Integrin-linked kinase expression in myeloid cells promotes colon tumorigenesis.

Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and treatment options for advanced CRC, which has a low 5-year survival rate, remain limited. Integrin-linked kinase (ILK), a multifunctional, scaffolding, pseudo-kinase regulating many integrin-mediated cellular processes, is highly expressed in many cancers. However, the role of ILK in cancer progression is yet to be fully understood. We have previously uncovered a pro-inflammatory role for myeloid-specific ILK in dextran sodium sulfate (DSS)-induced colitis. To establish a correlation between chronic intestinal inflammation and colorectal cancer (CRC), we investigated the role of myeloid-ILK in mouse models of CRC. When myeloid-ILK deficient mice along with the WT control mice were subjected to colitis-associated and APCmin/+-driven CRC, tumour burden was reduced by myeloid-ILK deficiency in both models. The tumour-promoting phenotype of macrophages, M2 polarization, in vitro was impaired by the ILK deficiency and the number of M2-specific marker CD206-expressing tumour-associated macrophages (TAMs) in vivo were significantly diminished in myeloid-ILK deficient mice. Myeloid-ILK deficient mice showed enhanced tumour infiltration of CD8+ T cells and reduced tumour infiltration of FOXP3+ T cells in colitis-associated and APCmin/+-driven CRC, respectively, with an overall elevated CD8+/FOXP3+ ratio suggesting an anti-tumour immune phenotypes. In patient CRC tissue microarrays we observed elevated ILK+ myeloid (ILK+ CD11b+) cells in tumour sections compared to adjacent normal tissues, suggesting a conserved role for myeloid-ILK in CRC development in both human and animal models. This study identifies myeloid-specific ILK expression as novel driver of CRC, which could be targeted as a potential therapeutic option for advanced disease.

Delineating Pixantrone Maleate's adroit activity against cervical cancer proteins through multitargeted docking-based MM\GBSA, QM-DFT and MD simulation.

Cervical cancer poses a substantial worldwide health challenge, especially in low- and middle-income nations, caused by high-risk types of human papillomavirus. It accounted for a significant percentage of cancer-related deaths among women, particularly in areas with limited healthcare resources, necessitating innovative therapeutic approaches, and single-targeted studies have produced significant results, with a considerable chance of developing resistance. Therefore, the multitargeted studies can work as a beacon of hope. This study is focused on performing the multitargeted molecular docking of FDA-approved drugs with the three crucial proteins TBK1, DNA polymerase epsilon, and integrin α-V ß-8 of cervical cancer. The docking studies using multisampling algorithms HTVS, SP, and XP reveal Pixantrone Maleate (DB06193) as a multitargeted inhibitor with docking scores of -8.147, -8.206 and -7.31 Kcal/mol and pose filtration with MM\GBSA computations with scores -40.55, -33.67, and -37.64 Kcal/mol. We also have performed QM-based DFT and pharmacokinetics studies of the compound and compared it with the standard values, which results in the compound being entirely suitable against cervical cancer proteins. The interaction fingerprints have revealed that PHE, VAL, SER and ALA are the residues among most interactions. We also explore the stability of the multitargeted potential of Pixantrone Maleate through 100ns MD simulations and investigate the RMSD, RMSF and intermolecular interactions between all three proteins-ligand complexes. All computational studies favour Pixantrone Maleate as a multitargeted inhibitor of the TBK1, DNA polymerase epsilon, and integrin α-V ß-8 and can be validated experimentally before use.

Design of Active Fault-Tolerant Control System for Air-Fuel Ratio control of Internal Combustion engine using nonlinear regression-based observer model.

Internal Combustion (IC) engines are prevalent in the process sector, and maintaining sufficient Air-Fuel Ratio (AFR) regulation in their fuel system is crucial for enhanced engine performance, fuel economy, and environmental safety. Faults in the AFR system's sensors cause the engine to shut down, hence, fault tolerance is essential. In order to avoid engine shutdown, this paper offers a novel Active Fault-Tolerant Control System (AFTCS) for air-fuel ratio control of an Internal Combustion (IC) engine in a process plant. In the Fault Detection and Isolation (FDI) unit, the proposed AFTCS uses a nonlinear regression-based observer model for analytical redundancy. The suggested system was simulated in the MATLAB / Simulink environment. The proposed system was tested at two different speeds (300 r/min and 600 r/min) and the results show that the system's response is within the acceptable bound without compromising the stability. The findings also demonstrate the higher fault tolerance capability for sensor defects of the AFR control system, particularly for the MAP sensor (at 300 r/min) in terms of reduced oscillatory response in comparison to the current literature. Compared to the linear regression-based and Genetic Algorithm (GA) based model, the nonlinear regression-based model results in a more accurate estimation of the faulty sensors. The proposed model is also efficient in terms of computation power and response time.

Integrin-Linked Kinase Expression Characterizes the Immunosuppressive Tumor Microenvironment in Colorectal Cancer and Regulates PD-L1 Expression and Immune Cell Cytotoxicity.

Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. However, a role for ILK in the tumor microenvironment (TME) and immune evasion has not been investigated. Here, we show a correlation of ILK expression with the immunosuppressive TME and cancer prognosis. We also uncover a role for ILK in the regulation of programmed death-ligand 1 (PD-L1) expression and immune cell cytotoxicity. Interrogation of web-based data-mining platforms, showed upregulation of ILK expression in tumors and adjacent-non tumor tissue of colorectal cancer (CRC) associated with poor survival and advanced stages. ILK expression was correlated with cancer-associated fibroblast (CAFs) and immunosuppressive cell infiltration including regulatory T cells (Treg) and M2 macrophages (M2) in addition to their gene markers. ILK expression was also significantly correlated with the expression of different cytokines and chemokines. ILK expression showed pronounced association with different important immune checkpoints including PD-L1. Deletion of the ILK gene in PD-L1 positive CRC cell lines using a doxycycline inducible-CRISPR/Cas9, resulted in suppression of both the basal and IFNγ-induced PD-L1 expression via downregulating NF-κB p65. This subsequently sensitized the CRC cells to NK92 immune cell cytotoxicity. These findings suggest that ILK can be used as a biomarker for prognosis and immune cell infiltration in colon cancer. Moreover, ILK could provide a therapeutic target to prevent immune evasion mediated by the expression of PD-L1.

False Data Injection Detection for Phasor Measurement Units.

Cyber-threats are becoming a big concern due to the potential severe consequences of such threats is false data injection (FDI) attacks where the measures data is manipulated such that the detection is unfeasible using traditional approaches. This work focuses on detecting FDIs for phasor measurement units where compromising one unit is sufficient for launching such attacks. In the proposed approach, moving averages and correlation are used along with machine learning algorithms to detect such attacks. The proposed approach is tested and validated using the IEEE 14-bus and the IEEE 30-bus test systems. The proposed performance was sufficient for detecting the location and attack instances under different scenarios and circumstances.

Advanced Fault-Tolerant Anti-Surge Control System of Centrifugal Compressors for Sensor and Actuator Faults.

Faults frequently occur in the sensors and actuators of process machines to cause shutdown and process interruption, thereby creating costly production loss. centrifugal compressors (CCs) are the most used equipment in process industries such as oil and gas, petrochemicals, and fertilizers. A compressor control system called an anti-surge control (ASC) system based on many critical sensors and actuators is used for the safe operation of CCs. In this paper, an advanced active fault-tolerant control system (AFTCS) has been proposed for sensor and actuator faults of the anti-surge control system of a centrifugal compressor. The AFTCS has been built with a dedicated fault detection and isolation (FDI) unit to detect and isolate the faulty part as well as replace the faulty value with the virtual redundant value from the observer model running in parallel with the other healthy sensors. The analytical redundancy is developed from the mathematical modeling of the sensors to provide estimated values to the controller in case the actual sensor fails. Dual hardware redundancy has been proposed for the anti-surge valve (ASV). The simulation results of the proposed Fault-tolerant control (FTC) for the ASC system in the experimentally validated CC HYSYS model reveal that the system continued to operate in the event of faults in the sensors and actuators maintaining system stability. The proposed FTC for the ASC system is novel in the literature and significant for the process industries to design a highly reliable compressor control system that would continue operation despite faults in the sensors and actuators, hence preventing costly production loss.

A Novel Technique to Detect False Data Injection Attacks on Phasor Measurement Units.

The power industry is in the process of grid modernization with the introduction of phasor measurement units (PMUs), advanced metering infrastructure (AMI), and other technologies. Although these technologies enable more reliable and efficient operation, the risk of cyber threats has increased, as evidenced by the recent blackouts in Ukraine and New York. One of these threats is false data injection attacks (FDIAs). Most of the FDIA literature focuses on the vulnerability of DC estimators and AC estimators to such attacks. This paper investigates FDIAs for PMU-based state estimation, where the PMUs are comparable. Several states can be manipulated by compromising one PMU through the channels of that PMU. A Phase Locking Value (PLV) technique was developed to detect FDIAs. The proposed approach is tested on the IEEE 14-bus and the IEEE 30-bus test systems under different scenarios using a Monte Carlo simulation where the PLV demonstrated an efficient performance.

A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity.

Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. ILK functions as an adaptor and mediator protein linking the extracellular matrix with downstream signaling pathways. ILK is broadly expressed in many human tissues and cells. It is also overexpressed in many cancers, including colorectal cancer (CRC). Inflammation, as evidenced by inflammatory bowel disease (IBD), is one of the highest risk factors for initiating CRC. This has led to the hypothesis that targeting ILK therapeutically could have potential in CRC, as it regulates different cellular processes associated with CRC development and progression as well as inflammation in the colon. A number of studies have indicated an ILK function in senescence, a cellular process that arrests the cell cycle while maintaining active metabolism and transcription. Senescent cells produce different secretions collectively known as the senescence-associated secretory phenotype (SASP). The SASP secretions influence infiltration of different immune cells, either positively for clearing senescent cells or negatively for promoting tumor growth, reflecting the dual role of senescence in cancer. However, a role for ILK in senescence and immunity in CRC remains to be determined. In this review, we discuss the possible role for ILK in senescence and immunity, paying particular attention to the relevance of ILK in CRC. We also examine how activating Toll-like receptors (TLRs) and their agonists in CRC could trigger immune responses against cancer, as a combination therapy with ILK inhibition.