The emerging role of FTY720 (Fingolimod) in cancer treatment

FTY720 (Fingolimod) is a clinically approved immunomodulating therapy for multiple sclerosis that sequesters T-cells to lymph nodes through functional antagonism of sphingosine-1-phosphate 1 receptor. FTY720 also demonstrates a proven efficacy in multiple in vitro and in vivo cancer models, suggesting a potential therapeutic role in cancer patients. A potential anticancer mechanism of FTY720 is through the inhibition of sphingosine kinase 1, a proto-oncogene with in vitro and clinical cancer association. In addition, FTY720's anticancer properties may be attributable to actions on several other molecular targets. This study focuses on reviewing the emerging evidence regarding the anticancer properties and molecular targets of FTY720. While the clinical transition of FTY720 is currently limited by its immune suppression effects, studies aiming at FTY720 delivery and release together with identifying its key synergetic combinations and relevant patient subsets may lead to its rapid introduction into the clinic

Molecular Targets in Campylobacter Infections

Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients develop abdominal pain and diarrhea. Post-infectious disorders following acute enteritis may occur and affect the nervous system, the joints or the intestines. Immunocompromising comorbidities in infected patients favor bacteremia, leading to vascular inflammation and septicemia. Prevention of human infection is achieved by hygiene measures focusing on the reduction of pathogenic food contamination. Molecular targets for the treatment and prevention of campylobacteriosis include bacterial pathogenicity and virulence factors involved in motility, adhesion, invasion, oxygen detoxification, acid resistance and biofilm formation. This repertoire of intervention measures has recently been completed by drugs dampening the pro-inflammatory immune responses induced by the Campylobacter endotoxin lipo-oligosaccharide. Novel pharmaceutical strategies will combine anti-pathogenic and anti-inflammatory effects to reduce the risk of both anti-microbial resistance and post-infectious sequelae of acute enteritis. Novel strategies and actual trends in the combat of Campylobacter infections are presented in this review, alongside molecular targets applied for prevention and treatment strategies

Molecular Targets of CNS Tumors

Molecular Targets of CNS Tumors is a selected review of Central Nervous System (CNS) tumors with particular emphasis on signaling pathway of the most common CNS tumor types. To develop drugs which specifically attack the cancer cells requires an understanding of the distinct characteristics of those cells. Additional detailed information is provided on selected signal pathways in CNS tumors

Similarity between positronium-atom and electron-atom scattering

We employ the impulse approximation for description of positronium-atom scattering. Our analysis and calculations of Ps-Kr and Ps-Ar collisions provide theoretical explanation of the similarity between the cross sections for positronium scattering and electron scattering for a range of atomic and molecular targets observed by S. J. Brawley et al. [Science 330, 789 (2010)].Comment: 10 pages, 3 figure

New molecular targets in bone metastases

Bone metastases have a major impact on morbidity and on mortality in cancer patients. Despite its clinical relevance, metastasis remains the most poorly elucidated aspect of carcinogenesis. The biological mechanisms leading to bone metastasis establishment have been referred as " vicious circle," a complex network between cancer cells and the bone microenvironment. This review is aimed to underline the new molecular targets in bone metastases management other than bisphosphonates. Different pathways or molecules such as RANK/RANKL/OPG, cathepsin K, endothelin-1, Wnt/DKK1, Src have recently emerged as potential targets and nowadays preclinical and clinical trials are underway. The results from those in the advanced clinical phases are encouraging and underlined the need to design large randomised clinical trials to validate these results in the next future.Targeting the bone by preventing skeletal related events (SREs) and bone metastases has major clinical impact in improving survival in bone metastatic patients and in preventing disease relapse in adjuvant setting. © 2010 Elsevier Ltd

From molecular targets to antitumor immunity

This thesis aimed at the development of strategies that could contribute to the evaluation of the clinical potential of new anticancer therapies. The work was divided into two main sections comprising the development of a therapeutic approach to target cancer genetic vulnerabilities and the development of 3D tumor models incorporating cues from the stromal and immune microenvironments. (...

Novel molecular targets in gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) is the third leading cause of cancer-related death worldwide. A high mortality rate and resistance to treatment protocols due to a heterogeneous molecular pathogenesis has made discovering the key etiologic molecular alterations of the utmost importance. The remarkable role played by epigenetic modifications in repressing or activating many cancer-related genes and forming new epigenetic signatures can affect cancer initiation and progression. Hence, targeting the key epigenetic drivers could potentially attenuate cancer progression. MLLs, ARID1A and EZH2 are among the major epigenetic players that are frequently mutated in GACs. In this paper, we have proposed the existence of a network between these proteins that, together with PCAF and KDM6A, control the 3D chromatin structure and regulate the expression of tumor suppressor genes (TSGs) and oncogenes in GAC. Therefore, we suggest that manipulating the expression of EZH2, PCAF, and KDM6A or their downstream targets may reduce the cancerous phenotype in GAC

Human metapneumovirus: Mechanisms and molecular targets used by the virus to avoid the immune system

Indexación: Scopus.This work was supported by Comisión Nacional de Investigación Científica y Tecnolígica (CONICYT) N◦21151028 and FONDECYT (N◦1070352 and N◦1170964) and the Millennium Institute on Immunology and Immunotherapy (P09/016-F).Human metapneumovirus (hMPV) is a respiratory virus, first reported the year 2001. Since then, it has been described as one of the main etiological agents that causes acute lower respiratory tract infections (ALRTIs), which is characterized by symptoms such as bronchiolitis, wheezing and coughing. Susceptible population to hMPV-infection includes newborn, children, elderly and immunocompromised individuals. This viral agent is a negative-sense, single-stranded RNA enveloped virus, that belongs to the Pneumoviridae family and Metapneumovirus genus. Early reports-previous to 2001-state several cases of respiratory illness without clear identification of the responsible pathogen, which could be related to hMPV. Despite the similarities of hMPV with several other viruses, such as the human respiratory syncytial virus or influenza virus, mechanisms used by hMPV to avoid the host immune system are still unclear. In fact, evidence indicates that hMPV induces a poor innate immune response, thereby affecting the adaptive immunity. Among these mechanisms, is the promotion of an anergic state in T cells, instead of an effective polarization or activation, which could be induced by low levels of cytokine secretion. Further, the evidences support the notion that hMPV interferes with several pattern recognition receptors (PRRs) and cell signaling pathways triggered by interferon-associated genes. However, these mechanisms reported in hMPV are not like the ones reported for hRSV, as the latter has two non-structural proteins that are able to inhibit these pathways. Several reports suggest that viral glycoproteins, such as G and SH, could play immune-modulator roles during infection. In this work, we discuss the state of the art regarding the mechanisms that underlie the poor immunity elicited by hMPV. Importantly, these mechanisms will be compared with those elicited by other common respiratory viruses. © 2018 Frontiers Media S.A. All rights reserved.https://www.frontiersin.org/articles/10.3389/fimmu.2018.02466/ful

Psoriasis: Molecular targets of denervation and therapy

In this thesis global transcriptomic effects of denervation were analyzed in unique cases showing unilateral resolution of psoriasis occurred following surgical denervation (chapter 2). In our studies, we focused on the epidermis, as this forms the main innate defence barrier of the skin. We analysed global transcriptomic effects of surgical denervation in a murine psoriasiform model (chapter 3). Because the contribution of neuromediators to innate defence is mostly unknown, we investigated the effects of SP, CGRP, and VIP on the epidermal expression of TLR and host defence peptides in an ex vivo skin explant model (chapter 4). The molecular epidermal targets of recombinant IL-4 in ex vivo stimulated biopsies from psoriatic and healthy skin were investigated (chapter 5). Furthermore, the effect of the biologic ustekinumab (anti IL-12/IL-23) on epidermal molecular markers of innate defence in uninvolved skin of patients with psoriasis was investigated (chapter 6). The following main conclusions were drawn: Denervation affected genes involved in epidermal barrier function, and TLR function, as the inflammatory response to the TLR7 ligand imiquimod is prevented in denervated skin. Denervation inhibited cutaneous CGRP expression and prevented the enhanced expression of CGRP by imiquimod. Ex vivo stimulation of skin with GCRP results in enhanced expression of epidermal TLR9. Established treatments reach beyond the dermal infiltrate and also target keratinocytes: IL-4 and ustekinumab therapy increase GATA3, which is a transcription factor critical for epidermal homeostasis, and down-regulate NGF expression, which is linked to inflammatory conditions