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In this study, a library of phthalimide Schiff base linked to 1,4-disubstituted-1,2,3-triazoles was designed, synthesised, and characterised by different spectral analyses. All analogues have been introduced for in vitro assay of their antiviral activity against COVID-19 virus using Vero cell as incubator with different concentrations. The data revealed most of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with no or weak cytotoxic effect on Vero cells. Furthermore, in vitro assay was done against this enzyme for all analogues and the results showed two of them have IC50 data by 90 µM inhibitory activity. An extensive molecular docking simulation was run to analyse their antiviral mechanism that found the proper non-covalent interaction within the Mpro protease enzyme. Finally, we profiled two reversible inhibitors, COOH and F substituted analogues that might be promising drug candidates for further development have been discovered.

Abstract Alzheimer’s disease (AD) is a chronic illness marked by increasing cognitive decline and nervous system deterioration. At this time, there is no known medication that will stop the course of Alzheimer’s disease; instead, most symptoms are treated. Clinical trial failure rates for new drugs remain high, highlighting the urgent need for improved AD modeling for improving understanding of the underlying pathophysiology of disease and improving drug development. The development of induced pluripotent stem cells (iPSCs) has made it possible to model neurological diseases like AD, giving access to an infinite number of patient-derived cells capable of differentiating neuronal fates. This advance will accelerate Alzheimer’s disease research and provide an opportunity to create more accurate patient-specific models of Alzheimer’s disease to support pathophysiological research, drug development, and the potential application of stem cell-based therapeutics. This review article provides a complete summary of research done to date on the potential use of iPSCs from AD patients for disease modeling, drug discovery, and cell-based therapeutics. Current technological developments in AD research including 3D modeling, genome editing, gene therapy for AD, and research on familial (FAD) and sporadic (SAD) forms of the disease are discussed. Finally, we outline the issues that need to be elucidated and future directions for iPSC modeling in AD.

Functional genomics is an emerging field focused on elucidating the functions of genes or proteins, which can help solve challenges related to reliable cancer therapy. One of the main challenges currently faced by cancer therapy is the variations in the number of mutations in patients, leading to drug resistance and cancer relapses. Drug intrinsic or acquired resistance, is generally associated with most cancer relapses. There are advanced tools that can help identify the mutant genes in cancer tissues causing cancer drug resistance (CDR). Such tools include but are not limited to DNA and RNA sequencing as well assynthetic lethality gene screen (CRISPR)-based diagnosis. This review discusses the role of functional genomics in understanding CDR and finding tools for discovering drug target genes for cancer therapy.

Abstract Cancer is still the leading cause of death globally. The approval of the therapeutic use of monoclonal antibodies against immune checkpoint molecules, notably those that target the proteins PD-1 and PD-L1, has changed the landscape of cancer treatment. In particular, first-line PD-1/PD-L1 inhibitor drugs are increasingly common for the treatment of metastatic cancer, significantly prolonging patient survival. Despite the benefits brought by immune checkpoint inhibitors (ICIs)-based therapy, the majority of patients had their diseases worsen following a promising initial response. To increase the effectiveness of ICIs and advance our understanding of the mechanisms causing cancer resistance, it is crucial to find new, effective, and tolerable combination treatments. In this article, we addressed the potential of ICIs for the treatment of solid tumors and offer some insight into the molecular pathways behind therapeutic resistance to ICIs. We also discuss cutting-edge therapeutic methods for reactivating T-cell responsiveness after resistance has been established.

This paper provides a stochastic framework for the energy management of multi-area hybrid microgrids to identify the optimal daily power dispatch in the islanded mode of operation. The primary goal of this framework is to minimize operational costs and power outages for customers by effectively managing the power resources of the hybrid microgrid. These resources include renewable energy sources, battery energy storage systems, and electric vehicles. To obtain accurate results, the costs related to active and reactive powers of diesel generator units are considered in this study. In addition, the uncertainties in the, power generated from renewable energy sources, electric vehicles charging and microgrid demand are modeled using the Monte Carlo Simulation as a scenario generation technique. The number of generated scenarios is reduced using the Fast Forward Scenario reduction technique. The proposed problem is formulated as a constrained mixed-integer nonlinear programming optimization problem and is solved using the Transient Search Optimization algorithm. The obtained solution is compared against other meta-heuristic optimization techniques to ensure the reliability of the results. To investigate the effectiveness of the proposed framework, several case studies are simulated on an islanded hybrid microgrid. The simulation results show the improvement in the economic performance and the reliability of the hybrid MG. The results also indicate the impact of increasing penetration levels of renewable energy resources on the operation cost and power exchange between AC and DC areas.

The urgent transition towards electric vehicles (EVs) may potentially result in expensive capacity upgrades for power system operators (PSOs), however, the recent uptake in bidirectional EV charging, often referred to as “Vehicle to Everything” (V2X), may defer this need while simultaneously generating revenue for participating EV owners. Yet, there is a lack of real-world investigation to elicit (a) the willingness of EV owners to participate in V2X programs (b) the alignment of these programs within existing electricity markets, and (c) how V2X may be combined with other distributed energy resources (DERs) to realize maximum energy savings. As such, this paper proposes the design and implementation of a V2X program that is informed by the socio-technical preferences of EV owners, including convenience, revenue, and emissions savings. A survey is distributed to 124 EV owners to characterize their degree of willingness to participate in the program, which leads to the design of several EV session types that enable EV owners to arbitrage at their convenience, or participate in demand response (DR) events for higher revenue. Real-world tests at residential and commercial buildings in Ontario successfully demonstrate the facilitation of both arbitrage and DR, leading to increased revenue, decreased emissions, and the ability to participate in DR with other building DERs to reduce the building load by 30 kW. The proposed work contributes a novel attempt to demonstrate pathways to realize the potential offerings of V2X programs to benefit both EV owners, building owners, and PSOs.

Abstract The primary purpose of ADCs is to increase the efficacy of anticancer medications by minimizing systemic drug distribution and targeting specific cells. Antibody conjugates (ADCs) have changed the way cancer is treated. However, because only a tiny fraction of patients experienced long-term advantages, current cancer preclinical and clinical research has been focused on combination trials. The complex interaction of ADCs with the tumor and its microenvironment appear to be reliant on the efficacy of a certain ADC, all of which have significant therapeutic consequences. Several clinical trials in various tumor types are now underway to examine the potential ADC therapy, based on encouraging preclinical results. This review tackles the potential use of ADCs in cancer therapy, emphasizing the essential processes underlying their positive therapeutic impacts on solid and hematological malignancies. Additionally, opportunities are explored to understand the mechanisms of ADCs action, the mechanism of resistance against ADCs, and how to overcome potential resistance following ADCs administration. Recent clinical findings have aroused interest, leading to a large increase in the number of ADCs in clinical trials. The rationale behind ADCs, as well as their primary features and recent research breakthroughs, will be discussed. We then offer an approach for maximizing the potential value that ADCs can bring to cancer patients by highlighting key ideas and distinct strategies.

Abstract The most common and aggressive primitive intracranial tumor of the central nervous system is the glioma. The blood–brain barrier (BBB) has proven to be a significant obstacle to the effective treatment of glioma. To effectively treat glioma, different ways have been used to cross the BBB to deliver drugs to the brain. Drug delivery through nanocarriers proves to be an effective and non-invasive technique for the treatment of glioma and has great potential in the treatment of glioma. In this review, we will provide an overview of nanocarrier-mediated drug delivery and related glioma therapy. Nanocarrier-mediated drug delivery techniques to cross the BBB (liposomes, micelles, inorganic systems, polymeric nanoparticles, nanogel system, and biomimetic nanoparticles) are explored. Finally, the use of nanotherapeutic approaches in the treatment of glioblastoma including chemotherapy, radiotherapy, photothermal therapy, gene therapy, glioma genome editing, immunotherapy, chimeric antigen receptor (CAR) T-cells, immune checkpoint modulators, immune photothermal therapy, vaccine-based immunotherapy, and combination therapy is summarized. Furthermore, this article offers various views on the clinical applicability of nanomedicine.

Abstract EV produced by tumour cells carry a diverse population of proteins, lipids, DNA, and RNA molecules throughout the body and appear to play an important role in the overall development of the disease state, according to growing data. Gliomas account for a sizable fraction of all primary brain tumours and the vast majority of brain malignancies. Glioblastoma multiforme (GBM) is a kind of grade IV glioma that has a very dismal prognosis despite advancements in diagnostic methods and therapeutic options. The authors discuss advances in understanding the function of extracellular vesicles (EVs), in overall glioma growth, as well as how recent research is uncovering the utility of EVs in glioma diagnostics, prognostic and therapeutics approaches.

Abstract Background Glioblastoma multiforme (GBM) is a heterogeneous CNS neoplasm which causes significant morbidity and mortality. One reason for the poor prognostic outcome of GBM is attributed to the presence of cancer stem cells (CSC) which confer resistance against standard chemo- and radiotherapeutics modalities. Two types of GBM-associated CSC were isolated from the same patient: tumor core- (c-CSC) and peritumor tissue-derived cancer stem cells (p-CSC). Our experiments are focused on glioblastoma–IDH-wild type, and no disease-defining alterations were present in histone, BRAF or other genes. Methods In the present study, potential differences in genetic variants between c-CSC versus p-CSC derived from four GBM patients were investigated with the aims of (1) comparing the exome sequences between all the c-CSC or p-CSC to identify the common variants; (2) identifying the variants affecting the function of genes known to be involved in cancer origin and development. Results By comparative analyses, we identified common gene single nucleotide variants (SNV) in all GBM c-CSC and p-CSC, a potentially deleterious variant was a frameshift deletion at Gln461fs in the MLLT1 gene, that was encountered only in p-CSC samples with different allelic frequency. Conclusions We discovered a potentially harmful frameshift deletion at Gln461fs in the MLLT1 gene. Further investigation is required to confirm the presence of the identified mutations in patient tissue samples, as well as the significance of the frameshift mutation in the MLLT1 gene on GBM biology and response to therapy based on genomic functional experiments.

Abstract The p53 protein is a transcription factor known as the "guardian of the genome" because of its critical function in preserving genomic integrity. The TP53 gene is mutated in approximately half of all human malignancies, including those of the breast, colon, lung, liver, prostate, bladder, and skin. When DNA damage occurs, the TP53 gene on human chromosome 17 stops the cell cycle. If p53 protein is mutated, the cell cycle is unrestricted and the damaged DNA is replicated, resulting in uncontrolled cell proliferation and cancer tumours. Tumor-associated p53 mutations are usually associated with phenotypes distinct from those caused by the loss of the tumor-suppressing function exerted by wild-type p53protein. Many of these mutant p53 proteins have oncogenic characteristics, and therefore modulate the ability of cancer cells to proliferate, escape apoptosis, invade and metastasize. Because p53 deficiency is so common in human cancer, this protein is an excellent option for cancer treatment. In this review, we will discuss some of the molecular pathways by which mutant p53 proteins might perform their oncogenic activities, as well as prospective treatment methods based on restoring tumor suppressive p53 functions.

Abstract Glioblastoma multiforme (GBM) is one of the deadliest brain tumors with an unfavorable prognosis and overall survival of approximately 20 months following diagnosis. The current treatment for GBM includes surgical resections and chemo‐ and radiotherapeutic modalities, which are not effective. CAR‐T immunotherapy has been proven effective for CD19‐positive blood malignancies, and the application of CAR‐T cell therapy for solid tumors including GBM offers great hope for this aggressive tumor which has a limited response to current treatments. CAR‐T technology depends on the use of patient‐specific T cells genetically engineered to express specific tumor‐associated antigens (TAAs). Interaction of CAR‐T cells with tumor cells triggers the destruction/elimination of these cells by the induction of cytotoxicity and the release of different cytokines. Despite the great promise of CAR‐T cell‐based therapy several challenges exist. These include the heterogeneity of GBM cancer cells, aberrant various signaling pathways involved in tumor progression, antigen escape, the hostile inhibitory GBM microenvironment, T cell dysfunction, blood‐brain barrier, and defective antigen presentation. All need to be addressed before full application at the clinical level can begin. Herein we provide a focused review of the rationale for the use of different types of CAR‐T cells (including FcγRs), the different GBM‐associated antigens, the challenges still facing CAR‐T‐based therapy, and means to overcome such challenges. Finally, we enumerate currently completed and ongoing clinical trials, highlighting the different ways such trials are designed to overcome specific problems. Exploitation of the full potential of CAR‐T cell therapy for GBM depends on their solution.

The higher the process efficiency, the lower the fuel consumption, and the less impact carbon emissions have on the environment. The flow characteristics around brick settings are an important field of investigation to acquire control over the energy intake and production process. The current work is a numerical CFD investigation to demonstrate fluid flow characterization inside the cooling zone in a brick tunnel kiln for lattice settings (the number of bricks in each layer is identical). Four different lattice settings were examined, and three were validated with published experimental data (settings 1, 2 and 3). In the current study, the BSL κ-ω turbulent model agrees well with the published experimental results. The numerical investigation presents the flow characteristics through four different lattice brick settings (e.g., velocity vectors, velocity contours and streamlines) that could not be measured experimentally. The investigation also looks at the flow zones of the vortex formation upstream, downstream and through the brick column. It was discovered that for settings 1 and 11, the quick air flow in the wall channels is much greater than in the column channels. Setting 3 has a larger vortex formation region, whereas setting 1 has a weaker vortex than the other settings. The cooling of the lattice bricks in Setting 3 is superior to the cooling in the other settings.

Residential energy trading systems (RETS) enable homeowners with distributed energy resources (DERs) to participate in virtualized energy markets that have the potential to reduce the peak demand of residential communities. Blockchains are key enablers of RETS, by virtue of providing a decentralized, self-governed network that mitigates concerns regarding privacy and transparency. However, more real-world case studies are needed to evaluate the techno-economic viability of blockchain-based RETS to improve their positive uptake. Thus, this article develops a permissioned blockchain-based RETS, which enables homeowners to select bidding strategies that consider the individual preferences of their DERs, and further evaluates the impact of the bidding strategies on reducing the peak demand of the community. The proposed system is implemented on the permissioned Hyperledger Fabric platform, where a decentralized ledger is used to store all energy bids, and a smart contract is used to execute a double auction mechanism and dispatch the homeowner DERs. The proposed system is validated by conducting simulations on a 8-home community using real-world data, and also by deploying the system to a Canadian microgrid, where the smart contract execution time is benchmarked. Simulation results demonstrate the efficacy of the proposed system by achieving a peak demand reduction of up to 48 kW (62%), which leads to an average savings of $1.02 M for the distribution system operator by avoiding transformer upgrades. Also, the simulation results show that the execution time of the proposed smart contract is 17.12 seconds across 12 nodes, which is sufficient for RETS.

Purpose The aim of this study was to evaluate the value of optical coherence tomography angiography (OCTA) in the detection of any suspected retinal complications associated with the use of combined therapy (sofosbuvir ‘Sovaldi’ and daclatasvir ‘Daklinza’) in patients with hepatitis C virus infection. Patients and methods This is a prospective cohort study that enrolled patients with chronic hepatitis C who did not receive any previous antiviral treatment and who were candidates for the dual therapy. During a 3-month duration (the treatment course duration), OCTA was performed for documented chronic hepatitis C-infected patients before and after receiving the dual therapy (daclatasvir–sofosbuvir). The minimum outcome measures were best-corrected visual acuity and vascular density by OCTA macula. Results There was a statistically significant reduction in the deep capillary plexus (P≤0.05). The whole macular vessel density was reduced from 51.56 to 47.68% after the treatment course (P=0.04). These vascular density changes were associated with statistically insignificant increase in thickness. In addition, the choriocapillaris had a statistically significant reduction in flow area from 2.145 to 2.063 mm2 (P=0.0001). The superficial capillary plexus changes in vessel density were statistically insignificant except at the temporal parafoveal area. There was also a statistically significant reduction in the foveal avascular zone flow density from 54.42% before starting the dual therapy course to 51.85% after finishing it (P=0.022). These changes were associated with a statistically significant reduction in best-corrected visual acuity from 0.83 to 0.63 (P

Purpose The purpose of this study was to detect single or multiple best-performing parameters of corneal tomography and dynamic corneal biomechanics with high sensitivity and specificity in the diagnosis of keratoconus, subclinical keratoconus (SCKC), and forme fruste keratoconus (FFKC). Design This was a prospective observational study. Patients and methods In this study, one eye of each of 40 participants was included. They were divided into four groups: keratoconus, SCKC, FFKC, and a normal control group, with 10 participants in each group. All participants underwent a full ophthalmologic examination, analysis of corneal tomography using Pentacam HR and analysis of corneal biomechanical response using the Corvis ST at the initial visit and after 3 months. Results For the diagnosis of keratoconus, the 100% sensitive and specific parameters were Belin/Ambrósio Enhanced Ectasia Display (BAD d), Ambrósio’s relational thickness maximum (ARTmax), and tomographic biomechanical index (TBI) with cutoff values of 1.905, 344, and 0.785, respectively. For detection of SCKC, the 100% sensitive parameters were maximum keratometry and thickness profile index with cutoff values of 44.7 and 0.945, respectively. After 3 months of follow-up, maximum keratometry, index of surface variance, deflection amplitude, and deflection area showed 100% sensitivity with specificities of 90, 80, 70, and 60%, respectively. The highest percentage of change over time was for the index of highest decentration by 200%, followed by TBI by 133%. For FFKC, the deformation amplitude and corneal velocity 1 showed sensitivity of 90 and 80%, respectively, and specificity of 83 and 90%, respectively. After follow-up BAD d, deformation amplitude, deformation amplitude ratio, and TBI showed 100% sensitivity and specificity. Conclusion This study illustrated the efficacy of Corvis parameters for the diagnosis of keratoconus, but with lower discriminative ability than corneal tomography. It could also be used as a supplementary tool for the diagnosis and follow-up of SCKC and FFKC patients.

Introduction The rapid shallow breathing index (RSBI) is considered an accurate weaning predictor. The diaphragmatic excursion (DE) and maximum inspiratory pressure (MIP) can be used as weaning parameters. Substitution of the tidal volume by the DE in the RSBI, that is, calculating the diaphragmatic RSBI (DRSBI, RR/DE), might yield a more precise weaning predictor. Objective The aim of this research was to evaluate the predictive value of the DRSBI, MIP, and the ratio between them (MIP/DRSBI) in the weaning of mechanically ventilated patients. Patients and methods In our study, 64 mechanically ventilated patients were enrolled. At the time of their first spontaneous breathing trial, ultrasonographic assessment of the DE was done, MIP was measured, and RSBI, DRSBI, and MIP/DRSBI were calculated. A total of 36 (56.25%) patients had successful weaning, whereas 28 (43.75%) failed the weaning trial. The new composite parameter (MIP/DRSBI) with a cutoff value greater than or equal to 17 cmH2O/min/mm/breath was the best tool to predict successful weaning with area under the receiver operating characteristics curve of 0.982, with sensitivity and specificity of 100 and 96%, respectively. Conclusion Combining the MIP and DRSBI in one composite parameter (MIP/DRSBI) improved the sensitivity, specificity, and accuracy of both parameters when compared with either parameter alone.

This paper investigates the rheological properties of methylcellulose-silica-ionic liquid nanocomposite (2-MCPS-MC) on the rheological properties (apparent viscosity (AV), plastic viscosity (PV), yield point (YP), 10-s gel strength, 10-min gel strength, and thixotropy according to API requirements) of water-based mud, and comparing these properties with the properties of the silica-free methylcellulose (MC) as drilling fluid additive. The physicochemical properties of the MC and 2-MCPS-MC compounds were studied using 1H NMR, FTIR, Raman-spectroscopy, XRD, FE-SEM, AFM, and TGA. By FE-SEM and AFM, it is proven that the silica had an excellent dispersion in a spherical shape on the MC polymer. Three samples were prepared: the first is the commercial water-based mud, while the second and the third samples are MC and 2-MCPS-MC, respectively. The samples of MC were prepared in four concentrations (2%, 1.5%, 1.0% and 0.5% by weight). Throughout the test, density remained at 7.6 (lbs/gal) for mud fluid and 8.5 (lbs/gal) for MC and 2-MCPS-MC at pH 9.0. The results confirmed that the optimum concentration of MC and 2-MCPS-MC, which meet the required API code, was between 1 and 1.5%. The addition of 2-MCPS-MC to water-based mud enhances filtration properties. Response surface technique (RSM) with central composite design (CCD) was also used to optimize the drilling fluid properties to achieve the optimal response to AV, PV, YP, Gl, and Thixotropic using a Design expert software. The results obtained by RSM showed consistency between the experimental and theoretical data.

The recent legalization of cannabis is facilitating very rapid growth in the cannabis cultivation industry, with the energy intensive indoor cultivation facilities becoming more prevalent. This presents a challenge to utilities as the high energy demand from this industry can overburden the existing utility infrastructure. Hence, from both planning and operational perspectives, it is crucial to understand the energy consumption of the rapidly growing load. This paper proposes a deterministic energy consumption model for indoor cannabis cultivation operations for the two major loads in these facilities, i.e., lighting and HVAC, over a 24-hour period based on equipment specifications and operational requirements of the facility. This model can further be used to estimate or forecast short-term and long-term energy demands and costs of indoor cannabis operation(s). The proposed model successfully simulated the environmental conditions in a real-world cannabis facility, and the model's energy consumption output is validated using actual measurements taken from this facility as well as model output using GridLab-D.

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2–20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (KIs; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12–17, and 19–20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27–195 and 3.2–19, respectively, while compounds 12, 14–17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48–158 and 5.4–31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.Highlights Quinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised. The new molecules potently inhibited the hCA isoforms I, II, IV, and IX. Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Compounds 12–17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 12, 14–17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Graphical Abstract Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12–17, and 19–20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12, 14–17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2–13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2–13 with inhibition constants (KIs) ranging from 57.8–740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2–13 with KI values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (KIs ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.

Background Dry eye is a very common disease in Egypt. Tear film stability and tear secretion are important factors in the assessment of dry eye disease. Schirmer’s test (ST) is used to assess tear secretion, whereas tear breakup time test (TBUT) is used to assess tear film stability. Purpose The aim of this study was to identify the normative data of the ST and TBUT in a sample of Egyptians and to highlight the variables that may significantly affect these values. Patients and methods The study included 150 normal healthy participants. They were divided into different groups according to age, sex, residency, and occupation. History was taken from all participants including ocular surface disease index questionnaire. All participants underwent full ophthalmological examination, ST, and TBUT. Results The mean ST for the population sample was 21.9±9.13 mm, whereas the mean TBUT was 16.04±4.99 s. Studying linear regression for ST with age, sex, occupation, and residency showed that ST was mostly affected by age, where it showed a negative correlation. Studying linear regression for TBUT with age, sex, occupation, and residency showed that TBUT was mostly affected by residency. Conclusion The study allowed us to take an idea about the normative data of ST and TBUT in an Egyptian population and the effect of different variables on both tests.

Introduction Prolonged unnecessary mechanical ventilation (MV) has a multitude of complications. The main goal after placing a critically ill patient on MV is to define the best time to begin the weaning process. The peak expiratory flow (PEF) and maximum inspiratory pressure (MIP) are measures of inspiratory and expiratory muscle efficiency and can be used as weaning predictors. Noninvasive ventilation (NIV) can be used as a tool to prevent reintubation after weaning of MV. Objective The aim of this study was to determine whether prophylactic NIV would benefit patients with various cough strengths and various level of MIP to decrease the incidence of reintubation. Patients and methods In this prospective observational study, 80 mechanically ventilated patients were enrolled. At the time of their first spontaneous breathing trial, PEF and MIP were measured. Then, patients were randomly assigned to facemask and NIV groups. Results A total of 36 (90%) patients in NIV group were successfully weaned from MV, whereas four (10%) patients failed to be weaned. On the contrary, 29 (72.5%) patients in face mask group were successfully weaned from MV, whereas 11 (27.5%) patients failed to be weaned. Conclusion NIV has an important role to prevent reintubation after weaning of MV. Moreover, MIP and PEF have an excellent accuracy in prediction of NIV success after extubation.

Given that CAR-T cell therapy is effective in CD19-positive blood malignancies, it offers great hope for a variety of aggressive tumors that have thus far shown very little response to available therapies [...]

Tumor treating fields (TTFields) are among clinically active anticancer modalities that utilize low‐intensity, intermediate frequency (IF), and alternating electric fields (AEFs) to selectively disrupt mitosis in cancerous cells. Application of TTFields in the range of 100–900 kHz in cancer therapy and its effect on normal and cancer cells have attracted a great deal of interest in recent years. TTFields affect solid tumors by introducing increased chromatid aberrations that reduce the capacity to repair DNA damage and chromosome segregation, resulting in autophagy and subsequent cell death. In this review, we present an overview of the applications of TTFields in the treatment of cancer. We discuss several practical applications of TTField frequencies combined with metallic nanoparticles (NPs) (magnetic or nonmagnetic NPs) for internalization into cancer cells. In addition, TTFields can be combined effectively with chemotherapy and radiotherapy.

Alzheimer's disease (AD) is the major cause of dementia worldwide. Early-onset familial AD accounts for about 0.5% of all AD and is caused by single major gene mutations and autosomal dominant inheritance. An N141I missense mutation is associated with a significant increase in basal cell death and apoptosis. In this work we generated hiPSC from skin fibroblasts obtained from an AD patient carrying a N141I missense mutation in PSEN2. The generated iPSC colonies grew and were characterized by pluripotency marker staining; the N141I missense mutation was corrected using genome editing technology.

Management of non-healing and slow to heal diabetic wounds is a major concern in healthcare across the world. Numerous techniques have been investigated to solve the issue of delayed wound healing, though, mostly unable to promote complete healing of diabetic wounds due to the lack of proper cell proliferation, poor cell-cell communication, and higher chances of wound infections. These challenges can be minimized by using hydrogel based wound healing patches loaded with bioactive agents. Gelatin methacrylate (GelMA) has been proven to be a highly cell friendly, cell adhesive, and inexpensive biopolymer for various tissue engineering and wound healing applications. In this study, S-Nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, was incorporated in a highly porous GelMA hydrogel patch to improve cell proliferation, facilitate rapid cell migration, and enhance diabetic wound healing. We adopted a visible light crosslinking method to fabricate this highly porous biodegradable but relatively stable patch. Developed patches were characterized for morphology, NO release, cell proliferation and migration, and diabetic wound healing in a rat model. The obtained results indicate that SNAP loaded visible light crosslinked GelMA hydrogel patches can be highly effective in promoting diabetic wound healing.

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite available therapeutic interventions, it is very difficult to treat, and a cure is not yet available. The intra-tumoral GBM heterogeneity is a crucial factor contributing to poor clinical outcomes. GBM derives from a small heterogeneous population of cancer stem cells (CSCs). In cancer tissue, CSCs are concentrated within the so-called niches, where they progress from a slowly proliferating phase. CSCs, as most tumor cells, release extracellular vesicles (EVs) into the surrounding microenvironment. To explore the role of EVs in CSCs and GBM tumor cells, we investigated the miRNA and protein content of the small EVs (sEVs) secreted by two GBM-established cell lines and by GBM primary CSCs using omics analysis. Our data indicate that GBM-sEVs are selectively enriched for miRNAs that are known to display tumor suppressor activity, while their protein cargo is enriched for oncoproteins and tumor-associated proteins. Conversely, among the most up-regulated miRNAs in CSC-sEVs, we also found pro-tumor miRNAs and proteins related to stemness, cell proliferation, and apoptosis. Collectively, our findings support the hypothesis that sEVs selectively incorporate different miRNAs and proteins belonging both to fundamental processes (e.g., cell proliferation, cell death, stemness) as well as to more specialized ones (e.g., EMT, membrane docking, cell junction organization, ncRNA processing).

A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide (5a–5h) has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (4-hydroxy-3-methoxybenzylidene) substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring (12a–12d) decreased inhibition, but a less flexible linker (14a–14d) resulted in selective micromolar inhibition of hMAO-B providing insight for ongoing design.

In our effort to develop novel and powerful agents with anti-proliferative activity, two new series of 1H-benzo[f]chromene derivatives, 4a–h and 6a–h, were synthesised using heterocyclocondensation methodologies under microwave irradiation condition. The structures of the target compounds were established on the basis of their spectral data, IR, 1H NMR, 13 C NMR, 13 C NMR-DEPT/APT, and MS data. The new compounds have been examined for their anti-proliferative activity against three cancer cell lines, MCF-7, HCT-116, and HepG-2. Vinblastine and Doxorubicin have been used as positive controls in the viability assay. The obtained results confirmed that most of the tested molecules revealed strong and selective cytotoxic activity against the three cancer cell lines. Moreover, these molecules exhibited weak cytotoxicity on the HFL-1 line, which suggested that they might be ideal anticancer candidates. The SAR study of the new benzochromene compounds verified that the substituents on the phenyl ring of 1H-benzo[f]chromene nucleus, accompanied with the presence of bromine atom or methoxy group at the 8-position, increases the ability of these molecules against the different cell lines. Due to their high anti-proliferative activity, compounds 4c and 6e were selected to be examined their proficiency to inhibit the invasiveness of the highly sensitive and invasive breast cancer cell line, MDA-MB-231. The anti-invasion behaviour of these molecules against the highly sensitive, non-oestrogen, and progesterone MDA-MB-231 cell line gave rise to their decreasing metastatic effect compared to the reference drug. Furthermore, this report explores the apoptotic mechanistic pathway of the cytotoxicity of the target compounds and reveals that most of these compounds enhance the Caspase 3/7 activity that could be considered as potential anticancer agents.

Ischemic stroke is one of the major health problems worldwide. The only FDA approved anti-thrombotic drug for acute ischemic stroke is the tissue plasminogen activator. Several studies have been devoted to assessing the therapeutic potential of different types of stem cells such as neural stem cells (NSCs), mesenchymal stem cells, embryonic stem cells, and human induced pluripotent stem cell-derived NSCs as treatments for ischemic stroke. The results of these studies are intriguing but many of them have presented conflicting results. Additionally, the mechanism(s) by which engrafted stem/progenitor cells exert their actions are to a large extent unknown. In this review, we will provide a synopsis of different preclinical and clinical studies related to the use of stem cell-based stroke therapy, and explore possible beneficial/detrimental outcomes associated with the use of different types of stem cells. Due to limited/short time window implemented in most of the recorded clinical trials about the use of stem cells as potential therapeutic intervention for stroke, further clinical trials evaluating the efficacy of the intervention in a longer time window after cellular engraftments are still needed.

The incidence of diabetes mellitus is rapidly increasing throughout the world. Although the exact cause of the disease is not fully clear, perhaps, genetics, ethnic origin, obesity, age, and lifestyle are considered as few of many contributory factors for the disease pathogenesis. In recent years, the disease progression is particularly linked with functional and taxonomic alterations in the gastrointestinal tract microbiome. A change in microbial diversity, referred as microbial dysbiosis, alters the gut fermentation profile and intestinal wall integrity and causes metabolic endotoxemia, low-grade inflammation, autoimmunity, and other affiliated metabolic disorders. This article aims to summarize the role of the gut microbiome in the pathogenesis of diabetes. Additionally, we summarize gut microbial dysbiosis in preclinical and clinical diabetes cases reported in literature in the recent years.

Exploitation of the potential ability of human olfactory bulb (hOB) cells to carry, release, and deliver an effective, targeted anticancer therapy within the central nervous system (CNS) milieu remains elusive. Previous studies have demonstrated the marked ability of several types of stem cells (such as mesenchymal stem cells (MSCs) to carry and release different anti-cancer agents such as paclitaxel (PTX). Herein we investigate the ability of human olfactory bulb neural stem cells (Hu-OBNSCs) to carry and release paclitaxel, producing effective cytotoxic effects against cancer cells. We isolated Hu-OBNSCs from the hOB, uploaded them with PTX, and studied their potential cytotoxic effects against cancer cells in vitro. Interestingly, the Hu-OBNSCs displayed a five-fold increase in their resistance to the cytotoxicity of PTX, and the PTX-uploaded Hu-OBNSCs were able to inhibit proliferation and invasion, and to trigger marked cytotoxic effects on glioblastoma multiforme (GBM) cancer cells, and Human Caucasian fetal pancreatic adenocarcinoma 1 (CFPAC-1) in vitro. Despite their ability to resist the cytotoxic activity of PTX, the mechanism by which Hu-OBNSCs acquire resistance to PTX is not yet explained. Collectively our data indicate the ability of the Hu-OBNSCs to resist PTX, and to trigger effective cytotoxic effects against GBM cancer cells and CFPAC-1. This indicates their potential to be used as a carrier/vehicle for targeted anti-cancer therapy within the CNS.

A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a–k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b–c, and 7e–g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 µM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a–c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 µM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets.

Some novel fluorinated quinazolines (5a–j) were designed and synthesized to be evaluated for their anticonvulsant activity and their neurotoxicity. Structures of all newly synthesized compounds were confirmed by their infrared (IR), mass spectrometry (MS) spectra, 1H nuclear magnetic resonance (NMR), 13C-NMR, and elemental analysis (CHN). The anticonvulsant activity was evaluated by a subcutaneous pentylenetetrazole (scPTZ) test and maximal electroshock (MES)-induced seizure test, while neurotoxicity was evaluated by a rotorod test. The molecular docking was performed for all newly-synthesized compounds to assess their binding affinities to the GABA-A receptor in order to rationalize their anticonvulsant activities in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticonvulsant activity for all newly-synthesized compounds. Compounds 5b, 5c, and 5d showed the highest binding affinities toward the GABA-A receptor, along with the highest anticonvulsant activities in experimental mice. These compounds also showed low neurotoxicity and low toxicity in the median lethal dose test compared to the reference drugs. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and explain the possible mechanism for anticonvulsant action. The most active compounds might be used as leads for future modification and optimization.

The adult human olfactory bulb neural stem/progenitor cells (OBNC/PC) are promising candidate for cell-based therapy for traumatic and neurodegenerative insults. Exogenous application of NGF was suggested as a promising therapeutic strategy for traumatic and neurodegenerative diseases, however effective delivery of NGF into the CNS parenchyma is still challenging due mainly to its limited ability to cross the blood-brain barrier, and intolerable side effects if administered into the brain ventricular system. An effective method to ensure delivery of NGF into the parenchyma of CNS is the genetic modification of NSC to overexpress NGF gene. Overexpression of NGF in adult human OBNSC is expected to alter their proliferation and differentiation nature, and thus might enhance their therapeutic potential. In this study, we genetically modified adult human OBNS/PC to overexpress human NGF (hNGF) and green fluorescent protein (GFP) genes to provide insight about the effects of hNGF and GFP genes overexpression in adult human OBNS/PC on their in vitro multipotentiality using DNA microarray, immunophenotyping, and Western blot (WB) protocols. Our analysis revealed that OBNS/PC-GFP and OBNS/PC-GFP-hNGF differentiation is a multifaceted process involving changes in major biological processes as reflected in alteration of the gene expression levels of crucial markers such as cell cycle and survival markers, stemness markers, and differentiation markers. The differentiation of both cell classes was also associated with modulations of key signaling pathways such MAPK signaling pathway, ErbB signaling pathway, and neuroactive ligand-receptor interaction pathway for OBNS/PC-GFP, and axon guidance, calcium channel, voltage-dependent, gamma subunit 7 for OBNS/PC-GFP-hNGF as revealed by GO and KEGG. Differentiated OBNS/PC-GFP-hNGF displayed extensively branched cytoplasmic processes, a significant faster growth rate and up modulated the expression of oligodendroglia precursor cells markers (PDGFRα, NG2 and CNPase) respect to OBNS/PC-GFP counterparts. These findings suggest an enhanced proliferation and oligodendrocytic differentiation potential for OBNS/PC-GFP-hNGF as compared to OBNS/PC-GFP.

The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool ‘Emergent Self-Organizing Maps’ for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity.

Global gene expression profiling was performed using RNA from human embryonic neural stem cells (hENSC), and adult human olfactory bulb-derived neural stem cells (OBNSCs), to define a gene expression pattern and signaling pathways that are specific for each cell lineage. We have demonstrated large differences in the gene expression profile of human embryonic NSC, and adult human OBNSCs, but less variability between parallel cultures. Transcripts of genes involved in neural tube development and patterning (ALDH1A2, FOXA2), progenitor marker genes (LMX1a, ALDH1A1, SOX10), proliferation of neural progenitors (WNT1 and WNT3a), neuroplastin (NPTN), POU3F1 (OCT6), neuroligin (NLGN4X), MEIS2, and NPAS1 were up-regulated in both cell populations. By Gene Ontology, 325 out of 3875 investigated gene sets were scientifically different. 41 out of the 307 investigated Cellular Component (CC) categories, 45 out of the 620 investigated Molecular Function (MF) categories, and 239 out of the 2948 investigated Biological Process (BP) categories were significant. KEGG Pathway Class Comparison had revealed that 75 out of 171 investigated gene sets passed the 0.005 significance threshold. Levels of gene expression were explored in three signaling pathways, Notch, Wnt, and mTOR that are known to be involved in NS cell fates determination. The transcriptional signature also deciphers the role of genes involved in epigenetic modifications. SWI/SNF DNA chromatin remodeling complex family, including SMARCC1 and SMARCE1, were found specifically up-regulated in our OBNSC but not in hENSC. Differences in gene expression profile of transcripts controlling epigenetic modifications, and signaling pathways might indicate differences in the therapeutic potential of our examined two cell populations in relation to in cell survival, proliferation, migration, and differentiation following engraftments in different CNS insults.

Neural stem cells (NSC) with self-renewal and multipotent properties serve as an ideal cell source for transplantation to treat neurodegenerative insults such as Parkinson's disease. We used Agilent's and Illumina Whole Human Genome Oligonucleotide Microarray to compare the genomic profiles of human embryonic NSC at a single time point in culture, and a multicellular tissue from postmortem adult substantia nigra (SN) which are rich in dopaminergic (DA) neurons. We identified 13525 up-regulated genes in both cell types of which 3737 (27.6%) genes were up-regulated in the hENSC, 4116 (30.4%) genes were up-regulated in the human substantia nigra dopaminergic cells, and 5672 (41.93%) were significantly up-regulated in both cell population. Careful analysis of the data that emerged using DAVID has permitted us to distinguish several genes and pathways that are involved in dopaminergic (DA) differentiation, and to identify the crucial signaling pathways that direct the process of differentiation. The set of genes expressed more highly at hENSC is enriched in molecules known or predicted to be involved in the M phase of the mitotic cell cycle. On the other hand, the genes enriched in SN cells include a different set of functional categories, namely synaptic transmission, central nervous system development, structural constituents of the myelin sheath, the internode region of axons, myelination, cell projection, cell somata, ion transport, and the voltage-gated ion channel complex. Our results were also compared with data from various databases, and between different types of arrays, Agilent versus Illumina. This approach has allowed us to confirm the consistency of our obtained results for a large number of genes that delineate the phenotypical differences of embryonic NSCs, and SN cells.