Traditional grid computing focuses on the movement of data to compute resources and the management of large scale simulations. Data grid computing focuses on moving the operations to the storage location and on operations on data collections. We present three types of data grid operations that facilitate data driven research: the manipulation of time series data, the reproducible execution of workflows, and the mapping of data access to software-defined networks. These data grid operations have been implemented as operations on collections within the NSF DataNet Federation Consortium project. The operations can be applied at the remote resource where data are stored, improving the ability of researchers to interact with large collections.
Endometrial cancer (EC) is the most common malignancy of the female genital tract and occurs primarily in postmenopausal women [
The epidermal growth factor system (EGF system) is present in human organs and plays an important role in cell proliferation, differentiation and apoptosis during embryogenesis and postnatal development [
Dysregulation of the EGF signaling network is implicated in various disorders [
The EGF system is present in human organs and play important role during embryogenesis and postnatal development [
ErbB receptors belong to subclass I of the superfamily of Receptor Tyrosine Kinases (RTKs) [
Moreover, EGF system has numerous ligands. According to their affinity for one or more ErbB receptors, the ligands divided into:
1) Ligands with binding specificity for EGFR: EGF, transforming growth factor-a (TGF-a) and amphiregulin (AR) [
2) Ligands with dual binding specificity for EGFR and ErbB-4: betacellulin (BTC), heparin-binding growth factor (HB-EGF) and epiregulin (EPR) [
3) Ligands with binding specificity for ErbB-3 and ErbB-4: neuregulins (NRGs) or heregulins (HRGs). They divided in two subgroups based on their ability to bind ErbB-3 and ErbB-4 (NRG-1 and NRG-2) or only ErbB-4 (NRG-3 and NRG-4) [
The ligands for ErbB receptors bind to the extracellular domain, resulting in receptor activation by homodimer and/or heterodimer formation and the subsequent transphosphorylation of tyrosine residues in the cytoplasmic region [
The extracellular region of EGFR, ErbB-3 and ErbB-4 has two distinct conformations: the closed conformation (inactive) and the open conformation (active) [
In the absence of ligand binding, the extracellular region of EGFR, ErbB-3 and ErbB-4 has equilibrium between closed and open conformation [
Ligand binding stabilizes extracellular region in the open conformation and leads to the formation of both homodimeric and heterodimeric ErbB receptor complexes [
The extracellular region of ErbB-2 has a conformation not suitable for ligand binding [
ErbB-3 lacks intrinsic tyrosine kinase activity [
The dimerization of ErbB receptors represents the fundamental mechanism that drives transformation [
Dimerization of ErbB receptors leads to intracellular kinase activation [
1) Ras/Raf/mitogen-activated protein kinase (MAPK) pathway [
2) Phosphatidylinositol 3-kinase (PI3K)/Akt pathway [
3) Signal transducers and activators of transcription (STAT) pathway [
4) Src Kinase pathway [
5) Phospholipase Cγ/protein kinase C pathway [
Dysregulation of the EGF signaling network is implicated in cancer, diabetes, autoimmune, inflammatory, cardiovascular and nervous system disorders [
Loss of control of the cell functions mediated by the EGF signaling network is a hallmark of oncogenesis, in which the balance between cell proliferation and differentiation is disturbed. Several types of human cancer associated with dysregulation of the EGF signaling network [
In cancer, the EGF signaling network becomes hyperactivated with various mechanisms (ligand overproduction, receptor overproduction, constitutive receptor activation) [
EC is the most common malignancy of the female genital tract [
1) Type I EC, represents the majority of sporadic EC cases (70% - 80%) [
2) Type II EC, represents the minority of sporadic EC cases (10% - 20%) [
Due to the inactive status of postmenopausal endometrium, it is expectable to find significantly higher expression of the ErbB receptors in EC tissue [
In endometrium, EGFR localized to the basal part of surface epithelial cells, only in stromal cells, or both to epithelial and stromal cells [
In unselected patients with EC, it has been reported EGFR expression in 43% - 67% of cases [
EGFR over expression may have a dual role in EC [
In endometrium, ErbB-2 localized baso-laterally in the glands and surface epithelial cells [
In unselected patients with EC, ErbB-2 amplification/overexpression represents a rare event [
In patients with papillary serous EC, it has been reported ΕrbB-2 receptor overexpression in 18% - 80% of cases and ΕrbB-2 gene amplification in 17% - 47% of cases [
In endometrium, ErbB-3 localized to surface epithelial cells [
The clinical significance of ErbB-3 has not been studied well in EC [
In endometrium, ErbB-4 localized to epithelial and stromal cells [
The clinical significance of ErbB-4 has not been studied well in EC [
EGFR and ErbB-2 as targets for cancer therapy have been investigated for over 30 years [
1) Anti-EGFR MoAbs (cetuximab, panitumumab) bind to the extracellular domain of EGFR and prevent ligand binding and ligand dependent receptor activation [
2) Anti-ErbB-2 MoAb (trastuzumab) binds to the extracellular domain of ErbB-2 and interferes with ligand independent receptor activation [
3) Anti-ErbB MoAb (pertuzumab) prevents receptor heterodimerization [
1) EGFR TKIs (gefitinib, erlotinib) block the binding of ATP to the intracellular domain of EGFR and prevent tyrosine kinase activity and subsequent intracellular signaling [
2) EGFR and ErbB-2 TKI (lapatinib) block the binding of ATP to the intracellular domain of EGFR and ErbB-2 and prevents tyrosine kinase activity and subsequent intracellular signaling [
Anti-ErbB-2 MoAb (trastuzumab) may be an attractive and viable therapeutic option in patients with advanced, recurrent and/or metastatic EC overexpressing ErbB-2 [
Clinical responses to trastuzumab as single agent or in combination with chemotherapy have been reported in several case reports [
However a phase II study of trastuzumab as single agent in unselected patients with advanced or recurrent EC overexpressing ErbB-2, failed to demonstrate significant activity [
Moreover a phase II study of carboplatin/paclitaxel with or without trastuzumab in patients with advanced or recurrent type II EC (papillary serous) overexpressing ErbB-2, is currently underway (NCT01367002) [
ErbB-specific TKIs (gefitinib, erlotinib, lapatinib) may be another viable therapeutic option in patients with advanced, recurrent and/or metastatic EC overexpressing EGFR and ErbB-2 [
However a phase II study of gefitinib as single agent in unselected patients with persistent or recurrent EC overexpressing EGFR, demonstrate 4.1% complete response rate and 16.6% progression free survival ≥6 months [
Also a phase II study of erlotinib as single agent in unselected patients with metastatic or recurrent EC, demonstrate 12.5% partial response rate [
Moreover a phase II study of lapatinib as single agent in unselected patients with persistent or recurrent EC, demonstrate 3.3% partial response rate and 10% progression free survival ≥6 months [
Recent years, molecular targeted therapies have still shown modest effect in unselected EC patients [
ErbB targeted therapies have not clinically tested in type II EC [
The role of ErbB targeted therapies in EC should be further investigated in clinical trials to evaluate their therapeutic efficacy [
We declare that we have no conflict of interest.