Exploring the potential of EphA2 receptor signaling pathway: a comprehensive review in cancer treatment.

The protein encoded by the ephrin type-A receptor 2 (EphA2) gene is a member of the ephrin receptor subfamily of the receptor tyrosine kinase family (RTKs). Eph receptors play a significant role in various biological processes, particularly cancer progression, development, and pathogenesis. They have been observed to regulate cancer cell growth, migration, invasion, tumor development, invasiveness, angiogenesis, and metastasis. To target EphA2 activity, various molecular, genetic, biochemical, and pharmacological strategies have been extensively tested in laboratory cultures and animal models. Notably, drugs, such as dasatinib, initially designed to target the kinase family, have demonstrated an additional capability to target EphA2 activity. Additionally, a novel monoclonal antibody named EA5 has emerged as a promising option to counteract the effects of EphA2 overexpression and restore tamoxifen sensitivity in EphA2-transfected MCF-7 cells during in vitro experiments. This antibody mimicked the binding of Ephrin A to EphA2. These methods offer potential avenues for inhibiting EphA2 activity, which could significantly decelerate breast cancer progression and restore sensitivity to certain drugs. This review article comprehensively covers EphA2's involvement in multiple malignancies, including ovarian, colorectal, breast, lung, glioma, and melanoma. Furthermore, we discuss the structure of EphA2, the Eph-Ephrin signaling pathway, various EphA2 inhibitors, and the mechanisms of EphA2 degradation. This article provides an extensive overview of EphA2's vital role in different types of cancers and outlines potential therapeutic approaches to target EphA2, shedding light on the underlying molecular mechanisms that make it an attractive target for cancer treatment.

Soft diamonds: poetic sentiment, poetic speech, and poetic specimen in the clinical hour.

Three links between poetry and psychoanalysis are highlighted in this paper. These refer to the presence, in the clinical hour, of (i) poetic sentiment, (ii) poetic speech, and (iii) poetic specimen. Each is elucidated in detail and with the help of socio-clinical vignettes. The aim of the paper is to demonstrate that, through the affirmative holding and partial unmasking of the instinctual-epistemic conflation in verse and free-association, both poetry and psychoanalysis seek to transform the private into shared, the hideous into elegant, and the unfathomable into accessible.

Entropy Analysis of the Peristaltic Flow of Hybrid Nanofluid Inside an Elliptic Duct with Sinusoidally Advancing Boundaries.

Peristaltic flow of hybrid nanofluid inside a duct having sinusoidally advancing boundaries and elliptic cross-section is mathematically investigated. The notable irreversibility effects are also examined in this mathematical research by considering a descriptive entropy analysis. In addition, this work provides a comparison analysis for two distinct nanofluid models: a hybrid model (Cu-Ag/water) and a phase flow model (Cu/water). A comprehensive graphical description is also provided to interpret the physical aspects of this mathematical analysis.

Repression: A Critical Assessment and Update of Freud's 1915 Paper.

The concept of repression has been relegated to the periphery in current psychoanalytic theorizing. This is in part due to a reflexive and ill-informed avoidance of Freudian metapsychology, and in part due to preoccupation with 'primitive' and 'deeper' states of mind, a perspective that presumes that repression operates exclusively in 'higher level' or 'neurotic' forms of psychopathology. A careful scrutiny of psychoanalytic theory and clinical practice does not uphold such compartmentalization. Repression is ubiquitous in mental life. It contributes to normality (e.g., onset of latency), undergirds the 'psychopathology of everyday life' (e.g., parapraxes), exists alongside splitting in severe character disorders (e.g., borderline patients "forgetting" their appointments) and, by permitting a modified return of exiled mental contents, gives birth to neurotic symptoms as well as creative imagination. Taking Freud's seminal discourse on repression (in: Repression. Standard Edition, vol 14. Hogarth, London, pp 141-158 1915a) as its starting point, this paper elucidates the complex, nuanced, and pervasive nature of this defense. It deconstructs Freud's unitary concept of repression into four implicit binaries and updates his proposals in the light of contemporary psychoanalytic theory. The paper offers clear guidelines for clinical applications of these ideas.

Humility.

This paper offers a nuanced discourse on the otherwise ignored topic of humility. It brings together scattered comments within psychoanalysis, secular lay-literature, sociocultural studies, and religious thought on humility. The paper also describes pathological variants of humility (excessive, deficient, false, and compartmentalized) and delineates five areas of clinical practice where humility plays an important role: (i) humility in selecting patients to treat, (ii) humility in daily conduct with patients, (iii) humility in the attitude of listening to clinical material, (iv) humility in the manner of intervening, and (v) humility in deciding upon the longevity of our professional careers.

In silico analysis of human Toll-like receptor 7 ligand binding domain.

Toll-like receptors recognizing pathogen-associated molecular patterns are preface actors for innate immunity. Among them TLR7 is a transmembrane protein playing very crucial role in the signaling pathways involved in innate immunity by recognizing viral ssRNA and specific small molecule agonists. The unavailability of experimental 3D structure of this receptor till date hampers the focused exploration of TLR7 interaction with its ligands. However, several proteins possessing high homology domain enabled us to construct a reliable 3D model of hTLR7 ECD, which was employed to generate the homodimer model using protein-protein docking strategy. Further molecular docking studies between developed homodimer model and ligands were performed to explore the most preferred site of hTLR7 ECD interacting with ligands. The comparative analysis of docking energies and protein-ligand interactions of all the ligands revealed resiquimod as the prominent agonist. Furthermore, molecular interactions between protein-ligand complexes suggested LRR15 and LRR16 region of hTLR7 ECD as the most preferential site for ligand binding. The Ser434 and Gly437 of LRR15 region of hTLR7 were found to be conserved with Drosophila Toll protein. The obtained complex model may lead to a better understanding of TLR7 functioning along with its inheritance from invertebrates to mammals.

Cross talk between Leishmania donovani CpG DNA and Toll-like receptor 9: an immunoinformatics approach.

The precise and potential contribution of Toll-like receptors (TLRs) signaling pathways in fighting parasitic infections of Leishmania spp., an intracellular protozoan parasite, has gained significant attention during the last decades. Although it is well established that TLR9 recognizes CpG motifs in microbial genomes, the specificity of the CpG DNA pattern of Leishmania parasite interacting with endosomal TLR9 is still unknown. Hence in our study to identify the CpG DNA pattern of Leishmania donovani acting as ligand for TLR9, consecutive homology searches were performed using known CpG ODN 2216 as initial template until a consistent CpG pattern in L. donovani was found. A reliable model of TLR9 ectodomains (ECDs) as well as CpG DNA patterns was predicted to develop the 3D structural complexes of TLR9 ECD-CpG DNA utilizing molecular modeling and docking approaches. The results revealed the preferential specificity of L. donovani CpG DNA to TLR9 compared to control ODN and other CpG patterns. The interface between TLR9 and L. donovani CpG DNA was also found to be geometrically complementary with the LRR11 region of TLR9, acting as the critical region for ligand recognition. The L. donovani CpG pattern identified can be employed to derive a platform for development of an innate immunomodulatory agent for deadly disease.

Some psychoanalytic reflections on the concept of dignity.

After reviewing the pertinent philosophical and psychoanalytic writings on the concept of dignity, this paper proposes three categories of dignity. Conceptualized as phenomenological clusters, heuristic viewpoints, and levels of abstraction, these include (i) metaphysical dignity which extends the concept of dignity beyond the human species to all that exists in this world, (ii) existential dignity which applies to human beings alone and rests upon their inherent capacity for moral transcendence, and (iii) characterological dignity which applies more to some human beings than others since they possess a certain set of personality traits that are developmentally derived. The paper discusses the pros and cons of each category and acknowledges the limitations of such classification. It also discusses the multiple ways in which these concepts impact upon clinical work and concludes with some remarks on the relationship of dignity to choice, narcissism, and suicide.

Mutation and protein expression analysis of CYP1A1 gene-a study on female breast cancer cases from India.

Increased risk may be associated with exposure to genotoxic agents during breast development because the undifferentiated ductal elements of breast are more susceptible to the action of genotoxic early in life and thus an impairment in Cytochrome P 4501A1 (CYP1A1) may contribute to the development of breast cancer. Therefore, we carried out the population-based study in a total of 105 Indian female breast cancer cases with equal normal adjacent controls. A total of 20 samples (20/105, 19.04 %) showed final mutations in the exon 7 of the CYP1A1 gene where 5 cases harbored frame shift mutation (deletion of G nucleotide), and the remaining were missense mutation observed in 15 cases of breast cancer with significant association to histological grade (chi square -7.20, p = 0.02), tumor stage (chi square -6.36, p = 0.01), menopausal stage (chi square -9.76, p = 0.001), and ER status (chi square -4.22, p = 0.03). We further did protein expression analysis of CYP1A1 through immunohistochemistry where 66 cases showed down or no expression (+) (66/105, 62.85 %), 28 cases with moderate expression (++) (28/105, 26.66 %), and 11 cases with high expression (+++) (11/105, 10.47 %). Highly significant associations were observed between protein expression and clinico-pathological variables like Her 2 category (chi square = 31.73, p < 0.0001) and tumor stage (chi square = 10.27, p = 0.005). Importantly, mutation(s) of the type like deletion of A nucleotide and missense mutation (Gly > Val) exclusively showed low (+) or no expression for the CYP1A1 protein when studied in relation to each other. In summary, CYP1A1 may be associated with breast cancer and its down regulation may serve as an important tool in the field of biomarker study.

Diabetes Driven Oncogenesis and Anticancer Potential of Repurposed Antidiabetic Drug: A Systemic Review.

Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.

In Silico Investigation against Inhibitors of Alpha-Amylase Using Structure-based Screening, Molecular Docking, and Molecular Simulations Studies.

Type-II diabetes mellitus is a chronic disorder that results from fluctuations in the glucose level leading to hyperglycemia with severe adverse effects increasing worldwide. Alpha-Amylase is the key enzyme involved in the mechanism of glucose formation therefore Alpha-Amylase inhibitors have become a therapeutic target in the development of new leads as they have the potential to suppress glucose levels. Existing drugs targeting Alpha-Amylase highlight major drawbacks in terms of poor absorption rate that causes several gastrointestinal issues. So, this research is aimed to develop novel inhibitors interacting with Alpha-Amylase's active site using structural-based screening, binding pattern analysis, and molecular dynamic simulation. Hence, to search for a potential lead, we analyzed a total of 133 valiolamine derivatives and 535 desoxynojirimycin derivatives that exhibited drug-like properties screened through Lipinski filters. Virtual screening followed by binding interaction analysis we identified ten compounds that exhibited better binding energy scores compared to the standard drugs voglibose and miglitol, used in our study. The docking analysis, ADMET and metabolic site prediction estimated the best top two compounds with good drug profiles. Further, top compounds VG9 and VG15 were promoted to simulation study using the Biovia Discovery study to access the stability at a time interval of 100 ns. MD simulation results revealed that our compound VG9 possesses better conformational stability in the complex to the active site residues of Alpha-Amylase target protein than standard drug voglibose. Thus, our investigation revealed that compound VG9 also exhibits the best pharmacokinetic as well as binding affinity results and could act as a potential lead compound targeting Alpha-Amylase for Type II diabetes.

Computational fluid dynamics analysis on endoscopy of main left coronary artery: An application of applied mathematics.

The endoscopy of a coronary arterial segment having a symmetric emergence of plaque at its innermost region is numerically modeled via computational fluid dynamics toolbox Open-FOAM. The considered left coronary artery for this model has a radius of 2 mm and span of 10 mm. The formation of plaque inside the artery that is a stenosis has length 2 mm and height 0.82 mm. The catheter used for this analysis has a diameter of 1 mm with a balloon over it with a height of 0.53 mm. The blood flow rate considered for this analysis has a range 2.00 ml/s to 2.50 ml/s. The fluid under consideration for this endoscopy review is the non-Newtonian Casson model. The mesh illustrations are arranged for the proposed model with numerical simulations of velocity, pressure profile and streamlines. The narrow channel formed due to assembly of stenosis and balloon over catheter inside this arterial segment has developed some swirling flow profile with turbulence effects just after the flow leaves the stenosis plus balloon region. Although this disturbance caused due to narrowing of channel has made the flow slightly turbulent, the flow eventually leaves the arterial segment again as a laminar flow. To cure coronary artery disease, catheterization, and balloon dilation of stenosed arteries is performed to locate the position and shape of stenosis. A catheter is inserted inside the body through a minor cut and then it is moved inside arteries to place it exactly at the stenosis location. A balloon is placed at front of that catheter and the stenosed region can be opened wide by using balloon dilation.

Nanoinformatics and Personalized Medicine: An Advanced Cumulative Approach for Cancer Management.

BACKGROUND: Even though the battle against one of the deadliest diseases, cancer, has advanced remarkably in the last few decades and the survival rate has improved significantly; the search for an ultimate cure remains a utopia. Nanoinformatics, which is bioinformatics coupled with nanotechnology, endows many novel research opportunities in the preclinical and clinical development of personalized nanosized drug carriers in cancer therapy. Personalized nanomedicines serve as a promising treatment option for cancer owing to their noninvasiveness and their novel approach. Explicitly, the field of personalized medicine is expected to have an enormous impact soon because of its many advantages, namely its versatility to adapt a drug to a cohort of patients. OBJECTIVE: The current review explains the application of this newly emerging field called nanoinformatics to the field of precision medicine. This review also recapitulates how nanoinformatics could hasten the development of personalized nanomedicine for cancer, which is undoubtedly the need of the hour. CONCLUSION: This approach has been facilitated by a humongous impending field named Nanoinformatics. These breakthroughs and advances have provided insight into the future of personalized medicine. Imperatively, they have been enabling landmark research to merge all advances, creating nanosized particles that contain drugs targeting cell surface receptors and other potent molecules designed to kill cancerous cells. Nanoparticle- based medicine has been developing and has become a center of attention in recent years, focusing primely on proficient delivery systems for various chemotherapy drugs.

Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFRwt and mutant EGFRT790M receptor tyrosine kinases.

Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFRwt inhibition and QU351, for EGFRmt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.

Oblique stagnation point flow of magnetized Maxwell fluid over a stretchable Riga plate with Cattaneo-Christov heat flux and convective conditions.

The current work deals with the oblique stagnation point flow phenomenon of a rate-type Maxwell fluid with the significance of the Cattaneo-Christov double diffusion theory. The Cattaneo-Christov theory is illustrated through the modified form of Fourier's and Fick's laws. The steady magnetized flow mechanism is observed in two dimensions through a stretchable convective Riga plate. In the mass and heat transfer analysis, the consequences of chemical reactions and thermal radiation are also incorporated. With the contribution of relevant dimensionless quantities, the setup of dimensionless equations is acquired which further takes the form of nonlinear equations. The physical significance of the numerous parameters on different features of the flow phenomenon is graphically exhibited. The interesting physical quantities are computed and numerically evaluated relative to the pertinent parameters. This study reveals that the thermal relaxation time parameter lowers the rate of heat transfer, and the thermal Biot number enhances the rate of heat transport. Moreover, the Deborah number minimizes the flow field of both tangential and axial velocities.

Entropy analysis for a novel peristaltic flow in a curved heated endoscope: an application of applied sciences.

Entropy interpretation with a descriptive heat generation analysis is carried out for the heated flow between two homocentric and sinusoidally fluctuating curved tubes. A novel peristaltic endoscope is considered for the first time inside a curved tube with evaluation of heat transfer and entropy. This flexible and novel endoscope with peristaltic locomotion is more efficient for endoscopy of complex mechanical structures and it is more comfortable for patients undergoing the endoscopy of a human organs. A comprehensive mathematical model is developed that also completely evaluates the heat transfer analysis for this novel endoscope. Certain and systematic computations are performed with the help of Mathematica software and exact mathematical as well as graphical solutions are obtained. Entropy has a lower rate that is almost zero entropy in the central region of these two curved tubes, but maximum entropy is noted near the sinusoidally deformable walls of both the endoscope and channel.

CFD analysis on blood flow inside a symmetric stenosed artery: Physiology of a coronary artery disease.

This research article interprets the computational fluid dynamics analysis on blood flow inside a symmetric stenosed artery. The current problem models the blood flow inside the left coronary artery as having a symmetric stenosis in the central region. A comprehensive physiological examination of coronary artery disease is numerically evaluated by using the computational fluid dynamics toolbox Open-Field Operation And Manipulation. There are no assumptions of mild stenosis taken into account since the considered stenosis has an exactly measured length, height and position, etc. The blood flow problem is modeled for the non-Newtonian Casson fluid with unsteady, laminar, and incompressible flow assumptions. The underlying problem is solved numerically in its dimensional form. A thorough graphical analysis is provided on the blood flow simulations, pressure profile, velocity line graphs, pressure line graphs, and streamlines for the left coronary artery having a symmetric stenosis formation. The considered artery is divided into three sections, i.e. pre-stenosis, post-stenosis, and stenosis region, and the velocity and pressure line graphs are plotted for these considered regions. The graphical illustrations provide a detailed analysis of how the blood flow is affected inside the left coronary artery due to coronary artery disease. These pre- and post-stenosis velocity line graphs reveal two intriguing results: In the pre-stenosis zone, the velocity increases with increasing axial coordinate length, whereas in the post-stenosis region, the velocity decreases with rising axial coordinate length. It is evident that as the flow moves toward the stenosis region, the flow profile rises; yet, after passing through the stenosis zone, the flow profile begins to fall as the flow moves away from the stenosis region.

Sacrifice: psychodynamic, cultural and clinical aspects.

Noting that the topic of sacrifice has remained largely unaddressed in psychoanalytic literature, the authors offer a discussion of it. Their elucidation of sacrifice opens with the definition and etymology of the word and moves on to the place of sacrifice in various religious traditions. They then summarize Freud's views on the topic and suggest that the subsequent analytic contributions have gone in three directions: the first extends and modifies Freud's proposal of triadic-hostile origins of sacrifice, the second locates such origins in dyadic and loving relations, and the third seeks to synthesize the foregoing trends. The authors then delineate the triad of altruism, masochism, and narcissism that underlie sacrifice. They propose that a spectrum of phenomena, ranging from healthy to pathological, is subsumed under the rubric of sacrifice. They also discuss the significance of such ideas to the conduct of psychotherapy and psychoanalysis.

Entropy and stability analysis on blood flow with nanoparticles through a stenosed artery having permeable walls.

In this research, the electro-osmotic effects are highlighted for a blood-based hybrid nanofluid flow across an artery infected with multiple stenosis. The artery has permeable walls together with slip boundary effects. The slip and permeable boundary conditions model the more realistic blood flow problems. The governing equations of the problem are converted into non-dimensional form by introducing adequate dimensionless variables and acquired the exact solutions. The detailed study of heat transfer is given by Joule heating and viscous dissipation effects. The disorder of fluid flow is investigated by the mathematical study of entropy generation. Analytically attained solutions are examined graphically for both symmetric and non-symmetric shapes of stenosis. Streamlines are analyzed for varying values of flow rate Q and electro-osmotic parameter m. The flow velocity has smallest values on the axis of channel and gets higher value near the boundary walls. The temperature profile delineates opposite behavior to the velocity, and it is parabolic in nature. The velocity reduces towards the non-uniform stenosis except for electroosmotic parameter m. The temperature has larger magnitude in the case of anti-symmetric stenosis. Moreover, the stability of velocity solution is also analyzed.

Structure-based pharmacophore modeling, virtual screening and simulation studies for the identification of potent anticancerous phytochemical lead targeting cyclin-dependent kinase 2.

Cyclin-dependent kinases are of critical importance in directing various cell cycle phases making them as potential tumor targets. Cyclin-dependent kinase 2 (CDK2) in particular plays a significant part during cell cycle events and its imbalance roots out tumorogenic environment. Herein, we built a structure-based pharmacophore model complementing the ATP pocket site of CDK2 with four pharmacophoric features, using a series of structures obtained from cluster analysis during MD simulation assessment. This was followed by its validation and further database screening against Taiwan indigenous plants database (5284 compounds). The screened compounds were subjected toward Lipinski's rule (RO5) and ADMET filter followed by docking analysis and simulation study. In filtering hits (10 compounds) via molecular docking against CDK2, Schinilenol with -8.1 kcal/mol fetched out as a best lead phytoinhibitor in the presence of standard drug (Dinaciclib). Additionally, pharmacophore mapping analysis also indicated relative fit values of dinaciclib and schinilenol as 2.37 and 2.31, respectively. Optimization, flexibility prediction and the stability of CDK2 in complex with the ligands were also ascertained by means of molecular dynamics for 50 ns, which further proposed schinilenol having better binding stability than dinaciclib with RMSD values ranging from 0.31 to 0.34 nm. Reactivity site, biological activity detection and cardiotoxicity assessment also proposed schinilenol as a better phytolead inhibitor than the existing dinaciclib. Abbreviations: CDK2: Cyclin dependent kinase2; ATP: Adenosine triphosphate; MD: Molecular dynamics, RO5: Rule of five; ADMET: Absorption, distribution, metabolism, and excretion; RMSD: Root mean square deviation; DS: Discovery Studio; SOM: Site of metabolism; RBPM: receptor based pharmacophore model; TIP: Schinilenol; hERG: human Ether-à-go-go - Related GeneCommunicated by Ramaswamy H. Sarma.