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O’Neil, Meghan M. „Drug Screenings in Practice“. Federal Sentencing Reporter 36, Nr. 4 (01.04.2024): 212–17. http://dx.doi.org/10.1525/fsr.2024.36.4.212.
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This research article will contextualize drug testing and conditions of supervision by analyzing eight original in-depth interview and survey narratives provided by persons are in treatment for substance use disorder. We identify a gap in the literature surrounding drug testing as part of community supervision. Specifically, the practice of drug testing from the perspective of the person ordered to test is not well documented. We consider how these experiences diverge from the intention of drug testing by supervising agencies as described in the prior scholarship. This cleavage between the expectations, experiences, and understanding of persons being tested relative to those of supervision agencies presents an avenue for the government to improve community relations, and specifically, improve trust among formerly incarcerated persons towards the supervision process, thereby increasing its legitimacy while enacting procedural justice. The persons under supervision describe broad criminal justice experiences and histories with illicit substances that resulted in drug screenings. The opinions from persons who use drugs towards drug testing and related conditions also vary and suggest evidence-based practices involving drug screening could be helpful to improve compliance with conditions and increase trust towards supervision agencies and courts. Opinions towards obligatory drug screens ranged from fear to one of gratitude. A common theme emerged: when drug tests were viewed as avoidable, respondents described changing their behavior to avoid testing—such as avoiding employers who may test for drug use; when screenings were understood as obligatory, like in the context of court ordered community-based addiction treatment, some respondents identified the broader context of the testing as helpful to their abstinence from drug use. Respondents described drug screenings as impacting their employment, economic well-being, and freedom—in particular, failed drug screens on community supervision, including drug court and other specialized supervision caseloads, could result in punitive action including incarceration and other adverse outcomes like job loss. The risk acknowledgement, however, of consequences of a failed drug screen, had not up to the point of our interview, resulted in long-term abstinence from substances for any of the respondents under community-based supervision.
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Liang, Qiying, Peng Ma, Qi Zhang, Youjie Yin, Ping Wang, Saifei Wang, Yao Zhang, Ruolei Han und Hansong Deng. „A gum Arabic assisted sustainable drug delivery system for adult Drosophila“. Biology Open 9, Nr. 6 (02.06.2020): bio052241. http://dx.doi.org/10.1242/bio.052241.
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ABSTRACTLarge-scale compound screening in adult flies is hampered by the lack of continuous drug delivery systems and poor solubility of numerous compounds. Here we found that gum Arabic (Acacia/Senegal gum), a widely used stabilizer, can also emulsify lipophilic compounds and profoundly increase their accessibility to target tissues in Drosophila and mice. We further developed a gum Arabic-based drug delivery system, wherein the drug was ground into gum Arabic and emulsified in liquid food fed to flies by siphoning through a U-shape glass capillary. This system did not affect food intake nor cell viability. Since drugs were continuously delivered by siphoning, minimal compound waste and less frequent food changes make this system ideal for large-scale long-term screenings. In our pilot screening for antitumor drugs in the NCI DTP library, we used a Drosophila model of colorectal cancer and identified two drugs that are especially hydrophobic and were not identified in previous screenings. Our data demonstrated that gum Arabic facilitates drug delivery in animal models and the system is suitable for long-term high-throughput drug screening in Drosophila. This system would accelerate drug discovery for chronic and cognitive conditions.
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Popova, Anna A., Claire Depew, Katya Manuella Permana, Alexander Trubitsyn, Ravindra Peravali, Jorge Ángel González Ordiano, Markus Reischl und Pavel A. Levkin. „Evaluation of the Droplet-Microarray Platform for High-Throughput Screening of Suspension Cells“. SLAS TECHNOLOGY: Translating Life Sciences Innovation 22, Nr. 2 (15.11.2016): 163–75. http://dx.doi.org/10.1177/2211068216677204.
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Phenotypic cell-based high-throughput screenings play a central role in drug discovery and toxicology. The main tendency in cell screenings is the increase of the throughput and decrease of reaction volume in order to accelerate the experiments, reduce the costs, and enable screenings of rare cells. Conventionally, cell-based assays are performed in microtiter plates, which exist in 96- to 1536-wells formats and cannot be further miniaturized. In addition, performing screenings of suspension cells is associated with risk of losing cell content during the staining procedures and incompatibility with high-content microscopy. Here, we evaluate the Droplet-Microarray screening platform for culturing, screening, and imaging of suspension cells. We demonstrate pipetting-free cell seeding and proliferation of cells in individual droplets of 3–80 nL in volume. We developed a methodology to perform parallel treatment, staining, and fixation of suspension cells in individual droplets. Automated imaging of live suspension cells directly in the droplets combined with algorithms for pattern recognition for image analysis is demonstrated. We evaluated the developed methodology by performing a dose–response study with antineoplastic drugs. We believe that the DMA screening platform carries great potential to be adopted for broad spectrum of screenings of suspension cells.
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Vacchina, Paola, und Miguel A. Morales. „In VitroScreening Test Using Leishmania Promastigotes Stably Expressing mCherry Protein“. Antimicrobial Agents and Chemotherapy 58, Nr. 3 (06.01.2014): 1825–28. http://dx.doi.org/10.1128/aac.02224-13.
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ABSTRACTTransgenicLeishmania majorandLeishmania donovaniaxenic promastigotes constitutively expressing mCherry were used forin vitroantileishmanial drug screening. This method requires minimal sample manipulation and can be easily adapted to automatic drug tests, allowing primary high-throughput screenings without the need for expensive and sophisticated instruments.
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Hann, Christina. „Random Drug Screenings: Nothing to Lose?“ American Pharmacy 27, Nr. 10 (Oktober 1987): 34–36. http://dx.doi.org/10.1016/s0160-3450(16)33340-2.
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Williams, Petal Petersen, Catherine Mathews, Esmé Jordaan, Yukiko Washio, Mishka Terplan und Charles DH Parry. „Validation of simple dichotomous self-report on prenatal alcohol and other drug use in women attending midwife obstetric units in the Cape Metropole, South Africa“. Clinical Ethics 15, Nr. 4 (31.05.2020): 181–86. http://dx.doi.org/10.1177/1477750920928885.
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Background This paper examines the degree of agreement among simple dichotomous self-report, validated screening results, and biochemical screening results of prenatal alcohol and other drug use among pregnant women. Method Secondary analysis was conducted on a cohort of pregnant women 16 years or older, presenting for prenatal care in the greater Cape Town, South Africa. Dichotomous verbal screening is a standard of care, and pregnant patients reporting alcohol and other drug use in dichotomous verbal screenings were asked to engage in screening using the Alcohol Smoking and Substance Involvement Screening Test (ASSIST) and urinalysis. Results Significant agreements between dichotomous and ASSIST scores were observed (K = 0.73–0.76). A higher rate of self-reported (36.9%) alcohol use was detected, relative to urine screening (19.6%) with a predictive value of 34.9; while underreporting of illicit substance use was observed (3.6% self-report vs. 8.8% urine screening) with an overall predictive value of 50.0. Conclusion Dichotomous verbal screening was considered valid after comparison with the ASSIST; however, combined use with urine screenings can be recommended especially for identifying illicit substance use in order to accurately detect alcohol and other drug use in pregnancy, so that women can be identified and referred for appropriate interventions where needed.
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Nguemeni Tiako, Max Jordan, Abby Dolan, Matthew Abrams, Kehinde Oyekanmi, Zachary Meisel und Shoshana V. Aronowitz. „Thematic Analysis of State Medicaid Buprenorphine Prior Authorization Requirements“. JAMA Network Open 6, Nr. 6 (15.06.2023): e2318487. http://dx.doi.org/10.1001/jamanetworkopen.2023.18487.
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ImportancePrior authorization (PA) requirements for buprenorphine are associated with lower provision of the medication for the treatment of opioid use disorder (OUD). While Medicare plans have eliminated PA requirements for buprenorphine, many Medicaid plans continue to require them.ObjectiveTo describe and classify buprenorphine coverage requirements based on thematic analysis of state Medicaid PA forms.Design, Setting, and ParticipantsThis qualitative study used a thematic analysis of 50 states’ Medicaid PA forms for buprenorphine between November 2020 and March 2021. Forms were obtained from the jurisdiction’s Medicaid websites and assessed for features suggesting barriers to buprenorphine access. A coding tool was developed based on a review of a sample of forms, including fields for behavioral health treatment recommendations or mandates, drug screening requirements, and dosage limitations.Main Outcomes and MeasuresOutcomes included PA requirements for different buprenorphine formulations. Additionally, PA forms were evaluated for various criteria such as behavioral health, drug screenings, dose-related recommendations or mandates or patient education.ResultsAmong the total of 50 US states in the analysis, most states’ Medicaid plans required PA for at least 1 formulation of buprenorphine. However, the majority did not require a PA for buprenorphine-naloxone. Four key themes of coverage requirements were identified: restrictive surveillance (eg, requirements for urine drug screenings, random drug screenings, pill counts), behavioral health treatment recommendations or mandates (eg, mandatory counseling or 12-step meeting attendance), interfering with or restricting medical decision-making (eg, maximum daily dosages of 16 mg, requiring additional steps for dosages higher than 16 mg), and patient education (eg, information about adverse effects and interactions with other medications). Eleven states (22%) required urine drug screenings, 6 states (12%) required random urine drug screenings, and 4 states (8%) required pill counts. Fourteen states’ forms (28%) recommended therapy, and 7 (14%) required therapy, counseling, or participation in group sessions. Eighteen states (36%) specified dosage maximums; among them, 11 (22%) required additional steps for a daily dosage higher than 16 mg.ConclusionIn this qualitative study of state Medicaid PA requirements for buprenorphine, themes were identified that included patient surveillance with drug screenings and pill counts, behavioral health treatment recommendations or mandates, patient education, and dosing guidance. These results suggest that state Medicaid plans’ buprenorphine PA requirements for OUD are in conflict with existing evidence and may negatively affect states’ efforts to address the opioid overdose crisis.
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Salas-Sarduy, Emir, Gabriela T. Niemirowicz, Juan José Cazzulo und Vanina E. Alvarez. „Target-based Screening of the Chagas Box: Setting Up Enzymatic Assays to Discover Specific Inhibitors Across Bioactive Compounds“. Current Medicinal Chemistry 26, Nr. 36 (13.12.2019): 6672–86. http://dx.doi.org/10.2174/0929867326666190705160637.
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Chagas disease is a neglected tropical illness caused by the protozoan parasite Trypanosoma cruzi. The disease is endemic in Latin America with about 6 million people infected and many more being at risk. Only two drugs are available for treatment, Nifurtimox and Benznidazole, but they have a number of side effects and are not effective in all cases. This makes urgently necessary the development of new drugs, more efficient, less toxic and affordable to the poor people, who are most of the infected population. In this review we will summarize the current strategies used for drug discovery considering drug repositioning, phenotyping screenings and target-based approaches. In addition, we will describe in detail the considerations for setting up robust enzymatic assays aimed at identifying and validating small molecule inhibitors in high throughput screenings.
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Degliesposti, Gianluca, Corinne Portioli, Marco Daniele Parenti und Giulio Rastelli. „BEAR, a Novel Virtual Screening Methodology for Drug Discovery“. Journal of Biomolecular Screening 16, Nr. 1 (17.11.2010): 129–33. http://dx.doi.org/10.1177/1087057110388276.
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BEAR (binding estimation after refinement) is a new virtual screening technology based on the conformational refinement of docking poses through molecular dynamics and prediction of binding free energies using accurate scoring functions. Here, the authors report the results of an extensive benchmark of the BEAR performance in identifying a smaller subset of known inhibitors seeded in a large (1.5 million) database of compounds. BEAR performance proved strikingly better if compared with standard docking screening methods. The validations performed so far showed that BEAR is a reliable tool for drug discovery. It is fast, modular, and automated, and it can be applied to virtual screenings against any biological target with known structure and any database of compounds.
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Bintener, Tamara, Maria Pires Pacheco und Thomas Sauter. „Towards the routine use of in silico screenings for drug discovery using metabolic modelling“. Biochemical Society Transactions 48, Nr. 3 (05.05.2020): 955–69. http://dx.doi.org/10.1042/bst20190867.
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Currently, the development of new effective drugs for cancer therapy is not only hindered by development costs, drug efficacy, and drug safety but also by the rapid occurrence of drug resistance in cancer. Hence, new tools are needed to study the underlying mechanisms in cancer. Here, we discuss the current use of metabolic modelling approaches to identify cancer-specific metabolism and find possible new drug targets and drugs for repurposing. Furthermore, we list valuable resources that are needed for the reconstruction of cancer-specific models by integrating various available datasets with genome-scale metabolic reconstructions using model-building algorithms. We also discuss how new drug targets can be determined by using gene essentiality analysis, an in silico method to predict essential genes in a given condition such as cancer and how synthetic lethality studies could greatly benefit cancer patients by suggesting drug combinations with reduced side effects.
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Fischer, Matthias, Stefan Unterecker und Jürgen Deckert. „False-Positive Phencyclidine Drug Screenings During Psychopharmacologic Treatment“. Journal of Clinical Psychiatry 75, Nr. 07 (15.07.2014): 728–30. http://dx.doi.org/10.4088/jcp.13cr08955.
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Moya, Elisa L. J., Elodie Vandenhaute, Eleonora Rizzi, Marie-Christine Boucau, Johan Hachani, Nathalie Maubon, Fabien Gosselet und Marie-Pierre Dehouck. „Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery“. Pharmaceutics 13, Nr. 6 (16.06.2021): 892. http://dx.doi.org/10.3390/pharmaceutics13060892.
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Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.
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Cai, Linda, Annina Kemmer, Niels Krausch, Peter Neubauer und M. Nicolas Cruz Bournazou. „Hochdurchsatz-Strategien für modellbasierte Bioprozessentwicklung“. BIOspektrum 30, Nr. 2 (März 2024): 177–79. http://dx.doi.org/10.1007/s12268-024-2142-9.
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AbstractHigh-throughput screening accelerates bioprocess development, e.g., drug development. The KIWI-biolab at Technische Universität Berlin developed various platforms for automated experiments in small-scale cultivation systems. These are connected with automated analytics via a workflow management system and following the FAIR data principles. Mathematical models support process control and optimization during screenings of new microbial strains and experimental conditions.
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Iannaccone, Teresa, Carmine Sellitto, Valentina Manzo, Francesca Colucci, Valentina Giudice, Berenice Stefanelli, Antonio Iuliano, Giulio Corrivetti und Amelia Filippelli. „Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters“. Pharmaceuticals 14, Nr. 3 (01.03.2021): 204. http://dx.doi.org/10.3390/ph14030204.
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Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient’s genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.
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Gallinger, Tom L., Samuel Y. Aboagye, Wiebke Obermann, Michael Weiss, Arnold Grünweller, Carlo Unverzagt, David L. Williams, Martin Schlitzer und Simone Haeberlein. „First In Silico Screening of Insect Molecules for Identification of Novel Anti-Parasitic Compounds“. Pharmaceuticals 15, Nr. 2 (19.01.2022): 119. http://dx.doi.org/10.3390/ph15020119.
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Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma. In silico screenings of compounds for the identification of novel anti-parasitic drug candidates have received considerable attention in recent years, including the screening of natural compounds. For the first time, we investigated molecules from insects, a rather neglected source in drug discovery, in an in silico screening approach to find novel antischistosomal compounds. Based on the Dictionary of Natural Products (DNP), we created a library of 1327 insect compounds suitable for molecular docking. A structure-based virtual screening against the crystal structure of a known druggable target in Schistosoma mansoni, the thioredoxin glutathione reductase (SmTGR), was performed. The top ten compounds predominantly originated from beetles and were predicted to interact particularly with amino acids in the doorstop pocket of SmTGR. For one compound from a jewel beetle, buprestin H, we tested and confirmed antischistosomal activity against adult and juvenile parasites in vitro. At concentrations with anti-parasitic activity, we could also exclude any unspecific cytotoxic activity against human HepG2 cells. This study highlights the potential of insect molecules for the identification of novel antischistosomal compounds. Our library of insect-derived molecules could serve not only as basis for future in silico screenings against additional target proteins of schistosomes, but also of other parasites.
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Rosa, João Gabriel Santos, Carla Lima und Monica Lopes-Ferreira. „Zebrafish Larvae Behavior Models as a Tool for Drug Screenings and Pre-Clinical Trials: A Review“. International Journal of Molecular Sciences 23, Nr. 12 (14.06.2022): 6647. http://dx.doi.org/10.3390/ijms23126647.
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To discover new molecules or review the biological activity and toxicity of therapeutic substances, drug development, and research relies on robust biological systems to obtain reliable results. Phenotype-based screenings can transpose the organism’s compensatory pathways by adopting multi-target strategies for treating complex diseases, and zebrafish emerged as an important model for biomedical research and drug screenings. Zebrafish’s clear correlation between neuro-anatomical and physiological features and behavior is very similar to that verified in mammals, enabling the construction of reliable and relevant experimental models for neurological disorders research. Zebrafish presents highly conserved physiological pathways that are found in higher vertebrates, including mammals, along with a robust behavioral repertoire. Moreover, it is very sensitive to pharmacological/environmental manipulations, and these behavioral phenotypes are detected in both larvae and adults. These advantages align with the 3Rs concept and qualify the zebrafish as a powerful tool for drug screenings and pre-clinical trials. This review highlights important behavioral domains studied in zebrafish larvae and their neurotransmitter systems and summarizes currently used techniques to evaluate and quantify zebrafish larvae behavior in laboratory studies.
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Sugimoto, Keiki, Fumihiko Hayakawa, Takahiko Yasuda und Tomoki Naoe. „Drug Development Targeting Microenvironment for Malignant Lymphoma“. Blood 120, Nr. 21 (16.11.2012): 1661. http://dx.doi.org/10.1182/blood.v120.21.1661.1661.
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Abstract Abstract 1661 Most cancer drug developments are focusing either in vitro target-based screening or cell-based phenotypic screening to identify potential compounds. The target-based screenings are powerful screening methods if the cancer relay on a single driver mutation. On the other hand, cell-based phenotypic screenings measure cell phenotypes such as growth inhibitory effect on established cancer cell lines. However, these established cell lines do not recapitulate human cancer in some aspects. For instance, most cell lines have the microenvironment-independent growth ability, while primary cancer cells can not survive in ex vivo culture. In this study, we established a new drug screening system targeting microenvironment-dependent primary lymphoma cells. First of all, we established primary lymphoma xenograft models, including three diffuse large B cell lymphoma (DLBCL), one follicular lymphoma, one intravascular large cell lymphoma (IVL), and one mantle cell lymphoma. Interestingly, lymphoma cells from the patient with severe extranodal invasion invaded extranodal organ also in mice. And pattern of invasion in tissue such as intravascular tumor invasion of IVL was maintained in the xenograft models. In addition, mRNA expression profiles were similar between primary lymphoma cells and the lymphoma cells obtained from NOG mice. Furthermore, the heterogeneity of primary tumor such as heterogenous expression of CD20 was maintained in the xenograft models. These data suggested that the lymphoma cells propagated in NOG mice kept the original patient's phenotype. Next, we investigated the microenvironment of lymphoma in primary lymphoma xenograft models. Fibroblastic reticular cell (FRC) and follicular dendritic cell (FDC) are reported to be important to support the survival of lymphoma cells in their microenvironment. In the spleen of DLBCL model mice, lymphoma cells colocalized with FRC, but FDC was not detected in NOG mouse. FRC is known to produce reticular fiber and forms fibroblastic reticular network (FRN). Lymphoma induced reticular fiber production and tumor formation on FRN were also observed in our system. Furthermore, co-culture with FRC cell line, BLS4, significantly enhanced viability of 2 out of 3 DLBCL cells obtained from primary lymphoma xenograft mice and enabled more than three weeks long-term ex vivo culture of them. These results indicated that FRC played an important role for lymphoma cell survival. Finally, we established a new drug screening system using this co-culture system. Primary DLBCL cells transplanted to NOG mice were collected and seeded on pre-seeded BLS4 in 96-well plates (lymphoma cell co-culture). Monoculture of BLS4 in 96-well plates was also prepared. Both lymphoma co-cultured cell and BLS4 monoculture cell were treated by 2613 kinds of pharmacologically active compounds for 72 h. DAPI-stained dead cells of lymphoma cells were counted by image analyzer, and the proliferation of BLS4 was measured by MTT assay. We calculated Drug Effect Index (DEI) by multiplication of dead cell number of lymphoma cells and MTT value of BLS4 and compared. The compound with the highest DEI was pyrvinium pamoate, oxyuricide. Pyrvinium pamoate aborogated the survival of lymphoma cells co-cultured with BLS4 dose-dependently. And subcutaneous tumor of primary lymphoma cells and BLS4 were diminished by single intratumoral injection of 20 mg/kg pyrvinium pamoate. These results indicated that our screening system could be performed in large scale and select drugs with anti-tumor activity to primary lymphoma cells. Screening against primary lymphoma cells sheds new light on lymphoma drug development. Disclosures: Sugimoto: Otsuka Pharmaceutical co ltd: Employment.
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Bellomo, Francesco, Ester De Leo, Anna Taranta, Laura Giaquinto, Gianna Di Giovamberardino, Sandro Montefusco, Laura Rita Rega et al. „Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis“. International Journal of Molecular Sciences 22, Nr. 23 (27.11.2021): 12829. http://dx.doi.org/10.3390/ijms222312829.
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Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.
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Fielmich, Lars-Eric, Annemarie Buijs, Daniele Mori, Bas Viergever, Nihed Draoui, Anna Schepers, Mariana M. Costa e Silva et al. „Abstract 189: Developing a patient-derived organoid biobank, suitable for large scale drug screenings“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 189. http://dx.doi.org/10.1158/1538-7445.am2023-189.
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Abstract Conventional models for preclinical drug screening offer poor predictive value for patient response, causing high attrition rates of new agents in the clinic. HUB’s proprietary Patient-Derived Organoid (PDO) Technology enables long-term expansion of primary patient material to generate ‘mini organs in a dish’ that can be used as patient avatars, thus bringing every “patient in the lab®”. We present the world’s first NMIBC PDO biobank comprising 50 PDO models from transurethral resection of bladder (TURB) biopsies collected at three hospitals. Clinical and pathological characterization of the PDOs confirmed the representation in the biobank of a range of tumor stages and differentiation grades, as well as patient treatment and follow-up. The genomic analyses of PDOs revealed mutations in known BC driver genes and genomic instability, a hallmark of cancer. Finally, transcriptomic analyses confirmed gene expression profiles familiar to BC and characterized gene fusions. Next, we successfully screened the biobank on a panel of two reference compounds for the treatment of bladder cancer and seven candidate drugs, indicating potential new leads for further development of some of the compounds. The work presented here shows the feasibility of building PDO biobanks representing a specific patient population, suitable for improving the drug development pipeline for the next generation of cancer drugs. Citation Format: Lars-Eric Fielmich, Annemarie Buijs, Daniele Mori, Bas Viergever, Nihed Draoui, Anna Schepers, Mariana M. Costa e Silva, Mathijs Scholtus, Tokameh Mahmoudi, Tahlita Zuiverloon, Merel Derksen, Paul Gavine, Sylvia F. Boj, Richard Meijer, Onno Kranenburg, Janine Arts, Robert Vries. Developing a patient-derived organoid biobank, suitable for large scale drug screenings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 189.
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Hagan, Daniel, und Martin Hagan. „Soft Computing Tools for Virtual Drug Discovery“. Journal of Artificial Intelligence and Soft Computing Research 8, Nr. 3 (01.07.2018): 173–89. http://dx.doi.org/10.1515/jaiscr-2018-0012.
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AbstractIn this paper, we describe how several soft computing tools can be used to assist in high throughput screening of potential drug candidates. Individual small molecules (ligands) are assessed for their potential to bind to specific proteins (receptors). Committees of multilayer networks are used to classify protein-ligand complexes as good binders or bad binders, based on selected chemical descriptors. The novel aspects of this paper include the use of statistical analyses on the weights of single layer networks to select the appropriate descriptors, the use of Monte Carlo cross-validation to provide confidence measures of network performance (and also to identify problems in the data), the addition of new chemical descriptors to improve network accuracy, and the use of Self Organizing Maps to analyze the performance of the trained network and identify anomalies. We demonstrate the procedures on a large practical data set, and use them to discover a promising characteristic of the data. We also perform virtual screenings with the trained networks on a number of benchmark sets and analyze the results.
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Fischer, M., S. Unterecker und J. Deckert. „EPA-1097 - False positive phencyclidine drug screenings during psychopharmacologic treatment“. European Psychiatry 29 (2014): 1. http://dx.doi.org/10.1016/s0924-9338(14)78374-9.
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Butterweck, Veronika, Hartmut Derendorf, Wilhelm Gaus, Adolf Nahrstedt, Volker Schulz und Matthias Unger. „Pharmacokinetic Herb-Drug Interactions: Are Preventive Screenings Necessary and Appropriate?“ Planta Medica 70, Nr. 9 (September 2004): 784–91. http://dx.doi.org/10.1055/s-2004-827223.
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Kim, Jungeun, Hoe Suk Kim, Ga Yeon Kim, Kyung hyeun Park, Seung yeon Ryu, Sangeun Lee, Dong Woo Lee, Bosung Ku, Han-Byoel Lee und Wonshik Han. „Abstract P5-02-02: Development of automated 3D high-throughput drug screening platform for patient-derived breast cancer organoids“. Cancer Research 82, Nr. 4_Supplement (15.02.2022): P5–02–02—P5–02–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-02-02.
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Abstract Background Patient-derived cancer organoids, which reliably conserve original features of tumors, are emerging as an excellent model for predicting therapy response and drug screening. Developing optimized 3D high-throughput drug screening platform to establish patient-derived cancer organoids and simultaneously perform drug screening is essential for personalized medicine. Methods We established normal breast organoids (n=4) and breast cancer organoids (n=10) from 20 fresh surgical specimen (normal 7, tumor 13 cases). A number (500-2000) of normal and cancer cells were automatically dispensed with the ASFA™ Spotter ST and organoids were generated by hydrogel hanging-drop culture on Cellvitro™ Pillar platform (Medical & Bio Decision, South Korea). Organoids were subjected to drug screening for 17 anticancer drugs including chemoreagents and targeted drugs in the 3D HTS system. Drug sensitivity was tested in triplicate in different concentration ranges for 5 days. Drug cytotoxic effect was assessed by calcein AM staining. Acquisition and analysis of high-content 3D organoid images were peformed using ASFA™ SCANNER (Medical & Bio Decision, South Korea). The IC50 for each drug was calculated by a sigmoidal dose-response curve, using the GraphPad Prism 9 program. We analyzed a drug response index (DRI) using a prediction alogorithm to evalute drug sensitivity (DRI<-0.5) and resistance (DRI>0.5). Results We summarized the DRI value of patient-derived breast organoids of 7 drugs (Table 1). 6 tumor organoids (2T, 6T, 8T, 10T, 13T, 15T) showed high sensitivity to Docetaxel, Doxorubicin, Paclitaxel, and Gemcitabin while 4 tumor organoids (1T, 9T, 14T, 16T) were less sensitive and resistant. 2 tumor organoids (10T, 16T) were sensitive to Tamoxifen and 2 tumor organoids (6T, 8T) show high sensitivity to palbociclib and erlotinib. Normal organoids show less sensitivity and resistance to chemotherapeutic drugs. Drug response index >0.5 : resistancy top 30%, Drug response index <-0.5 : sensitivity top 30%. Conclusions Herein, we developed the hydrogel hanging-drop culture on Cellvitro™ Pillar platform for easily and rapidly high-throughput drug screening in patient-derived organoids using a small number of cells by testing clinically actionable drugs at different concentrations. There were different drug response indeces for each individual organoids to chemoreagents and targeted drugs. We anticipate that 3D high-throughput drug screenings platform based on patient-derived organoids can provide the information to predict drug response and allow for finding more appropriate therapy for individual patients. Table 1.DRI values of patient-derived breast organoids of 7 drugs.Patient No.Tumor/NormalDocetaxelPaclitaxelDoxorubicinTamoxifenGemcitabinePalbociclibErlotinib1TTumor1.051.261.080.060.590.26-2TTumor-0.64-0.72-0.60-0.08-0.79--6TTumor-0.98-0.99-2.330.00-1.44-2.31-1.608TTumor-0.32-0.50-0.250.64-1.07-1.47-0.669TTumor1.050.980.610.870.430.610.4410TTumor-0.84-0.77-0.78-1.680.790.610.0913TTumor-0.87-0.430.560.70-0.510.611.1714TTumor0.861.261.180.481.81--15TTumor-1.59-1.45-1.41--0.71-0.13-16TTumor1.051.261.18-1.70-1.22-2NNormal1.051.260.650.741.810.610.7810NNormal1.05-0.910.810.870.880.610.084NNormal-0.31-0.25-0.530.25-0.190.61-1.575NNormal1.051.130.380.75-0.630.610.10 Citation Format: Jungeun Kim, Hoe Suk Kim, Ga Yeon Kim, Kyung hyeun Park, Seung yeon Ryu, Sangeun Lee, Dong Woo Lee, Bosung Ku, Han-Byoel Lee, Wonshik Han. Development of automated 3D high-throughput drug screening platform for patient-derived breast cancer organoids [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-02-02.
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Kojima, Yuki, Fumihiko Hayakawa, Takanobu Morishita, Keiki Sugimoto, Mizuho Iwase, Hideyuki Yamamoto, Daiki Hirano, Naoto Imoto, Seiji Okada und Hitoshi Kiyoi. „YM155 Induces Apoptosis through Proteasome-Dependent Degradation of MCL-1 in Primary Effusion Lymphoma“. Blood 128, Nr. 22 (02.12.2016): 3013. http://dx.doi.org/10.1182/blood.v128.22.3013.3013.
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Abstract Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma caused by human herpes virus 8 (HHV-8), which mainly occurs in patients with acquired immunodeficiency. It is highly refractory to conventional chemotherapies, and has a very poor prognosis. We recently developed patient-derived xenograft (PDX) screening, a novel high-throughput drug screening system using PDX cells that were established by transplantations of primary tumor cells into immunodeficient mice and maintained primary cell phenotype. PDX screening is expected to discover anti-tumor drugs that have been overlooked by conventional screenings using cell lines. Here, we performed a PDX screening to develop a new therapeutic agent for PEL. We previously established a PDX and a cell line designated as GTO from the same primary cells of PEL. We performed screenings of a library containing 3518 known pharmacologically active substance and off-patent drugs using the PDX cells (PDX screening) and GTO (Cell-line screening). We compared the results of both screenings and found that PDX cells and cell lines had quite different drug sensitivity profiles. The correlation coefficient between them was 0.67. Twenty-six drugs (0.7%) were at least 2 times more effective for PDX cells than for GTO and designated as PDX-preferred drugs (Figure A). The opposites were named as cell line-preferred drugs and existed 80 (2.2%). We found that PDX-preferred drugs significantly higher activity to induce reactive oxygen species (ROS) production (P<0.001), indicating the sensitivity of PDX cells to oxidative stress. We examined the reproducibility of anti-tumor effect of top 10 compounds of PDX screening in different system including in vivo mouse model and finally selected YM155, a possible survivin inhibitor, as the best candidate for an anti-tumor drug for PEL. It showed strong and dose-dependent anti-tumor effect on both PDX cells and cell lines of PEL. Its GI50 was 7.8 nM in the PDX cells, and 1.2 - 7.9 nM in three kinds of PEL cell lines. YM155 treatment increased the cleavage of caspase-3, caspase-7, and PARP and caused apoptosis of GTO, which was inhibited by a caspase inhibitor, Z-VAD-FMK. Although YM155 was discovered as a survivin inhibitor, we observed that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein prior to survivin reduction by time course experiments. Observed MCL-1 reduction by YM155 was attenuated by a proteasome inhibitor, MG132, suggesting that MCL-1 reduction was due to proteasome-dependent degradation. Furthermore, we confirmed the importance of MCL-1 for survival by its knockdown by siRNA in PEL cell line. Finally, we assessed the in vivo effect of YM155. NOD/SCID/IL-2Rgnull mice were injected intraperitoneally with PEL-PDX cells and were treated with vehicle or YM155 (5mg/kg) from day 1 to 21. YM155 was administered by continuous subcutaneous injection using osmotic pumps. Treatment with YM155 significantly inhibited progression of ascites compared with control mice (Figure B). These results suggested that YM155 was a promising anti-cancer agent for PEL. Figure Figure. Disclosures Sugimoto: Otsuka Pharmaceutical Co., Ltd.: Employment. Kiyoi:Chugai Pharmaceutical Co. LTD.: Research Funding; Alexion Pharmaceuticals: Research Funding; MSD K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Phizer Japan Inc.: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Celgene Corporation: Consultancy; Eisai Co., Ltd.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding.
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Degiacomi, Giulia, Juan Manuel Belardinelli, Maria Rosalia Pasca, Edda De Rossi, Giovanna Riccardi und Laurent Roberto Chiarelli. „Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3“. Applied Sciences 10, Nr. 2 (15.01.2020): 623. http://dx.doi.org/10.3390/app10020623.
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The development and spread of Mycobacterium tuberculosis multi-drug resistant strains still represent a great global health threat, leading to an urgent need for novel anti-tuberculosis drugs. Indeed, in the last years, several efforts have been made in this direction, through a number of high-throughput screenings campaigns, which allowed for the identification of numerous hit compounds and novel targets. Interestingly, several independent screening assays identified the same proteins as the target of different compounds, and for this reason, they were named “promiscuous” targets. These proteins include DprE1, MmpL3, QcrB and Psk13, and are involved in the key pathway for M. tuberculosis survival, thus they should represent an Achilles’ heel which could be exploited for the development of novel effective drugs. Indeed, among the last molecules which entered clinical trials, four inhibit a promiscuous target. Within this review, the two most promising promiscuous targets, the oxidoreductase DprE1 involved in arabinogalactan synthesis and the mycolic acid transporter MmpL3 are discussed, along with the latest advancements in the development of novel inhibitors with anti-tubercular activity.
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Porto, Raquel, Ana C. Mengarda, Rayssa A. Cajas, Maria C. Salvadori, Fernanda S. Teixeira, Daniel D. R. Arcanjo, Abolghasem Siyadatpanah, Maria de Lourdes Pereira, Polrat Wilairatana und Josué de Moraes. „Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni“. Pharmaceuticals 14, Nr. 7 (16.07.2021): 686. http://dx.doi.org/10.3390/ph14070686.
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The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Praziquantel is the only drug available to treat schistosomiasis and there is an urgent demand for new anthelmintic agents. Adopting a phenotypic drug screening strategy, here, we evaluated the antiparasitic properties of 46 commercially available cardiovascular drugs against S. mansoni. From these screenings, we found that amiodarone, telmisartan, propafenone, methyldopa, and doxazosin affected the viability of schistosomes in vitro, with effective concentrations of 50% (EC50) and 90% (EC90) values ranging from 8 to 50 µM. These results were further supported by scanning electron microscopy analysis. Subsequently, the most effective drug (amiodarone) was further tested in a murine model of schistosomiasis for both early and chronic S. mansoni infections using a single oral dose of 400 mg/kg or 100 mg/kg daily for five consecutive days. Amiodarone had a low efficacy in chronic infection, with the worm and egg burden reduction ranging from 10 to 30%. In contrast, amiodarone caused a significant reduction in worm and egg burden in early infection (>50%). Comparatively, treatment with amiodarone is more effective in early infection than praziquantel, demonstrating the potential role of this cardiovascular drug as an antischistosomal agent.
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Popova, Anna A., Konstantin Demir, Titus Genisius Hartanto, Eric Schmitt und Pavel A. Levkin. „Droplet-microarray on superhydrophobic–superhydrophilic patterns for high-throughput live cell screenings“. RSC Advances 6, Nr. 44 (2016): 38263–76. http://dx.doi.org/10.1039/c6ra06011k.
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Droplet-microarray platform based on superhydrophobic–superhydrophilic patterning allows for miniaturized high throughput drug and transfection screenings of live cells in separated nanoliter droplets.
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Xie, Yujiang, Genpei Shi, Jie Sun, Si Li, Wei Gao, Yimin Hu, Chang Zu, Weiwei Tang und Junbo Gong. „Computational Screening and Experimental Validation on Multicomponent Crystals of a New Class of Janus Kinase (JAK) Inhibitor Drug with Improved Solubility“. Crystals 12, Nr. 12 (27.11.2022): 1722. http://dx.doi.org/10.3390/cryst12121722.
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Developing multicomponent crystal forms, especially cocrystals and salts, is becoming a promising pathway to improve the solubility and bioavailability of drugs. Herein, new multicomponent crystals of SHR0302, a new generation of Janus Kinase (JAK) inhibitor that suffers from poor solubility, were developed based on a cooperative approach of computational and experimental coformer screenings. Virtual screening methods, including the conductor-like screening model for realistic solvents (COSMO-RS) and molecular complementary (MC) analysis, were employed to predict the binding affinity between SHR0302 and selected coformers. The developed screening method was capable of reducing the screening database to 30 coformers from a total of 42 proposed coformers. The proof-of-concept experimental screening study was performed to demonstrate the efficiency of computational screening, wherein three new multicomponent crystalline forms were found and fully characterized by powder X-ray diffraction, thermal analysis, and IR and 1H-NMR spectroscopy. Further, the measurements of the solubility property of these new multicomponent crystal forms reveal an apparent promotion compared with the drug alone. Finally, the receiver operator characteristic (ROC) curve was used to assess the prediction performance of the COSMO-RS model. It was found that the established screening model can effectively shorten the experimental screening time and efforts.
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Sun, Wei, Chwee Teck Lim und Nicholas Agung Kurniawan. „Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy“. Journal of The Royal Society Interface 11, Nr. 99 (06.10.2014): 20140638. http://dx.doi.org/10.1098/rsif.2014.0638.
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Cancer metastasis involves the dissemination of cancer cells from the primary tumour site and is responsible for the majority of solid tumour-related mortality. Screening of anti-metastasis drugs often includes functional assays that examine cancer cell invasion inside a three-dimensional hydrogel that mimics the extracellular matrix (ECM). Here, we built a mechanically tuneable collagen hydrogel model to recapitulate cancer spreading into heterogeneous tumour stroma and monitored the three-dimensional invasion of highly malignant breast cancer cells, MDA-MB-231. Migration assays were carried out in the presence and the absence of drugs affecting four typical molecular mechanisms involved in cell migration, as well as under five ECMs with different biophysical properties. Strikingly, the effects of the drugs were observed to vary strongly with matrix mechanics and microarchitecture, despite the little dependence of the inherent cancer cell migration on the ECM condition. Specifically, cytoskeletal contractility-targeting drugs reduced migration speed in sparse gels, whereas migration in dense gels was retarded effectively by inhibiting proteolysis. The results corroborate the ability of cancer cells to switch their multiple invasion mechanisms depending on ECM condition, thus suggesting the importance of factoring in the biophysical properties of the ECM in anti-metastasis drug screenings.
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Zaveri, Anurag D., Dilip N. Zaveri und Lakshmi Bhaskaran. „Genetyping of Carbapenem-resistant Organisms Isolated from Clinical Isolates Received from Tertiary Care Hospitals of Ahmedabad, Gujarat“. Journal of Pure and Applied Microbiology 15, Nr. 3 (31.08.2021): 1689–96. http://dx.doi.org/10.22207/jpam.15.3.65.
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The world is seeing a continuous rise in the levels of antibiotic resistance1. Organisms develop new resistance mechanisms, emerge, and spread the resistance worldwide, making it challenging to treat common infectious diseases. In the current study, clinical isolates received between the years 2017 to 2020 were cultured and the isolated organisms were screened for antibiotic resistance; isolates with multiple drug resistance were further subjected to confirmatory screening through Combined Disc Test (CDT) and Modified Hodge Test (M.H.T.), and molecular characterization to be finally tested for gene expression analysis. Molecular characterization involved screening of genes blaVIM-2, blaKPC-3, blaNDM-1, and blaIMP-11 responsible for imparting carbapenem drug resistance2. From the laboratories of tertiary care hospitals, a total of 1452 clinical isolates were collected and identified. The organisms were subjected to antibiotic susceptibility screening and carbapenem resistance screening. The isolates found positive in the screenings were subjected to molecular characterization for genes, blaVIM-2, blaKPC-3, blaNDM-1, and blaIMP-11, responsible for imparting carbapenem drug resistance. Most of the isolates were resistant variably to aminoglycosides but were found to be resistant to fluoroquinolones and β-lactams group of antibiotics. Carbapenem activity was detected in twelve percent of total isolates and 27 percent among multidrug-resistant isolates. blaNDM-1 gene was found present in 77% isolates, and five organisms among the total number of organisms showed pan drug resistance.
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Mitchell, Ann M., Holly Hagle, Kathy Puskar, Irene Kane, Dawn Lindsay, Kimberly Talcott, Peter F. Luongo und Eric Goplerud. „Alcohol and Other Drug Use Screenings by Nurse Practitioners: Policy Implications“. Journal for Nurse Practitioners 11, Nr. 7 (Juli 2015): 730–32. http://dx.doi.org/10.1016/j.nurpra.2014.11.025.
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Sanz, Laura M., M. Belen Jiménez-Díaz, Benigno Crespo, Cristina De-Cozar, M. Jesus Almela, Iñigo Angulo-Barturen, Pablo Castañeda et al. „Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen“. Antimicrobial Agents and Chemotherapy 55, Nr. 12 (03.10.2011): 5740–45. http://dx.doi.org/10.1128/aac.05188-11.
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ABSTRACTMalaria is one of the deadliest infectious diseases in the world, with the eukaryotic parasitePlasmodium falciparumcausing the most severe form of the disease. Discovery of new classes of antimalarial drugs has become an urgent task to counteract the increasing problem of drug resistance. Screening directly for compounds able to inhibit parasite growthinvitrois one of the main approaches the malaria research community is now pursuing for the identification of novel antimalarial drug leads. Very recently, thousands of compounds with potent activity against the parasiteP. falciparumhave been identified and information about their molecular descriptors, antiplasmodial potency, and cytotoxicity is publicly available. Now the challenges are how to identify the most promising chemotypes for further development and how best to progress these compounds through a lead optimization program to generate antimalarial drug candidates. We report here the first chemical series to be characterized from one of those screenings, a completely novel chemical class with the generic name cyclopropyl carboxamides that has never before been described as having antimalarial or other pharmacological activities. Cyclopropyl carboxamides are potent inhibitors of drug-sensitive and -resistant strains ofP. falciparuminvitroand showinvivooral efficacy in malaria mouse models. In the present work, we describe the biological characterization of this chemical family, showing that inhibition of their still unknown target has very favorable pharmacological consequences but the compounds themselves seem to select for resistance at a high frequency.
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Nasseri, S. Soroush, Erika M. J. Siren, Jayachandran N. Kizhakkedathu und Karen Cheung. „HyClear: A Novel Tissue Clearing Solution for One-Step Clearing of Microtissues“. Cells 11, Nr. 23 (30.11.2022): 3854. http://dx.doi.org/10.3390/cells11233854.
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3-D cell cultures are being increasingly used as in vitro models are capable of better mimicry of in vivo tissues, particularly in drug screenings where mass transfer limitations can affect the cancer biology and response to drugs. Three-dimensional microscopy techniques, such as confocal and multiphoton microscopy, have been used to elucidate data from 3-D cell cultures and whole organs, but their reach inside the 3-D tissues is restrained by the light scattering of the tissues, limiting their effective reach to 100–200 µm, which is simply not enough. Tissue clearing protocols, developed mostly for larger specimens usually involve multiple steps of viscous liquid submersion, and are not easily adaptable for much smaller spheroids and organoids. In this work, we have developed a novel tissue clearing solution tailored for small spheroids and organoids. Our tissue clearing protocol, called HyClear, uses a mixture of DMSO, HPG and urea to allow for one-step tissue clearing of spheroids and organoids, and is compatible with high-throughput screening studies due to its speed and simplicity. We have shown that our tissue clearing agent is superior to many of the commonly used tissue clearing agents and allows for elucidating better quality data from drug screening experiments.
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Bruch, Eduardo M., Stéphanie Petrella und Marco Bellinzoni. „Structure-Based Drug Design for Tuberculosis: Challenges Still Ahead“. Applied Sciences 10, Nr. 12 (20.06.2020): 4248. http://dx.doi.org/10.3390/app10124248.
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Structure-based and computer-aided drug design approaches are commonly considered to have been successful in the fields of cancer and antiviral drug discovery but not as much for antibacterial drug development. The search for novel anti-tuberculosis agents is indeed an emblematic example of this trend. Although huge efforts, by consortiums and groups worldwide, dramatically increased the structural coverage of the Mycobacterium tuberculosis proteome, the vast majority of candidate drugs included in clinical trials during the last decade were issued from phenotypic screenings on whole mycobacterial cells. We developed here three selected case studies, i.e., the serine/threonine (Ser/Thr) kinases—protein kinase (Pkn) B and PknG, considered as very promising targets for a long time, and the DNA gyrase of M. tuberculosis, a well-known, pharmacologically validated target. We illustrated some of the challenges that rational, target-based drug discovery programs in tuberculosis (TB) still have to face, and, finally, discussed the perspectives opened by the recent, methodological developments in structural biology and integrative techniques.
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Cheng, Lijun, Abhishek Majumdar, Daniel Stover, Shaofeng Wu, Yaoqin Lu und Lang Li. „Computational Cancer Cell Models to Guide Precision Breast Cancer Medicine“. Genes 11, Nr. 3 (28.02.2020): 263. http://dx.doi.org/10.3390/genes11030263.
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Background: Large-scale screening of drug sensitivity on cancer cell models can mimic in vivo cellular behavior providing wider scope for biological research on cancer. Since the therapeutic effect of a single drug or drug combination depends on the individual patient’s genome characteristics and cancer cells integration reaction, the identification of an effective agent in an in vitro model by using large number of cancer cell models is a promising approach for the development of targeted treatments. Precision cancer medicine is to select the most appropriate treatment or treatments for an individual patient. However, it still lacks the tools to bridge the gap between conventional in vitro cancer cell models and clinical patient response to inhibitors. Methods: An optimal two-layer decision system model is developed to identify the cancer cells that most closely resemble an individual tumor for optimum therapeutic interventions in precision cancer medicine. Accordingly, an optimal grid parameters selection is designed to seek the highest accordance for treatment selection to the patient’s preference for drug response and in vitro cancer cell drug screening. The optimal two-layer decision system model overcomes the challenge of heterology data comparison between the tumor and the cancer cells, as well as between the continual variation of drug responses in vitro and the discrete ones in clinical practice. We simulated the model accuracy using 681 cancer cells’ mRNA and associated 481 drug screenings and validated our results on 315 breast cancer patients drug selection across seven drugs (docetaxel, doxorubicin, fluorouracil, paclitaxel, tamoxifen, cyclophosphamide, lapitinib). Results: Comparing with the real response of a drug in clinical patients, the novel model obtained an overall average accordance over 90.8% across the seven drugs. At the same time, the optimal cancer cells and the associated optimal therapeutic efficacy of cancer drugs are recommended. The novel optimal two-layer decision system model was used on 1097 patients with breast cancer in guiding precision medicine for a recommendation of their optimal cancer cells (30 cancer cells) and associated efficacy of certain cancer drugs. Our model can detect the most similar cancer cells for each individual patient. Conclusion: A successful clinical translation model (optimal two-layer decision system model) was developed to bridge in-vitro basic science to clinical practice in a therapeutic intervention application for the first time. The novel tool kills two birds with one stone. It can help basic science to seek optimal cancer cell models for an individual tumor, while prioritizing clinical drugs’ recommendations in practice. Tool associated platform website: We extended the breast cancer research to 32 more types of cancers across 45 therapy predictions.
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Abdelkawy, Khaled, Maged Kharouba, Khloud Shendy, Omar Abdelmagged, Naira Galal, Mai Tarek, Mohamed Abdelgaied, Amr Y. Zakaria und Sherif Hanafy Mahmoud. „Prevalence of Drug–Drug Interactions in Primary Care Prescriptions in Egypt: A Cross-Sectional Retrospective Study“. Pharmacy 11, Nr. 3 (18.06.2023): 106. http://dx.doi.org/10.3390/pharmacy11030106.
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In clinical practice, drug–drug interactions (DDIs) pose significant risks to a large number of patients. Consequently, healthcare providers are required to diligently identify, monitor, and effectively handle these interactions in order to enhance patient outcomes. In Egypt, DDIs are poorly addressed, with no reports for DDIs in primary care. In our cross-sectional, retrospective, observational study, we collected a total of five thousand, eight hundred and twenty prescriptions across eight major governorates in Egypt. Prescriptions were collected over a span of 15 months between 1 June 2021 and 30 September 2022. These prescriptions were analyzed for potential DDIs using the Lexicomp® drug interactions tool. The prevalence of DDIs was found to be 18%, with 22% of the prescriptions having two or more potential DDIs. Moreover, we found 1447 DDIs of categories C (monitoring therapy recommended), D (therapy modification suggested), and X (avoid combination). The most commonly interacting drugs in our study were diclofenac, aspirin, and clopidogrel, while non-steroidal anti-inflammatory drugs (NSAIDs) were the most reported therapeutic class implicated in pharmacologic DDIs. Pharmacodynamic agonistic activity was the most common mechanism of interaction. Therefore, it is crucial to conduct screenings, detect early signs, and closely monitor drug–drug interactions (DDIs) to enhance patients’ overall health outcomes, medication responses, and safety. In this regard, the clinical pharmacist assumes a vital role in implementing these preventive measures.
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Regenbrecht, Manuela, Rica Sauer, Maya Niethard, Christian RA Regenbrecht und Jürgen Loskutov. „Establishment of PD3D models of sarcomas: A promising preclinical tool for improvement of sarcoma treatment.“ Journal of Clinical Oncology 40, Nr. 16_suppl (01.06.2022): e23538-e23538. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e23538.
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e23538 Background: Compared to the progress in understanding and treating carcinomas in the past decade, the options and related clinical benefit in terms of response rates and overall survival for sarcoma patients lacks behind. Increasing incidence, low 5-year-survival rates and nearly endless heterogeneity of sarcomas are challenging oncologists every day. The necessity of so far missing representative preclinical models is obvious. PD3D cell culture models have already proven to be a useful tool to reverse clinical engineer patient outcome in carcinomas. Here we report the establishing and refining of PD3D models for the plethora of sarcoma entities. Methods: We obtained viable sarcoma tissue samples from incisional biopsies or tumor resections. We continuously optimized media conditions. For quality control and pathological evaluation, we embedded the cells in FFPE, stained patient-specific models according to original tumor samples and evaluated them pathologically. Upon histopathological evaluation, we performed semi-automated drug response assays on patient-specific models with up to 12 drugs and drug combinations, including standard of care drugs plus a selection of additional drugs. In the fashion of a prospective observatory study, we compared the results from the in vitro screen with the actual clinical outcome. Results: More than 25 patient derived 3D-cell culture models have been established from various subtypes of sarcomas. Optimized media conditions and sampling operation improved the take rates from ca. 10 to 80% irrespective of the tumor subtype. Pathological examination of the models confirmed original diagnoses and revealed that the patient-specific models recapitulate the key properties of the original tumor. Negative predictive value of drug sensitivity testing was close to 100 %, while the positive predictive value was > 80 %. These results in a limited number of cases puts the predictive value en par with recently published data about the predictive value of patient-derived organoids in carcinomas. Conclusions: Patient derived 3D-cell culture models of sarcomas can be routinely established, irrespective of subtype Models can be used for multi-omics analyses including drug sensitivity screenings Pretherapeutic drug sensitivity screenings could support clinical decision making Findings need to be confirmed in a prospective observatory trial.
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Mahan, Rebecca J., Trista Askins Bailey, Teryn J. Bibb, Megan Fenney und Tara Williams. „Drug Therapy for Gender Transitions and Health Screenings in Transgender Older Adults“. Journal of the American Geriatrics Society 64, Nr. 12 (Dezember 2016): 2554–59. http://dx.doi.org/10.1111/jgs.14350.
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Ferrari, Elisa, Chiara Lucca und Marco Foiani. „A lethal combination for cancer cells: Synthetic lethality screenings for drug discovery“. European Journal of Cancer 46, Nr. 16 (November 2010): 2889–95. http://dx.doi.org/10.1016/j.ejca.2010.07.031.
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Jungwirth, Gerhard, Tao Yu, Cao Junguo, Catharina Lotsch, Andreas Unterberg und Christel Herold-Mende. „TMOD-29. STANDARDIZED GENERATION OF TUMOR-ORGANOIDS AS NOVEL DRUG SCREENING MODEL IN MENINGIOMA“. Neuro-Oncology 23, Supplement_6 (02.11.2021): vi221—vi222. http://dx.doi.org/10.1093/neuonc/noab196.890.
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Abstract Tumor-organoids (TOs) are novel, complex three-dimensional ex vivo tissue cultures that under optimal conditions accurately reflect genotype and phenotype of the original tissue with preserved cellular heterogeneity and morphology. They may serve as a new and exciting model for studying cancer biology and directing personalized therapies. The aim of our study was to establish TOs from meningioma (MGM) and to test their usability for large-scale drug screenings. We were capable of forming several hundred TO equal in size by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples. In total, standardized TOs from 60 patients were formed, including eight grade II and three grade III MGMs. TOs reaggregated within 3 days resulting in a reducted diameter by 50%. Thereafter, TO size remained stable throughout a 14 days observation period. TOs consisted of largely viable cells, whereas dead cells were predominantly found outside of the organoid. H&E stainings confirmed the successful establishment of dense tissue-like structures. Next, we assessed the suitability and reliability of TOs for a robust large-scale drug testing by employing nine highly potent compounds, derived from a drug screening performed on several MGM cell lines. First, we tested if drug responses depend on TO size. Interestingly, drug responses to these drugs remained identical independent of their sizes. Based on a sufficient representation of low abundance cell types such as T-cells and macrophages an overall number of 25.000 cells/TO was selected for further experiments revealing FDA-approved HDAC inhibitors as highly effective drugs in most of the TOs with a mean z-AUC score of -1.33. Taken together, we developed a protocol to generate standardized TO from MGM containing low abundant cell types of the tumor microenvironment in a representative manner. Robust and reliable drug responses suggest patient-derived TOs as a novel drug testing model in meningioma research.
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Barbosa, Mélanie A. G., Cristina P. R. Xavier, Rúben F. Pereira, Vilma Petrikaitė und M. Helena Vasconcelos. „3D Cell Culture Models as Recapitulators of the Tumor Microenvironment for the Screening of Anti-Cancer Drugs“. Cancers 14, Nr. 1 (31.12.2021): 190. http://dx.doi.org/10.3390/cancers14010190.
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Today, innovative three-dimensional (3D) cell culture models have been proposed as viable and biomimetic alternatives for initial drug screening, allowing the improvement of the efficiency of drug development. These models are gaining popularity, given their ability to reproduce key aspects of the tumor microenvironment, concerning the 3D tumor architecture as well as the interactions of tumor cells with the extracellular matrix and surrounding non-tumor cells. The development of accurate 3D models may become beneficial to decrease the use of laboratory animals in scientific research, in accordance with the European Union’s regulation on the 3R rule (Replacement, Reduction, Refinement). This review focuses on the impact of 3D cell culture models on cancer research, discussing their advantages, limitations, and compatibility with high-throughput screenings and automated systems. An insight is also given on the adequacy of the available readouts for the interpretation of the data obtained from the 3D cell culture models. Importantly, we also emphasize the need for the incorporation of additional and complementary microenvironment elements on the design of 3D cell culture models, towards improved predictive value of drug efficacy.
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Dubois, Clémence, Pierre Daumar, Corinne Aubel, Jean Gauthier, Bernard Vidalinc, Emmanuelle Mounetou, Frédérique Penault-Llorca und Mahchid Bamdad. „The New Synthetic Serum-Free Medium OptiPASS Promotes High Proliferation and Drug Efficacy Prediction on Spheroids from MDA-MB-231 and SUM1315 Triple-Negative Breast Cancer Cell Lines“. Journal of Clinical Medicine 8, Nr. 3 (21.03.2019): 397. http://dx.doi.org/10.3390/jcm8030397.
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Triple-negative breast cancers are particularly aggressive. In vitro cultures are one of the major pathways for developing anticancer strategies. The effectiveness and reproducibility of the drug screenings depend largely on the homogeneity of culture media. In order to optimize the predictive responses of triple-negative breast cancer 3D cell culture models, these works were focused on the development of SUM1315 and MDA-MB-231 cell lines in OptiPASS medium, a new serum-free formulation (BIOPASS). In monolayer cell culture, OptiPASS medium was more suitable for MDA-MB-231 than SUM1315 cell line but maintained cell phenotype and allowed sufficient proliferation. For spheroids produced in OptiPASS, the size monitoring showed a 1.3 and 1.5-fold increase for MDA-MB-231 and SUM1315 cell lines, respectively and viability/mortality profiles were maintained. Spheroids drug sensitivity thresholds were also improved allowing quicker high throughput drug screenings. These results showed the suitability of OptiPASS for 2D and 3D cell cultures of these two triple-negative breast cancer cell lines, with reproducibility of spheroid formation superior to 98%. This opens the way to the common use of this synthetic medium in future preclinical breast cancer research studies.
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Bay, Marie L., Aikaterini Skorda, Benita S. Rasmussen, Jaume R. Arias, Anna R. Lauridsen, Kaisa Huhtinen, Sampsa Hautaniemi, Johanna Hynninen und Tuula Kallunki. „Abstract B027: Screening of drug candidates to repurpose for high-grade serous ovarian cancer treatment“. Cancer Research 84, Nr. 5_Supplement_2 (04.03.2024): B027. http://dx.doi.org/10.1158/1538-7445.ovarian23-b027.
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Abstract Introduction: Ovarian cancer (OVC) is the most lethal gynecological cancer. The 5-year survival rate of OVC in Europe is 47% and in Denmark it is only 41%, indicating need for identifying novel efficient treatments. More than 75% of ovarian cancers are characterized as high-grade serous ovarian cancer (HGSC), and almost all HGSC patients experience recurrence and development of platinum-taxane treatment resistance. Here we established a drug screening and evaluation platform using HGSC cell lines and patient organoid samples in 3D cultures for testing drugs approved for treatment of different types of cancer and other diseases.Materials and methods: The drugs tested in this project have been selected according to screenings of the NCI Approved Oncology Drugs library and the Prestwick chemical library® on MCF7, LR-MT2, and SKOV3 cells, analyzing for change in lysosomal localization. The selected drugs were tested as monotherapy or in combination with carboplatin and paclitaxel, and drug responses in standard culture medium were compared to human plasma-like medium (PlasmaX™, XimBio). Drug responses were evaluated with two relatively platinum-resistant cell lines of HGSC representing different genetic backgrounds: OVSAHO and OVCAR3. In addition, promising drug candidates were tested on patient organoids, which were established from tissues collected from OVC patients and grown as 3-dimensional (3D) ex vivo long-term tumor organoid cultures as part of the DECIDER project (https://www.deciderproject.eu/, NCT04846933). Invasive growth and cell death was assessed by high-throughput imaging using the ImageXpress Confocal microscope (Molecular Devices). Image analysis was performed using MetaXpress software. Viable and reliable xenotransplant models of OVSAHO and OVCAR3 were established by rederiving the original cell lines (Permission no: 2018-15-0201-01391). Results: This screening identified several interesting drug candidates from both the NCI Approved Oncology Drugs library and the Prestwick chemical library® that show promising induction of cell death and/or inhibition of growth. Most promising was an anti-inflammatory agent, which induced more than 80% cell death in the OVSAHO cell line at a concentration of 5 uM. Interestingly, some drugs induced significantly different responses in human plasma-like medium (HPLM) compared to the standard culture medium, while others were not affected, and some drugs also showed interaction with carboplatin and/or paclitaxel. Mouse models of xenotransplants have been established for future experiments. Conclusion: We have identified promising drug candidates that could serve as alternative treatment for platinum-resistant HGSC. This study is supported by Fabrikant Chas. Otzen´s Fond, Købmand Niels Erik Munk Pedersen Fonden, and by the Horizon2020 project DECIDER (grant no. 965193). Citation Format: Marie L. Bay, Aikaterini Skorda, Benita S. Rasmussen, Jaume R. Arias, Anna R. Lauridsen, Kaisa Huhtinen, Sampsa Hautaniemi, Johanna Hynninen, Tuula Kallunki. Screening of drug candidates to repurpose for high-grade serous ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B027.
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Zietek, Tamara, Wolfgang A. D. Boomgaarden und Eva Rath. „Drug Screening, Oral Bioavailability and Regulatory Aspects: A Need for Human Organoids“. Pharmaceutics 13, Nr. 8 (17.08.2021): 1280. http://dx.doi.org/10.3390/pharmaceutics13081280.
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The intestinal epithelium critically contributes to oral bioavailability of drugs by constituting an important site for drug absorption and metabolism. In particular, intestinal epithelial cells (IEC) actively serve as gatekeepers of drug and nutrient availability. IECs’ transport processes and metabolism are interrelated to the whole-body metabolic state and represent potential points of origin as well as therapeutic targets for a variety of diseases. Human intestinal organoids represent a superior model of the intestinal epithelium, overcoming limitations of currently used in vitro models. Caco-2 cells or rodent explant models face drawbacks such as their cancer and non-human origin, respectively, but are commonly used to study intestinal nutrient absorption, enterocyte metabolism and oral drug bioavailability, despite poorly correlative data. In contrast, intestinal organoids allow investigating distinct aspects of bioavailability including spatial resolution of transport, inter-individual differences and high-throughput screenings. As several countries have already developed strategic roadmaps to phase out animal experiments for regulatory purposes, intestinal organoid culture and organ-on-a-chip technology in combination with in silico approaches are roads to go in the preclinical and regulatory setup and will aid implementing the 3Rs (reduction, refinement and replacement) principle in basic science.
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Tsuji, Motonori. „Virtual Screening and Quantum Chemistry Analysis for SARS-CoV-2 RNA-Dependent RNA Polymerase Using the ChEMBL Database: Reproduction of the Remdesivir-RTP and Favipiravir-RTP Binding Modes Obtained from Cryo-EM Experiments with High Binding Affinity“. International Journal of Molecular Sciences 23, Nr. 19 (20.09.2022): 11009. http://dx.doi.org/10.3390/ijms231911009.
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The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning.
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Onishi, Iichiroh, Kouhei Yamamoto, Yuko Kinowaki, Masanobu Kitagawa und Morito Kurata. „To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases“. International Journal of Molecular Sciences 22, Nr. 22 (15.11.2021): 12322. http://dx.doi.org/10.3390/ijms222212322.
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CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies.
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Ibrahim, Mohammed, Md Aslam Hossain, Md Shafiullah Shajib und Mohammad A. Rashid. „Preliminary Phytochemical and Pharmacological Screenings of Plumbago indica L. and Alpinia conchigera Griff.“ Dhaka University Journal of Pharmaceutical Sciences 17, Nr. 1 (24.06.2018): 73–79. http://dx.doi.org/10.3329/dujps.v17i1.37121.
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The present study was conducted to evaluate the phytochemical constituents, anti-inflammatory, antipyretic, thrombolytic and CNS modulatory activities of the methanol, chloroform and n-hexane extracts of Plumbago indica L. and Alpinia conchigera Griff. The plants are used in the treatment of inflammations and fever in traditional systems of medicine in Bangladesh. Qualitative tests revealed that the crude extracts of the plants contain reducing sugars, steroids, alkaloids and flavonoids. The anti-inflammatory activity was evaluated by means of protein denaturation and membrane stabilization assay. The methanol extract of P. indica and A. conchigera demonstrated inhibition of protein denaturation by 34.55 and 29.55% while their n-hexane soluble extract exhibited 46.87 and 37.21% inhibition of lysis of erythrocyte membrane, respectively which were considerable as compared to the standard drug acetyl salicylic acid. The methanol extract of P. indica and A. conchigera prominently reduced Brewer’s yeast-induced pyrexia which were close to the standard drug, paracetamol. A considerable thrombolytic activity was exhibited by the chloroform soluble extract of A. conchigera (48.27%) compared to the reference drug, streptokinase (72.13%) in red blood cell clot lysis test. The chloroform soluble materials of P. indica extract demonstrated noticeable reduction of CNS depression activity (63.52 % inhibition of locomotion), compared to reference drug diazepam (80.69 %) in open field experiment. The study justifies the medicinal applications of P. indica and A. conchigera in traditional systems and reveals the bioactivity of the plants which could be suitable for isolation and identification of the bioactive compounds.Dhaka Univ. J. Pharm. Sci. 17(1): 73-79, 2018 (June)
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Barron, Nadine, Stephan Dickgiesser, Markus Fleischer, Angelika-Nicole Bachmann, Daniel Klewinghaus, Jens Hannewald, Elke Ciesielski et al. „A Generic Approach for Miniaturized Unbiased High-Throughput Screens of Bispecific Antibodies and Biparatopic Antibody–Drug Conjugates“. International Journal of Molecular Sciences 25, Nr. 4 (08.02.2024): 2097. http://dx.doi.org/10.3390/ijms25042097.
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The toolbox of modern antibody engineering allows the design of versatile novel functionalities exceeding nature’s repertoire. Many bispecific antibodies comprise heterodimeric Fc portions recently validated through the approval of several bispecific biotherapeutics. While heterodimerization methodologies have been established for low-throughput large-scale production, few approaches exist to overcome the bottleneck of large combinatorial screening efforts that are essential for the identification of the best possible bispecific antibody. This report presents a novel, robust and miniaturized heterodimerization process based on controlled Fab-arm exchange (cFAE), which is applicable to a variety of heterodimeric formats and compatible with automated high-throughput screens. Proof of applicability was shown for two therapeutic molecule classes and two relevant functional screening read-outs. First, the miniaturized production of biparatopic anti-c-MET antibody–drug conjugates served as a proof of concept for their applicability in cytotoxic screenings on tumor cells with different target expression levels. Second, the automated workflow enabled a large unbiased combinatorial screening of biparatopic antibodies and the identification of hits mediating potent c-MET degradation. The presented workflow utilizes standard equipment and may serve as a facile, efficient and robust method for the discovery of innovative therapeutic agents in many laboratories worldwide.
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Pudelko, Linda, Steven Edwards, Mirela Balan, Daniel Nyqvist, Jonathan Al-Saadi, Johannes Dittmer, Ingrid Almlöf, Thomas Helleday und Lars Bräutigam. „An orthotopic glioblastoma animal model suitable for high-throughput screenings“. Neuro-Oncology 20, Nr. 11 (10.05.2018): 1475–84. http://dx.doi.org/10.1093/neuonc/noy071.
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Abstract Background Glioblastoma (GBM) is an aggressive form of brain cancer with poor prognosis. Although murine animal models have given valuable insights into the GBM disease biology, they cannot be used in high-throughput screens to identify and profile novel therapies. The only vertebrate model suitable for large-scale screens, the zebrafish, has proven to faithfully recapitulate biology and pathology of human malignancies, and clinically relevant orthotopic zebrafish models have been developed. However, currently available GBM orthotopic zebrafish models do not support high-throughput drug discovery screens. Methods We transplanted both GBM cell lines as well as patient-derived material into zebrafish blastulas. We followed the behavior of the transplants with time-lapse microscopy and real-time in vivo light-sheet microscopy. Results We found that GBM material transplanted into zebrafish blastomeres robustly migrated into the developing nervous system, establishing an orthotopic intracranial tumor already 24 hours after transplantation. Detailed analysis revealed that our model faithfully recapitulates the human disease. Conclusion We have developed a robust, fast, and automatable transplantation assay to establish orthotopic GBM tumors in zebrafish. In contrast to currently available orthotopic zebrafish models, our approach does not require technically challenging intracranial transplantation of single embryos. Our improved zebrafish model enables transplantation of thousands of embryos per hour, thus providing an orthotopic vertebrate GBM model for direct application in drug discovery screens.
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Mitchell, Ann M., Holly Hagle, Kathy Puskar, Irene Kane, Dawn Lindsay, Kimberly Talcott, Peter F. Luongo und Eric Goplerud. „Alcohol and Other Drug Use Screenings by Nurse Practitioners: Clinical Issues and Costs“. Journal for Nurse Practitioners 11, Nr. 3 (März 2015): 347–51. http://dx.doi.org/10.1016/j.nurpra.2014.12.007.
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