Bipartite network models to design combination therapies in acute myeloid leukaemia

Combination therapy is preferred over single-targeted monotherapies for cancer treatment due to its efficiency and safety. However, identifying effective drug combinations costs time and resources. We propose a method for identifying potential drug combinations by bipartite network modelling of patient-related drug response data, specifically the Beat AML dataset. The median of cell viability is used as a drug potency measurement to reconstruct a weighted bipartite network, model drug-biological sample interactions, and find the clusters of nodes inside two projected networks. Then, the clustering results are leveraged to discover effective multi-targeted drug combinations, which are also supported by more evidence using GDSC and ALMANAC databases. The potency and synergy levels of selective drug combinations are corroborated against monotherapy in three cell lines for acute myeloid leukaemia in vitro. In this study, we introduce a nominal data mining approach to improving acute myeloid leukaemia treatment through combinatorial therapy.Peer reviewe

Rigosertib potently protects against colitis-associated intestinal fibrosis and inflammation by regulating PI3K/AKT and NF-kappa B signaling pathways

Aims: Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. This study was aimed to explore the regulatory effects of RGS on proliferative, pro-fibrotic and inflammatory factors in DSS- induced colitis mice model. Materials and methods: The present study integrates systems and molecular biology approaches to investigate the therapeutic potency of RGS in an experimental model of colitis specifically examining its effects on the PI3K/AKT and NF-kappa B signaling pathways. Key findings: Analysis of time-resolved proteome profiling showed that PI3K-AKT inhibitors regulate expression of many proteins in all stages of inflammation, fibrogenesis and extracellular matrix remodeling. Consistent with our in-silico findings, RGS improved colitis disease activity as assessed by changes in body weight, degree of stool consistency, rectal bleeding and prolapse. RGS also reduced oxidative stress markers and colon histopathological score by decreasing inflammatory responses in colon tissues. Moreover, expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1 beta, TNF-alpha, INF-gamma, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways. Significance: This study clearly demonstrates the anti-proliferative, anti-inflammatory and anti-fibrotic effects of RGS in colitis that may have implications for the treatment of colitis and colitis-associated cancer.Peer reviewe

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway

Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action. Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC). Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9. Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.Peer reviewe

Intraperitoneal administration of Telmisartan prevents postsurgical adhesion band formation

Background Angiotensin II receptor blockers (ARBs) have a potential role in reducing inflammation and fibrosis. We have integrated systems and molecular biology approaches to investigate the therapeutic potential of ARBs in preventing postsurgical adhesion band formation. Material and methods we have followed the ARRIVE guidelines point by point during experimental studies. Telmisartan (1 and 9 mg/kg), valsartan (1 and 9 mg/kg), and losartan (1 and 10 mg/kg) were administered intraperitoneally in different groups of male albino Wistar rat. After 7 d of treatment, macroscopic evidence and score of fibrotic bands based on scaling methods was performed. Moreover, the anti-inflammatory and antifibrosis effects of telmisartan on reduction of fibrotic bands were investigated by using histopathology, ELISA, and real-time polymerase chain reaction methods. Results Telmisartan, but not losartan or valsartan, prevented the frequency as well as the stability of adhesion bands. Telmisartan appears to elicit anti-inflammatory responses by attenuating submucosal edema, suppressing proinflammatory cytokines, decreasing proinflammatory cell infiltration, and inhibiting oxidative stress at the site of peritoneal surgery. We also showed that telmisartan prevents fibrotic adhesion band formation by reducing excessive collagen deposition and suppression of profibrotic genes expression at the peritoneum adhesion tissues. Conclusions These results support the potential application of telmisartan in preventing postsurgical adhesion band formation by inhibiting key pathologic responses of inflammation and fibrosis in postsurgery patients

Angiotensin receptor blocker losartan inhibits tumor growth of colorectal cancer

The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan’s anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment

Metformin inhibits polyphosphate-induced hyper-permeability and inflammation

Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic shortand systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/ anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.Peer reviewe

Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1

Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers

Fabrication and characterization of biodegradable polymeric films as a corneal stroma substitute

Background: Biodegradable elastomeric materials such as poly glycerol sebacate (PGS) have gained much current attention in the field of soft tissue engineering. The present study reports the synthesis of PGS with molar ratios of 1:1, 2:3, and 3:2 of glycerol and sebacic acid via polycondensation reaction and tests the effect of PGS on human corneal epithelial (HCE) cells viability in vitro. Materials and Methods: PGS films were prepared by the casting method. We tried to fabricate PGS with different compositions and various properties as being a viable alternative to the corneal stroma in cornea tissue engineering. The chemical properties of the prepared polymer were investigated by means of attenuated total reflectance - Fourier transform infrared spectroscopy (ATR-FTIR) analysis and the in vitro cytotoxicity was investigated by the Alamarblue method. Results: The functional groups observed in the PGS FTIR spectrums of PGS with various molar ratios were the same. However, the main difference was the time of completing the cross-linking reaction. The PGS prepared by 2:3 ratio as a molar ratio had the fastest and the 3:2 ratio had the lowest cross-linking rate because of the higher amount of sebacic acid. Results of the Alamarblue cytotoxicity test assay showed no deleterious effect on HCE cell viability and proliferation. Conclusions: PGS is a potentially good candidate material for corneal tissue engineering because of its lack of in vitro HCE cell toxicity