PROTAC-Mediated GSPT1 Degradation Impairs the Expression of Fusion Genes in Acute Myeloid Leukemia.

Background: Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin-proteasome system to selectively degrade target proteins. This innovative technology has shown remarkable efficacy and specificity in degrading oncogenic proteins and has progressed through various stages of preclinical and clinical development for hematologic malignancies, including adult acute myeloid leukemia (AML). However, the application of PROTACs in pediatric AML remains largely unexplored.

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia.

Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or 'cold' tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls.

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.

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia.

Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or 'cold' tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls.

A RUNX1/ETO-SKP2-CDKN1B axis regulates expression of telomerase in t (8;21) acute myeloid leukemia.

The fusion oncoprotein RUNX1/ETO which results from the chromosomal translocation t (8;21) in acute myeloid leukemia (AML) is an essential driver of leukemic maintenance. We have previously shown that RUNX1/ETO knockdown impairs expression of the protein component of telomerase, TERT. However, the underlying molecular mechanism of how RUNX1/ETO controls TERT expression has not been fully elucidated.

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.

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 short- and systemic long-term approaches in murine models.

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.

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.

RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia.

The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukemia. Here we show that the RUNX1/RUNX1T1 oncogene is a regulator of alternative RNA splicing in leukemic cells. The comprehensive analysis of RUNX1/RUNX1T1-associated splicing events identifies two principal mechanisms that underlie the differential production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start site selection, and (ii) direct or indirect control of the expression of genes encoding splicing factors.

t(8;21) Acute Myeloid Leukemia as a Paradigm for the Understanding of Leukemogenesis at the Level of Gene Regulation and Chromatin Programming.

Acute myeloid leukemia (AML) is a heterogenous disease with multiple sub-types which are defined by different somatic mutations that cause blood cell differentiation to go astray. Mutations occur in genes encoding members of the cellular machinery controlling transcription and chromatin structure, including transcription factors, chromatin modifiers, DNA-methyltransferases, but also signaling molecules that activate inducible transcription factors controlling gene expression and cell growth. Mutant cells in AML patients are unable to differentiate and adopt new identities that are shaped by the original driver mutation and by rewiring their gene regulatory networks into regulatory phenotypes with enhanced fitness.

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

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.

Two Novel Tri-Aryl Derivatives Attenuate the Invasion-Promoting Effects of Stromal Mesenchymal Stem Cells on Breast Cancer.

Background: The concept of Epithelial-Mesenchymal Transition (EMT) to promote carcinoma progression has been recognized as a venue for research on novel anticancer drugs. Triaryl template-based structures are one of the pivotal structural features found in a number of compounds with a wide variety of biological properties including anti-breast cancer. Among the various factors triggering EMT program, cyclooxygenase-2 (COX-2), NF-κB as well as the transforming growth factor-beta (TGF-β) have been widely investigated.

Valproic acid inhibits the protective effects of stromal cells against chemotherapy in breast cancer: Insights from proteomics and systems biology.

Interaction between tumor and stromal cells is beginning to be decoded as a contributor to chemotherapy resistance. Here, we aim to take a system-level approach to explore a mechanism by which stromal cells induce chemoresistance in cancer cells and subsequently identify a drug that can inhibit such interaction. Using a proteomic dataset containing quantitative data on secretome of stromal cells, we performed multivariate analyses and found that bone-marrow mesenchymal stem cells (BM-MSCs) play the most protective role against chemotherapeutics.

Integrated use of bioinformatic resources reveals that co-targeting of histone deacetylases, IKBK and SRC inhibits epithelial-mesenchymal transition in cancer.

With the advent of high-throughput technologies leading to big data generation, increasing number of gene signatures are being published to predict various features of diseases such as prognosis and patient survival. However, to use these signatures for identifying therapeutic targets, use of additional bioinformatic tools is indispensible part of research. Here, we have generated a pipeline comprised of nearly 15 bioinformatic tools and enrichment statistical methods to propose and validate a drug combination strategy from already approved drugs and present our approach using published pan-cancer epithelial-mesenchymal transition (EMT) signatures as a case study.

A rapid and sensitive method for EphB4 identification as a diagnostic and therapeutic biomarker in invasive breast cancer.

Background: In the roadmap to design diagnostic and therapeutic markers for breast cancer, EphB4 is of special interest due to its multiple roles in tumor initiation, progression and invasion. The aim of present study was to characterize a rapid and sensitive ELISA-based method to measure EphB4 level and its phosphorylation status following stimulation with its ligand, ephrinB2, in an invasive breast cancer cell line.

Materials And Methods: MDA-MB-231 breast cancer cells were lysed and EphB4 level was measured using ELISA.

Testis-Specific Y-Centric Protein-Protein Interaction Network Provides Clues to the Etiology of Severe Spermatogenic Failure.

Pinpointing causal genes for spermatogenic failure (SpF) on the Y chromosome has been an ever daunting challenge with setbacks during the past decade. Since complex diseases result from the interaction of multiple genes and also display considerable missing heritability, network analysis is more likely to explicate an etiological molecular basis. We therefore took a network medicine approach by integrating interactome (protein-protein interaction (PPI)) and transcriptome data to reconstruct a Y-centric SpF network.

Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database.

Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology.

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.

EphB4 tyrosine kinase stimulation inhibits growth of MDA-MB-231 breast cancer cells in a dose and time dependent manner.

Background: EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc.