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OPEN ACCESS PLUS
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Contents
6(2): Pp. 126 - 137
Nathalie Garcon and Oberdan Leo
[Open Access Plus] |
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New vaccine technology has led to vaccines containing highly purified antigens with improved safety profiles, but increased antigen purity often results in weakened immunogenicity. A better understanding of innate and adaptive immunity and their interaction at the molecular level has led to the use of innovative adjuvants combined with careful antigen selection. Adjuvants can be used to amplify the immune response, and the combination of antigens with more than one adjuvant, the Adjuvant System approach, allows the development of vaccines which generate specific and effective immune responses adapted to both the pathogen and the target population. One of those Adjuvant Systems is AS04, a combination of the TLR4 agonist MPL (3-O-desacyl-4-monophosphoryl lipid A) and aluminum salt. The added value of MPL in AS04-based formulation above Aluminium was evidenced for a prophylactic human papillomavirus (HPV)-16/18 vaccine by higher vaccine-elicited antibody responses, as well as the induction of higher levels of memory B-cells. This review focuses on the role of AS04 for development of Cervarix™, a vaccine for the prevention of cervical cancer.
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5(4): Pp. 261 - 270
Nima Tirgan, Zhe Tang and Patrick C. Ma
[Open Access Plus] |
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MET is a member of the semaphorins, plexins and MET/RON receptor family, which is stimulated by the ligand hepatocyte growth factor (HGF) and uniquely regulates a wide range of cellular functions. When dysregulated and activated, as in the case of human cancers with MET amplification or overexpression, mutation or alternative splicing, it has been implicated to play pivotal role in human tumor cell progression and metastasis. MET-HGF signal path has been shown to be attractive therapeutic target for human cancer novel therapy. In recent years, substantial progresses have been achieved to advance MET-HGF inhibitory strategies from the bench-top preclinical studies to clinical trial studies. Targeting agents being developed include not only various small molecule MET inhibitors, but also specific anti-MET or anti- HGF antibodies. Current emerging knowledge of the kinases signaling cross-talk networks will eventually facilitate rational design of optimal treatment strategies combining MET inhibition with other inhibitors, such as erlotinib (against EGFR). In this review, we summarize the relevant MET receptor biology, mutations (especially non-kinase domain mutations) and other genomic alterations in human cancers. The strategies to inhibit MET-HGF as novel therapy in human cancer as well as agents undergoing clinical trial studies would be discussed. Finally, we also summarize the various challenges to be met, including predictive biomarkers identification, patient selection, and rational combinational treatment approaches.
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5(4): Pp. 232 - 242
Albrecht Reichle
[Open Access Plus] |
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Background: A tumor system not only consists of diverse cell types but also comprises all components of action insofar that these components are oriented in terms of diverse cell types. Methods: Thus, it is necessary to decode paradox situations of cellular rationalization, deformation, and communication processes or, in other words, to uncover inconsistencies within tumor cell compartments or distinct topologies of aggregated action effects. Here, a theory may be helpful that discharges into an action-theoretical abstraction and simultaneously includes evolutionary tumor developments. In an evolutionary process, tumor cells may exploit the whole extent of the rationalization features of stroma cells to implement the functional diversity of systems behavior aimed at maintaining homeostasis, and robustness in tumor systems. The introduction of genomic/non-genomic systems-directed therapeutic approaches may allow both, the uncovering of systems topologies of aggregated action effects and the broadening of therapeutic options via systems-directed approaches. Results: (1) Tumor systems biology is now turning into a scientific co-subject. (2) Developing actiontheoretical systems terms with the corresponding conceptual equipment may contribute to the classification of tumor subsystems. (3) Systems-directed therapies may meet new therapeutic requirements, which might help to create therapeutic approaches that are specifically designed for the demand of tumor stages, corresponding systems stages. Conclusions: Therefore, patients would probably not have to be selected according to age and/or co-morbidities because of known adverse toxicities of standard therapies (maximal tolerable doses). In contrast, therapies may meet the (individual) tumor systems characteristics by a systems-orientated selection of biomodulatory acting agents. As shown, toxicities may be modest.
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5(2): Pp. 111 - 121
Nagendra K. Prasad
[Open Access Plus] |
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Obesity is a well-recognized cancer risk factor. The increase in risk for colorectal, endometrial, breast and esophageal cancers associated with obesity ranges from 1.5- to as much as 3-fold. Obese patients develop more aggressive cancers that are less responsive to treatment. Here, we review the available data on an obesity-linked gene, SH2-domaincontaining inositol 5-phosphatase-2 (SHIP2), in light of new experimental and clinical evidence of its pro-oncogenic role. A putative diabetes drug target, SHIP2 is an important negative regulator of insulin signaling that acts downstream of phosphoinositide 3-kinase (PI3-kinase). In mice, SHIP2 levels are increased by a high-fat diet, and its knockout prevents diet-induced obesity. Taking together these findings, we propose that SHIP2 is a potential anti-cancer target with a high therapeutic index owing to its cancer-specific overexpression and/or differential function combined with the absence of major untoward effects upon its loss of function in normal cells. We compare and contrast the pro-oncogenic function of SHIP2 with the current understanding of cancer-relevant functions of PTEN and PTP-1B, two negative regulators of insulin function. The provocative idea that a negative regulator of insulin function will positively influence oncogenesis presents the intriguing possibility that its inhibition will be a beneficial strategy for two major therapeutic areas: metabolic diseases (such as obesity and diabetes) and cancer.
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4(3): Pp. 188 - 195
Lena Motoda, Motomi Osato and Yoshiaki Ito
[Open Access Plus] |
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An oncogenic stimulus in a cell primarily results in hyperproliferation. However, uncontrolled cell proliferation is sensed by the cell and triggers a fail-safe mechanism resulting in senescence, apoptosis, or differentiation. This phenomenon is considered to be a cellular fail-safe mechanism to eliminate undesirable cells from a population of healthy cells. The RUNX1/AML1 gene, one of the most frequently targeted genes in human leukemia, is induced by the Ras oncogene in hematopoietic stem/progenitor cells and required to maintain the fail-safe mechanism. The stem cell pool is thereby protected from oncogenic insults and cancer-initiating cells, which would become cancer stem cells after accumulation of sequential genetic changes, are eliminated. This fail-safe mechanism and the consequence of its disruption in oncogenesis seems to be a fundamentally important concept, but have not been fully recognized to date. Gaining a better understanding of this mechanism might lead to new strategies to treat cancer stem cell-associated resistance to chemotherapy which is the subject of intense discussion in recent years.
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