The isolation of sclerotinin A as an anti-malarial compound by utilization of a global secondary metabolism regulator, laeA gene.

Previously, we successfully introduced laeA gene into a fungal strain in order to significantly increase the production of a bioactive compound, allowing use to discover novel biological activity. To demonstrate the universal applicability of the laeA gene introduction strategy for taping the potential of fungal secondary metabolism, in this present study, we created a library of microorganisms which we had the laeA gene inserted, and from that library we aimed to isolate compounds which are produced at significantly greater quantities compared to the respective wild type strains. From this investigation, we were able to isolate sclerotinin A (1) from Pochonia sp. KTF-0504 strain. We revealed that 1 showed anti-malarial activity against Plasmodium falciparum parasite strains. On the other hands, 1 showed no anti-fungal activity against multidrug-sensitive budding yeast. Our study implies that the utilization of the laeA gene in fungi is a versatile method for the discovery of drug candidates.

Insights into autotaxin- and lysophosphatidate-mediated signaling in the pancreatic ductal adenocarcinoma tumor microenvironment: a survey of pathway gene expression.

Lysophosphatidate (LPA)-mediated signaling is a vital component of physiological wound healing, but the pathway is subverted to mediate chronic inflammatory signaling in many pathologies, including cancers. LPA, as an extracellular signaling molecule, is produced by the enzyme autotaxin (ATX, gene name ENPP2) and signals through six LPA receptors (LPARs). Its signaling is terminated by turnover via the ecto-activity of three lipid phosphate phosphatases (LPPs, gene names PLPP1-3). Many pharmacological developments against the LPA-signaling axis are underway, primarily against ATX. An ATX inhibitor against pancreatic ductal adenocarcinoma (PDAC), a very aggressive disease with limited systemic therapeutic options, is currently in clinical trials, and represents the first in-class drug against LPA signaling in cancers. In the present study, we surveyed the expression of ATX, LPARs, and LPPs in human PDACs and their clinical outcomes in two large independent cohorts, the Cancer Genome Atlas (TCGA) and GSE21501. Correlation among gene expressions, biological function and the cell composition of the tumor microenvironment were analysed using gene set enrichment analysis and cell cyber-sorting with xCell. ENPP2, LPAR1, LPAR4, LPAR5, LPAR6, PLPP1, and PLPP2 were significantly elevated in PDACs compared to normal pancreatic tissue, whereas LPAR2, LPAR3, and PLPP3 where downregulated (all P≤0.003). Only ENPP2 demonstrated survival differences, with overall survival favoring ENPP2-high patients (hazard ration 0.5-0.9). ENPP2 was also the only gene with enriched gene patterns for inflammatory and tissue repair gene sets. Epithelial (cancer) cells had increased LPAR2, LPAR5 and PLPP2 expression, and decreased ENPP2, LPAR1, PLPP1, and PLPP3 gene expression (all P<0.02). Tumor fibroblasts had increased ENPP2, LPAR2, LPAR4, PLPP1, and PLPP3 expression and decreased LPAR2, LPAR5, and PLPP2 expression in both cohorts (all P≤0.01). Immune cell populations were not well correlated to gene expression in PDACs, but across both cohorts, cytolytic scores were increased in high-expressing ENPP2, LPAR1, LPAR6, PLPP1, and PLPP3 tumors (P<0.01). Overall, in PDACs, ENPP2 may switch from an anti-to-pro tumor promoting gene with disease progression. LPAR2 and PLPP2 inhibition are also predicted to have potential therapeutic utility. Future multi-omics investigations are necessarily to validate which LPA signaling components are high-value candidates for pharmacological manipulation in PDAC treatment.

Twelve-month results from a randomized controlled trial comparing differential target multiplexed spinal cord stimulation and conventional spinal cord stimulation in subjects with chronic refractory axial low back pain not eligible for spine surgery.

Background: Successful treatments for intractable chronic low back pain (CLBP) in patients who are not eligible for surgical interventions are scarce. The superior efficacy of differential target multiplexed spinal cord stimulation (DTM SCS) to conventional SCS (Conv-SCS) on the treatment of CLBP in patients with persistent spinal pain syndrome (PSPS) who have failed surgical interventions (PSPS-T2) motivated the evaluation of DTM SCS versus Conv-SCS on PSPS patients who are non-surgical candidates (PSPS-T1). Methods: This is a prospective, open label, crossover, post-market randomized controlled trial in 20 centers across the United States. Eligible patients were randomized to either DTM SCS or Conv-SCS in a 1:1 ratio. Primary endpoint was CLBP responder rate (percentage of subjects with ≥50% CLBP relief) at 3-month in randomized subjects who completed trialing (modified intention-to-treat population). Patients were followed up to 12 months. Secondary endpoints included change of CLBP and leg pain, responder rates, changes in disability, quality of life, patient satisfaction and global impression of change, and safety profile. An optional crossover was available at 6-month to all patients. Results: About 121 PSPS-T1 subjects with CLBP and leg pain mostly associated with degenerative disc disease and radiculopathy and who were not eligible for spine surgery were randomized. CLBP responder rate with DTM SCS (93.5%) was superior to Conv-SCS (36.4%) at the primary endpoint. Superior CLBP responder rates (88.1%-90.5%) were obtained with DTM SCS at all other timepoints. Mean CLBP reduction with DTM SCS (6.52 cm) was superior to that with Conv-SCS (3.01 cm) at the primary endpoint. Similar CLBP reductions (6.23-6.43 cm) were obtained with DTM SCS at other timepoints. DTM SCS provided significantly better leg pain reduction and responder rate, improvement of disability and quality of life, and better patient satisfaction and global impression of change. 90.9% of Conv-SCS subjects who crossed over were CLBP responders at completion of the study. Similar safety profiles were observed between the two groups. Conclusion: DTM SCS for chronic CLBP in nonsurgical candidates is superior to Conv-SCS. Improvements were sustained and provided significant benefits on the management of these patients.

Ethics of Residency Candidates Using Application Consulting Services.

While the prevalence is still being determined, more medical students are utilizing application consulting companies when applying to competitive residencies such as dermatology. We outline the structure of these companies, the scope of services provided, and the costs associated. We also discuss the ethical implications for the use in the residency application process of such firms and the impact of these practices on the candidate selection process. Finally, we offer possible solutions and measures that mitigate the impact of the use of consulting firms in residency applications. Application consulting services are meant to assist clients in maximizing their chances for a successful application cycle. Many companies cater to both prospective residency and pre-medical candidates, including "Med School Insiders," "BeMo Academic Consulting," and "Elite Medical Prep." The scope of application consulting services is vast. Clients can request services such as personalized school selection, application advising, document preparation review [e.g., curriculum vitae (CV), personal statements, and essays), electronic residency application service (ERAS)], and interview coaching. Another service offered is residency match advising, which details specific requirements programs desire. Prospective clients would gain a significant advantage, mainly when used at the outset of medical school training when planning a trajectory for competitive specialties. We review the ethical issues associated with using these consulting services.

Cryptococcosis in wait-listed liver transplant candidates: Prevalence, manifestations, and risk factors.

BACKGROUND: Liver cirrhosis compromises immunity against cryptococcosis, and liver transplant recipients tend to develop the disease earlier after transplantation, possibly due to unrecognized pretransplant infection. We assessed the prevalence and characteristics of cryptococcosis among liver transplant candidates and whether pre-transplant cryptococcal antigen (CrAg) can detect the disease before transplantation. METHODS: We retrospectively included liver transplant candidates in a tertiary hospital during 2017-2022. Serum CrAg and pulmonary computed tomography were incorporated in routine transplant evaluation. Other investigations were done if indicated. Cryptococcosis was diagnosed by positive culture or CrAg. Risk factors for cryptococcosis were also assessed. RESULTS: Of the 377 candidates with a median MELD-Na score of 18, 84.4% had hepatitis B virus (HBV) infection. Cryptococcosis was diagnosed in 10 (2.6%) candidates, by CrAg in 6, culture in 2, or both in 2. Only 3 had fever, and 3 were asymptomatic; 7 had pulmonary cryptococcosis. Of the 10 candidates with cryptococcosis, one underwent transplantation after 143-day antifungals. Of the 87 candidates undergoing liver transplantation, one (1.2%) recipient developed cryptococcosis 14 days post-transplant with negative CrAg three weeks before transplantation. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis (odds ratio 4.4, 95% confidence interval 1.2-16.5, p = 0.03) after the adjustment of MELD-Na score. CONCLUSIONS: The prevalence of cryptococcosis was 2.6% among our liver transplant candidates and CrAg detected 80% of the cases. Disease presentation was mild and pulmonary disease predominated. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis.

Preliminary screening of biomarkers and drug candidates in a mouse model of ß-thalassemia based on quasi-targeted metabolomics.

Background: ß-thalassemia (ß-TH) is a hereditary hemolytic anemia that results in deficient hemoglobin (Hb) synthesis. It is characterized by ineffective erythropoiesis, anemia, splenomegaly, and systemic iron overload. Exploration new potential biomarkers and drug candidates is important to facilitate the prevention and treatment of ß-TH. Methods: We applied quasi-targeted metabolomics between wild type (Wt) and heterozygous ß-TH mice (Th3/+), a model of non-transfusion-dependent ß-TH intermedia, in plasma and peripheral blood (PB) cells. Futher data was deeply mined by Kyoto Encyclopedia of Genomes (KEGG) and machine algorithms methods. Results: Using KEGG enrichment analysis, we found that taurine and hypotaurine metabolism disorders in plasma and alanine, aspartate and glutamate metabolism disorders in PB cells. After systematically anatomize the metabolites by machine algorithms, we confirmed that alpha-muricholic acidUP and N-acetyl-DL-phenylalanineUP in plasma and Dl-3-hydroxynorvalineUP, O-acetyl-L-serineUP, H-abu-OHUP, S-(Methyl) glutathioneUP, sepiapterinDOWN, and imidazoleacetic acidDOWN in PB cells play key roles in predicting the occurrence of ß-TH. Furthermore, Sepiapterin, Imidazoleacetic acid, Methyl alpha-D-glucopyranoside and alpha-ketoglutaric acid have a good binding capacity to hemoglobin E through molecular docking and are considered to be potential drug candidates for ß-TH. Conclusion: Those results may help in identify useful molecular targets in the diagnosis and treatment of ß-TH and lays a strong foundation for further research.

International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates-2024.

The "International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates-2024" updates and replaces the "Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates-2006" and the "2016 International Society for Heart Lung Transplantation Listing Criteria for Heart Transplantation: A 10-year Update." The document aims to provide tools to help integrate the numerous variables involved in evaluating patients for transplantation, emphasizing updating the collaborative treatment while waiting for a transplant. There have been significant practice-changing developments in the care of heart transplant recipients since the publication of the International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 and the 10-year update in 2016. The changes pertain to 3 aspects of heart transplantation: (1) patient selection criteria, (2) care of selected patient populations, and (3) durable mechanical support. To address these issues, 3 task forces were assembled. Each task force was cochaired by a pediatric heart transplant physician with the specific mandate to highlight issues unique to the pediatric heart transplant population and ensure their adequate representation. This guideline was harmonized with other ISHLT guidelines published through November 2023. The 2024 ISHLT guidelines for the evaluation and care of cardiac transplant candidates provide recommendations based on contemporary scientific evidence and patient management flow diagrams. The American College of Cardiology and American Heart Association modular knowledge chunk format has been implemented, allowing guideline information to be grouped into discrete packages (or modules) of information on a disease-specific topic or management issue. Aiming to improve the quality of care for heart transplant candidates, the recommendations present an evidence-based approach.

Application and evaluation of minimally invasive surgical treatment options for early endometrial cancer.

BACKGROUND: Laparoscopic and robotic-assisted techniques have gained popularity, and endometrial cancer (EC) remains a significant health problem among women. OBJECTIVE: Minimally invasive surgical (MIS) therapy options for early endometrial cancer will be evaluated for their effectiveness and safety is the aim of this paper. We also investigate the differences in oncologic outcomes between MIS and open surgery (OS) for individuals with early-stage EC. The patient was diagnosed with early-stage EC and treated with laparoscopic surgery and was the focus of a retrospective analysis. 162 patients with early EC were analyzed, with diagnoses occurring between 2002 and 2022. METHODS: The patients were fragmented into two groups, one for OS and another for laparoscopic procedures. The total tumor excision and recurrence rates were identical across the two methods, indicating similar oncologic results. Rates of complications were likewise comparable across the two groups. RESULTS: The quality of life ratings of patients with robotic-assisted surgery was higher than those with laparoscopic surgery. Sixty-two (62.2%) of the 162 patients in this research had OS, whereas Fifty-six (57.8%) had MIS. The probability of recurrence of EC from stages III to IV was significanitly higher in women who had OS. CONCLUSION: Minimally invasive procedures were shown to be effective in treating early-stage EC, and while these findings provide support for their usage, larger multicenter randomized controlled studies are required to verify these results and further examine possible long-term advantages. Patients with early-stage EC, regardless of histologic type, had superior survival rates with MIS compared to OS.

Macrocyclic-based strategy in drug design: From lab to the clinic.

Macrocyclic compounds have emerged as potent tools in the field of drug design, offering unique advantages for enhancing molecular recognition, improving pharmacokinetic properties, and expanding the chemical space accessible to medicinal chemists. This review delves into the evolutionary trajectory of macrocyclic-based strategies, tracing their journey from laboratory innovations to clinical applications. Beginning with an exploration of the defining structural features of macrocycles and their impact on drug-like characteristics, this discussion progresses to highlight key design principles that have facilitated the development of diverse macrocyclic drug candidates. Through a series of illustrative representative case studies from approved macrocyclic drugs and candidates spanning various therapeutic areas, particular emphasis is placed on their efficacy in targeting challenging protein-protein interactions, enzymes, and receptors. Additionally, this review thoroughly examines how macrocycles effectively address critical issues such as metabolic stability, oral bioavailability and selectivity. Valuable insights into optimization strategies employed during both approved and clinical phases underscore successful translation of promising leads into efficacious therapies while providing valuable perspectives on harnessing the full potential of macrocycles in drug discovery and development endeavors.

Potential of Raman scattering in probing magnetic excitations and their coupling to lattice dynamics.

Raman scattering is an excellent method for simultaneously determining the dynamics of lattice, spin, and charge degrees of freedom. Furthermore, polarization selection rules in Raman scattering enable momentum-resolved quasiparticle dynamics. In this review, we highlight the potential of Raman scattering in probing magnetic quasiparticles or excitations in various magnetic materials. We demonstrate how temperature-dependent Raman scattering data can confirm the existence of magnons in long-range ordered magnets and fractionalized excitations in Kitaev spin liquid candidates. To make this review easily understandable to novices, we provide background information on magnons and fractionalized excitations, and explain how they become visible in the Raman scattering process. We also show how to estimate magnetic exchange interactions from the data. For both types of magnetic materials, we discuss the impact of spin-phonon coupling on the lineshape of the phonon modes. In terms of materials, we present magnetic Raman scattering data of antiferromagnetic Sr2IrO4and La2CuO4, ferromagnetic CrI3monolayers, and Kitaev spin liquid candidatesα-RuCl3andß-Li2IrO3. Overall, our review demonstrates the versatility of the Raman scattering technique in probing quasiparticles in magnetic quantum materials. The review aims to inform young experimental researchers about the potential of Raman scattering, thereby motivating them to use this technique in their research.

Comparative study on metabolite variations of two rose teas by plant metabolomics and revealing their skin-whitening candidates by spectrum-effect relationship analysis.

INTRODUCTION: Rosa rugosa var. plena Rehd (CBR) and Rosa chinensis cv. "JinBian" (JBR) are two common species used in rose tea among different original species. CBR, the officially documented original plant of the rose species for food and medicinal purposes, is more costly than JBR. With increasing demand for different rose teas, it is meaningful to compare the chemical constituents for their quality control and reveal their skin-whitening components that will provide in-depth insights for the expansion of the rose tea industry. OBJECTIVE: This study aims to reveal the chemical variances between CBR and JBR and determine their skin-whitening components. METHODOLOGY: A strategy obtained by combining MS-based plant-metabolomics with spectrum-effect relationship analysis has been proposed for unveiling chemical differences between CBR and JBR and further exploring their potential skin-whitening components. RESULTS: A total of 2030 metabolites were found that revealed considerable differences between CBR and JBR. The results of bioactivity assay demonstrated that JBR exhibited stronger tyrosinase inhibition activity than CBR. Six potential skin-whitening compounds (di-O-galloyl-HHDP-glucoside, tri-O-galloyl-HHDP-glucoside, spiraeoside, quinic acid, rugosin A, and 1,2,3,6-tetra-O-galloyl-glucose) were discovered as potential tyrosinase inhibitors, via spectrum-effect relationship analysis. This is the first time that di-O-galloyl-HHDP-glucoside, tri-O-galloyl-HHDP-glucoside, rugosin A, and 1,2,3,6-tetra-O-galloyl-glucose have been reported with tyrosinase inhibitory activity. Additionally, molecular docking analysis was used to reveal the inhibition mechanism of these compounds toward tyrosinase. CONCLUSION: The finding of this study will be of great importance for the quality control of the two types of rose teas, and the revealed active ingredients will provide in-depth insights for the expansion of the rose tea industry.

Exploring COVID-19 Pandemic Disparities with Transcriptomic Meta-analysis from the Perspective of Personalized Medicine.

Infection with SARS-CoV2, which is responsible for COVID-19, can lead to differences in disease development, severity and mortality rates depending on gender, age or the presence of certain diseases. Considering that existing studies ignore these differences, this study aims to uncover potential differences attributable to gender, age and source of sampling as well as viral load using bioinformatics and multi-omics approaches. Differential gene expression analyses were used to analyse the phenotypic differences between SARS-CoV-2 patients and controls at the mRNA level. Pathway enrichment analyses were performed at the gene set level to identify the activated pathways corresponding to the differences in the samples. Drug repurposing analysis was performed at the protein level, focusing on host-mediated drug candidates to uncover potential therapeutic differences. Significant differences (i.e. the number of differentially expressed genes and their characteristics) were observed for COVID-19 at the mRNA level depending on the sample source, gender and age of the samples. The results of the pathway enrichment show that SARS-CoV-2 can be combated more effectively in the respiratory tract than in the blood samples. Taking into account the different sample sources and their characteristics, different drug candidates were identified. Evaluating disease prediction, prevention and/or treatment strategies from a personalised perspective is crucial. In this study, we not only evaluated the differences in COVID-19 from a personalised perspective, but also provided valuable data for further experimental and clinical efforts. Our findings could shed light on potential pandemics.

Mass Spectrometric and Artificial Intelligence-Based Identification of the Secretome of Plasmodium falciparum Merozoites to Provide Novel Candidates for Vaccine Development Pipeline.

PURPOSE: Merozoites are the only extracellular form of blood stage parasites, making it a worthwhile target. Multiple invasins that are stored in the merozoite apical organelles, are secreted just prior to invasion, and mediates its interaction with RBC. A comprehensive identification of all these secreted invasins is lacking and this study addresses that gap. EXPERIMENTAL DESIGN: Pf3D7 merozoites were enriched and triggered to discharge apical organelle contents by exposure to ionic conditions mimicking that of blood plasma. The secreted proteins were separated from cellular contents and both the fractions were subjected to proteomic analysis. Also, the identified secreted proteins were subjected to GO, PPI network analysis, and AI-based in silico approach to understand their vaccine candidacy. RESULTS: A total of 63 proteins were identified in the secretory fraction with membrane and apical organellar localization. This includes various MSPs, micronemal EBAs and rhoptry bulb proteins, which play a crucial role in initial and late merozoite attachment, and majority of them qualified as vaccine candidates. CONCLUSION AND CLINICAL RELEVANCE: We, for the first time, report the secretory repertoire of merozoite and its status for vaccine candidacy. This information can be utilized to develop better invasion blocking multisubunit vaccines, comprising of immunological epitopes from several secreted invasins.

First voltammetric analysis of two possible anticancer drug candidates using an unmodified glassy carbon electrode.

Dimethyl 2-[2-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)hydrazinylidene]butanedioate (DIHB) and 8-(3-chlorophenyl)-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-dione (HDIT) are promising candidates for anticancer agents, the first analytical procedures of which are presented in this paper. The commercially available unmodified glassy carbon electrode (GCE) was used as a sensor for the individual and simultaneous differential pulse voltammetric (DPV) determination of these possible anticancer drugs. The findings concerning the electrochemical behaviour indicated that DIHB and HDIT display at GCE, as a sensor, the oxidation peaks at 1.18 and 0.98 V, respectively (vs. Ag/AgCl, 3.0 mol L-1 KCl) in the 0.125 mol L-1 acetate buffer of pH = 4.5, which were employed for their quantification. Various experimental parameters were carefully investigated, to achieve high sensitivity in voltammetric measurements. Finally, under the optimised conditions (t of 60 s, ΔEA of 75 mV, ν of 225 mV s-1, and tm of 2 ms), the proposed DPV procedure with the GCE demonstrated broad linear sensing ranges (1-200 nmol L-1-DIHB and 5-200 nmol L-1-HDIT), boasting the detection limits of 0.18 nmol L-1 for DIHB and 1.1 nmol L-1 for HDIT. Moreover, the developed procedure was distinguished by good selectivity, repeatability of DIHB and HDIT signals and sensor reproducibility. The practical application of this method was demonstrated by analysing the urine reference material without any prior treatment. The results showed that this environmentally friendly approach, with a modification-free sensor, is suitable for the sensitive, selective and rapid quantification of DIHB and HDIT.

Chitosan-alginate/R8 ternary polyelectrolyte complex as an oral protein-based vaccine candidate induce effective mucosal immune responses.

Vaccination is the most effective method for preventing infectious diseases. Oral vaccinations have attracted much attention due to the ability to boost intestinal and systemic immunity. The focus of this study was to develop a poly (lactide-co-glycolide) acid (PLGA)-based ternary polyelectrolyte complex (PEC) with chitosan, sodium alginate, and transmembrane peptides R8 for the delivery of antigen proteins. In this study, the antigen protein (HBf), consisting of the Mycobacterium avium subspecies paratuberculosis (MAP) antigens HBHA, Ag85B, and Bfra, was combined with R8 to generate self-assembled conjugates. The results showed that PEC presented a cross-linked reticular structure to protect the encapsulated proteins in the simulated gastric fluid. Then, the nanocomposite separated into individual nanoparticles after entering the simulated intestinal fluid. The ternary PEC with R8 promoted the in vivo uptake of antigens by intestinal lymphoid tissue. Moreover, the ternary PEC administered orally to mice promoted the secretion of specific antibodies and intestinal mucosal IgA. In addition, in the mouse models of MAP infection, the ternary PEC enhanced splenic T cell responses, thus reducing bacterial load and liver pathology score. These results suggested that this ternary electrolyte complex could be a promising delivery platform for oral subunit vaccine candidates, not limited to MAP infection.

Exploratory screening for micro-RNA biomarkers in canine multicentric lymphoma.

Lymphoma is one of the most frequent hematopoietic tumors in dogs and shares similar features with human counterparts. MicroRNAs (miRNA, small non-coding RNAs) are pivotal in gene regulation fine tuning and cancer hallmarks are influenced by their aberrant expression. Consequently, miRNA biomarkers may assist predicting therapeutic response and clinical outcome by providing less-invasive novel diagnostics tools. The aim of this study was to detect dysregulated miRNAs in lymphomatous lymph node tissues in comparison to lymph node material or PBMCs from healthy control dogs. Potential significant differences in miRNA expression profiles between four lymphoma entities were evaluated. A customized PCR array was utilized to profile 89 canine target miRNAs. Quantification was performed using qPCR, relative expression was determined by the delta-delta Ct method, and p-values were calculated with student's t-test. In the 14 diffuse large B-cell lymphoma (DLBCL) patients, 28 and 24 different miRNAs were significantly dysregulated compared to lymph node material or PBMCs. Sixteen miRNAs occurred in both control groups, with 12 miRNAs being down- and four miRNAs being upregulated. The six peripheral T-cell lymphoma (PTCL) samples showed 24 and 25 dysregulated miRNAs when compared to the healthy controls. A combined analysis of DLBCL and PTCL samples revealed seven shared and 19 differently expressed miRNAs. Potential biomarkers in T- and B-cell lymphoma could be the miRNA-17/92 cluster and miRNA-181-family together with miRNA-34a and miRNA-150. Diagnostic utility of potential biomarkers must be validated in larger, prospective cohorts of canine lymphoma cases and in higher numbers of physiological patient material.

Synthetic Modifications of Andrographolide Targeting New Potential Anticancer Drug Candidates: A Comprehensive Overview.

This review collects the synthetic modifications performed on andrographolide, a natural molecule derived from Andrographis paniculata, for oncology applications. Various pharmacomodulations were carried out, and the products were tested on different cancer cell lines. The impact of these modifications was analyzed with the aim of mapping the positions essential for activity to facilitate future research in this field. However, this study makes it clear that, in addition to structural modifications of the molecule, which can result in varying degrees of effectiveness in targeting interactions, the lipophilic capacity of the structures obtained through hemisynthesis is of significant importance.

Seven-membered N-heterocycles as approved drugs and promising leads in medicinal chemistry as well as the metal-free domino access to their scaffolds.

Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are often found in nature (e.g. alkaloids), the natural compounds of this group are rather rare as approved therapeutics. Thus, recently studied and approved azepane or azepine-congeners predominantly consist of semi-synthetically or synthetically-obtained scaffolds. In this review a comparison of approved drugs and recently investigated leads was proposed taking into regard their structural aspects (stereochemistry), biological activities, pharmacokinetic properties and confirmed molecular targets. The 7-membered N-heterocycles reveal a wide range of biological activities, not only against CNS diseases, but also as e.g. antibacterial, anticancer, antiviral, antiparasitic and against allergy agents. As most of the approved or investigated potential drugs or lead structures, belonging to 7-membered N-heterocycles, are synthetic scaffolds, this report also reveals different and efficient metal-free cascade approaches useful to synthesize both simple azepane or azepine-containing congeners and those of oligocyclic structures. Stereochemistry of azepane/azepine fused systems, in view of biological data and binding with the targets, is discussed. Apart from the approved drugs, we compare advances in SAR studies of 7-membered N-heterocycles (mainly from 2018 to 2023), whereas the related synthetic part concerning various domino strategies is focused on the last ten years.

Machine Learning to Predict Drug-Induced Liver Injury and Its Validation on Failed Drug Candidates in Development.

Drug-induced liver injury (DILI) poses a significant challenge for the pharmaceutical industry and regulatory bodies. Despite extensive toxicological research aimed at mitigating DILI risk, the effectiveness of these techniques in predicting DILI in humans remains limited. Consequently, researchers have explored novel approaches and procedures to enhance the accuracy of DILI risk prediction for drug candidates under development. In this study, we leveraged a large human dataset to develop machine learning models for assessing DILI risk. The performance of these prediction models was rigorously evaluated using a 10-fold cross-validation approach and an external test set. Notably, the random forest (RF) and multilayer perceptron (MLP) models emerged as the most effective in predicting DILI. During cross-validation, RF achieved an average prediction accuracy of 0.631, while MLP achieved the highest Matthews Correlation Coefficient (MCC) of 0.245. To validate the models externally, we applied them to a set of drug candidates that had failed in clinical development due to hepatotoxicity. Both RF and MLP accurately predicted the toxic drug candidates in this external validation. Our findings suggest that in silico machine learning approaches hold promise for identifying DILI liabilities associated with drug candidates during development.