Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent.

Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI50 values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.

Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance.

Microtubules are dynamic structures that form spindle fibers during cell division; pharmacological inhibition of microtubule dynamics arrests cells in mitosis, leading to apoptosis, and they have been extensively used to treat various cancers. However, the efficacy of such drugs is often limited by multidrug resistance. This study synthesized and evaluated 30 novel derivatives of podophyllotoxin, a natural antimitotic compound, for their antiproliferative activities. Compound SSE1806 exhibited the most potent antiproliferative activity with GI50 values ranging from 1.29 ± 0.01 to 21.15 ± 2.1 µM in cancer cell lines of different origins; it directly inhibited microtubule polymerization, causing aberrant mitosis and G2/M arrest. Prolonged treatment with SSE1806 increased p53 expression, induced cell death in monolayer cultures, and reduced the growth of mouse- and patient-derived human colon cancer organoids. Importantly, SSE1806 overcame multidrug resistance in a cell line overexpressing MDR-1. Thus, SSE1806 represents a potential anticancer agent that can overcome multidrug resistance.

Repurposing of investigational cancer drugs: Early phase discovery of dengue virus NS2B/NS3 protease inhibitors.

Dengue fever is a neglected vector-borne disease and is more prevalent in Asia. Currently, no specific treatment is available. Given the time and cost of de novo drug discovery and development, an alternative option of drug repurposing is becoming an effective tool. We screened a library of 1127 pharmacologically active, metabolically stable, and structurally diverse small anticancer molecules to identify inhibitors of the dengue virus (DENV) NS2B/NS3 protease. Enzyme kinetics and inhibition data revealed four B-cell lymphoma 2 inhibitors, that is, ABT263, ABT737, AT101, and TW37, as potent inhibitors of DENV NS2B/NS3 protease, with IC50 values of 0.86, 1.15, 0.81, and 0.89 µM, respectively. Mode of inhibition experiments and computational docking analyses indicated that ABT263 and ABT737 are competitive inhibitors, whereas AT101 and TW37 are noncompetitive inhibitors of the protease. With further evaluation, the identified inhibitors of the DENV NS2B/NS3 protease have the potential to be developed into specific anti-dengue therapeutics.

A Case Study of Depression in High Achieving Students Associated With Moral Incongruence, Spiritual Distress, and Feelings of Guilt.

Psychosocial and cultural factors play an important, but often neglected, role in depression in young individuals. In this article, we present two cases of young, educated males with major depressive disorder and prominent themes of guilt and spiritual distress. We explore the relationship between moral incongruence, spiritual distress, and feelings of guilt with major depressive episodes by presenting two cases of depression in young individuals who were high-achieving students. Both cases presented with low mood, psychomotor slowing, and selective mutism. Upon detailed history, spiritual distress and feelings of guilt due to internet pornographic use (IPU) and the resulting self-perceived addiction and moral incongruence were linked to the initiation and progression of major depressive episodes. The severity of the depressive episode was measured using the Hamilton Depression Scale (HAM-D). Themes of guilt and shame were measured using the State of Guilt and Shame Scale (SSGS). High expectations from the family were also a source of stress. Hence, it is important to keep these factors in mind while managing mental health problems in young individuals. Late adolescence and early adulthood are periods of high stress and vulnerabe to mental illness. Psychosocial determinants of depression in this age group generally go unexplored and unaddressed leading to suboptimal treatment, particularly in developing countries. Further research is needed to assess the importance of these factors and to determine ways to mitigate them.

Spontaneous NETosis in diabetes: A role of hyperglycemia mediated ROS and autophagy.

Type 2-diabetes, particularly poorly controlled diabetes, is a risk factor for several infections such as lower respiratory tract and skin infections. Hyperglycemia, a characteristic downstream effect of poorly controlled diabetes, has been shown to impair the function of immune cells, in particular neutrophils. Several studies have demonstrated that hyperglycemia-mediated priming of NADPH oxidase results in subsequent elevated levels of reactive oxygen species (ROS). In healthy neutrophils, ROS plays an important role in pathogen killing by phagocytosis and by induction of Neutrophil Extracellular Traps (NETs). Given the key role of ROS in autophagy, phagocytosis and NETosis, the relationship between these pathways and the role of diabetes in the modulation of these pathways has not been explored previously. Therefore, our study aimed to understand the relationship between autophagy, phagocytosis and NETosis in diabetes. We hypothesized that hyperglycemia-associated oxidative stress alters the balance between phagocytosis and NETosis by modulating autophagy. Using whole blood samples from individuals with and without type 2-diabetes (in the presence and absence of hyperglycemia), we demonstrated that (i) hyperglycemia results in elevated levels of ROS in neutrophils from those with diabetes, (ii) elevated levels of ROS increase LCIII (a marker for autophagy) and downstream NETosis. (iii) Diabetes was also found to be associated with low levels of phagocytosis and phagocytic killing of S. pneumoniae. (iv) Blocking either NADPH oxidase or cellular pathways upstream of autophagy led to a significant reduction in NETosis. This study is the first to demonstrate the role of ROS in altering NETosis and phagocytosis by modulating autophagy in type 2-diabetes. GRAPHICAL ABSTRACT.

Chemical Synthesis of Selenium-containing Peptides.

Selenium (Se), a semi-metallic element, has chemical properties similar to sulfur; however, it has comparatively low electronegativity as well as a large atomic radius than sulfur. These features bestow selenium-containing compounds with extraordinary reactivity, sensitivity, and potential for several applications like chemical alteration, protein engineering, chemical (semi)synthesis, etc. Organoselenium chemistry is emerging fastly, however, examples of effective incorporation of Se into the peptides are relatively scarce. Providentially, there has been a drastic interest in synthesizing and applying selenoproteins and selenium-containing peptides over the last few decades. In this minireview, the synthetic methodologies of selenium-containing peptides and a brief description of their chemistry and biological activities are summarized. These methodologies enable access to various natural and unnatural selenium-containing peptides that have been used in a range of applications, from modulating protein characteristics to structure-activity relationship (SAR) studies for applications in nutraceuticals and drug development. This review aims at the audience interested in learning about the synthesis as well as will open new dimensions for their future research by aiding in the design of biologically interesting selenium-containing peptides.

Centrosome Clustering & Chemotherapy.

Centrosome abnormalities are the hallmark of cancer. How it affects tumorigenesis is still a mystery. However, the presence of more than two centrosomes at the onset of mitosis often leads to chromosomal instability and subsequent tumorigenesis. Unlike normal cells that undergo repair or apoptosis in response to this instability, cancer cells learn to cope with supernumerary centrosomes through various mechanisms and survive. Centrosome clustering is the most prevalent mechanism, allowing the cancer cells to form two daughter cells through a pseudo-bipolar spindle. Since healthy cells are devoid of the mechanisms involved in clustering, the de-clustering of centrosomes can be considered a promising approach to selectively eliminate cells with extra centrosomes. Several proteins such as PARP, KIFC1, Hsp70, Cortical actin, APC/C-CDH1 complex and Eg5 have been discussed in this review which participate in centrosome clustering, and the inhibition of these proteins can facilitate in impeding tumor growth specifically by declustering centrosomes. In this review, we also present the role of the centrosome in the cell cycle, centrosome amplification, clustering mechanism and reported centrosome de-clustering agents to present the current state of work in the field.

Combined 3D-QSAR, molecular docking and dynamics simulations studies to model and design TTK inhibitors.

Tyrosine threonine kinase (TTK) is the key component of the spindle assembly checkpoint (SAC) that ensures correct attachment of chromosomes to the mitotic spindle and thereby their precise segregation into daughter cells by phosphorylating specific substrate proteins. The overexpression of TTK has been associated with various human malignancies, including breast, colorectal and thyroid carcinomas. TTK has been validated as a target for drug development, and several TTK inhibitors have been discovered. In this study, ligand and structure-based alignment as well as various partial charge models were used to perform 3D-QSAR modelling on 1H-Pyrrolo[3,2-c] pyridine core containing reported inhibitors of TTK protein using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches to design better active compounds. Different statistical methods i.e., correlation coefficient of non-cross validation (r2), correlation coefficient of leave-one-out cross-validation (q2), Fisher's test (F) and bootstrapping were used to validate the developed models. Out of several charge models and alignment-based approaches, Merck Molecular Force Field (MMFF94) charges using structure-based alignment yielded highly predictive CoMFA (q2 = 0.583, Predr2 = 0.751) and CoMSIA (q2 = 0.690, Predr2 = 0.767) models. The models exhibited that electrostatic, steric, HBA, HBD, and hydrophobic fields play a key role in structure activity relationship of these compounds. Using the contour maps information of the best predictive model, new compounds were designed and docked at the TTK active site to predict their plausible binding modes. The structural stability of the TTK complexes with new compounds was confirmed using MD simulations. The simulation studies revealed that all compounds formed stable complexes. Similarly, MM/PBSA method based free energy calculations showed that these compounds bind with reasonably good affinity to the TTK protein. Overall molecular modelling results suggest that newly designed compounds can act as lead compounds for the optimization of TTK inhibitors.

Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors.

Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several quinones as inhibitors. IC50 determination against Aurora A and B kinases revealed the inhibition of both kinases with selectivity toward Aurora A. Two of the compounds, natural quinone naphthazarin (1) and a pseudo anthraquinone, 2-(chloromethyl)quinizarin (11), potently inhibited the proliferation of various cancer cell lines with IC50 values ranging from 0.16 ± 0.15 to 1.7 ± 0.06 and 0.15 ± 0.04 to 6.3 ± 1.8 µM, respectively. Treatment of cancer cells with these compounds for 24 h resulted in abrogated mitosis and apoptotic cell death. Direct binding of both the compounds with Aurora A kinase was also confirmed through STD NMR analysis. Docking studies predicted the binding of both compounds to the ATP binding pocket of Aurora A kinase. We have, therefore, identified quinones as Aurora kinase inhibitors that can serve as a lead for future drug discovery endeavors.

The Impact of Telemonitoring on Improving Glycemic and Metabolic Control in Previously Lost-to-Follow-Up Patients with Type 2 Diabetes Mellitus: A Single-Center Interventional Study in the United Arab Emirates.

Background: Telemonitoring (TM), mobile-phone technology for health, and bluetooth-enabled self-monitoring devices represent innovative solutions for proper glycemic control, compliance and monitoring, and access to providers. Objective: In this study, we evaluated the impact of TM devices on glycemic control and the compliance of 38 previously lost-to-follow-up (LTFU) patients with type 2 diabetes mellitus (T2DM). Methods: This was an interventional single-center study that randomly recruited LTFU patients from the Dubai Diabetes Center (DDC), UAE. After contact and recruitment by phone, patients had an initial visit at which they were provided with home-based TM devices. A follow-up visit was conducted three months later. Results: The mean HbA1c decreased significantly from 10.3 ± 1.9% at baseline to 7.4 ± 1.5% at the end of follow-up, with a mean difference (MD) of -2.9% [95% CI: -3.6 to -2.2]. The percentage of patients with HbA1c <7% was 50% after three months. Home-based blood sugar monitor devices showed a significant reduction in fasting blood glucose (FBG) after three months (MD = -40.1 mg/dL, 95% CI: -70.8 to -9.3). A significant reduction was observed in terms of body weight after three months (MD = -1.3 kg, 95% CI: -2.5 to -0.08). The mean number of days the participants used a device was the highest for portable pill dispensers (86.5 ± 22.8 days), followed by a OneTouch® blood glucose monitor (72.9 ± 23.5 days). Conclusions: TM led to significant improvements in overall diabetes outcomes, including glycemic control and body weight, indicating its effectiveness in a challenging population of T2DM patients who had previously been lost to follow-up.

Selenium-containing Peptides and their Biological Applications.

Selenium (Se) has been known for its beneficial biological roles for several years, but interest in this trace element has seen a significant increase in the past couple of decades. It has been reported to be a part of important bioactive organic compounds, such as selenoproteins and amino acids, including selenocysteine (SeCys), selenomethionine (SeMet), selenazolidine (SeAzo), and selenoneine. The traditional Se supplementations (primarily as selenite and selenomethionine), though have been shown to carry some benefits, also have associated toxicities, thereby paving the way for the organoselenium compounds, especially the selenoproteins and peptides (SePs/SePPs) that offer several health benefits beyond fulfilling the elementary nutritional Se needs. This review aims to showcase the applications of selenium-containing peptides that have been reported in recent decades. This article summarizes their bioactivities, including neuroprotective, antiinflammatory, anticancer, antioxidant, hepatoprotective, and immunomodulatory roles. This will offer the readers a sneak peek into the current advancements to invoke further developments in this emerging research area.

CT-MRI Dual Information Registration for the Diagnosis of Liver Cancer: A Pilot Study Using Point-based Registration.

BACKGROUND: Early diagnosis of liver cancer may increase life expectancy. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) play a vital role in diagnosing liver cancer. Together, both modalities offer significant individual and specific diagnosis data to physicians; however, they lack the integration of both types of information. To address this concern, a registration process has to be utilized for the purpose, as multimodal details are crucial in providing the physician with complete information. OBJECTIVE: The aim was to present a model of CT-MRI registration used to diagnose liver cancer, specifically for improving the quality of the liver images and provide all the required information for earlier detection of the tumors. This method should concurrently address the issues of imaging procedures for liver cancer to fasten the detection of the tumor from both modalities. METHODS: In this work, a registration scheme for fusing the CT and MRI liver images is studied. A feature point-based method with normalized cross-correlation has been utilized to aid in the diagnosis of liver cancer and provide multimodal information to physicians. Data on ten patients from an online database were obtained. For each dataset, three planar views from both modalities were interpolated and registered using feature point-based methods. The registration of algorithms was carried out by MATLAB (vR2019b, Mathworks, Natick, USA) on an Intel (R) Core (TM) i5-5200U CPU @ 2.20 GHz computer. The accuracy of the registered image is being validated qualitatively and quantitatively. RESULTS: The results show that an accurate registration is obtained with minimal distance errors by which CT and MRI were accurately registered based on the validation of the experts. The RMSE ranges from 0.02 to 1.01 for translation, which is equivalent in magnitude to approximately 0 to 5 pixels for CT and registered image resolution. CONCLUSION: The CT-MRI registration scheme can provide complementary information on liver cancer to physicians, thus improving the diagnosis and treatment planning process.

Reduction-Sensitive Dextran-Paclitaxel Polymer-Drug Conjugate: Synthesis, Self-Assembly into Nanoparticles, and In Vitro Anticancer Efficacy.

Delivery systems that can encapsulate a precise amount of drug and offer a spatiotemporally controlled drug release are being actively sought for safe yet effective cancer therapy. Compared to polymer nanoparticle (NP)-based delivery systems that rely on physical drug encapsulation, NPs derived from stimuli-sensitive covalent polymer-drug conjugates (PDCs) have emerged as promising alternatives offering precise control over drug dosage and spatiotemporal drug release. Herein, we report a reduction-sensitive PDC "Dex-SS-PTXL" synthesized by conjugating dextran and paclitaxel (PTXL) through a disulfide bond-bearing linker. The synthesized Dex-SS-PTXL PDC with a precise degree of substitution in terms of the percentage of repeat units of dextran covalently conjugated to PTXL (27 ± 0.6%) and the amount of drug carried by the PDC (39 ± 1.4 wt %) was found to self-assemble into spherical NPs with an average size of 110 ± 34 nm and a ζ-potential of -14.09 ± 8 mV. The reduction-sensitive Dex-SS-PTXL NPs were found to release PTXL exclusively in response to the reducing agent concentration reflective of the intracellular reducing environment of the tumor cells. Challenging BT-549 and MCF-7 cells with Dex-SS-PTXL NPs revealed significant cytotoxicity, while the IC50 values and the mode of action (mitotic arrest) of Dex-SS-PTXL NPs were found to be comparable to those of free PTXL, highlighting the active nature of the intracellularly released drug. The developed PDC with its unique ability to self-assemble into NPs and stimuli-responsive drug release can enhance the success of the NP-based drug delivery systems during clinical translation.

Polycomb Requires Chaperonin Containing TCP-1 Subunit 7 for Maintaining Gene Silencing in Drosophila.

In metazoans, heritable states of cell type-specific gene expression patterns linked with specialization of various cell types constitute transcriptional cellular memory. Evolutionarily conserved Polycomb group (PcG) and trithorax group (trxG) proteins contribute to the transcriptional cellular memory by maintaining heritable patterns of repressed and active expression states, respectively. Although chromatin structure and modifications appear to play a fundamental role in maintenance of repression by PcG, the precise targeting mechanism and the specificity factors that bind PcG complexes to defined regions in chromosomes remain elusive. Here, we report a serendipitous discovery that uncovers an interplay between Polycomb (Pc) and chaperonin containing T-complex protein 1 (TCP-1) subunit 7 (CCT7) of TCP-1 ring complex (TRiC) chaperonin in Drosophila. CCT7 interacts with Pc at chromatin to maintain repressed states of homeotic and non-homeotic targets of PcG, which supports a strong genetic interaction observed between Pc and CCT7 mutants. Depletion of CCT7 results in dissociation of Pc from chromatin and redistribution of an abundant amount of Pc in cytoplasm. We propose that CCT7 is an important modulator of Pc, which helps Pc recruitment at chromatin, and compromising CCT7 can directly influence an evolutionary conserved epigenetic network that supervises the appropriate cellular identities during development and homeostasis of an organism.

A Personalized Therapeutics Approach Using an In Silico Drosophila Patient Model Reveals Optimal Chemo- and Targeted Therapy Combinations for Colorectal Cancer.

In silico models of biomolecular regulation in cancer, annotated with patient-specific gene expression data, can aid in the development of novel personalized cancer therapeutic strategies. Drosophila melanogaster is a well-established animal model that is increasingly being employed to evaluate such preclinical personalized cancer therapies. Here, we report five Boolean network models of biomolecular regulation in cells lining the Drosophila midgut epithelium and annotate them with colorectal cancer patient-specific mutation data to develop an in silico Drosophila Patient Model (DPM). We employed cell-type-specific RNA-seq gene expression data from the FlyGut-seq database to annotate and then validate these networks. Next, we developed three literature-based colorectal cancer case studies to evaluate cell fate outcomes from the model. Results obtained from analyses of the proposed DPM help: (i) elucidate cell fate evolution in colorectal tumorigenesis, (ii) validate cytotoxicity of nine FDA-approved CRC drugs, and (iii) devise optimal personalized treatment combinations. The personalized network models helped identify synergistic combinations of paclitaxel-regorafenib, paclitaxel-bortezomib, docetaxel-bortezomib, and paclitaxel-imatinib for treating different colorectal cancer patients. Follow-on therapeutic screening of six colorectal cancer patients from cBioPortal using this drug combination demonstrated a 100% increase in apoptosis and a 100% decrease in proliferation. In conclusion, this work outlines a novel roadmap for decoding colorectal tumorigenesis along with the development of personalized combinatorial therapeutics for preclinical translational studies.

CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells.

BACKGROUND: Activating mutations in the Fms-like tyrosine kinase 3 (FLT3) are among the most prevalent oncogenic mutations in acute myeloid leukaemia. Inhibitors selectively targeting FLT3 kinase have shown promising clinical activity; their success in the clinic, however, has been limited due to the emergence of acquired resistance. METHODS: CCT245718 was identified and characterised as a dual Aurora A/FLT3 inhibitor through cell-based and biochemical assays. The ability of CCT245718 to overcome TKD-mediated resistance was evaluated in a cell line-based model of drug resistance to FLT3 inhibitors. RESULTS: CCT245718 exhibits potent antiproliferative activity towards FLT3-ITD + AML cell lines and strongly binds to FLT3-ITD and TKD (D835Y) mutants in vitro. Activities of both FLT3-ITD and Aurora A are also inhibited in cells. Inhibition of FLT3 results in reduced phosphorylation of STAT5, downregulation of survivin and induction of apoptotic cell death. Moreover, CCT245718 overcomes TKD-mediated resistance in a MOLM-13-derived cell line containing FLT3 with both ITD and D835Y mutations. It also inhibits FLT3 signalling in both parental and resistant cell lines compared to FLT3-specific inhibitor MLN518, which is only active in the parental cell line. CONCLUSIONS: Our results demonstrate that CCT245718 is a potent dual FLT3/Aurora A inhibitor that can overcome TKD-mediated acquired resistance.

An Overview of Deep Learning Techniques on Chest X-Ray and CT Scan Identification of COVID-19.

Pneumonia is an infamous life-threatening lung bacterial or viral infection. The latest viral infection endangering the lives of many people worldwide is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. This paper is aimed at detecting and differentiating viral pneumonia and COVID-19 disease using digital X-ray images. The current practices include tedious conventional processes that solely rely on the radiologist or medical consultant's technical expertise that are limited, time-consuming, inefficient, and outdated. The implementation is easily prone to human errors of being misdiagnosed. The development of deep learning and technology improvement allows medical scientists and researchers to venture into various neural networks and algorithms to develop applications, tools, and instruments that can further support medical radiologists. This paper presents an overview of deep learning techniques made in the chest radiography on COVID-19 and pneumonia cases.

Glyceryl Monostearate based Solid Lipid Nanoparticles for Controlled Delivery of Docetaxel.

BACKGROUND: Solid lipid nanoparticles (SLNs) is the drug delivery system that has the capability to improve drug release at the desired tumor site. The aim of the present study is to develop glyceryl monostearate (GMS) based SLNs for the controlled delivery of docetaxel. METHODS: Hot melt encapsulation (HME) method was employed avoiding the use of organic solvents and, therefore, regarded as green synthesis of SLNs. RESULTS: Optimized DTX-SLNs showed desirable size (100 nm) with low poly dispersity index and excellent entrapment efficiency. Surface charge confirmed the stability of formulation. transmission electron microscope (TEM) analysis showed spherical shaped particles and fourier transform infrared microscopy (FTIR) revealed compatibility among formulation excipients. Differential scanning calorimeter (DSC) analysis revealed that the melting transition peak of optimized formulation was also greater than 40°C indicating that SLNs would be solid at body temperature. In-vitro release profile (68% in 24 hours) revealed the controlled release profile of DTX-SLNs, indicating lipophilic docetaxel drug was entrapped inside high melting point lipid core. Cytotoxicity study revealed that blank SLNs were found to be biocompatible while dose dependent cytotoxicity was shown by DTX-SLNs. CONCLUSION: These studies suggest that DTX-SLNs have the potential for controlled delivery of docetaxel and improved therapeutic outcome.