scholarly journals Analysis of interaction mechanisms between main objects of tuberculosis-target therapy and corresponding selective inhibitors

2021 ◽  
Vol 28 ◽  
pp. 140-145
Author(s):  
D. O. Samofalova ◽  
O. V. Rayevsky ◽  
S. P. Ozheredov ◽  
S. I. Spivak ◽  
m. m. Stykhylias ◽  
...  
Keyword(s):  
Search Algorithm ◽  
Target Therapy ◽  
Geometry Optimization ◽  
3D Models ◽  
Biologically Active ◽  
Selective Inhibitors ◽  
Reference Library ◽  
Mitotic Apparatus ◽  
Keywords Tuberculosis ◽  
Genus Mycobacterium

Aim. Search for new inhibitors of the mitotic apparatus of mycobacterium and a number of enzymatic targets. Methods. 3D models of key targets reconstruction and geometry optimization and analysis of biologically active conformations of inhibitors were performed according to a previously developed technique. Results. A revision of mycobacterial inhibitors, which exhibit antimicrobial action against representatives of the genus Mycobacterium, was carried out, which made it possible to create an appropriate reference library of compounds. The complete spatial structure of a number of the main targets of targeted therapy for tuberculosis was reconstructed and verified, and the features of their interaction with selective inhibitors were established. Chemogenomic profiling was performed, which made it possible to draw conclusions regarding the uniqueness of the studied sites and the potential toxicity of compounds related to these sites for humans. Conclusions. A well-developed search algorithm for known inhibitors of proteins with M. tuberculosis allows further study of the features of their interaction with the corresponding homologues of M. bovis and the development of new, more selective compounds using molecular dynamics and docking methods. Keywords: tuberculosis, in silico, anti-tuberculosis drugs.

Circulating tumor and endothelial cells as pharmacodynamic biomarkers in a phase I clinical trial of intravenous bevacizumab in combination with escalating doses of oral cediranib for patients with advanced malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3525-3525
Author(s):  
D. W. Davis ◽  
W. Liu ◽  
R. Kurzrock ◽  
A. Naing ◽  
J. Wheler ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Laser Scanning ◽  
Target Therapy ◽  
Biologically Active ◽  
Laser Scanning Cytometry ◽  
Fold Induction ◽  
Investigational Agents ◽  
Pharmacodynamic Biomarkers ◽  
Erk Activity ◽  
Dose Dependent

3525 Background: Rare circulating tumor cells (CTCs) and endothelial cells (CECs) offer a feasible approach for studying the pharmacodynamic effects of investigational agents. We investigated the effects of bevacizumab (B) and cediranib (C) on inhibition of the VEGFR pathway and correlated these changes with dose and clinical response. Methods: Peripheral blood was obtained at baseline, 24hrs and at C2D26–30 post-treatment from patients (n=14) undergoing dose escalation of intravenous B and oral C. CTCs and CECs (CD31+ or CD105+) were isolated and immunofluorescently stained. Laser scanning cytometry (LSC) was used to quantify phosphorylated and total-VEGFR2 (pVEGFR2/VEGFR2), pERK/ERK, and apoptosis in each phenotype. Changes in each biomarker were correlated with partial response (PR) or stable disease and progression > 2 months, evaluated using RECIST. Results: Overall, immature CECs (CD105+) enumerated by CellSearch™ revealed a dose-dependent significant decrease (p=0.0001). A 3-fold induction in apoptosis was observed at 24 hrs compared to baseline in the CD105+ CECs. Mature CD31+ cells assessed for VEGFR2 activity revealed an 83% and 1.9% significant (p=0.019) inhibition in pVEGFR2 expression at low (B;3mg/kg) and high (B;5mg/kg) doses, respectively. In the non-responders, mature CECs revealed a dose-dependent significant increase (-6.8% to 63%;p=0.031) in pERK/ERK expression levels. No significant changes were observed in CTC enumeration by CellSearch™. LSC-mediated CTC enumeration revealed a 4.77 % and 2.33% increase in CTCs following treatment in the non- responders and responder (p=0.809), respectively. Analysis of pVEGFR2 in CTCs revealed a 58% inhibition in the responder versus a 163% increase in expression in the non-responders (p=0.63). Conclusions: Inhibition of pVEGFR2 and induction of apoptosis in CECs confirmed the target therapy. An increase in CD105+ CECs is consistent with the hypothesis that anti-angiogenic efficacy induces endothelial cell shedding. Assessment of CECs indicates that B and C are more biologically active at lower doses, and resistance may be attributed to ERK activity. Support: UO1 CA062461 (RK) No significant financial relationships to disclose.

scholarly journals VIRAL DELIVERY USING SCAFFOLDS

2021 ◽  
Vol 20 (2) ◽  
pp. 19-30
Author(s):  
A. A. Laevskaya ◽  
V. V. Kosenchuk ◽  
S. I. Yakushov ◽  
P. S. Timashev ◽  
I. V. Ulasov
Keyword(s):  
Viral Vectors ◽  
Materials Science ◽  
Viral Vector ◽  
3D Models ◽  
Premature Aging ◽  
Biologically Active ◽  
Target Cells ◽  
Bioactive Polymers ◽  
Material Chemistry ◽  
Potential Benefits

In experimental oncology there are multiple approaches have been developed to target tumor cells. Many of them are based on scaffolds, a 3D models that mimics the structure of tissue in normal and pathophysiological state. It  is known that to deliver a viral load to target cells, cells-carriers undergo limited differentiation, and premature aging. Since viral agents require cells to be in specific proliferative state, the delivery of the virus to the target cell is the main goal of the functional framework such as scaffold. Over decade, multiple studies demonstrate the production of scaffolds using matrigel, polyalacinic acid, poly-lactide-co-glycolide, vinyl stilbens, or bioactive polymers. Our review will describe the potential benefits of delivering the viral vector using 3D scaffolds for virus-mediated expression of biologically active substances that prevent angiogenesis, neoplasm proliferation, or, conversely, stimulate wound healing. 3D materials such as hydrogels and scaffolds are among the key innovations in the field of material chemistry. Moreover, viral vectors provide specific delivery of genes to target cells. However, the immunogenicity of a viral capsid consisting of viral proteins hinders the clinical use of such vectors widely. These limitations can be surmounted by using scaffolds. Therefore, our review might interest researchers working in the fields of chemistry, materials science and natural sciences, as well as in the field of bioengineering and medical technologies.

Minimum Height Packing for Layered Manufacturing Using an Extended Pattern Search Algorithm

2003 ◽  
Author(s):  
Chandankumar Aladahalli ◽  
Jonathan Cagan ◽  
Kenji Shimada
Keyword(s):  
Search Algorithm ◽  
3D Models ◽  
Layered Manufacturing ◽  
Pattern Search ◽  
Maximum Height ◽  
Pattern Search Algorithm ◽  
Time To Build ◽  
Component Layout ◽  
Minimum Height ◽  
Extended Pattern Search

This paper introduces an approach to solve the minimum height layout problem for layered manufacturing using a pattern search based algorithm called Extended Pattern Search. In the batch processing of several components in a typical layered manufacturing run, it is efficient in terms of cost and time to build the components after packing their 3D models such that the maximum height of the components is minimized. 3D component layout based on a pattern search algorithm provides a framework to accomplish such minimum height packing. A method to determine the objective function weights for a class of problems is also provided. Finally error minimizing build directions are incorporated in the 3D layout framework by imposing suitable spatial orientation constraints on individual components.

On the inter-instrument and the inter-laboratory transferability of a tandem mass spectral reference library: 2. Optimization and characterization of the search algorithm

2009 ◽  
Vol 44 (4) ◽  
pp. 494-502 ◽  
Author(s):  
Herbert Oberacher ◽  
Marion Pavlic ◽  
Kathrin Libiseller ◽  
Birthe Schubert ◽  
Michael Sulyok ◽  
...  
Keyword(s):  
Search Algorithm ◽  
Tandem Mass ◽  
Reference Library ◽  
Mass Spectral

scholarly journals A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 14
Author(s):  
Marzia Di Donato ◽  
Pia Giovannelli ◽  
Maria Vittoria Barone ◽  
Ferdinando Auricchio ◽  
Gabriella Castoria ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
3D Models ◽  
Biologically Active ◽  
New Drugs ◽  
Filamin A ◽  
Complex Assembly ◽  
Prostate Cancer Development ◽  
Hormone Antagonists ◽  
Peptide Targeting

Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. We report here that the AR associates with Filamin A (FlnA) promoting migration and invasiveness of various PC-derived cells after androgen challenging. Inhibition of the AR/FlnA complex assembly by a very low concentration of Rh-2025u, an AR-derived peptide specifically interfering with this association, impairs such phenotype in monolayer cells and in 3D models. This study, together with our recent data in cancer-associated fibroblasts (CAFs), indicates that targeting the AR/FlnA complex could improve the clinical management of invasive PC, as the limited number of new drugs reaching the market suggests that we must re-examine the way invasive PC is currently treated. In this context, the synthesis of new biologically active molecules, such as the Rh-2025u peptide, which has been shown to efficiently interfere in the complex assembly in CAFs and PC cells, should overcome the limits of current available therapies, mostly based on hormone antagonists.

Pattern Search Automation for Combinational Logic Analysis

2018 ◽  
Author(s):  
Ravikumar Venkat Krishnan ◽  
Seah Yi Xuan ◽  
Lim Gabriel ◽  
Tan Abel ◽  
Lua Winson ◽  
...  
Keyword(s):  
Search Algorithm ◽  
Pattern Search ◽  
Combinational Logic ◽  
Laser Interaction ◽  
Reference Library ◽  
Standard Cells ◽  
Laser Probing ◽  
Precise Understanding ◽  
Turn Around Time ◽  
Probe Placement

Abstract Combinational logic analysis (CLA) using laser voltage probing allows studying standard cells such as NOR or NAND gates as a whole, instead of individual transistors. The process involves building a reference library of laser probing (LP) waveforms and comparing them to signals from the real device. While CLA has greatly increased the success rate and turn-around time for LP, there are difficulties in signal interpretation. This is partly due to the lack of precise understanding of the laser interaction area and probe placement and partly due to difficulties identifying the correct logic states in the waveform. In this work, we have significantly improved the CLA process by first predicting the shape of the waveform based on laser interaction with the target circuitry and second, implementing an automated pattern search algorithm to further increase the speed and reliability of CLA using LP.

Synthesis, DFT Calculations, DNA Binding and Molecular Docking Studies on Biologically Active N-((3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)naphthyl Derivatives

2021 ◽  
Vol 6 (4) ◽  
pp. 292-301
Author(s):  
P.V. Sandhya ◽  
K.S. Femina ◽  
A.V. Pradeep
Keyword(s):  
Molecular Docking ◽  
Dna Binding ◽  
Biological Activities ◽  
Condensation Reaction ◽  
Geometry Optimization ◽  
Docking Study ◽  
Biologically Active ◽  
Molecular Docking Study ◽  
Binding Interaction

The biologically active pyrazole clubbed imino naphthyl derivatives have been designed and synthesized from 1-phenyl-3-methoxy phenyl-1H-pyrazol-4-carboxaldehyde and substituted naphthyl amines via acid catalyzed condensation reaction. All the synthesized compounds were well characterized by different spectroscopic and mass spectral techniques. The in vitro antibacterial, antifungal and antituberculosis studies were carried out. The molecular docking study was also done with the software Arguslab 4.0.1. The studied compounds showed moderate to good biological activities both experimentally and theoretically. Geometry optimization, DNA binding interaction and FMO analysis were also investigated with the help of Gaussian 16 package at B3LYP/6-31G(d,p) level.

Structural Studies on Mitotic Spindle Fibres

1978 ◽  
Vol 36 (3) ◽  
pp. 615-626
Author(s):  
J.R. Mcintosh
Keyword(s):  
Chemical Composition ◽  
Mitotic Spindle ◽  
Structural Studies ◽  
Mitotic Apparatus ◽  
Chemical Studies ◽  
Medical Interest ◽  
Spindle Fibres

The mitotic apparatus is a structure of obvious biological and medical interest, but it has proved to be a difficult cellular machine to understand. The chemical composition of the spindle is only slightly elucidated, largely because of the difficulties in preparing useful isolates of the structure. Chemical studies of the mitotic spindle have been reviewed elsewhere (Mcintosh, 1977), and will not be discussed further here. One would think that structural studies on the mitotic apparatus (MA) in situ would be straightforward, but even with this approach there is some disagreement in the results obtained with various methods and by different investigators. In this paper I will review briefly the approaches which have been used in structural studies of the MA, pointing out the strengths and problems of each approach. I will summarize the principal findings of the different methods, and identify what seem to be fruitful avenues for further work.

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