Gibbs Energy and Gene Expression Combined as a New Technique for Selecting Drug Targets for Inhibiting Specific Protein-Protein Interactions.

One of the most important aspects of successful cancer therapy is the identification of a target protein for inhibition interaction. Conventionally, this consists of screening a panel of genes to assess which is mutated and then developing a small molecule to inhibit the interaction of two proteins or to simply inhibit a specific protein from all interactions. In previous work, we have proposed computational methods that analyze protein-protein networks using both topological approaches and thermodynamic quantification provided by Gibbs free energy.

Personalized therapy design for systemic lupus erythematosus based on the analysis of protein-protein interaction networks.

We analyzed protein expression data for Lupus patients, which have been obtained from publicly available databases. A combination of systems biology and statistical thermodynamics approaches was used to extract topological properties of the associated protein-protein interaction networks for each of the 291 patients whose samples were used to provide the molecular data. We have concluded that among the many proteins that appear to play critical roles in this pathology, most of them are either ribosomal proteins, ubiquitination pathway proteins or heat shock proteins.

Comprehensive Molecular Profiling for Relapsed/Refractory Pediatric Burkitt Lymphomas-Retrospective Analysis of Three Real-Life Clinical Cases-Addressing Issues on Randomization and Customization at the Bedside.

Unlabelled: In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry.

Individualization of Treatment Improves the Survival of Children With High-Risk Solid Tumors: Comparative Patient Series Analysis in a Real-Life Scenario.

The individualization of treatment is attractive, especially in children with high-risk cancer. In such a rare and very heterogeneous group of diseases, large population-based clinical randomized trials are not feasible without international collaboration. We therefore propose comparative patient series analysis in a real-life scenario.

Normal Wound Healing and Tumor Angiogenesis as a Game of Competitive Inhibition.

Both normal wound healing and tumor angiogenesis are mitigated by the sequential, carefully orchestrated release of growth stimulators and inhibitors. These regulators are released from platelet clots formed at the sites of activated endothelium in a temporally and spatially controlled manner, and the order of their release depends on their affinity to glycosaminoglycans (GAG) such as heparan sulfate (HS) within the extracellular matrix, and platelet open canallicular system. The formation of vessel sprouts, triggered by angiogenesis regulating factors with lowest affinities for heparan sulfate (e.

Personalized anticancer therapy selection using molecular landscape topology and thermodynamics.

Personalized anticancer therapy requires continuous consolidation of emerging bioinformatics data into meaningful and accurate information streams. The use of novel mathematical and physical approaches, namely topology and thermodynamics can enable merging differing data types for improved accuracy in selecting therapeutic targets. We describe a method that uses chemical thermodynamics and two topology measures to link RNA-seq data from individual patients with academically curated protein-protein interaction networks to select clinically relevant targets for treatment of low-grade glioma (LGG).

Insulin-like Growth Factor Receptor Inhibition as Maintenance Therapy for Metastatic Ewing Sarcoma.

Despite the advances in oncology, the survival of children with Ewing Sarcoma metastatic at diagnosis continues to be 27% 3-year event-free survival and 34% 3-year overall survival. In other words, 7 of 10 children die within 3 years of their initial diagnosis despite intense chemotherapy, local treatment (radiation/surgery), and/or high dose busulfan-melphalan and autologous stem-cell transplantation. A chief contributor to this morbidity and mortality is the difficulty eradicating the tumor using present therapeutic modalities.

Future paradigms for precision oncology.

Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.

Thermodynamic measures of cancer: Gibbs free energy and entropy of protein-protein interactions.

Thermodynamics is an important driving factor for chemical processes and for life. Earlier work has shown that each cancer has its own molecular signaling network that supports its life cycle and that different cancers have different thermodynamic entropies characterizing their signaling networks. The respective thermodynamic entropies correlate with 5-year survival for each cancer.

Design principles for cancer therapy guided by changes in complexity of protein-protein interaction networks.

Background: The ever-increasing expanse of online bioinformatics data is enabling new ways to, not only explore the visualization of these data, but also to apply novel mathematical methods to extract meaningful information for clinically relevant analysis of pathways and treatment decisions. One of the methods used for computing topological characteristics of a space at different spatial resolutions is persistent homology. This concept can also be applied to network theory, and more specifically to protein-protein interaction networks, where the number of rings in an individual cancer network represents a measure of complexity.

Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance.

The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified.

The toxicity of anti-VEGF agents when coupled with standard chemotherapeutics.

Bevacizumab (Avastin®, Genentech, CA) was granted accelerated approval by the FDA for metastatic breast cancer in 2008. This occurred after the initial clinical trial, E2100, demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of bevacizumab to a standard chemotherapy. Unfortunately, the approval was rescinded in 2011 when two subsequent trials, AVADO and RIBBON-1, failed to show survival benefit.

[Platelets in the pathogenesis of solid tumors].

Cancer cells trigger platelet aggregation. Reciprocally, platelet aggregation promotes tumor growth and metastasis. Within the tumor microenvironment, platelet regulates tumor growth via several mechanisms involving stimulation of angiogenesis, inflammation, coagulation, and stabilizing of vessel wall.

Chronic low dose-rate radiation down-regulates transcription related to mitosis and chromosomal movement similar to acute high dose in prostate cells.

Purpose: Despite concerns over risks from exposure to low-dose ionizing radiations encountered in the environment and workplace, the molecular consequences of these exposures, particularly at representative doses and dose-rates, remains poorly understood.

Materials And Methods: Using a novel flood source construct, we performed a direct comparison of genome-wide gene expression regulations resulting from exposure of primary human prostate fibroblast cultures to acute (10 cGy and 200 cGy) and longer-term chronic (1.0-2.

Addition of platelet concentrate to dermo-epidermal skin graft in deep burn trauma reduces scarring and need for revision surgeries.

Background: [corrected] Deep skin burn injuries, especially those on the face, hands, feet, genitalia and perineum represent significant therapeutic challenges. Autologous dermo-epidermal skin grafts (DESG) have become standard of care for treating deep burns. Additionally, human autologous thrombin activated autologous platelet concentrate (APC) has gained acceptance in the setting of wounds.

Interdisciplinary management of congenital infiltrating lipomatosis.

Congenital infiltrating lipomatosis is a benign yet locally invasive lipomatous tumor. Current treatment involves surgical excision and reconstruction of craniofacial deformity. Invasion of vital structures often makes complete resection problematic and recurrence is common.

Role of platelet chemokines, PF-4 and CTAP-III, in cancer biology.

With the recent addition of anti-angiogenic agents to cancer treatment, the angiogenesis regulators in platelets are gaining importance. Platelet factor 4 (PF-4/CXCL4) and Connective tissue activating peptide III (CTAP-III) are two platelet-associated chemokines that modulate tumor angiogenesis, inflammation within the tumor microenvironment, and in turn tumor growth. Here, we review the role of PF-4 and CTAP-III in the regulation of tumor angiogenesis; the results of clinical trial using recombinant PF-4 (rPF-4); and the use of PF-4 and CTAP-III as cancer biomarkers.

Center of cancer systems biology second annual workshop--tumor metronomics: timing and dose level dynamics.

Metronomic chemotherapy, the delivery of doses in a low, regular manner so as to avoid toxic side effects, was introduced over 12 years ago in the face of substantial clinical and preclinical evidence supporting its tumor-suppressive capability. It constituted a marked departure from the classic maximum-tolerated dose (MTD) strategy, which, given its goal of rapid eradication, uses dosing sufficiently intense to require rest periods between cycles to limit toxicity. Even so, upfront tumor eradication is frequently not achieved with MTD, whereupon a de facto goal of longer-term tumor control is often pursued.

Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets.

Acidosis is one of the hallmarks of tissue injury such as trauma, infection, inflammation, and tumour growth. Although platelets participate in the pathophysiology of all these processes, the impact of acidosis on platelet biology has not been studied outside of the quality control of laboratory aggregation assays or platelet transfusion optimization. Herein, we evaluate the effect of physiologically relevant changes in extracellular acidosis on the biological function of platelets, placing particular emphasis on haemostatic and secretory functions.

The role of angiogenesis in the transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1.

Purpose: The role of angiogenesis in the transformation of peripheral neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) remains elusive and forms the objective of this study.

Experimental Design: Archival tissue from 5 children with NF1 and PNF, who developed MPNST between the ages of 8 and 15 years were analyzed for differences in microvasculature. The role of proangiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF), and its receptors Flk-1 and Flt-1, and vessel maturity, defined as von Willebrand factor (vWf), α-smooth muscle actin+ (SMA+), were evaluated by immuno-histochemistry.

Platelet proteome and tumor dormancy: can platelets content serve as predictive biomarkers for exit of tumors from dormancy?

Although tumor dormancy is highly prevalent, the underling mechanisms are still mostly unknown. It is unclear which lesions will progress and become a disseminated cancer, and which will remain dormant and asymptomatic. Yet, an improved ability to predict progression would open the possibility of timely treatment and improvement in outcomes.

Platelets actively sequester angiogenesis regulators.

Clinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non-tumor-bearing animals.