SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures.

CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.

Network Pharmacology-Based Pharmacological Mechanism of the Chinese Medicine Rhizoma drynariae Against Osteoporosis.

d_abstr_R Rhizoma drynariae is the main traditional Chinese medicine used for the treatment of osteoporosis, but its anti-osteoporotic targeting mechanism has not been fully elucidated due to the complexity of its active ingredients. In this study, the pharmacological mechanism of action of Rhizoma drynariae against osteoporosis was studied by integrating pharmacological concepts. The pharmacokinetic characteristics of selected major active constituents of Rhizoma drynariae and the SMILES structural similarity were used to predict related targets. A literature search was conducted to identify known osteoporosis treatment targets, which were then combined with the predicted targets to construct the direct or indirect target interaction network map of Rhizoma drynariae against osteoporosis. Finally, data on the key targets of the interactions, ranked according to relevant node parameters obtained through pathway enrichment analysis and screening of key targets and active ingredients of Rhizoma drynariae, were used to perform molecular docking simulation. We screened 16 active ingredients of Rhizoma drynariae, and 7 key targets with direct or indirect effects with a high frequency were obtained. These main pathways were found to play important roles in the PI3k-akt signaling pathway, osteoclast differentiation, Wnt signaling pathway, and estrogen signaling pathway. Molecular docking showed that most active ingredients of Rhizoma drynariae had strong binding efficiency with key targets. Based on network pharmacology, we conclude that Rhizoma drynariae plays an anti-osteoporotic role by directly or indirectly targeting multiple major signaling pathways and influencing the proliferation and differentiation of multiple types of cells.

Discovery of the Anti-Tumor Mechanism of Calycosin Against Colorectal Cancer by Using System Pharmacology Approach.

BACKGROUND The aim of our study was to elucidate the biological targets and pharmacological mechanisms for calycosin (CC) against colorectal cancer (CRC) through an approach of system pharmacology. MATERIAL AND METHODS Using a web-based platform, all CRC-causing genes were identified using a database of gene-disease associations (DisGeNET), and all well-known genes of CC identified using the databases of prediction of protein targets of small molecules (Swiss Target Prediction), drug classification, and target prediction (SuperPred). The carefully selected genes of CRC and CC were concurrently constructed by using a database of functional protein association networks (STRING), and use of software for visualizing complex networks (Cytoscape), characterized with production of protein-protein interaction (PPI) network of CC against CRC. The important biological targets of CC against CRC were identified through topological analysis, then the biological processes and molecular pathways of CC against CRC were further revealed for testing these important biotargets by enrichment assays. RESULTS We found that the key predictive targets of CC against CRC were estrogen receptor 2 (ESR2), ATP-binding cassette sub-family G member 2 (ABCG2), breast cancer type 1 susceptibility protein (BRCA1), estrogen receptor 1 (ESR1), cytochrome p450 19A1 (CYP19A1), and epidermal growth factor receptor (EGFR). Visual analysis revealed that the biological processes of CC against CRC were positively linked to hormonal metabolism, regulation of genes, transport, cell communication, and signal transduction. Further, the interrelated molecular pathways were chiefly related to endogenous nuclear estrogen receptor alpha network, forkhead box protein A1 (FOXA1) transcription factor network, activating transcription factor 2 (ATF2) transcription factor network, regulation of telomerase, plasma membrane estrogen receptor signaling, estrogen biosynthesis, androgen receptor, FOXA transcription factor networks, estrogen biosynthesis, and phosphorylation of repair proteins. CONCLUSIONS Use of system pharmacology revealed the biotargets, biological processes, and pharmacological pathways of CC against CRC. Intriguingly, the identifiable predictive biomolecules are likely potential targets for effectively treating CRC.

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations.

Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the "connectivity" framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics.

Reações adversas na cavidade oral em decorrência do uso de medicamentos / Side effects in oral cavity in consequent of medication use

Introdução: as reações adversas a medicamentos constituem um problema importante na prática do profissional da área da saúde, já que essas reações são causas de hospitalização, aumento no tempo de permanência hospitalar e da morbimortalidade. Muitas das reações adversas aos fármacos apresentam-se na cavidade oral. Objetivo: descrever os principais medicamentos com potencial de efeitos colaterais na cavidade oral, agrupando os que causam efeitos adversos semelhantes. Método: trata-se de estudo bibliográfico e descritivo por meio de utilização de estudos originais e atualizados a partir dos bancos de dados oficiais SciELO, PUBMED e LILACS. Priorizaram-se artigos em língua portuguesa, inglesa e espanhola, que incluíam revisões bibliográficas, meta-análises e relatos de casos publicados entre 2000 e 2015. Foram utilizados como descritores os termos: manifestações orais e medicamentos, lesões orais e medicamentos, mucosa oral e medicamentos e reação medicamentosa na cavidade oral. Resultados e Discussão: dezenove artigos foram analisados detalhadamente e mostram predominância de relatos de caso. Vários medicamentos foram associados com alterações patológicas nos tecidos orais, sobretudo os medicamentos utilizados em oncologia e medicamentos com ação no sistema nervoso central. As reações adversas às drogas dependem do fármaco e são bastante variáveis, e dentre as encontradas destacam-se ulceração de mucosa, hiperplasia gengival, xerostomia e diminuição do fluxo salivar. Conclusão: algumas lesões são comuns a diferentes medicamentos e, dessa forma, é fundamental a observação correta da possibilidade de sequela associada à terapia medicamentosa. Uma anamnese adequada com um levantamento do histórico médico completo do paciente é essencial para o profissional de saúde estar apto a fazer o diagnóstico das alterações e concluir o tratamento adequado para a solução do problema. (AU)

Introduction: adverse drug reactions are an important problem in the practice of health professionals, since these reactions may cause hospitalization, increase in length of hospital stay and morbidity and mortality. Many adverse drug reactions occur in the oral cavity. Objective: to describe the main drugs with potential side effects in the oral cavity, grouping those that cause similar adverse effects. Methods: bibliographic and descriptive study through use of original studies from three databases: SciELO, PubMed and LILACS. Selected papers were in Portuguese, English and Spanish, which included literature reviews, meta-analysis and case reports published between 2000 and 2015. The terms used were: oral medications and manifestations, oral lesions and medicines, oral mucosa and drugs and adverse drug reaction in the oral cavity. Results and Discussion: nineteen articles were analyzed in detail and case reports were predominant. Several drugs have been associated with pathological changes in oral tissue, in particular drugs used in oncology and those acting on the central nervous system. Adverse drug reactions depend on the medication and are quite variable. Among the found reaction are: ulcerative mucosa, gingival hyperplasia, xerostomia and decreased salivary flow. Conclusion: some lesions are common to different drugs, making critical the proper observation of possible sequelae associated with drug therapy. Detailed anamnesis with a complete medical history of the patient is essential for the proper diagnosis and a better therapeutic decision. (AU)

Pharmacological characterization of venoms from three theraphosid spiders: Poecilotheria regalis, Ceratogyrus darlingi and Brachypelma epicureanum

BackgroundTarantulas (Theraphosidae) represent an important source of novel biologically active compounds that target a variety of ion channels and cell receptors in both insects and mammals. In this study, we evaluate and compare the pharmacological activity of venoms from three taxonomically different theraphosid spiders bred in captivity: Poecilotheria regalis, an aggressive arboreal tarantula from southeastern India; Ceratogyrus darlingi, an aggressive tarantula from southern Africa; and Brachypelma epicureanum, a docile tarantula from the Yucatan dry forest of Mexico. Prior to this study, no research had been conducted with regard to the composition and pharmacological activity of these venoms.MethodsThe pharmacological characterization of the venoms was described for the first time by the assessment of their toxicity in crickets (LD50) along with their nociceptive (by using the formalin test), hyaluronidase, phospholipase A2, edematogenic and caseinolytic activity.ResultsP. regalis and B. epicureanum venoms induced a similar lethal effect on crickets (LD50 = 5.23 ± 3.1 and 14.4 ± 5.0 μg protein/g 48 h post-injection, respectively), whereas C. darlingi venom (119.4 ± 29.5 μg protein/g 48 h post-injection) was significantly less lethal than the other two venoms. All three venoms induced similar edematogenic activity on rats but did not induce nociceptive behavior. The assessment of enzymatic activity indicated that P. regalis venom induces significantly higher hyaluronidase activity (27.6 ± 0.9 TRU/mg) than both C. darlingi (99.7 ± 1.9 TRU/mg) and B. epicureanum (99.6 ± 1.6 TRU/mg); these latter venoms did not display phospholipase A2or caseinolytic activity.ConclusionsThis study demonstrates that these theraphosid spiders of different habitats produce venoms with different activities. P. regalis venom displays a high level of hyaluronidase activity, which may be associated with its potentially medically significant bite.(AU)