Clinical Drugs Research Articles

Rac2 mediate foam cell formation and associated immune responses in THP-1 to promote the process of atherosclerotic plaques

Macrophages play an important role in the pathogenesis of atherosclerosis (AS) by mediating oxidative stress, inflammation and lipid metabolism, which can lead to the formation of vascular plaque. The Rac family isoforms of small molecules GTPase are active by binding to GTPase, but are inactivated by binding to GDP, and play a role in the switch of cell information conduction. This experiment adopts shRNA interference THP-1 cells respectively each subtype expression and inhibiting Rac1, Rac2, Rac3 activity, each subtype of Rac family on lipid metabolism, inflammatory reaction and oxidative stress. THP-1 cells were stimulated with Ox-LDL to establish AS cell models including lipid loading, adhesion, migration and chemotaxis. Oil Red O staining, cell immunofluorescence, scratching test, transwell, Western blot and other experiments were performed. To observe the different effects of three subtypes of Rac family on multiple links in the foaming process of THP-1 cells. ApoE-/- mice on a high-fat diet were used as animal models to examine the effects of Rac subtypes in vivo. The results showed that the activation of immune cells induced by ox-LDL was inhibited when Rac1, Rac2 and Rac3 in THP-1 were decreased, respectively. Thus, Rac1 and Rac3 act in combination with ox-LDL and are associated with cellular oxidative stress and inflammation. This study provides new means and ideas for finding potential intervention targets that have important regulatory effects on atherosclerosis, and provides a new direction for the development of clinical drugs.

Dauricine attenuates Oct4/sonic hedgehog co-activated stemness and induces reactive oxygen species-mediated mitochondrial apoptosis via AKT/β-catenin signaling in human neuroblastoma and glioblastoma stem-like cells.

Neuroblastoma and glioblastoma are primary malignant tumors of the nervous system, with frequent relapse and limited clinical therapeutic drugs. The failure of their treatment is due to the tumor cells exhibiting cancer stem-like cells (CSLCs) properties. Octamer binding transcription factor 4 (Oct4) is involved in mediating CSLCs, our previous work found that Oct4-driven reprogramming of astrocytes into induced neural stem cells was potentiated with continuous sonic hedgehog (Shh) stimulation. In this study, we aimed to study the importance of Oct4 and Shh combination in the stemness properties induction of neuroblastoma and glioblastoma cells, and evaluate the anti-stemness effect of dauricine (DAU), a natural product of bis-benzylisoquinoline alkaloid. The effect of Oct4 and Shh co-activation on cancer stemness was evaluated by tumor spheres formation model and flow cytometry analysis. Then the effects of DAU on SH-SY5Y and T98-G cells were assessed by the MTT, colony formation, and tumor spheres formation model. DAU acts on Oct4 were verified using the Western blotting, MTT, and so on. Mechanistic studies were explored by siRNA transfection assay, Western blotting, and flow cytometry analysis. We identified that Shh effectively improved Oct4-mediated generation of stemness in SH-SY5Y and T98-G cells, and Oct4 and Shh co-activation promoted cell growth, the resistance of apoptosis. In addition, DAU, a natural product, was found to be able to attenuate Oct4/Shh co-activated stemness and induce cell cycle arrest and apoptosis via blocking AKT/β-catenin signaling in neuroblastoma and glioblastoma, which contributed to the neuroblastoma and glioblastoma cells growth inhibition by DAU. In summary, our results indicated that the treatment of DAU may be served as a potential therapeutic method in neuroblastoma and glioblastoma.

VARIDT 3.0: the phenotypic and regulatory variability of drug transporter.

The phenotypic and regulatory variability of drug transporter (DT) are vital for the understanding of drug responses, drug-drug interactions, multidrug resistances, and so on. The ADME property of a drug is collectively determined by multiple types of variability, such as: microbiota influence (MBI), transcriptional regulation (TSR), epigenetics regulation (EGR), exogenous modulation (EGM) and post-translational modification (PTM). However, no database has yet been available to comprehensively describe these valuable variabilities of DTs. In this study, a major update of VARIDT was therefore conducted, which gave 2072 MBIs, 10610 TSRs, 46748 EGRs, 12209 EGMsand 10255 PTMs. These variability data were closely related to the transportation of 585 approved and 301 clinical trial drugs for treating 572 diseases. Moreover, the majority of the DTs in this database were found with multiple variabilities, which allowed a collective consideration in determining the ADME properties of a drug. All in all, VARIDT 3.0 is expected to be a popular data repository that could become an essential complement to existing pharmaceutical databases, and is freely accessible without any login requirement at: https://idrblab.org/varidt/.

Nanodrug Delivery Strategies to Signaling Pathways in Alopecia.

Over 50% of the global population suffers from hair loss. The mixed results in the treatment of hair loss reveal the limitations of conventional commercial topical drugs. One the one hand, the definite pathogenesis of hair loss is still an enigma. On the other hand, targeted drug carriers ensure the drug therapeutic effect and low side effects. This review highlights the organization and overview of nine crucial signaling pathways associated with hair loss, as well as the development of nanobased topical delivery systems loading the clinical drugs, which will fuel emerging hair loss treatment strategies.

Bacterial Tyrosinase Inhibition, Hemolytic and Thrombolytic Screening, and In Silico Modeling of Rationally Designed Tosyl Piperazine-Engrafted Dithiocarbamate Derivatives.

Piperazine is a privileged moiety that is a structural part of many clinical drugs. Piperazine-based scaffolds have attracted the attention of pharmaceutical and medicinal scientists to develop novel, efficient therapeutic agents owing to their significant and promising biological profile. In the current study, an ecofriendly ultrasonic-assisted synthetic approach was applied to achieve a novel series of 1-tosyl piperazine dithiocarbamate acetamide hybrids 4a-4j, which was evaluated for in vitro tyrosinase inhibition and thrombolytic and hemolytic cytotoxic activities. Among all the piperazine-based dithiocarbamate acetamide target molecules 4a-4j, the structural analogs 4d displayed excellent tyrosinase inhibition efficacy (IC50 = 6.88 ± 0.11 µM) which was better than the reference standard drugs kojic acid (30.34 ± 0.75 µM) and ascorbic acid (11.5 ± 1.00 µM), respectively, which was further confirmed by in silico induced-fit docking (IFD) simulation Good tyrosinase activities were exhibited by 4g (IC50 = 7.24 ± 0.15 µM), 4b (IC50 = 8.01 ± 0.11 µM) and 4c (IC50 = 8.1 ± 0.30 µM) dithiocarbamate acetamides, which were also better tyrosinase inhibitors than the reference drugs but were less active than the 4d structural hybrid. All the derivatives are less toxic, having values in the 0.29 ± 0.01% to 15.6 ± 0.5% range. The scaffold 4b demonstrated better hemolytic potential (0.29 ± 0.01%), while a remarkably high thrombolytic chemotherapeutic potential was displayed by analog 4e (67.3 ± 0.2%).

In Silico Screening, In Vitro Mpro Inhibitory, and Adjunctive Therapy Value of Minocycline for the Treatment of COVID-19

What Is Known and Objective. Novel coronavirus disease (COVID-19) is still ravaging globally since its first discovery in 2019. With the continuous emergence of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) mutant strains, therapeutic entities are still needed to be discovered. This study was to explore SARS-CoV-2 inhibitors and therapeutic entities for COVID-19. Methods. Based on Lipinski’s rule of 5, a small-scale “old” drug database (clinical drugs being used in Ordos Central Hospital) was established, and in silico screening of Mpro inhibitors was conducted. Binding affinity and interaction as well as structure-affinity relationship were analyzed. Furthermore, molecular dynamic (MD) simulation of the selected drugs was performed to understand the conformational changes in docked complex. In vitro Mpro inhibition tests were performed according to established methods. Finally, literature review of potential “old” drug for the treatment of COVID-19 was conducted. Results and Discussion. The antibiotic minocycline, an inhibitor of bacterial ribosomal RNA, was screened out which showed the highest binding affinity (−9.6 kcal/mol). Beside the hydrogen bond with Cys145 and hydrophobic interactions, minocycline formed a pi-cation with His41, which strongly supported minocycline as a Michael addition acceptor to bind with the catalytic site of Mpro. MD simulation results show that minocycline displayed less conformational changes. The structure-affinity relationship was summarized based on minocycline analogs, and minocycline showed in vitro Mpro inhibitory activity with IC50 of 5 mM. More importantly, the literature review found that minocycline had both in vitro and in vivo broad-spectrum antiviral as well as anti-inflammatory activities, and the levels of a broad spectrum of biological markers during minocycline administration were opposed to those of COVID-19 conditions (both severe and nonsevere). What is New and Conclusion. Minocycline deserves an adjunctive therapeutic option for COVID-19 condition (both severe and nonsevere). This study shed a new light on drug-repurposing strategy for the viral disease.

Bioinformatics approach to identify the hub gene associated with COVID-19 and idiopathic pulmonary fibrosis.

The coronavirus disease 2019 (COVID-19) has developed into a global health crisis. Pulmonary fibrosis, as one of the complications of SARS-CoV-2 infection, deserves attention. As COVID-19 is a new clinical entity that is constantly evolving, and many aspects of disease are remain unknown. The datasets of COVID-19 and idiopathic pulmonary fibrosis were obtained from the Gene Expression Omnibus. The hub genes were screened out using the Random Forest (RF) algorithm depending on the severity of patients with COVID-19. A risk prediction model was developed to assess the prognosis of patients infected with SARS-CoV-2, which was evaluated by another dataset. Six genes (named NELL2, GPR183, S100A8, ALPL, CD177, and IL1R2) may be associated with the development of PF in patients with severe SARS-CoV-2 infection. S100A8 is thought to be an important target gene that is closely associated with COVID-19 and pulmonary fibrosis. Construction of a neural network model was successfully predicted the prognosis of patients with COVID-19. With the increasing availability of COVID-19 datasets, bioinformatic methods can provide possible predictive targets for the diagnosis, treatment, and prognosis of the disease and show intervention directions for the development of clinical drugs and vaccines.

Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine

Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.

Acoustic droplet ejection facilitates cell-based high-throughput screenings using natural products

Natural Products (NPs) are one of the main sources for drug discovery. Many clinical drugs are NPs or NP-inspired compounds, and recently discovered New Chemical Entities (NCEs) of NPs are emerging as promising new drugs. High-Throughput Screening (HTS) of large sample sets or libraries has grown to be vital for the drug discovery field. Industrial-scale HTS of NP libraries can be limited due to the difficulties entailed in working with tiny extract volumes and the variability in viscosity of NP extracts. For these reasons, the implementation of new technologies to miniaturize different reagent volumes grows to be fundamental. Since Acoustic Droplet Ejection (ADE) emerged as a helpful tool in HTS campaigns for the transference of compound libraries. The aim of this work was to test the effectiveness of ADE for the dispensation of NP extract libraries in cell-based HTS assays.

Establishment of organoid models for pancreatic ductal adenocarcinoma and screening of individualized therapy strategy.

Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and receive effective chemotherapy have the best chance for long-term survival. Unfortunately, because of the heterogeneity of pancreatic cancer, it is difficult to find a personalized treatment strategy for patients. Organoids are ideal preclinical models for personalized medicine. Therefore, we explore the cultivation conditions and construction methods of PDAC organoid models to screen the individualized therapy strategy. Fresh PDAC tissues from surgical resection were collected and digested with digestive enzymes; then the tumor cells were embedded in Matrigel with a suitable medium to establish the PDAC organoid models. The genetic stability of the organoids was analyzed using whole exon sequencing; hematoxylin and eosin staining and immunohistochemistry of organoids were performed to analyze their consistency with the pathological morphology of the patient's tumor tissue; After 2 days of organoid culture, we selected four commonly used clinical chemotherapy drugs for single or combined treatment to analyze drug sensitivity. Two cases of PDAC organoid models were successfully established, and the results of their pathological characteristics and exome sequencing were consistent with those of the patient's tumor tissue. Both PDAC organoids showed more sensitivity to gemcitabine and cisplatin, and the combined treatment was more effective than monotherapy. Both organoids better retained the pathological characteristics, genomic stability, and heterogeneity with the original tumor. Individual PDAC organoids exhibited different sensitivities to the same drugs. Thus, this study provided ideal experimental models for screening individualized therapy strategy for patients with PDAC.

B-307 Direct Quantitation of 77 Therapeutic and Clinical Toxicology Drugs in Dried Blood Spots Using the Fully Automated Transcend DSX-1 System

Abstract Background The dried blood spot (DBS) sampling technique is advantageous over the traditional liquid blood collection due to its minimal invasiveness, smaller sample volume, improved analyte stability, and ease of storage and transportation, resulting in its increasing usage in therapeutic drug monitoring and clinical toxicology. Here, we describe a fully automated workflow to rapidly extract and quantify a wide range of therapeutic drugs and drugs of abuse in DBS using the Thermo Scientific™ Transcend™ DSX-1 system, fulfilling the routine drug monitoring needs in the clinical laboratories. Methods Calibrators in blood are spotted on the DBS cards, analytes are extracted with the innovative flow-through desorption technology, and their corresponding internal standards (IS) are introduced via an automated IS addition module in the dried spot autosampler. The 2-dimensional TurboFlow technology allows the removal of interferences from the extracted samples before analytical separation. An integrated software controls every step of the sample desorption and separation. Analyte quantitation is performed on the Thermo Scientific™ TSQ Altis™ Plus triple quadrupole mass spectrometer, and the data is analyzed in TraceFinder™ software. Results A total of 77 therapeutic and clinical toxicology drugs from eleven classes, including anticonvulsants, antidepressants, antihistamines, antipsychotics, benzodiazepines, cocaine, dissociatives, opioids, and stimulants, are quantified in a single injection from DBS cards using a rapid automated method on a Transcend DSX-1 system. DSX-1 combines a dried spot module for direct analyte extraction with Transcend™ UHPLC for online sample separation using the TurboFlow technology. The method only takes 4.3 min from analyte extraction to MS detection. Good calibration curves with R2 > 0.98 are achieved using a weighting factor of 1/x, and the limit of quantification (LOQ) values are established with % RSD and % CV < 15, │% Diff│ < 20, and relative ion ratio < %20. The LOQ values are all in the low ng/mL levels, which largely meet the screening and confirmation sensitivity needs of analytical methodologies in routine clinical laboratories. Conclusion A fully automated LC-MS-based workflow is developed to rapidly and reliably quantitate 77 compounds therapeutic and clinical toxicology drugs in dried blood spots.

Streptomyces albidoflavus Q antifungal metabolites inhibit the ergosterol biosynthesis pathway and yeast growth in fluconazole-resistant Candida glabrata: phylogenomic and metabolomic analyses.

There is an urgent need to develop new antifungals due to the increasing prevalence of multidrug-resistant fungal infections and the recent emergence of COVID-19-associated candidiasis. A good study model for evaluating new antifungal compounds is Candida glabrata, an opportunistic fungal pathogen with intrinsic resistance to azoles (the most common clinical drugs for treating fungal infections). The aim of the current contribution was to conduct in vitro tests of antifungal metabolites produced by the bacteria Streptomyces albidoflavus Q, identify their molecular structures, and utilize several techniques to provide evidence of their therapeutic target. S. albidoflavus was isolated from maize rhizospheric soil in Mexico and identified by phylogenomic analysis using a 92-gene core. Of the 66 metabolites identified in S. albidoflavus Q by a liquid chromatography-high resolution mass spectrometry (LC-HRMS) metabolomic analysis of the lyophilized supernatant, six were selected by the Way2drug server based on their in silico binding to the likely target, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR, the key enzyme in the ergosterol biosynthesis pathway). Molecular modeling studies show a relatively high binding affinity for the CgHMGR enzyme by two secondary metabolites: isogingerenone B (diaryl heptanoid) and notoginsenoside J (polycyclic triterpene). These secondary metabolites were able to inhibit ergosterol synthesis and affect yeast viability in vitro. They also caused alterations in the ultrastructure of the yeast cytoplasmic membrane, as evidenced by transmission electron microscopy. The putative target of isogingerenone B and notoginsenoside J is distinct from that of azole drugs (the most common clinical antifungals). The target for the latter is the lanosterol 14 alpha-demethylase enzyme (Erg11). IMPORTANCE Multidrug resistance has emerged among yeasts of the genus Candida, posing a severe threat to global health. The problem has been exacerbated by the pandemic associated with COVID-19, during which resistant strains of Candida auris and Candida glabrata have been isolated from patients infected with the SARS-CoV-2 virus. To confront this challenge, the World Health Organization has invoked scientists to search for new antifungals with alternative molecular targets. This study identified 66 metabolites produced by the bacteria Streptomyces albidoflavus Q, 6 of which had promising properties for potential antifungal activity. The metabolites were tested in vitro as inhibitors of ergosterol synthesis and C. glabrata growth, with positive results. They were also found to damage the cytoplasmic membrane of the fungus. The corresponding molecular structures and their probable therapeutic target were established. The target is apparently distinct from that of azole drugs.

Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes

BackgroundPolymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca2+ handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro.MethodsPreviously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs.ResultsThe voltage-dependent Ca2+ channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca2+ in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control.ConclusionsBy testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca2+ release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest.

Metabolic diversity of tumor-infiltrating T cells as target for anti-immune therapeutics.

Tumor-infiltrating T cells are promising drug targets to modulate the tumor microenvironment. However, tumor-infiltrating T lymphocytes, as central targets of cancer immunotherapy, show considerable heterogeneity and dynamics across tumor microenvironments and cancer types that may fundamentally influence cancer growth, metastasis, relapse, and response to clinical drugs. The T cell heterogeneity not only refers to the composition of subpopulations but also divergent metabolic states of T cells. Comparing to the diversity of tumor-infiltrating T cell compositions that have been well recognized, the metabolic diversity of T cells deserves more attention for precision immunotherapy. Single-cell sequencing technology enables panoramic stitching of the tumor bulk, partly by showing the metabolic-related gene expression profiles of tumor-infiltrating T cells at a single-cell resolution. Therefore, we here discuss T cell metabolism reprogramming triggered by tumor microenvironment as well as the potential application of metabolic targeting drugs. The tumor-infiltrating T cells metabolic pathway addictions among different cancer types are also addressed in this brief review.

Ilexchinene, a new seco-ursane triterpenoid from the leaves of Ilex chinensis with therapeutic effect on neuroinflammation by attenuating the MAPK/NF-κB signaling pathway

BackgroundNeuroinflammation is a vital factor participating in the whole pathogenetic process of diverse neurodegenerative disorders, but accessible clinical drugs are still insufficient due to their inefficacy and side effects. Triterpenoids are reported to possess potential anti-neuroinflammatory activities, and the leaves of Ilex chinensis are a commonly used herbal medicine containing many ursane-type and oleanane-type triterpenoids. However, the novel triterpenoids from I. chinensis and their underlying mechanisms are still elusive. PurposeTo isolate novel seco-ursane triterpenoids with anti-neuroinflammatory effects from the leaves of I. chinensis and reveal their underlying mechanisms. Study design and methodsThe novel compound was purified by column chromatography and identified by comprehensive spectroscopic experiments. The LPS-induced BV-2 cell model and LPS-induced acute murine brain inflammation model were used to assess the anti-neuroinflammatory effect of the structure and further understand its underlying mechanisms by cell viability, ELISA, Western blot analysis, qRT‒PCR analysis, behavior analysis, H&E staining, and immunofluorescence staining experiments. ResultsIlexchinene is a novel ursane-type triterpenoid with a rare 18,19-seco-ring skeleton that was first isolated and identified from I. chinensis. Ilexchinene evidently reduced the overexpression of inflammatory substances in vitro. A mechanistic study suggested that ilexchinene could decrease NF-κB activation to prevent the formation of the NLRP3 inflammasome in the early neuroinflammatory response; in addition, it could prevent the phosphorylation of ERK and JNK. In vivo, ilexchinene remarkably improved LPS-induced mouse behavioral deficits and diminished the number of overactivated microglial cells. Furthermore, ilexchinene evidently diminished the overexpression of inflammatory substances in mouse brains. A mechanistic study confirmed that ilexchinene markedly suppressed the MAPK/NF-κB pathway to relieve the neuroinflammatory response. ConclusionWe identified a novel 18,19-seco-ursane triterpenoid from the leaves of I. chinensis and revealed its underlying mechanism of neuroinflammation for the first time. These findings suggest that ilexchinene might possess promising therapeutic effects in neuroinflammation.

The Dawn of a New Era: Tumor-Targeting Boron Agents for Neutron Capture Therapy.

Cancer is widely recognized as one of the most devastating diseases, necessitating the development of intelligent diagnostic techniques, targeted treatments, and early prognosis evaluation to ensure effective and personalized therapy. Conventional treatments, unfortunately, suffer from limitations and an increased risk of severe complications. In light of these challenges, boron neutron capture therapy (BNCT) has emerged as a promising approach for cancer treatment with unprecedented precision to selectively eliminate tumor cells. The distinctive and promising characteristics of BNCT hold the potential to revolutionize the field of oncology. However, the clinical application and advancement of BNCT technology face significant hindrance due to the inherent flaws and limited availability of current clinical drugs, which pose substantial obstacles to the practical implementation and continued progress of BNCT. Consequently, there is an urgent need to develop efficient boron agents with higher boron content and specific tumor-targeting properties. Researchers aim to address this need by integrating tumor-targeting strategies with BNCT, with the ultimate goal of establishing BNCT as an effective, readily available, and cutting-edge treatment modality for cancer. This review delves into the recent advancements in integrating tumor-targeting strategies with BNCT, focusing on the progress made in developing boron agents specifically designed for BNCT. By exploring the current state of BNCT and emphasizing the prospects of tumor-targeting boron agents, this review provides a comprehensive overview of the advancements in BNCT and highlights its potential as a transformative treatment option for cancer.

Characterization of tumor microenvironment and sensitive chemotherapy drugs based on cuproptosis-related signatures in renal cell carcinoma.

Cuproptosis is a novel type of copper-induced cell death and is considered as a new therapeutic target for many cancers. Distant metastases occur in about 40% of patients with advanced renal cell carcinoma (RCC), with a poor 5-year prognosis of about 10%. Through a series of comprehensive analyses, four differentially expressed cuproptosis-related lncRNAs (DECRLs) were identified as candidate biomarkers for RCC. The risk model constructed by using these four DECRLs can better predict the prognosis of patients with RCC, which is determined by the receiver operating characteristic (Time dependent area under curve value at 1-year, 3-year, 5-year, and 10-year were 0.82, 0.80, 0.76, and 0.73 respectively). There were significant differences in immune status between high-risk and low-risk RCC patients. The differentially expressed gene enrichment terms between high- and low-risk patients was also dominated by immune-related terms. The risk score was also correlated with immunotherapy as measured by the tumor immune dysfunction and exclusion (TIDE) score. In addition, we also found that the sensitivity of many chemotherapy drugs varies widely between high- and low-risk patients. The sensitivity of the three chemotherapy drugs (AZD4547, Vincristine, and WEHI-539) varied among high- and low-risk patients, and was significantly negatively correlated with risk values, suggesting that they could be used as clinical treatment drugs for RCC. Our study not only obtained four potential biomarkers, but also provided guidance for immunotherapy and chemotherapy treatment of RCC, as well as new research strategies for the screening of other cancer biomarkers and sensitive drugs.

The international clinical trials registry platform (ICTRP): data integrity and the trends in clinical trials, diseases, and drugs.

Introduction: Clinical trials are the gold standard for testing new therapies. Databases like ClinicalTrials.gov provide access to trial information, mainly covering the US and Europe. In 2006, WHO introduced the global ICTRP, aggregating data from ClinicalTrials.gov and 17 other national registers, making it the largest clinical trial platform by June 2019. This study conducts a comprehensive global analysis of the ICTRP database and provides framework for large-scale data analysis, data preparation, curation, and filtering. Materials and methods: The trends in 689,793 records from the ICTRP database (covering trials registered from 1990 to 2020) were analyzed. Records were adjusted for duplicates and mapping of agents to drug classes was performed. Several databases, including DrugBank, MESH, and the NIH Drug Information Portal were used to investigate trends in agent classes. Results: Our novel approach unveiled that 0.5% of the trials we identified were hidden duplicates, primarily originating from the EUCTR database, which accounted for 82.9% of these duplicates. However, the overall number of hidden duplicates within the ICTRP seems to be decreasing. In total, 689 793 trials (478 345 interventional) were registered in the ICTRP between 1990 and 2020, surpassing the count of trials in ClinicalTrials.gov (362 500 trials by the end of 2020). We identified 4 865 unique agents in trials with DrugBank, whereas 2 633 agents were identified with NIH Drug Information Portal data. After the ClinicalTrials.gov, EUCTR had the most trials in the ICTRP, followed by CTRI, IRCT, CHiCTR, and ISRCTN. CHiCTR displayed a significant surge in trial registration around 2015, while CTRI experienced rapid growth starting in 2016. Conclusion: This study highlights both the strengths and weaknesses of using the ICTRP as a data source for analyzing trends in clinical trials, and emphasizes the value of utilizing multiple registries for a comprehensive analysis.

The prognostic and immunological role of FKBP1A in an integrated muti-omics cancers analysis, especiallylung cancer.

FKBP1A, a gene encoding the FK506-binding protein 1A, has emerged as a significant player in cancer progression and prognosis. This study aimed to comprehensively investigate the multifaceted role of FKBP1A in cancer, focusing on its differential expression patterns, prognostic implications, genetic alterations, and associations with the tumor microenvironment. Using large-scale datasets, including GTEx, TCGA, HPA, and cBioPortal, we analyzed FKBP1A expression across normal tissues and various cancer types. Our findings revealed that FKBP1A exhibited aberrant upregulation in most human cancers, making it a potential biomarker for malignancy. Moreover, FKBP1A expression correlated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in several cancers, indicating its prognostic significance. Genetic alteration analysis showed that FKBP1A gene amplification was prevalent, particularly in ovarian cancer. Furthermore, FKBP1A expression was associated with tumor mutational burden and microsatellite instability, highlighting its potential involvement in tumor-immune response. Notably, FKBP1A expression positively correlated with stromal and immune cell scores, suggesting its role in shaping the tumor microenvironment. Additionally, according to the functional enrichment analysis, experimental validation in lung adenocarcinoma confirmed the role of FKBP1A through the regulation of EGFR signaling by apoptosis, which is consistent with drug sensitivity analysis to some extent. In conclusion, FKBP1A exhibits differential expression in cancer, serves as a prognostic indicator, undergoes genetic alterations, and influences the tumor-immune microenvironment. These findings shed light on the multifaceted role of FKBP1A in cancer development and progression, suggesting its potential as a therapeutic target and guidance of clinical drugs selection, and provide valuable insights into patient prognosis for interventions based on pharmaceuticals.

Analysis of the cluster efficacy and prescription characteristics of traditional Chinese medicine intervention for non-small cell lung cancer based on a clustering algorithm.

In recent years, malignant tumors have gradually become one of the main causes of death for Chinese residents, of which lung cancer ranks first in both the incidence and mortality in China. To mine the text of traditional Chinese medicine (TCM) clinical medical cases after data cleaning, analyze it, and study the experience of TCM doctors in treating non-small cell lung cancer (NSCLC). The applied approach was based on the data mining methods of decentralized and hierarchical system clustering of data from a drug and prescription database. This study involved 215 patients, 287 cases, and 147 types of clinical drugs. The data analysis of the clinical treatment of NSCLC in TCM showed that Erchen Decoction was the main method for the treatment of non-small cell lung cancer in clinical treatment of non-small cell lung cancer. Junjian recipes were close to each other, with Banzhilian, Lobelia, Shanci Mushroom, Hedyotis diffusa to anticancer and detoxify. This study analyzed the core TCM prescription for NSCLC by collecting the empirical essence and characteristics of specific medications. It has some guiding scientific significance for the clinical treatment of lung cancer.