Molecular concepts analysis links tumors, pathways, mechanisms, and drugs.
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ABSTRACT:
SUBMITTER: Rhodes DR
PROVIDER: S-EPMC1877973 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hypertension is a leading age-related disease in our society and if left untreated, leads to fatal cardiovascular complications. The prevalence of hypertension has increased and becomes a significant global health economic burden, particularly in lower-income societies. Many loci associated with blood pressure and hypertension have been reported by genome-wide association studies that provided potential targets for pharmacotherapy. Pharmacogenetic research had shown interindividual variations in drug efficacy, safety, and tolerability. This could be due to genetic polymorphisms in the pharmacokinetics (genes involved in a transporter, plasma protein binding, and metabolism) or pharmacodynamic pathway (receptors, ion channels, enzymes). Pharmacogenetics promises great hope toward targeted therapy, but challenges remain in implementing pharmacogenetic aided antihypertensive therapy in clinical practice. Using various databases, we analyzed the underlying mechanisms between the candidate gene polymorphisms and antihypertensive drug interactions and the challenges of implementing precision medicine. We review the emergence of pharmacogenetics and its relevance to clinical pharmacological practice.
| S-EPMC8411967 | biostudies-literature
Project description:Using laser capture microdissection to isolate over 100 specific cell populations, we report the profiling of prostate cancer progression from benign epithelium to metastatic disease. By analyzing these expression signatures in the context of over 15,000 “molecular concepts”, or sets of biologically connected genes, we generated an integrative model of prostate cancer progression. Keywords: disease state analysis
2006-12-17 | GSE6099 | GEO
Project description:BackgroundWe investigated the role of diabetes mellitus (DM) and the molecular mechanisms of antidiabetic drugs in prostate cancer (PCa).Patients and methods167 patients with both DM and PCa underwent radical prostatectomy (RPE). We divided our patient collective into "metformin" users, "insulin" users, "other antidiabetic drug" users and those with "no antidiabetic drug/diet only" (control group) and analyzed differences in PCa aggressiveness and laboratory parameters among treatment groups. In addition, we generated a tissue-micro-array (TMA) from RPE specimens for the analysis of candidate target pathways of antidiabetic drugs by immunohistochemistry (IHC).ResultsGleason score of both biopsy and RPE, biopsy undergrading, tumor stage as well as positive resection margins did not significantly change among groups. Preoperative body mass-index, PSA, fPSA and prostate volume/weight did not change among the treatment groups. As well, CRP, GOT, GPT, yGT, LDH, amylase, hemoglobin, TSH, FT3 and FT4 did not differ. Metformin or insulin use was not associated with changes in biochemical tumor recurrence or PCa specific mortality rates. However, tissue TMA analyses by IHC showed decreased mTOR activation, as indicated by phospho-mTOR in cancer tissue of patients with metformin and also with insulin use compared to the control group. In addition, we were able to show that the androgen receptor and the epithelial-cell contact marker E-cadherin decreased upon metformin use compared to the control group.ConclusionWe did not find a connection between antidiabetic drugs and PCa aggressiveness or progression. However, tumor biology seems to be different among patients with and without antidiabetic drugs.
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Project description:Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive 'omic' analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.
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Project description:Substance abuse is on the rise, and while many people may use illicit drugs mainly due to their rewarding effects, their societal impact can range from severe, as is the case for opioids, to promising, as is the case for psychedelics. Common with all these drugs' mechanisms of action are G protein-coupled receptors (GPCRs), which lie at the center of how these drugs mediate inebriation, lethality, and therapeutic effects. Opioids like fentanyl, cannabinoids like tetrahydrocannabinol, and psychedelics like lysergic acid diethylamide all directly bind to GPCRs to initiate signaling which elicits their physiological actions. We herein review recent structural studies and provide insights into the molecular mechanisms of opioids, cannabinoids, and psychedelics at their respective GPCR subtypes. We further discuss how such mechanistic insights facilitate drug discovery, either toward the development of novel therapies to combat drug abuse or toward harnessing therapeutic potential.
| S-EPMC10514560 | biostudies-literature
Project description:Using laser capture microdissection to isolate over 100 specific cell populations, we report the profiling of prostate cancer progression from benign epithelium to metastatic disease. By analyzing these expression signatures in the context of over 15,000 â??molecular conceptsâ??, or sets of biologically connected genes, we generated an integrative model of prostate cancer progression. Keywords: disease state analysis Experiment Design: â?¢ Type of experiment: This study used microarray experiments to profile prostate cancer progression through the isolation of pure cell populations using laser capture microdissection (LCM) and OmniPlex Whole Transcriptome (WTA) Amplification. â?¢ Experimental factors: This study profiled various pure cell populations isolated by LCM from prostate tissue. â?¢ The number of hybridizations performed in the experiment: A total of 104 hybridizations were performed. â?¢ The type of reference used for the hybridizations: A single commercially available pool of benign prostate tissue (CPP, Clontech) was used as the reference in all hybridizations. For the reference sample, 10 ng of CPP total RNA was converted into a WTA cDNA library in a volume of 25 µl and five 5 µl aliquots were amplified by WTA PCR and purified. Five ng aliquots of the pooled products were subjected to a second WTA PCR amplification in the presence of amino-allyl dUTP and all products were pooled before labeling to ensure equal representation across all of the hybridizations. â?¢ Hybridization design: For all hybridizations, the experimental prostate sample isolated by LCM was labeled with Cy5 and the common reference of benign pooled prostate as described above was labeled with Cy3. â?¢ Quality control steps taken: In order to assess biological and technical reproducibility, we captured identical regions from two specimens (PCA_11 and MET_HR_3) and subjected one sample, PCA_30, to two hybridizations. For PCA_11, adjacent regions of the same section were captured and treated as separate samples. For MET_HR_3, two separate foci of the liver metastasis (from separate frozen blocks) were captured and treated as separate samples. For PCA_30, two aliquots of the primary WTA PCR products were separately subjected to a second round of WTA PCR amplification. Replicates from PCA_30 and MET_HR_3 were also hybridized to arrays from each of the print runs utilized in this study. Samples used, extract preparation and labeling: â?¢ The origin of the biological sample (for instance, name of the organism, the provider of the sample) and its characteristics: All samples used were of human origin. The table in the MIAME Checklist (Supplmentary Methods) summarizes the samples used. Hybridizations are named according to the class of sample profiled and the background color is the same as shown in Figure S3. Two print runs were used during the course of the study and the indicated run for each hybridization is given. For prostate cancer samples, the Gleason patterns present on the sample section used are indicated, as well as the Gleason patterns of the actual cells isolated by LCM. A unique case number for all profiled samples is given. Descriptions of samples are given where applicable, including the location of metastatic foci. â?¢ Manipulation of biological samples and protocols used: Laser Capture Microdissection (LCM) was performed from frozen tissue sections with the SL Microtest device using µCUT software (MMI). Approximately 10,000 cells were captured for each sample. Serial sections were used if cells could not be obtained from a single section. Total RNA was isolated from captured cells with the RNAqueous Micro kit (Ambion) and treated with DNAse I according to the manufacturer's instructions. RNA quantification was perfomed using Ribogreen (Molecular Probes). â?¢ Protocol for preparing the hybridization extract: For each sample, total RNA (~10ng) in a volume of 25 µl was converted into an OmniPlex WTA cDNA library and amplified by WTA PCR using reagents and protocols according to the beta-commercial TransPlex WTA kit (Rubicon Genomics, Ann Arbor, MI). For each sample, a single 10 µl aliquot of the WTA cDNA library was amplified by WTA PCR and products were purified. Four or five 5 ng aliquots of product were subjected to a second WTA PCR amplification in the presence of amino-allyl dUTP for post amplification labeling and products were pooled before proceeding with the hybridization. Yields after all WTA PCR amplifications were between 2 to 5 μg per reaction, and reaction progress was monitored in real time using SYBR green I (Molecular Probes) on the iCycler IQ (BioRad) or ABI 7300 Real Time PCR system (Applied Biosystems). Real-time PCR amplifications were terminated at or before plateau phase as measured by fluorescence incorporation to preserve maximum representation. â?¢ Labeling protocol(s): For all WTA amplified cDNA samples with amino-allyl dUTP incorporated (10-20 ï?g), nuclease free water was added to 500 ï?l, the sample was transferred to a Microcon YM-30 filter, and centrifuged at 13,000 rcf at RT for 12 minutes. The spin column was inverted in a new collection tube and centrifuged at 13,000 rcf for 2 min at RT. The amount of sample was measured and the volume was adjusted to 5 ï?l with nuclease free water. For labeling, 5 ï?l of 1 M sodium bicarbonate (pH 9.0) was added and allowed to incubate at RT for 15 min. Nine ï?l of anhydrous DMSO were added to Mono Reactive Cy3 and Cy5 dye packs (Amersham, Buckinghamshire, England), mixed thoroughly, and 1 ï?l of the proper dye was added to each sample. The labeling mixture was incubated in the dark at RT for 1 hour. The reaction was stopped by the addition of 9 ï?l of 4 M Hydroxylamine for 15 min. For each labeling mixture, RNase free water was added to 100 ï?l, 500 ï?l of PB buffer was added and Cy3 and Cy5 mixtures were added to separate Qiaquick (Qiagen, Valencia, CA) spin columns and centrifuged at 13,000 rcf. Columns were washed twice with 700 ï?l of buffer PE, and centrifuged dry at 13,000 rcf for 2 min. To elute, 60 ï?l of EB buffer was placed on the column, incubated for 5 min and centrifuged at 13,000 rcf for 1 min. The Cy3 labeled and Cy5 labeled cDNA for each hybridization were mixed and 1.5 ï?l were used for analysis on a ND-1000 spectrophotometer. â?¢ External controls (spikes): Not utilized Hybridization procedures and parameters: â?¢ The protocol and conditions used during hybridization, blocking and washing: For hybridization, 40 ï?g of human Cot-1 DNA (Invitrogen, Carlsbad, CA) was added to 120 ï?l of labeled cDNA, the probe was transferred to a Microcon YM-30 filter and centrifuged at 13,000 rcf for 6 min at RT. The spin column was inverted in a new collection tube and centrifuged at 13,000 rcf for 2 min at RT. The eluted probe volume was adjusted to 18.6 ï?l with nuclease free water and the following were added: 4 ï?l of yeast tRNA (10 ï?g/ï?l, Invitrogen, Carlsbad, CA), 4.9 ï?l of 20X SSC and 0.84 ï?l of 10% SDS. The probe was denatured at 100 Co for 3 min and centrifuged at 13,000 rcf for 45 sec. The probe was added directly to the microarray and a cover slip was added. Slides were hybridized overnight in DIE-TECH 1 or 5 slide hybridization chambers in a 65 Co water bath. After hybridization, cover slips were removed by incubation in 2x SSC / 0.05% SDS. Slides were then washed in 2x SSC / 0.05% SDS for 5 min and 0.2x SSC / 0.05% SDS for five minutes. Slides were then washed in 0.2x SSC for 10 sec and centrifuged dry at 500 rpm for 5 min. Measurement data and specifications: â?¢ Type of scanning hardware and software used: Microarrays were scanned using a GenePix 4000B scanner (Axon Instruments, Union City, CA). â?¢ Type of image analysis software used: Images were gridded and spots were quantified using GenePix Pro 4.0 software (Axon Instruments, Union City, CA). â?¢ A description of the measurements produced by the image-analysis software and a description of which measurements were used in the analysis: The measurements made by GenePix Pro 4.0 are described in the sample files. For all hybridizations, the log2 normalized Median of Ratios (as described below) was used. â?¢ Data selection and transformation procedures: Arrays were auto-gridded by GenePix 4.0. Features flagged by GenePix as not found during grid
2010-06-05 | E-GEOD-6099 | biostudies-arrayexpress
Project description:Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.
| S-EPMC5081129 | biostudies-literature
Project description:With the identification of activating mutations in BRAF across a wide variety of malignancies, substantial effort was placed in designing safe and effective therapeutic strategies to target BRAF. These efforts have led to the development and regulatory approval of three BRAF inhibitors as well as five combinations of a BRAF inhibitor plus an additional agent(s) to manage cancer such as melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer. To date, each regimen is effective only in patients with tumors harboring BRAFV600 mutations and the duration of benefit is often short-lived. Further limitations preventing optimal management of BRAF-mutant malignancies are that treatments of non-V600 BRAF mutations have been less profound and combination therapy is likely necessary to overcome resistance mechanisms, but multi-drug regimens are often too toxic. With the emergence of a deeper understanding of how BRAF mutations signal through the RAS/MAPK pathway, newer RAF inhibitors are being developed that may be more effective and potentially safer and more rational combination therapies are being tested in the clinic. In this review, we identify the mechanics of RAF signaling through the RAS/MAPK pathway, present existing data on single-agent and combination RAF targeting efforts, describe emerging combinations, summarize the toxicity of the various agents in clinical testing, and speculate as to where the field may be headed.
| S-EPMC9616966 | biostudies-literature
Project description:Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase-signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage-targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage-targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.
| S-EPMC10495745 | biostudies-literature
Project description:BACKGROUND Accumulating evidence suggests that cardiotoxicity is one of the main manifestations of aconitine (AC) poisoning. However, the molecular mechanism of AC-induced cardiotoxicity remains unclear, there is little direct evidence for therapeutic targets and drugs of AC-induced cardiotoxicity. MATERIAL AND METHODS Zebrafish were exposed to AC to evaluate cardiotoxicity by calculating the heart rates and observing the changes of cardiac and vascular structure. RNA-seq (RNA sequencing) and bioinformatics analysis were used to obtain differentially expressed genes (DEGs). The anti-AC cardiotoxicity compound was identified via connectivity map (CMAP) analysis and molecular docking. RESULTS AC-induced cardiotoxicity in zebrafish predominantly included arrhythmias, extended sinus venous and bulbus arteriosus (SV-BA) distance, and larger pericardial edema aera. A total of 1380 DEGs were identified by RNA-seq and bioinformatics analysis. cyclin-dependent kinase-1 (CDK1) was screened as the hub gene and the most potential therapeutic target due to its significant downregulation in cardiotoxicity based on protein-protein interaction (PPI) and drug-gene interaction (DGIdb) network analysis. Cell cycle signal pathway was the most significant pathways identified in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Furthermore, the expression of CDK1 was validated in the Gene Expression Omnibus (GEO) database GSE71906, GSE65705, and GSE95140. Finally, heptaminol was identified as a novel anti-AC cardiotoxicity compound via CMAP analysis and molecular docking. CONCLUSIONS Totally, hub genes and key pathways identified in this study can aid in the understanding of the molecular changes in AC-induced cardiotoxicity. Meanwhile, we provide a systematic method to explore drug toxicity prevention and treatment.
| S-EPMC7341694 | biostudies-literature