum on a variety of physiological systems [1,2]. Pungent capsaicinoids (capsaicin, dihydrocapsaincin), antioxidant vitamins (ascorbic acid, vitamin E), carotenoids (β-carotene, β-cryptoxanthine) and several organic acids and minerals are the major active chemical substance found in Capsicum frutescens [2]. Capsaicin (CPS) (8-methyl-N-vanillyl-6-nonenamide) is an irritant for mammals, including humans. The burning and painful sensations associated with CPS result from its chemical interaction with sensory neurons. CPS, is a derivative of vanillyl amide (8-methyl-N-vanillyl-6-nonenamide). It binds to a receptor called the vanilloid receptor subtype 1 (VR1 or TRPV1) belonging to the Transient Receptor Potential Vanillod subfamily [3]. CPS has been used medicinally for centuries because it can reduce cholesterol, blood lipid content, blood sugar content and it also has properties of anti-oxidative, anti-inflammatory, anti-obesity and analgesic [4]. At present, it has been demonstrated that CPS exerts anti-cancer activity and immunomodulatory functions [5]. Indeed, the engagement of TRPV1 on dendritic cells by CPS modulates their function by upregulating antigen-presenting and costimulatory molecules, in addition to initiating their migration to draining lymph nodes [6]. Moreover, CPS induces damage-associated molecular patterns of immunogenic cell death in human bladder cancer cells [7].
Bladder cancer has been characterized as a tumor group in which the immunological response is relatively well preserved [8]. A number of immune checkpoint inhibitors have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. However, only 30% of patients with metastatic urothelial carcinoma will respond to this type of immunotherapy [9]. Among the immunocheckpoints, programmed death-ligand 1 (PD-L1) seems to predict response to immune checkpoint inhibitors in such patients. PD-L1 is the transmembrane protein ligand of PD-1, expressed on the cell membrane in T and B lymphocytes, antigen presenting cells and can be induced in tumor cells within the tumor microenvironment. The PD-1/PD-L1 pathway negatively regulates T cell activation, thus it plays an important role in controlling anti-tumor immunity response [10]. Recently, several clinical trials targeting PD-1/PD-L1 pathways using anti-PD-1 or anti PD-L1 antibodies demonstrated the clinical benefit for the patients with bladder cancer and one of this antibodies, atezolizumab, was approved by Food and Drug Administration in USA [11]. Therefore, compounds able to affect the expression of PD-L1 deserve further study.
Herein, we evaluated the ability of CPS, at not cytotoxic dose, to influence PD-L1 expression, both at mRNA and protein levels, in 5637 and T24 bladder cancer cell lines. We found that the exposure of both cell lines to CPS at 50 μM for 12 h and 24 h can increase the expression of PD-L1 evaluated by RT-PCR, western blot and immunohystochemistry analyses. Preliminary results showed that the mechanism involved in CPS-mediated upregulation of PD-L1 expression is ROS-independent and TRPV1-mediated. Moreover, the involvement of interferon 1/1, through the activation of the NME/NM23 nucleoside diphosphate kinase 4 (NME4)/STATs signaling pathway has been evaluated.
Further studies in vivo and in vitro are definitely required to completely address the CPS immunomodulatory capability in bladder cancer and to elucidate the related anti-tumor effects
Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents
No full textThe aggressive behavior of Glioblastoma multiforme (GBM) is mainly due to high invasiveness and proliferation rate as well as to high resistance to standard chemotherapy. Several chemotherapeutic agents like temozolomide (TMZ), carmustine (BCNU) or doxorubicin (DOXO) have been employed for treatment of GBM, but they display limited efficacy. Therefore, it is important to identify new treatment modalities to improve therapeutic effects and enhance GBM chemosensitivity. Recently, activation of the transient receptor potential vanilloid type 2 (TRPV2) has been found to inhibit human GBM cell proliferation and overcome BCNU resistance of GBM cells. Herein, we evaluated the involvement of cannabidiol (CBD)-induced TRPV2 activation, in the modulation of glioma cell chemosensitivity to TMZ, BCNU and DOXO. We found that CBD increases TRPV2 expression and activity. CBD by triggering TRPV2-dependent Ca(2+) influx increases drug uptake and synergizes with cytotoxic agents to induce apoptosis of glioma cells, whereas no effects were observed in normal human astrocytes. Moreover, as the pore region of transient receptor potential (TRP) channels is critical for ion channel permeation, we demonstrated that deletion of TRPV2 poredomain inhibits CBD-induced Ca(2+) influx, drug uptake and cytotoxic effects. Overall, we demonstrated that co-administration of cytotoxic agents together with the TRPV2 agonist CBD increases drug uptake and parallelly potentiates cytotoxic activity in human glioma cells
Expression localisation and functional activity of pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal polypeptide and their receptors in mouse ovary
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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