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Yu, Bingting, Ruslan Mamedov, Gwenny M. Fuhler, and Maikel P. Peppelenbosch. "Drug Discovery in Liver Disease Using Kinome Profiling." International Journal of Molecular Sciences 22, no. 5 (March 5, 2021): 2623. http://dx.doi.org/10.3390/ijms22052623.
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The liver is one of the most important organs, playing critical roles in maintaining biochemical homeostasis. Accordingly, disease of the liver is often debilitating and responsible for untold human misery. As biochemical nexus, with kinases being master regulators of cellular biochemistry, targeting kinase enzymes is an obvious avenue for treating liver disease. Development of such therapy, however, is hampered by the technical difficulty of obtaining comprehensive insight into hepatic kinase activity, a problem further compounded by the often unique aspects of hepatic kinase activities, which makes extrapolations from other systems difficult. This consideration prompted us to review the current state of the art with respect to kinome profiling approaches towards the hepatic kinome. We observe that currently four different approaches are available, all showing significant promise. Hence we postulate that insight into the hepatic kinome will quickly increase, leading to rational kinase-targeted therapy for different liver diseases.
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Martínez, Antón Leandro, José Brea, Marián Castro, Ángel García, Eduardo Santamaría, Óscar Lestón, and María Isabel Loza. "An Experience of Using a Canvas-Based Template for Blended-Learning in a Master in Drug Discovery." International Journal of Emerging Technologies in Learning (iJET) 17, no. 06 (March 29, 2022): 257–67. http://dx.doi.org/10.3991/ijet.v17i06.28149.
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Drug development is a complex process that requires multidisciplinary teamwork to overcome the uncertainty associated to the process. From this point, problem-based learning (PBL) methodologies are helpful to train future professionals dedicated to drug development in multidisciplinary environments. One of the strategies developed to design novel business models is Business Model Canvas (BMC), a strategy that has been widely employed in business schools, but not in scientific education. Thus, we wanted to verify if a BMC-like template was suitable for a PBL experience in the field of drug development using a blended-learning approach. The students of a research master subject were asked to create a joint project plan for the development of a novel drug for an unmet clinical need by making use of a BMC-like template as support for discussions on the project strategy, while combining online and face-to-face sessions. The methodology helped the students to learn about drug development, even in a blended-learning format. Most students considered that this methodology enhanced their participation in the working group and helped them to focus their arguments, proving that the employment of BMC-like templates is helpful to overcome the disadvantages of PBL experiences.
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Gusev, K. A., O. A. Terenteva, D. N. Maimistov, Yu E. Generalova, K. O. Sidorov, and E. V. Flisyuk. "Development of Suppositories Silicone Molds Using Additive Technologies." Drug development & registration 11, no. 4 (November 27, 2022): 116–24. http://dx.doi.org/10.33380/2305-2066-2022-11-4-116-124.
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Introduction. In modern practice, suppositories are prepared by hand rolling method or fusion. 3D printing can overcome the disadvantages of traditional suppository manufacturing methods and solve the problems of personalization. 3D printing makes it possible to manufacture drug-loaded suppositories without the use of molds or other physical support. The current studies have a number of limitations, and the printing of one suppository requires a long time. This report proposes a method of 3D modeling and 3D printing to produce personalized suppositories by fusion.Aim. Various sizes and shapes suppositories silicone molds development by molding method from hydrophilic, lipophilic and amphiphilic bases.Materials and methods. Suppository bases: cocoa butter (Luker, Colombia), polyethylene glycol (PEG) 1500 (Merck KGaA, Germany), PEG-400 (Merck KGaA, Germany), Witepsol H-15 (Chimmed Group, Russia); pharmaceutical substance: paracetamol (Hebei Jiheng (Group) Pharmaceutical Co. Ltd, China); filaments for 3D printing: polyethylene terephthalate (PET-G natural, LLC "PrintProdakt", Russia); silicone two-component platinum, hardness Shore 30A (China); solvents: Acetonitrile Grade HPLC (Merck KGaA, Germany). The design of the both casting and master molds of suppositories was carried out using the KOMPAS-3D version 17.1. Master molds were printed by Picaso PRO 250 and Picaso X Pro 3D printers. Mold segments were obtained by filling master molds with a mixture of two-component silicone. Suppositories were obtained by molding method. Their average weight and standard deviation were determined. Paracetamol concentration in suppositories was carried out by UV spectrophotometry on a UV-1240 mini spectrophotometer (Shimadzu, Япония). Silicone molds were soaked and washed in hot water with surfactants. Washouts from the molds were taken by soaking the mold.Results and discussion. The torpedo-shaped form was chosen as the model form of suppositories. For the chosen form, three volumes of suppositories were designed: 3.32 ml; 1.5 ml and 0.25 ml. Silicone molds were designed and manufactured for all volumes. The cast suppositories were examined for compliance with the regulatory documentation for the dosage form, the average weight and mass uniformity were evaluated. Suppositories with paracetamol were made. A procedure for cleaning the obtained silicone molds has been developed.Conclusion. The resulting silicone molds make it possible to obtain suppositories in accordance with the regulatory documentation for the suppositories. Silicone molds have significant advantages compared to analogues of metal or polymeric molds.
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Zheng, Hailin, Mati Fridkin, and Moussa Youdim. "New Approaches to Treating Alzheimer's Disease." Perspectives in Medicinal Chemistry 7 (January 2015): PMC.S13210. http://dx.doi.org/10.4137/pmc.s13210.
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To date, no truly efficacious drugs for Alzheimer's disease (AD) have been developed; moreover, all new anti-AD drugs developed since 2003 have failed. To succeed where previous ones have failed in drug development, new approaches for AD therapy are needed. Here we discuss the potential application of network medicine as a new approach to AD treatment. Unlike traditional approaches focused on a single target/pathway, network medicine targets and restores disease-disrupted networks through simultaneous modulation of numerous proteins (targets)/pathways involved in AD pathogenesis. We consider several drug candidates under development for AD therapy, including Keap1–Nrf2 regulators, endogenous neurogenic agents, and hypoxia-inducible factor 1 (HIF-1) activators. These drug candidates are multi-target ligands with the potential to further develop as network medicines, since they act as master regulators to initiate a broad range of cellular defense mechanisms/cytoprotective genes that exert their efficacy in a holistic way. We also explore their diverse mechanisms of action and potential disease-modifying effects, which may have profound implications for drug discovery.
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Kaizer, Alexander M., Joseph S. Koopmeiners, Michael J. Kane, Satrajit Roychoudhury, David S. Hong, and Brian P. Hobbs. "Basket Designs: Statistical Considerations for Oncology Trials." JCO Precision Oncology, no. 3 (December 2019): 1–9. http://dx.doi.org/10.1200/po.19.00194.
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Progress in the areas of genomics, disease pathways, and drug discovery has advanced into clinical and translational cancer research. The latest innovations in clinical trials have followed with master protocols, which are defined by inclusive eligibility criteria and devised to interrogate multiple therapies for a given tumor histology and/or multiple histologies for a given therapy under one protocol. The use of master protocols for oncology has become more common with the desire to improve the efficiency of clinical research and accelerate overall drug development. Basket trials have been devised to ascertain the extent to which a treatment strategy offers benefit to various patient subpopulations defined by a common molecular target. Conventionally conducted within the phase II setting, basket designs have become popular as drug developers seek to effectively evaluate and identify preliminary efficacy signals among clinical indications identified as promising in preclinical study. This article reviews basket trial designs in oncology settings and discusses several issues that arise with their design and analysis.
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Shirakawa, Tomohiko, Takashi Toyono, Asako Inoue, Takuma Matsubara, Tatsuo Kawamoto, and Shoichiro Kokabu. "Factors Regulating or Regulated by Myogenic Regulatory Factors in Skeletal Muscle Stem Cells." Cells 11, no. 9 (April 29, 2022): 1493. http://dx.doi.org/10.3390/cells11091493.
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MyoD, Myf5, myogenin, and MRF4 (also known as Myf6 or herculin) are myogenic regulatory factors (MRFs). MRFs are regarded as master transcription factors that are upregulated during myogenesis and influence stem cells to differentiate into myogenic lineage cells. In this review, we summarize MRFs, their regulatory factors, such as TLE3, NF-κB, and MRF target genes, including non-myogenic genes such as taste receptors. Understanding the function of MRFs and the physiology or pathology of satellite cells will contribute to the development of cell therapy and drug discovery for muscle-related diseases.
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Buxton, Meredith Becker, Brian Michael Alexander, Donald A. Berry, Webster K. Cavenee, Howard Colman, John Frederick De Groot, Benjamin M. Ellingson, et al. "GBM AGILE: A global, phase II/III adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS2579. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps2579.
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TPS2579 Background: Glioblastoma (GBM) is an aggressive brain tumor with few effective therapies and is invariably fatal. Developing new therapies for patients with GBM requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. Industry is wary of developing drugs for GBM due to the high failure rate and high cost of drug development. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase II/III development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research (GCAR), a non-profit organization. GCAR’s mission is to speed the discovery and development of treatments for patients with rare and deadly diseases by serving as sponsor of innovative trials. Methods: GBM AGILE is an international, seamless phase II/III platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs/drug combinations from different pharmaceutical companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, enrolling its first patient in June 2019. Site activation is ongoing in the US, with approximately 40 US planned. The trial received CTA approval from Health Canada in January 2020. Expansion to Europe, China, and Australia is also underway. Clinical trial information: NCT03970447 .
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Chen, Po-Ling, Tsai-Teng Tzeng, Alan Yung-Chih Hu, Lily Hui-Ching Wang, and Min-Shi Lee. "Development and Evaluation of Vero Cell-Derived Master Donor Viruses for Influenza Pandemic Preparedness." Vaccines 8, no. 4 (October 25, 2020): 626. http://dx.doi.org/10.3390/vaccines8040626.
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The embryonated egg-based platform currently produces the majority of seasonal influenza vaccines by employing a well-developed master donor virus (MDV, A/PR/8/34 (PR8)) to generate high-growth reassortants (HGRs) for A/H1N1 and A/H3N2 subtypes. Although the egg-based platform can supply enough seasonal influenza vaccines, it cannot meet surging demands during influenza pandemics. Therefore, multi-purpose platforms are desirable for pandemic preparedness. The Vero cell-based production platform is widely used for human vaccines and could be a potential multi-purpose platform for pandemic influenza vaccines. However, many wild-type and egg-derived influenza viruses cannot grow efficiently in Vero cells. Therefore, it is critical to develop Vero cell-derived high-growth MDVs for pandemic preparedness. In this study, we evaluated two in-house MDVs (Vero-15 and VB5) and two external MDVs (PR8 and PR8-HY) to generate Vero cell-derived HGRs for five avian influenza viruses (AIVs) with pandemic potentials (H5N1 clade 2.3.4, H5N1 clade 2.3.2.1, American-lineage H5N2, H7N9 first wave and H7N9 fifth wave). Overall, no single MDV could generate HGRs for all five AIVs, but this goal could be achieved by employing two in-house MDVs (vB5 and Vero-15). In immunization studies, mice received two doses of Vero cell-derived inactivated H5N1 and H7N9 whole virus antigens adjuvanted with alum and developed robust antibody responses.
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Chavan, Sandeep, Sonali Tayade, Vidya Gupta, Vineeta Deshmukh, and Sadanand Sardeshmukh. "Pharmaceutical Standardization and Physicochemical Characterization of Traditional Ayurvedic Marine Drug: Incinerated Conch Shell (Shankha Bhasma)." Marine Drugs 16, no. 11 (November 15, 2018): 450. http://dx.doi.org/10.3390/md16110450.
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Natural resources such as plants, animals and minerals have always been used by mankind to develop drugs and marine world is no exception. Marine by-products like conches, pearls, mother of pearl shells, corals and so forth have been used by traditional Ayurvedic practitioners for centuries. The unique methods of these preparations are scientifically designed to eliminate unwanted impurities and convert them into bioavailable form. In this study, Conch (Xanchus pyrum) was used as a marine resource of calcium carbonate and was converted pharmaceutically from its aragonite form to calcite. All the steps of preparations and changes in the properties therein were documented and validated. Further, traditional as well as modern analytical tools were used to study its physical and chemical characters to develop a monograph. The physical characterization included particle size, X-ray diffraction (XRD), Scanning Electron Microscopy (SEM), Thermogravimetric Analysis (TGA) and Fourier Transform Infra-red (FTIR). Metal composition and heavy metal limits were determined using Inductively Coupled Plasma Optical Emission Spectrometry (ICPOES). This study revealed the rearrangement of aragonite crystals into calcite form by grinding, trituration with aloe vera juice and incineration under controlled conditions. Moreover, the finished product was found to be devoid of organic matrix that is nacre. This study creates a foundation for the development of a master formula for commonly used Shankha Bhasma in Ayurvedic medicines.
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Wu, Guoyu, Junyang Yi, Ling Liu, Pengcheng Wang, Zhijie Zhang, and Zhen Li. "Pseudoginsenoside F11, a Novel Partial PPARγAgonist, Promotes Adiponectin Oligomerization and Secretion in 3T3-L1 Adipocytes." PPAR Research 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/701017.
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PPARγis a nuclear hormone receptor that functions as a master regulator of adipocyte differentiation and development. Full PPARγagonists, such as the thiazolidinediones (TZDs), have been widely used to treat type 2 diabetes. However, they are characterized by undesirable side effects due to their strong agonist activities. Pseudoginsenoside F11 (p-F11) is an ocotillol-type ginsenoside isolated fromPanax quinquefolium L.(American ginseng). In this study, we found that p-F11 activates PPARγwith modest adipogenic activity. In addition, p-F11 promotes adiponectin oligomerization and secretion in 3T3-L1 adipocytes. We also found that p-F11 inhibits obesity-linked phosphorylation of PPARγat Ser-273 by Cdk5. Therefore, p-F11 is a novel partial PPARγagonist, which might have the potential to be developed as a new PPARγ-targeted therapeutics for type 2 diabetes.
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Chen, Dongmei, Xiao Z. Zhou, and Tae H. Lee. "Death-Associated Protein Kinase 1 as a Promising Drug Target in Cancer and Alzheimer’s Disease." Recent Patents on Anti-Cancer Drug Discovery 14, no. 2 (August 2, 2019): 144–57. http://dx.doi.org/10.2174/1574892814666181218170257.
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Background:Death-Associated Protein Kinase 1 (DAPK1) plays an important role in apoptosis, tumor suppression and neurodegeneration including Alzheimer’s Disease (AD).Objective:This review will describe the diverse roles of DAPK1 in the development of cancer and AD, and the current status of drug development targeting DAPK1-based therapies.Methods:Reports of DAPK1 regulation, function and substrates were analyzed using genetic DAPK1 manipulation and chemical DAPK1 modulators.Results:DAPK1 expression and activity are deregulated in cancer and AD. It is down-regulated and/or inactivated by multiple mechanisms in many human cancers, and elicits a protective effect to counteract numerous death stimuli in cancer, including activation of the master regulator Pin1. Moreover, loss of DAPK1 expression has correlated strongly with tumor recurrence and metastasis, suggesting that lack of sufficient functional DAPK1 might contribute to cancer. In contrast, DAPK1 is highly expressed in the brains of most human AD patients and has been identified as one of the genetic factors affecting susceptibility to late-onset AD. The absence of DAPK1 promotes efficient learning and better memory in mice and prevents the development of AD by acting on many key proteins including Pin1 and its downstream targets tau and APP. Recent patents show that DAPK1 modulation might be used to treat both cancer and AD.Conclusion:DAPK1 plays a critical role in diverse physiological processes and importantly, its deregulation is implicated in the pathogenesis of either cancer or AD. Therefore, manipulating DAPK1 activity and/or expression may be a promising therapeutic option for cancer or AD.
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Taylor, Kimberly L., Lynda Lanning, Lawrence Wolfraim, Sonia Shrivastava Gales, Colleen Sico, William E. Dowling, Lucy A. Ward, William C. Florence, Edwin Nuzum, and Paula R. Bryant. "A U.S. Government-Coordinated Effort to Leverage Non-Human Primate Data to Facilitate Ebolavirus Vaccine Development." Vaccines 10, no. 8 (July 28, 2022): 1201. http://dx.doi.org/10.3390/vaccines10081201.
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A United States Government (USG) interagency group, the Filovirus Animal Non-Clinical Group (FANG), has been established to support the development of biodefense medical countermeasures (MCMs). As both vaccines and therapeutics are licensed using “non-traditional pathways”, such as the U.S. Food and Drug Administration’s (FDA) Animal Rule (AR), non-human primate (NHP) models and associated assays have been developed and standardized across BSL4 testing sites to evaluate candidate products. Vaccine candidates are evaluated using these NHP models, and through this public–private partnership, a meta-analysis of NHP control data has been conducted and submitted to the FDA as a master file. This is an example of how existing NHP control data can be leveraged in lieu of conducting separate natural history studies at multiple testing facilities to demonstrate the consistency of a standardized animal model for vaccine development. As a result, animal use can be minimized and the duplication of effort avoided, thus reducing the amount of time needed to conduct additional studies, as well as the cost of vaccine candidate development. This successful strategy may be applied to other pathogens of high consequence for vaccine development, and shows how strategic preparedness for biodefense can be leveraged in response to outbreaks and public health emergencies.
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Taghvaei, Somayye, and Leila Saremi. "Molecular Dynamics Simulation and Essential Dynamics of Deleterious Proline 12 Alanine Single-Nucleotide Polymorphism in PPARγ2 Associated with Type 2 Diabetes, Cardiovascular Disease, and Nonalcoholic Fatty Liver Disease." PPAR Research 2022 (May 2, 2022): 1–10. http://dx.doi.org/10.1155/2022/3833668.
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Background. Peroxisome proliferator-activated receptor-γ (PPARγ) gene is located at 3p25 position. PPARγ functions as the master regulator of glucose homeostasis and lipoprotein metabolism, and recent studies have reported that it is involved in various metabolic diseases such as diabetes mellitus, hyperlipidemia, coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). PPARγ1 and PPARγ2 are necessary for the development of adipose tissue and insulin sensitivity regulation. But PPARγ2 is the isoform that was controlled in response to nutrient intake and obesity. Methodology. In this study, we used computational techniques to show the impact of Pro12Ala polymorphism on PPARγ2. The 3-D structure of PPARγ2 was modeled using I-TASSER server. The modeled structure was validated with the ZLab server, and the mutation was created with SPDB viewer. Stability prediction tools were used. Molecular dynamics simulation (MDS) was used to understand the structural and functional behavior of the wild type and mutant. Essential dynamics was also applied. Results and Conclusions. Stability prediction tools were showed that this mutation has a destabilizing effect on the PPARγ2 structure. The RMSD, RMSF, Rg, SASA, and DSSP were in line with H-bond results that showed less flexibility in the mutant structure. Essential dynamics was used to verify MDS results. Pro12Ala polymorphism leads to rigidity of the PPARγ2 protein and might disturb the conformational changes and interactions of PPARγ2 and results in type 2 diabetes mellitus (T2DM), CAD, and NAFLD. This study can help scientists to develop a drug therapy against these diseases.
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Carpenter, Richard L., and Yesim Gökmen-Polar. "HSF1 as a Cancer Biomarker and Therapeutic Target." Current Cancer Drug Targets 19, no. 7 (August 2, 2019): 515–24. http://dx.doi.org/10.2174/1568009618666181018162117.
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Heat shock factor 1 (HSF1) was discovered in 1984 as the master regulator of the heat shock response. In this classical role, HSF1 is activated following cellular stresses such as heat shock that ultimately lead to HSF1-mediated expression of heat shock proteins to protect the proteome and survive these acute stresses. However, it is now becoming clear that HSF1 also plays a significant role in several diseases, perhaps none more prominent than cancer. HSF1 appears to have a pleiotropic role in cancer by supporting multiple facets of malignancy including migration, invasion, proliferation, and cancer cell metabolism among others. Because of these functions, and others, of HSF1, it has been investigated as a biomarker for patient outcomes in multiple cancer types. HSF1 expression alone was predictive for patient outcomes in multiple cancer types but in other instances, markers for HSF1 activity were more predictive. Clearly, further work is needed to tease out which markers are most representative of the tumor promoting effects of HSF1. Additionally, there have been several attempts at developing small molecule inhibitors to reduce HSF1 activity. All of these HSF1 inhibitors are still in preclinical models but have shown varying levels of efficacy at suppressing tumor growth. The growth of research related to HSF1 in cancer has been enormous over the last decade with many new functions of HSF1 discovered along the way. In order for these discoveries to reach clinical impact, further development of HSF1 as a biomarker or therapeutic target needs to be continued.
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Kalathiya, Padariya, Pawlicka, Verma, Houston, Hupp, and Alfaro. "Insights into the Effects of Cancer Associated Mutations at the UPF2 and ATP-Binding Sites of NMD Master Regulator: UPF1." International Journal of Molecular Sciences 20, no. 22 (November 11, 2019): 5644. http://dx.doi.org/10.3390/ijms20225644.
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Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that recognizes post-transcriptionally abnormal transcripts and mediates their degradation. The master regulator of NMD is UPF1, an enzyme with intrinsic ATPase and helicase activities. The cancer genomic sequencing data has identified frequently mutated residues in the CH-domain and ATP-binding site of UPF1. In silico screening of UPF1 stability change as a function over 41 cancer mutations has identified five variants with significant effects: K164R, R253W, T499M, E637K, and E833K. To explore the effects of these mutations on the associated energy landscape of UPF1, molecular dynamics simulations (MDS) were performed. MDS identified stable H-bonds between residues S152, S203, S205, Q230/R703, and UPF2/AMPPNP, and suggest that phosphorylation of Serine residues may control UPF1-UPF2 binding. Moreover, the alleles K164R and R253W in the CH-domain improved UPF1-UPF2 binding. In addition, E637K and E833K alleles exhibited improved UPF1-AMPPNP binding compared to the T499M variant; the lower binding is predicted from hindrance caused by the side-chain of T499M to the docking of the tri-phosphate moiety (AMPPNP) into the substrate site. The dynamics of wild-type/mutant systems highlights the flexible nature of the ATP-binding region in UPF1. These insights can facilitate the development of drug discovery strategies for manipulating NMD signaling in cell systems using chemical tools.
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Okazaki, Tatsuma, Momoko Matashiro, Gaku Kodama, Takeshi Tshubota, Yoshihito Furusawa, and Shin-Ichi Izumi. "Frequent Onsets of Cellulitis in Lower Limbs with Lymphedema Following COVID-19 mRNA Vaccination." Vaccines 10, no. 4 (March 26, 2022): 517. http://dx.doi.org/10.3390/vaccines10040517.
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Four patients with secondary lower limb lymphedema developed cellulitis at their lymphedema lesion following COVID-19 mRNA vaccinations. They did not develop adverse effects at their vaccination site. All the patients were Japanese females aged <60 years. Three patients developed cellulitis following the first vaccination. The date of onset of cellulitis following the first vaccination varied from 0 to 21 days. Two received BNT162b2 mRNA vaccines and the others received mRNA-1273 vaccines. All the patients were treated with oral antibiotics and recovered. Two patients had repeated cellulitis. The patients with the repeated development of cellulitis could not perform good skincare. One patient had joint contractures in their lower limbs and could not reach her lymphedema lesions, and the other patient could not master the skincare. According to previous studies, the development of cellulitis following vaccination was rare. In this study, four patients aged <60 years developed cellulitis among the eight patients that regularly visited our hospital for rehabilitation for their lower limb lymphedema. In patients with lymphedema, prolonged inflammation may impair lymphatic functions and worsen edema. Therefore, at the time of vaccination, we should keep in mind the prevention and immediate management of cellulitis using intensive skincare and antibiotic treatment.
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Halmos, Tamás, and Ilona Suba. "Physiological and pathophysiological role of the circadian clock system." Orvosi Hetilap 153, no. 35 (September 2012): 1370–79. http://dx.doi.org/10.1556/oh.2012.29436.
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It has been well known for ages that in living organisms the rhythmicity of biological processes is linked to the ~ 24-hour light–dark cycle. However, the exact function of the circadian clock system has been explored only in the past decades. It came to light that the photosensitive primary “master clock” is situated in the suprachiasmatic photosensitive nuclei of the special hypothalamic region, and that it is working according to ~24-hour changes of light and darkness. The master clock sends its messages to the peripheral “slave clocks”. In many organs, like pancreatic β-cells, the slave clocks have autonomic functions as well. Two essential components of the clock system are proteins encoded by the CLOCK and BMAL1 genes. CLOCK genes are in interaction with endonuclear receptors such as peroxisoma-proliferator activated receptors and Rev-erb-α, as well as with the hypothalamic-pituitary-adrenal axis, regulating the adaptation to stressors, energy supply, metabolic processes and cardiovascular system. Melatonin, the product of corpus pineale has a significant role in the functions of the clock system. The detailed discovery of the clock system has changed our previous knowledge about the development of many diseases. The most explored fields are hypertension, cardiovascular diseases, metabolic processes, mental disorders, cancers, sleep apnoe and joint disorders. CLOCK genes influence ageing as well. The recognition of the periodicity of biological processes makes the optimal dosing of certain drugs feasible. The more detailed discovery of the interaction of the clock system might further improve treatment and prevention of many disorders. Orv. Hetil., 2012, 153, 1370–1379.
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Zheng, Bin, QingYun Mai, JinXing Jiang, and QinQin Zhou. "The Therapeutic Potential of Small Activating RNAs for Colorectal Carcinoma." Current Gene Therapy 19, no. 3 (September 18, 2019): 140–46. http://dx.doi.org/10.2174/1566523219666190708111404.
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Small double-strand RNAs have been recognized as master regulators of gene expression. In contrast to the evolutionary conserved RNA interference machinery, which degrades or inhibits the translation of target mRNAs, small activating RNA (saRNA) activates the specific gene in a target dependent manner through a similar mechanism as RNAi. Recently, saRNA mediated expression regulation of specific genes has been extensively studied in cancer researches. Of particular interest is the application of the RNA mediated gene activation within colorectal cancer (CRC) development, due to the high incidence of the CRC. In this review, we summarize the current knowledge of saRNA mediated genetic activation and its underlying mechanisms. Furthermore, we highlight the advantages of the utilization of saRNAs induced gene expression as an investigating tool in colorectal cancer research. Finally, the possibility and the challenge of the saRNA application as a potential therapy for colorectal cancer are addressed.
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Ghareghomi, Somayyeh, Mahdie Rahban, Zainab Moosavi-Movahedi, Mehran Habibi-Rezaei, Luciano Saso, and Ali Akbar Moosavi-Movahedi. "The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications." Molecules 26, no. 24 (December 17, 2021): 7658. http://dx.doi.org/10.3390/molecules26247658.
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Oxidative stress is the leading player in the onset and development of various diseases. The Keap1-Nrf2 pathway is a pivotal antioxidant system that preserves the cells’ redox balance. It decreases inflammation in which the nuclear trans-localization of Nrf2 as a transcription factor promotes various antioxidant responses in cells. Through some other directions and regulatory proteins, this pathway plays a fundamental role in preventing several diseases and reducing their complications. Regulation of the Nrf2 pathway occurs on transcriptional and post-transcriptional levels, and these regulations play a significant role in its activity. There is a subtle correlation between the Nrf2 pathway and the pivotal signaling pathways, including PI3 kinase/AKT/mTOR, NF-κB and HIF-1 factors. This demonstrates its role in the development of various diseases. Curcumin is a yellow polyphenolic compound from Curcuma longa with multiple bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Since hyperglycemia and increased reactive oxygen species (ROS) are the leading causes of common diabetic complications, reducing the generation of ROS can be a fundamental approach to dealing with these complications. Curcumin can be considered a potential treatment option by creating an efficient therapeutic to counteract ROS and reduce its detrimental effects. This review discusses Nrf2 pathway regulation at different levels and its correlation with other important pathways and proteins in the cell involved in the progression of diabetic complications and targeting these pathways by curcumin.
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Kutnjak-Mravlinčić, Suzana, Ana Sutlović, Martinia Ira Glogar, Sanja Ercegović Ražić, and Damir Godec. "Innovative Development of Batch Dyed 3D Printed Acrylonitrile/Butadiene/Styrene Objects." Molecules 26, no. 21 (November 2, 2021): 6637. http://dx.doi.org/10.3390/molecules26216637.
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According to the great impact of additive technology on the development of modern industry, a lot of research is being done to obtain 3D printed parts with better properties. This research is extremely important because there are no scientific papers in the field of post dyeing of acrylonitrile/butadiene/styrene (ABS) 3D printed parts. The experiment was carried out using disperse dyes on ABS specimens. The obtained coloration of the specimens was in the primary colors (yellow, red, and blue) in the specified dyestuff concentration range and was evaluated using an objective CIELab system. Based on the obtained color parameters, remission values and Kubelka-Munk coefficient, dye mixtures and an ombre effect were performed to obtain patterns in the desired hues. Abrasion resistance of disperse dyed specimens was tested using different abrasive materials over a wide range of fineness to simulate different indoor and outdoor soils and was compared to abrasion resistance of specimens produced from the industrially dyed wire with the master batch. The results show that 3D printed ABS products can be produced in one or more desired shades with satisfactory abrasion resistance. This undoubtedly represents the added value of 3D printed ABS parts and extends their application to the field of creative industries and design, specifically footwear design.
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Guo, Fusheng, Yihui Gao, Xiaobao Li, and Xiaoguang Lei. "Natural Product 2-Oxokolavenol Is a Novel FXR Agonist." Molecules 27, no. 24 (December 16, 2022): 8968. http://dx.doi.org/10.3390/molecules27248968.
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Acetaminophen (APAP) toxicity is a common cause of hepatic failure, and the development of effective therapy is still urgently needed. Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been identified as a master gene for regulating enterohepatic metabolic homeostasis and has proven to be a promising drug target for various liver diseases. Through high-throughput chemical screening, the natural product 2-oxokolavenol was identified as a novel and selective FXR agonist. Further investigations revealed that 2-oxokolavenol exerts therapeutic efficacy against APAP-induced hepatocyte damage in an FXR-dependent manner. Mechanistically, 2-oxokolavenol forms two hydrogen bonds with M265 and Y369 of human FXR to compatibly fit into the ligand binding pocket of FXR, which potently leads to the recruitment of multiple co-regulators and selectively induces the transcriptional activity of FXR. Our findings thus not only reveal the direct target of natural product 2-oxokolavenol, but also provide a promising hit compound for the design of new FXR modulators with potential clinical value.
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Kang, Mingyu, Hyeon Ji Kim, Tae-Jun Kim, Jin-Seok Byun, Jae-Ho Lee, Deok Heon Lee, Wanil Kim, and Do-Yeon Kim. "Multiple Functions of Fubp1 in Cell Cycle Progression and Cell Survival." Cells 9, no. 6 (May 28, 2020): 1347. http://dx.doi.org/10.3390/cells9061347.
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The discovery of novel and critical genes implicated in malignant development is a topic of high interest in cancer research. Intriguingly, a group of genes named “double-agent” genes were reported to have both oncogenic and tumor-suppressive functions. To date, less than 100 “double-agent” genes have been documented. Fubp1 is a master transcriptional regulator of a subset of genes by interacting with a far upstream element (FUSE). Mounting evidence has collectively demonstrated both the oncogenic and tumor suppressive roles of Fubp1 and the debate regarding its roles in tumorigenesis has been around for several years. Therefore, the detailed molecular mechanisms of Fubp1 need to be determined in each context. In the present study, we showed that the Fubp1 protein level was enriched in the S phase and we identified that Fubp1 deficiency altered cell cycle progression, especially in the S phase, by downregulating the mRNA expression levels of Ccna genes encoding cyclin A. Although this Fubp1-cyclin A axis appears to exist in several types of tumors, Fubp1 showed heterogeneous expression patterns among various cancer tissues, suggesting it exhibits multiple and complicated functions in cancer development. In addition, we showed that Fubp1 deficiency confers survival advantages to cells against metabolic stress and anti-cancer drugs, suggesting that Fubp1 may play both positive and negative roles in malignant development.
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Isakova-Sivak, Irina, Victoria Matyushenko, Tatiana Kotomina, Irina Kiseleva, Elena Krutikova, Svetlana Donina, Andrey Rekstin, et al. "Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge." Vaccines 7, no. 3 (July 8, 2019): 61. http://dx.doi.org/10.3390/vaccines7030061.
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The development of universal influenza vaccines has been a priority for more than 20 years. We conducted a preclinical study in ferrets of two sets of live attenuated influenza vaccines (LAIVs) expressing chimeric hemagglutinin (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but had antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. The viral nucleoproteins (NPs) in the two sets of universal LAIV candidates were from different sources: one LAIV set contained NP from A/Leningrad/17 master donor virus (MDV), while in the other set this gene was from wild-type (WT) H1N1pdm09 virus, in order to better match the CD8 T-cell epitopes of currently circulating influenza A viruses. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Naïve ferrets were sequentially immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). All vaccination regimens were safe, producing no significant increase in body temperature or weight loss, in comparison with the placebo group. The two groups of cHA-based vaccines induced a broadly reactive HA stalk-directed antibody, while classical LAIVs did not. A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) > cHA LAIVs (NP-MDV) > LAIVs (NP-MDV). This ferret study showed that prototype universal cHA-based LAIVs are highly promising candidates for further clinical development.
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Thiel, Gerald, Tobias M. Backes, Lisbeth A. Guethlein, and Oliver G. Rössler. "Critical Protein–Protein Interactions Determine the Biological Activity of Elk-1, a Master Regulator of Stimulus-Induced Gene Transcription." Molecules 26, no. 20 (October 11, 2021): 6125. http://dx.doi.org/10.3390/molecules26206125.
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Elk-1 is a transcription factor that binds together with a dimer of the serum response factor (SRF) to the serum-response element (SRE), a genetic element that connects cellular stimulation with gene transcription. Elk-1 plays an important role in the regulation of cellular proliferation and apoptosis, thymocyte development, glucose homeostasis and brain function. The biological function of Elk-1 relies essentially on the interaction with other proteins. Elk-1 binds to SRF and generates a functional ternary complex that is required to activate SRE-mediated gene transcription. Elk-1 is kept in an inactive state under basal conditions via binding of a SUMO-histone deacetylase complex. Phosphorylation by extracellular signal-regulated protein kinase, c-Jun N-terminal protein kinase or p38 upregulates the transcriptional activity of Elk-1, mediated by binding to the mediator of RNA polymerase II transcription (Mediator) and the transcriptional coactivator p300. Strong and extended phosphorylation of Elk-1 attenuates Mediator and p300 recruitment and allows the binding of the mSin3A-histone deacetylase corepressor complex. The subsequent dephosphorylation of Elk-1, catalyzed by the protein phosphatase calcineurin, facilitates the re-SUMOylation of Elk-1, transforming Elk-1 back to a transcriptionally inactive state. Thus, numerous protein–protein interactions control the activation cycle of Elk-1 and are essential for its biological function.
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Wadhokar, Om C. "DEVELOPMENTAL DELAY IN 14 MONTH OLD BOY WITH GRADE I MALNUTRITION." Journal of Medical pharmaceutical and allied sciences 10, no. 4 (October 15, 2021): 3377–79. http://dx.doi.org/10.22270/jmpas.v10i4.1272.
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When a child does not meet his or her developmental milestones within the predicted time or age, this is referred to as developmental delay. Developmental milestones are activities that certain children master or acquire at specific ages. Head balance, rolling, crawling, driving, and talking are a few examples. The mechanism of growth and the completion of such developmental milestones are referred to as child development. The patient was a 14 months old male child came to the hospital with complaint of inability to sit also he is unable to hold anything in his hand. As narrated by the mother the child was born to G2P1L1A1 mother at 9 months 5 days of gestation. The child has not yet attained gross motor milestone such as rolling over and no sit with support. The child attained immature pincer grasp at 12 months of age and has not attained mature pincer grasp. Social smile was attained at 6 months, stranger anxiety at 12 months and the child has not attained bye-bye. The child was alert to sounds by the age of 9 months .babbles at 10 months and says mama-dada at 12 months. The child is immunized till age. The marriage of the parents was non-consanguineous marriage. The child was born with a weight of 2.5 kg the mother had LSCS and breech delivery. The child did not cry immediately after birth. The child has history of fever after 3 months of delivery. The child is also interpreted as grade 1 mild malnutritious (71-80) %. Developmental delay and grade 1 mild malnutrition. The above study shows that Neck facilitation exercises in prone lying, Ice technique and proper brush technique for neck facilitation improves neck holding. Rolling facilitation in side lying position and proper handling positions helps in attaining milestones such as Rolling over. Facilitation of extension tone with vestibular rehabilitation helps to facilitate extensors. Family plays an important role in the management of such cases all the exercises should be properly explained to them for more improvement. Supporting the child while sitting, for example, might help him or her develop weight shifting, rotation, coordination, and balance.
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Bogin, Vladimir. "Master protocols: New directions in drug discovery." Contemporary Clinical Trials Communications 18 (June 2020): 100568. http://dx.doi.org/10.1016/j.conctc.2020.100568.
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Glew, Robert H. "Drug discovery and development, Vol. 1: Drug discovery." Biochemistry and Molecular Biology Education 35, no. 2 (2007): 162. http://dx.doi.org/10.1002/bmb.38.
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Vázquez-Cano, Esteban, and Blas Campos Barrionuevo. "Difficulties and challenges for admission to the position of schools inspector in Spain and early career development." IJERI: International Journal of Educational Research and Innovation, no. 17 (June 23, 2022): 84–100. http://dx.doi.org/10.46661/ijeri.6440.
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This article presents research that analyzed the most significant needs, difficulties and problems for admission into Spain’s school inspectorates, the expectations of new inspectors and the challenges they face in their assessment of different school settings in the Spanish educational system. Firstly, the research addressed the central questions of school inspection and supervision in the European Union, then a methodology was applied based on virtual ethnography and the reticular-categorical approach to network analysis, with matrix representations and social graphs devised using UCINET and yED Graph Editor visor. This methodological approach was used to analyze the opinions of 140 students between 2017 and 2019 enrolled on the only Masters course in Spain dedicated to schools inspection and supervision, delivered by UNED (Spain’s National Distance Education University). Their open responses to a questionnaire, and course forum interaction, were analyzed from the Social Network Analysis perspective. The results show that the main difficulties, challenges and needs coalesced around four central nodes: the politicization of tribunals and the entrance exam format, the lack of training courses for potential inspectors, the absence of a national study pathway for potential inspectors as an entry requirement, and the need for training in supervision techniques to perform their functions as inspectors.
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Nakhli, Habiba. "Developing Students’ Translation Competence: The Role of Tasks and Teaching Activities." International Journal of Linguistics, Literature and Translation 4, no. 11 (November 29, 2021): 119–28. http://dx.doi.org/10.32996/ijllt.2021.4.11.13.
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The aim of this study is to identify the teaching procedures generally conducted by translation teachers, and investigate their impact on the development of students’ translation competence (TC). The study emphasizes the importance of substituting the traditional “read and translate” method for a student-centered teaching approach that relies on hands-on tasks and engaging activities. These teaching procedures include intra- and extra-mural activities and tasks addressing different sub-competencies and skills and aiming at developing students' general TC. In order to study the impact of these teaching procedures on TC, we implemented a descriptive method that draws upon self-report data and observation of translation teachers and students in a classroom setting. We observed a group of MA translation students in the Faculty of Letters and Humanities in Tetouan and King Fahd School of Translation in Tangiers- Abdelmalek Essaadi University, Morocco. The observation reports and teachers questionnaires provided significant data about classroom practices, while the survey of students’ levels of TC revealed that the respondents’ mastery level of TC ranges from low to high across the different sub-competences. We subsequently compared students’ mastery levels to the general patterns governing the teachers’ teaching procedures, and the findings showed a clear correlation between the two. Accordingly, the type and focus of the tasks and activities performed by students have a direct impact on their TC development.
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Hashmi, Tayba Saleha, Aqsa Tazarrat, Sadia Muzafar, Sidra Ashfaq, Iqra Anwar, and Nafeesa Kiran. "Association of C(-1019)G with Risk of Development of Major Depression in Diabetics with Respect to Various Pakistani Ethnicities." Pakistan Journal of Medical and Health Sciences 16, no. 7 (July 30, 2022): 845–47. http://dx.doi.org/10.53350/pjmhs22167845.
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Objective: To determine whether the ethnicity is associated with the risk of development of Major Depressive Disorder (MDD) in adult diabetic population with respect to the genetic association with single nucleotide polymorphism (SNP) C(-1019)G. Material and Methods: A total of 400 subjects were included in the study, out of which 200 were cases and 200 were age, gender and ethnicity matched healthy controls. Out of 200 cases , 100 cases had diabetes mellitus (DM) only and 100 cases had DM with MDD. Both males and females were included in the study having ages 25 years and above. Cases of both type I and type II DM were included in the study. Blood samples were collected and DNA was extracted by Chelax method. Real-time PCR was carried out to determine respective allelic frequencies of C(-1019)G genotype using TaqMan SNP genotyping assays and master mix. Results: According to our results no significant association was found between C(-1019)G genotype and risk of development of MDD in Pakistani diabetic population with respect to Ethnicity but diseased genotype was found more in Pathan population. Conclusion: There is no significant association of SNP C(-1019)G of 5-Hydroxytryptamine 1A receptor gene with MDD in Pakistani diabetics with respect to ethnicity. Keywords: Diabetes mellitus, major depressive disorder, 5-hydroxytryptamine 1A receptor gene, single nucleotide polymorphism, polymerase chain reaction.
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Mahendra, Dr Little. "Development in Drug Discovery." International Journal of Current Research and Review 12, no. 24 (2020): 01. http://dx.doi.org/10.31782/ijcrr.2020.122441.
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HILEMAN, BETTE. "DRUG DISCOVERY AND DEVELOPMENT." Chemical & Engineering News 84, no. 47 (November 20, 2006): 97–111. http://dx.doi.org/10.1021/cen-v084n047.p097.
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Zainudin, Zainudin, Firri Ilaalloh, Didik Hermanto, Rica Wijayanti, Moh Affaf, Mety Liesdiany, Ria Faulina, and Abdus Salam. "Pelatihan Penggunaan Aplikasi Administrasi Kependudukan Berbasis Website Bagi Perangkat Desa Tlangoh." Sasambo: Jurnal Abdimas (Journal of Community Service) 4, no. 4 (November 1, 2022): 611–17. http://dx.doi.org/10.36312/sasambo.v4i4.860.
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Permasalahan yang dihadapi oleh Pemerintah Desa Tlangoh adalah pengelolaan administrasi kependudukan masih manual dengan menggunakan buku induk kependudukan desa dan kesadaran masyarakat Desa Tlangoh bahwa tertib administrasi masih rendah tidak melaporkan bila ada perubahan dalam data penduduk. Oleh karena itu, mengingat jumlah penduduk yang terus berubah dan harus selalu diperbaharui, maka diperlukan pemanfaatan teknologi informasi dalam pengelolaan administrasi kependudukan. Potensi pemanfaatan teknologi informasi meliputi keterampilan perangkat desa terkait teknologi informasi, dan sesuai RKPDes 2022 yaitu percepatan pencapaian SDGs desa dan tuntutan desa digital. Solusi yang direncanakan untuk mengatasi permasalahan tersebut antara lain substitusi teknologi, pelatihan dan pendampingan. Tujuan dari kegiatan ini adalah menghasilkan aplikasi sistem administrasi kependudukan sebagai sistem database kependudukan di Desa Tlangoh. Keberhasilan pengabdian tersebut adalah perubahan pola kerja administrasi kependudukan dari manual menggunakan Buku Induk Kependudukan menjadi menggunakan aplikasi sistem administrasi kependudukan berbasis website. Hal ini memudahkan desa Tlangoh dalam mengelola data kependudukan di desa Tlangoh. Aplikasi sistem administrasi kependudukan dapat melakukan update, tambah dan hapus data kependudukan, sehingga data kependudukan Desa Tlangoh valid dan terupdate. Ekspor database aplikasi sistem administrasi kependudukan dapat digunakan untuk database Sustainable Development Goals (SDGs) desa. Penerapan sistem administrasi kependudukan mempercepat pendataan SGD desa yang merupakan program desa prioritas. Training on Using the Website-Based Population Administration Application for Tlangoh Village Officials The problem faced by the Tlangoh Village Government is that the management of population administration is still manual, using the village population master book and the awareness of the people of Tlangoh Village that administrative order is still low, not reporting when there is a change in population data. Therefore, considering the population changes and must be updated, it is necessary to utilize information technology in population administration management. The potential for utilizing information technology includes the skills of village officials regarding information technology, and in accordance with the 2022 RKPDes, namely the acceleration of achieving village SDGs and the demands of digital villages. The solutions planned to solve these problems include technology substitution, training and mentoring. The purpose of this activity is to produce a population administration system application as a population database system in Tlangoh Village. The success of the service is a change in the population administration work pattern from manually using the Population Parent Book to using a website-based population administration system application. This makes it easier for Tlangoh village to manage population data in Tlangoh village. The population administration system application can update, add and delete population data, so that the population data of Tlangoh Village is valid and updated. The population administration system application database export can be used for the village's Sustainable Development Goals (SDGs) database. The application of the population administration system accelerates the data collection of village SGDs, which is a priority village program.
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Frasinyuk, Mykhaylo, Dimple Chhabria, Victor Kartsev, Haritha Dilip, Samvel N. Sirakanyan, Sivapriya Kirubakaran, Anthi Petrou, Athina Geronikaki, and Domenico Spinelli. "Benzothiazole and Chromone Derivatives as Potential ATR Kinase Inhibitors and Anticancer Agents." Molecules 27, no. 14 (July 20, 2022): 4637. http://dx.doi.org/10.3390/molecules27144637.
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Despite extensive studies and the great variety of existing anticancer agents, cancer treatment remains an aggravating and challenging problem. Therefore, the development of novel anticancer drugs with a better therapeutic profile and fewer side effects to combat this persistent disease is still necessary. In this study, we report a novel series of benzothiazole and chromone derivatives that were synthesized and evaluated for their anticancer activity as an inhibitor of ATR kinase, a master regulator of the DDR pathway. The cell viability of a set of 25 compounds was performed using MTT assay in HCT116 and HeLa cell lines, involving 72 h incubation of the compounds at a final concentration of 10 µM. Cells incubated with compounds 2c, 7h and 7l were found to show viability ≤50%, and were taken forward for dose–response studies. Among the tested compounds, three of them (2c, 7h and 7l) showed higher potency, with compound 7l exhibiting the best IC50 values in both the cell lines. Compounds 2c and 7l were found to be equally cytotoxic towards both the cell lines, namely, HCT116 and HeLa, while compound 7h showed better cytotoxicity towards HeLa cell line. For these three compounds, an immunoblot assay was carried out in order to analyze the inhibition of phosphorylation of Chk1 at Ser 317 in HeLa and HCT116 cells. Compound 7h showed inhibition of pChk1 at Ser 317 in HeLa cells at a concentration of 3.995 µM. Further analysis for Chk1 and pChk1 expression was carried out in Hela cells by treatment against all the three compounds at a range of concentrations of 2, 5 and 10 µM, wherein compound 7h showed Chk1 inhibition at 2 and 5 µM, while pChk1 expression was observed for compound 7l at a concentration of 5 µM. To support the results, the binding interactions of the compounds with the ATR kinase domain was studied through molecular docking, wherein compounds 2c, 7h and 7l showed binding interactions similar to those of Torin2, a known mTOR/ATR inhibitor. Further studies on this set of molecules is in progress for their specificity towards the ATR pathway.
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Hong, Vu, Ravi Krishna Babu, Cecile Blaustein, Sophia Nguyen, Venkateshwar Rao, Will Savage, Brian MacDonald, Maria G. Beconi, and Srikanth Venkatraman. "DISC-a, the First in a Novel Class of Potent and Selective Matriptase-2 Inhibitors for the Treatment of Hematologic Disorders Characterized By Low Hepcidin." Blood 136, Supplement 1 (November 5, 2020): 41–42. http://dx.doi.org/10.1182/blood-2020-138509.
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Hepcidin is known as the master regulator of systemic iron homeostasis with reduction in synthesis leading to the development of iron overload. Hepcidin gene expression is negatively modulated by matriptase-2 (MT-2), a liver-specific type II transmembrane serine protease. MT-2 cleaves hemojuvelin (HJV), leading to the extracellular release of soluble HJV fragments and suppression of hepcidin expression. Loss-of-function of MT-2 leads to increased hepcidin expression, as has been established by human genetics (Finberg et al., 2008) and genetic mouse models (Du et al., 2008). Therefore, inhibition of MT-2 represents a potential therapeutic strategy for diseases caused by inappropriately low hepcidin leading to iron overload or where therapeutic iron restriction may be used to control excessive erythrocytosis. Here we describe the characteristics of DISC-A, a potent (low nM Ki) small molecule MT-2 inhibitor for treatment of low hepcidin disorders, with a favorable pharmacokinetics profile in rats (Clp 6.4 ml/min/kg, and t ½ 4.6 hr) and monkeys (Clp 8.1 ml/min/kg, and t ½ 2.8 hr) and drug-like properties. DISC-A inhibits proteolytic activity of MT-2 expressed on the surface of transfected HEK293 cells and prevents shedding of MT-2 from the membrane (autocleavage). In addition, in MT-2 and HJV co-transfected HEK293A cells, DISC-A shows a dose dependent inhibition of HJV cleavage. The efficacy of DISC-A was evaluated in a rat model of low hepcidin. In this model, when Sprague-Dawley rats who are fed a standard iron diet (45 ppm) reach 8 - 9 weeks of age, they are administered erythropoietin (EPO) at 30 IU/animal/day for 4-consecutive days, before dosing with DISC-A. Under the conditions of the model, the increased erythropoiesis leads to increased iron utilization and consequently suppressed hepcidin levels. We determine hepcidin changes by measuring the changes in the expression of liver HAMP (the gene that encodes hepcidin) mRNA expression. Circulating soluble HJV is assayed as a direct measure of MT-2 activity. In this model, a single subcutaneous administration of DISC-A at 20 mg/kg resulted in a 50% reduction in soluble HJV, 14-fold increase in liver HAMP expression and >50% reduction in serum iron and transferrin saturation (TSAT) at 2, 4, 6, and 8 hours. The pharmacokinetics/pharmacodynamics response was robust. In summary, we have identified DISC-A, a novel, potent inhibitor of MT-2. We have demonstrated that DISC-A inhibits MT-2 proteolytic activity, prevents cleavage of HJV, and modulates hepcidin gene expression and iron homeostasis in vitro and in vivo. The favorable pharmacokinetics suggest compounds from these chemical series have the potential for clinical therapeutic benefit. Disclosures Hong: Disc Medicine: Current Employment, Current equity holder in private company. Babu:Aurigene Discovery Technologies: Current Employment. Blaustein:Disc Medicine: Current Employment, Current equity holder in private company. Nguyen:Disc Medicine: Current Employment, Current equity holder in private company. Rao:Aurigene Discovery Technologies: Current Employment. Savage:Disc Medicine: Current Employment, Current equity holder in private company. MacDonald:Disc Medicine: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Beconi:Disc Medicine: Current Employment, Current equity holder in private company. Venkatraman:Disc Medicine: Current Employment, Current equity holder in private company.
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Lloyd, Andrew. "Modifying the drug discovery/drug development paradigm." Drug Discovery Today 2, no. 10 (October 1997): 397–98. http://dx.doi.org/10.1016/s1359-6446(97)01096-9.
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Zhang, Zhoupeng, and Wei Tang. "Drug metabolism in drug discovery and development." Acta Pharmaceutica Sinica B 8, no. 5 (September 2018): 721–32. http://dx.doi.org/10.1016/j.apsb.2018.04.003.
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Kanaujiya, Jitendra K., Elizabeth G. Lingenheld, William C. Skarnes, and Hideyuki Oguro. "p53 Is a Crucial Regulator of Hemogenic Endothelial Cell Differentiation from Human Induced Pluripotent Stem Cells." Blood 138, Supplement 1 (November 5, 2021): 1085. http://dx.doi.org/10.1182/blood-2021-154243.
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Abstract De novo generation of hematopoietic stem cells (HSCs) from human induced pluripotent stem cells (hiPSCs) could provide a virtually unlimited supply of autologous HSCs for clinical transplantation, and offer various approaches that enable gene therapy, drug discovery, disease modeling, and in vitro modeling of human hematopoietic development. However, the derivation of long-term self-renewing HSCs from hiPSCs in culture remains elusive. The tumor suppressor protein p53 plays important roles in normal and malignant hematopoiesis, and Trp53-deficient mice exhibit increased number of HSCs. Although activation of p53 is known to promote differentiation of hPSCs and hPSCs recurrently acquire TP53 dominant negative mutations, its role in hematopoietic differentiation of hiPSCs has not been explored. To differentiate hiPSCs into hematopoietic stem and progenitor cells (HSPCs), we used embryoid body (EB) formation method to first differentiate hiPSCs into hemogenic endothelial (HE) cells that express the CD34 highCD144 +CD73 -CD184 -CD43 -CD235a - cell-surface markers. HE cells were then transferred onto a Matrigel-coated plate to undergo endothelial-to-hematopoietic transition (EHT) to generate HSPCs that express the CD34 midCD45 mid cell-surface markers. Developed HSPCs were functionally evaluated by colony forming assay. We observed that the expression of CDKN1A, a p53 target gene, was upregulated in hiPSC-derived EBs and HSPCs over the course of differentiation. To investigate the role of p53 in the generation of HSPCs from hiPSCs, we genetically deleted TP53 in hiPSCs followed by hematopoietic differentiation. While TP53 deletion increased the growth of EBs, it resulted in severe impairment of differentiation into HE cells and overall production of HSPCs that can form colonies. During HE differentiation from hiPSCs, TP53-deficient EBs showed significant reduction of endothelial-lineage gene expression, such as ETV2, CDH5, and PECAM1, as well as expression of RUNX1, a master transcription factor required for HE specification. These results indicate the indispensable role of p53 in HE differentiation from hiPSCs. We then examined the effect of p53 activation on HE differentiation from hiPSCs by pharmacological activation of p53 in hiPSC-derived cells. Transient activation of p53 by Nutlin-3, a small molecule that inhibits the p53-HDM2 interaction and protects p53 from proteasomal degradation, only during HE differentiation but not during EHT significantly promoted HSPC generation as compared to the vehicle treated control. Our findings shed light on the importance of selecting hiPSC lines that retain normal p53 activity for HE differentiation, and provide an approach to promote hematopoietic differentiation of hiPSCs by transiently activating p53 during HE differentiation. Disclosures Kanaujiya: Synthego: Other: Scientific Advisory; eGenesis: Other: Scientific Advisory.
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Workman, Paul. "Abstract ND08: NXP800: A first-in-class orally active, small-molecule HSF1 pathway inhibitor." Cancer Research 82, no. 12_Supplement (June 15, 2022): ND08. http://dx.doi.org/10.1158/1538-7445.am2022-nd08.
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Abstract We report the discovery of NXP800 — a first-in-class orally active HSF1 pathway inhibitor identified in our academic laboratory at the Institute of Cancer Research, London — and its progression into Phase I clinical trials in collaboration with our partner Nuvectis Pharma. HSF1 (Heat Shock Factor 1) is an ancient stress-inducible transcription factor that plays a key role in the transcriptional activation of the eukaryotic heat shock response. This leads to expression of many heat shock proteins, including molecular chaperones, and through this HSF1 acts as a master transcriptional regulator of proteostasis. Importantly, HSF1 is hijacked by cancer cells to activate a set of genes that overlaps with, but is not identical to, the classical heat shock response. The HSF1 pathway has been shown to play a key role in oncogenesis and the hallmark features of malignancy and is important in the initiation and progression of many experimental cancer models. Importantly, while HSF1 has been demonstrated to be important in mouse models of oncogenesis, knockout of the homologue of HSF1 has only modest effects in mice and flies under non-stressed laboratory conditions – supporting the potential for a therapeutic window. In addition, gene amplification, expression and activation of HSF1 has been shown to predict clinical outcome in many human cancers. Despite strong scientific rationale and pre-clinical validation, pharmaceutical exploitation has been limited because analysis of the available molecular structures of HSF1 shows it to be very difficult to drug. Because of this, we set out to discover inhibitors of the HSF1 pathway using an initial phenotypic screen that reports on the activation of the HSF1-regulated gene HSP72. This identified the bisamide series that was followed up by a detailed understanding of structure-activity relationships and medicinal chemistry optimization, particularly to improve pharmaceutical properties, leading to the selection of NXP800 (CCT361814) as the development candidate. NXP800 has good pharmacokinetic properties in mice, including oral bioavailability; also, pharmacodynamic studies show modulation of biomarkers of the HSF1 pathway and stress response in human tumour xenograft models. NXP800 exhibits striking therapeutic activity in xenografts of human ovarian clear cell ovarian cancer (OCCC) and endometrioid ovarian cancer, two serious conditions of high unmet medical need with limited treatment options – including prolonged tumour growth inhibition and regression at doses that show good toleration. The efficacy and tolerability data indicate a clear therapeutic window, supported by selectivity and safety profiting in pharmacology and kinome panels. In addition, we identified deficiency in ARID1A, a component of the SWI/SNF chromatin remodelling complex, as indicative of greater therapeutic responsiveness. This was confirmed through broader evaluation in human cancer cell line panels that also indicates therapeutic potential for NXP800 in additional cancer types. Studies to support mechanism of action and identify patient selection biomarkers will be described. A Phase 1 trial of NXP800 is now open, incorporating validated predictive, pharmacokinetic and pharmacodynamic biomarkers that provide a robust Pharmacological Audit Trail and support the prediction of dose-to-human. Citation Format: Paul Workman. NXP800: A first-in-class orally active, small-molecule HSF1 pathway inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND08.
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Yamamoto, Tsuyoshi, Moeka Nakatani, Keisuke Narukawa, and Satoshi Obika. "Antisense drug discovery and development." Future Medicinal Chemistry 3, no. 3 (March 2011): 339–65. http://dx.doi.org/10.4155/fmc.11.2.
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Maubach, Karen. "Psychiatric Drug Discovery and Development." Expert Opinion on Investigational Drugs 12, no. 9 (September 2003): 1571–75. http://dx.doi.org/10.1517/13543784.12.9.1571.
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Hurko, Orest. "Future drug discovery and development." Molecular Genetics and Metabolism 100 (January 2010): S92—S96. http://dx.doi.org/10.1016/j.ymgme.2010.01.010.
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Bates, Susan E., Laleh Amiri-Kordestani, and Giuseppe Giaccone. "Drug Development: Portals of Discovery." Clinical Cancer Research 18, no. 1 (January 1, 2012): 23–32. http://dx.doi.org/10.1158/1078-0432.ccr-11-1001.
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Mizuno, Naomi, and Takuro Niwa. "Drug transporter studies in drug discovery and development." Folia Pharmacologica Japonica 125, no. 4 (2005): 200–206. http://dx.doi.org/10.1254/fpj.125.200.
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Driscoll, Jennifer, Ron Delmendo, Roeland Papen, and David Sawutz. "MultiPROBE nL Complements Drug Discovery Assay Miniaturization." Journal of Biomolecular Screening 3, no. 3 (April 1998): 237–39. http://dx.doi.org/10.1177/108705719800300311.
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The Packard MultiPROBE® nL is designed to enable the MultiPROBE Automated Liquid Handling System to aspirate and dispense nanoliter volumes. Several features add confidence to small volume transfers. A preview of nanoliter dispensing can be seen on a video camera monitor. In addition to the standard wash station, syringe and ultrasonic flushes can be run at the start of a program to prevent dirt or air obstructions. The MultiPROBE nL can transfer ionic, nonionic, and solutions containing organic solvents such as DMSO directly from master to assay plates and into high-density plate arrays. Additionally, the MultiPROBE nL increases the efficiency of generating dose response curves for secondary screening by eliminating a dilution step. IC50 values obtained after compound preparation with the instrument are consistent with those values previously determined using an MultiPROBE 208.
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ODA, Yoshiya. "Biomarkers for Drug Discovery and Development." Journal of the Mass Spectrometry Society of Japan 64, no. 2 (2016): 55–59. http://dx.doi.org/10.5702/massspec.s16-12.
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Liu, Qiang, and Hong-Gang Wang. "Anti-cancer drug discovery and development." Communicative & Integrative Biology 5, no. 6 (November 2012): 557–65. http://dx.doi.org/10.4161/cib.21554.
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Pandey, Saurabh, Preeti Pandey, Gaurav Tiwari, and Ruchi Tiwari. "Bioanalysis in drug discovery and development." Pharmaceutical Methods 1, no. 1 (2010): 14. http://dx.doi.org/10.4103/2229-4708.72223.
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Cheung, Eugene, Yan Xia, Marc A. Caporini, and Jamie L. Gilmore. "Tools shaping drug discovery and development." Biophysics Reviews 3, no. 3 (September 2022): 031301. http://dx.doi.org/10.1063/5.0087583.
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Spectroscopic, scattering, and imaging methods play an important role in advancing the study of pharmaceutical and biopharmaceutical therapies. The tools more familiar to scientists within industry and beyond, such as nuclear magnetic resonance and fluorescence spectroscopy, serve two functions: as simple high-throughput techniques for identification and purity analysis, and as potential tools for measuring dynamics and structures of complex biological systems, from proteins and nucleic acids to membranes and nanoparticle delivery systems. With the expansion of commercial small-angle x-ray scattering instruments into the laboratory setting and the accessibility of industrial researchers to small-angle neutron scattering facilities, scattering methods are now used more frequently in the industrial research setting, and probe-less time-resolved small-angle scattering experiments are now able to be conducted to truly probe the mechanism of reactions and the location of individual components in complex model or biological systems. The availability of atomic force microscopes in the past several decades enables measurements that are, in some ways, complementary to the spectroscopic techniques, and wholly orthogonal in others, such as those related to nanomechanics. As therapies have advanced from small molecules to protein biologics and now messenger RNA vaccines, the depth of biophysical knowledge must continue to serve in drug discovery and development to ensure quality of the drug, and the characterization toolbox must be opened up to adapt traditional spectroscopic methods and adopt new techniques for unraveling the complexities of the new modalities. The overview of the biophysical methods in this review is meant to showcase the uses of multiple techniques for different modalities and present recent applications for tackling particularly challenging situations in drug development that can be solved with the aid of fluorescence spectroscopy, nuclear magnetic resonance spectroscopy, atomic force microscopy, and small-angle scattering.