07.11.2013

Clinical cancer research journal impact factor list

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Compared to traditional cancer chemotherapy, targeted cancer therapy was designed to target molecules that were aberrantly activated in cancer. Phosphoinositide 3-kinases (PI3Ks) are conserved lipid kinases that phosphorylate the 3′-hydroxyl group of phosphoinositides (Cantley, 2002). In addition to class I PI3Ks, a number of other key components of the PI3K pathway that are mutated in cancer, have been identified as targets for intervention in cancer therapy. Inhibitors targeting HER receptors and nodal kinases of the PI3K pathway have been developed. At least 10 inhibitors target PI3Ks are in clinical Phase I–II trials for treatment of various cancers, including breast, lung, ovarian cancers, and hematological malignancies.
Inhibitors of Akt include MK2206 (Merck), GDC-0068 (Genentech), AZD5363 (Astrazeneca), Perifosine (Keryx), VQD-002 (VioQuest), and XL418 (Exelixis). The role of the HER2-PI3K pathway in cardiac physiology and pathophysiology has been extensively studied during the past 10 years.
To study the effects of HER2 inhibition in the adult heart, two mouse models with cardiac ventricular myocyte-specific conditional deletion of the HER2 gene were generated (HER2-CKO).
Two types of transgenic mouse models with conditional deletion of the PDK1 gene have been generated. Both PDK1-MckCre and PDK1-MerCre mice developed dilated cardiomyopathy within weeks after the onset of PDK1 gene deletion. The p85 regulatory subunit of the class 1A PI3Ks is essential for stabilizing p110 catalytic subunit and recruiting it to activated RTKs at the cell membrane (Fruman et al., 1998). Dr Burstein is Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts.
The endocrine society australia, The endocrine society of australia (esa) is a national non-profit organisation of scientists and clinicians who conduct research and practice in the field of.
Endocrine society india, Welcome to the endocrine society of india, the largest national organization for clinical endocrinologists and for basic scientists in endocrinology.. To submit a manuscript and see journal-specific instructions, please click the appropriate link below. Copyright © 2012 Autos Weblog, All trademarks are the property of the respective trademark owners. Sanctioned by the United Nations, the Global Defense Initiative has one goal: to eliminate multi-national terrorism in an effort to preserve freedom.
This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Several drugs targeting the major kinases of this pathway have been approved by the Food and Drug Administration and many are being tested in clinical trials for the treatment of various cancers. This strategy was therefore thought to be more specific and restricted to the tumor tissues. The HER receptors are composed of an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic region with kinase activity.
The best studied are class I PI3Ks, and these also represent the major targets for cancer therapy (Zhao and Vogt, 2008).
These include Akt, PDK1 (3-phosphoinositide-dependent kinase-1), and mTOR (mammalian target of rapamycin; Garcia-Echeverria and Sellers, 2008).
Rapamycin, Temsirolimus, and Everolimus are inhibitors of mTOR and approved by the FDA for treatment of certain types of tumors. Transgenic mice with cardiomyocyte-specific overexpression of the mutants of nodal kinases of this pathway were generated.
The class IA PI3Ks are activated by RTKs in cardiomyocytes, whereas the class IB PI3Ks are activated by GPCRs. The LV chamber of dnPI3K mice became dilated with thinning of the LV wall, increased fibrosis and decreased LV systolic function.


It is also crucial for maintaining normal cardiac function in the presence of cardiac stress (Table 2).
However, the cardiac systolic function and cardiomyocyte contractility were increased which were associated with increased cAMP in cardiomyocytes. Meta-analysis of the decision impact of the 21-gene breast cancer Recurrence Score in clinical practice.
Is this the second-place diagnostic in the race for Colorectal cancer blood tests?Based in Lausanne (Switzerland), Novigenix is developing molecular diagnostics from a new generation of predictive gene expression profiles and tumor-derived protein markers (biomarkers).Novigenix first product (Colox) is targeting colorectal cancer. However, the HER2-PI3K pathway is also pivotal for maintaining the physiological function of the heart, especially in the presence of cardiac stress. Trastuzumab (Herceptin), a monoclonal antibody that blocks the HER2 receptor, was one of the first drugs of this class approved by the US Food and Drug Administration (FDA) for cancer therapy.
It was expected that these agents would cause much less damage to normal tissues (Hait and Hambley, 2009).
Upon ligand-binding, HER receptors form hetero- or homo-dimers, followed by auto-phosphorylation of the tyrosine kinase residues on the receptors.
Other pathways include STATs, JNK, and PLCs (Yarden and Sliwkowski, 2001; Citri and Yarden, 2006).
PIP3 recruits Akt to the cell membrane, where it is phosphorylated by PDK1 on Thr308 and kinases such as mTORC2 on Ser473. Cardiomyocyte-specific overexpression of the HER2 gene in the HER2KO mice restored normal ventricular trabeculation and prolonged survival of HER2KO mice (Morris et al., 1999).
HER2-CKO mice survived to the adulthood, but progressively developed dilated cardiomyopathy, with increased LV hypertrophy, chamber dilation, and dysfunction. The MCK promoter induces expression of Cre specifically in skeletal muscle and heart just prior to birth (Bruning et al., 1998). LV mass and cardiomyocyte volume were decreased in PDK1-MckCre, but not in PDK1-MerCre mice. To understand the physiological role of class I PI3Ks in the heart, transgenic mice with cardiomyocyte-specific expression of PI3K isoform-specific mutants were generated (Table 2). On the other hand, aortic banding induced concentric hypertrophy in caPI3K mice, with preserved LV function.
Subsequent clinical trials had shown that Trastuzumab significantly improved survival in breast cancer patients (Slamon et al., 2001). While this may still be true, but because Tyrosine Kinase Inhibitors (TKIs) are presently introduced to clinics as adjuvant therapies and are tested in combination with standard chemotherapeutic regimens, unexpected toxicities are being observed.
These residues then serve as docking sites for recruiting cytosolic signaling molecules to the cell membrane. Systems biology studies revealed that this signaling network is highly organized and precisely regulated through a network of positive and negative feed-back loops and cross-talk among pathways. Amplification of p110α was found in 53% of squamous cell lung cancer and 69% of cervical cancer.
Here, we will focus on the cardiac physiology in mice with perturbation of key nodal kinases of this network, with emphasis on those where the activities of these kinases are inhibited.
The HER2 protein expression was decreased in HER2-CKO hearts with no changes of HER4 expression.
This is because polyps can be either benign or malignant, and a test is needed to tell which.Colorectal cancer develops from lesions in the colon and polyps. Since then, multiple drugs targeting the HER2-PI3K pathway have been approved by FDA for cancer treatment.
The activation and integration of all signaling pathways lead to the regulation of key functions of the cell, which include growth, proliferation, differentiation, survival, and metabolism (Yarden and Sliwkowski, 2001; Citri and Yarden, 2006). In response to the RTKs activation, class IA PI3Ks are recruited, and bind, to the tyrosine phosphate motifs on the activated RTKs via the regulatory subunits.
Akt activates mTORC1 by releasing the inhibitory effects of PRAS40 and TSC2 (tuberous sclerosis 2 protein, also known as tuberin; Shaw and Cantley, 2006). These findings may provide clues of whether inhibitors of these kinases may cause significant impact on the heart.


Electron microscopy studies showed an increase in the numbers of mitochondria and vacuoles in the HER2-CKO myocardium. Studies in PDK1-MerCre mice further showed that β-adrenergic responsiveness was impaired in the heart.
Cardiovascular toxicities, have been frequently reported in patients treated with targeted cancer therapies, and have resulted in widespread concern regarding the cardiac safety of using these drugs. Although TUNEL staining was not increased in HER2-CKO hearts, expression of Bcl-xL partially rescued dilated cardiomyopathy in HER2-CKO mice. Studies, however, have also shown that inhibition of PI3Kγ improve cardiac function of a failing heart. In addition, more than 20 new drugs targeting this pathway are currently being tested in clinical trials1. There are no-known ligands for the HER2 receptor, while HER3 lacks intrinsic kinase activity. The catalytic subunit of the PI3Ks produces phosphatidylinositol-3,4,5-triphosphate (PIP3), a key signaling messenger that recruits and activates a spectrum of signaling molecules. Akt1, Akt2, and Akt3 mutations were found in breast, colon, ovarian, lung, gastric, pancreas, and skin cancers in the range of 2–20%.
Class I PI3K inhibitors include XL147 (Exelixis), BKM120 (Novartis), and GDC0941 (Genentech).
Disruption of this complex reduced cardiac dysfunction in PDK1-MerCre mice (Ito et al., 2009).
In addition, results from transgenic mouse models are not always consistent with the outcome of the pharmacological inhibition of this pathway. The PIP3 signal is negatively regulated by PTEN (phosphatase and tensin homolog), which converts PIP3 back to PIP2 (Shaw and Cantley, 2006). Here, we will review these findings and discuss how we can address the cardiac side-effects caused by inhibition of this important pathway in both cancer and cardiac biology.
Cardiomyocytes isolated from HER2-CKO mice were more susceptible to doxorubicin (Crone et al., 2002) (Table 2). Similarly, the FDA recently revoked the approval of Bevacizumab (Avastin), a drug that blocks VEGF (vascular endothelial growth factor), for breast cancer treatment. The anthracyclines are perhaps the most notorious offenders in the setting of clinical use of growth factor pathway inhibitors such as TKIs (Hershman and Shao, 2009).
The results of early clinical trials suggest that the introduction of targeted therapies to clinical settings must include a careful consideration for the mechanism of action of these agents, and future development of cardio, lung, and kidney protective strategies. Required fields are marked * Labiotech.eu is the leading digital media covering the European Biotech industry. Results from clinical studies of Trastuzumab and animal studies using transgenic mouse models or pharmacological approaches have demonstrated that major kinases of the HER2-PI3K pathway are important for regulating and maintaining cardiac physiological function, especially in the presence of cardiac stress (Heineke and Molkentin, 2006).
It is used by over 40,000 people monthly to keep a watch on the business and innovations of biotechnologies. Preclinical studies also suggest that this pathway is delicately regulated (Klein and Dybdal, 2003), and depending on the type of nodal kinase inhibited within this pathway cardiac function may be either augmented or depressed. Join them for free and enjoy reading our stories!« Let?s change how people get informed about Biotechs in Europe. The cardiac outcome of inhibiting the nodal kinases within this pathway also depends on the specific disease setting. In this review, we will revisit the specific findings in transgenic mice with cardiomyocyte-specific expression of mutants of key kinases of the HER2-PI3K pathway.




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