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Background: Quorum sensing is bacteria's ability to communicate and regulate their behavior based on population density. Anti-quorum sensing agents (anti-QSA) is promising strategy to treat resistant infections, as well as reduce selective pressure that leads to antibiotic resistance of clinically relevant pathogens. This study analyzes the output, hotspots, and trends of research in the field of anti-QSA against clinically relevant pathogens. Methods: The literature on anti-QSA from the Web of Science Core Collection database was retrieved and analyzed. Tools such as CiteSpace and Alluvial Generator were used to visualize and interpret the data. Results: From 1998 to 2023, the number of publications related to anti-QAS research increased rapidly, with a total of 1,743 articles and reviews published in 558 journals. The United States was the largest contributor and the most influential country, with an H-index of 88, higher than other countries. Williams was the most productive author, and Hoiby N was the most cited author. Frontiers in Microbiology was the most prolific and the most cited journal. Burst detection indicated that the main frontier disciplines shifted from MICROBIOLOGY, CLINICAL, MOLECULAR BIOLOGY, and other biomedicine-related fields to FOOD, MATERIALS, NATURAL PRODUCTS, and MULTIDISCIPLINARY. In the whole research history, the strongest burst keyword was cystic-fibrosis patients, and the strongest burst reference was Lee and Zhang (2015). In the latest period (burst until 2023), the strongest burst keyword was silver nanoparticle, and the strongest burst reference was Whiteley et al. (2017). The co-citation network revealed that the most important interest and research direction was anti-biofilm/antivirulence drug development, and timeline analysis suggested that this direction is also the most active. The key concepts alluvial flow visualization revealed seven terms with the longest time span and lasting until now, namely Escherichia coli, virulence, Pseudomonas aeruginosa, virulence factor, bacterial biofilm, gene expression, quorum sensing. Comprehensive analysis shows that nanomaterials, marine natural products, and artificial intelligence (AI) may become hotspots in the future. Conclusion: This bibliometric study reveals the current status and trends of anti-QSA research and may assist researchers in identifying hot topics and exploring new research directions. [ABSTRACT FROM AUTHOR]

Introduction: People with haemophilia rely on specialists for their care, yet the specific dosing regimens of treatments prescribed by these specialists have not been widely studied. Aim: The objective of this study is to describe trends in clinician prescribing practices for the management of haemophilia in the United States (US). Methods: We administered surveys to members of the Hemostasis and Thrombosis Research Society via paper surveys at its in‐person annual symposia in 1999 and 2015, and an online survey in 2021. The surveys collected information on haemophilia treatments including factor dosing, inhibitor therapy and gene therapy. Results: Clinicians treating haemophilia for more than 50% of their practice time have increased from 37.5% of respondents in 1999 to 46.3% in 2021. Clinicians prescribing factor concentrates at >40 units/kg for routine bleeding events increased from 0% in 1999 to 29.3% in 2021 in haemophilia A (HA) and from 22.5% to 87.8% in haemophilia B (HB). In 2021, the clinicians reported prescribing emicizumab to treat HA patients (>89.5% paediatric, >85.7% adult) with or without inhibitors at least some of the time. Approximately 78.0% of respondents reported that they expected to recommend gene therapy at least some of time. Conclusion: These data indicate changing trends in prescribing practices among US haemophilia specialists during the past 22 years. Preference for high doses of factor (>40 units/kg) has increased during this period. Emicizumab prophylaxis has been prescribed for patients with and without HA inhibitors. Clinicians expect gene therapy to have value for some haemophilia patients. [ABSTRACT FROM AUTHOR]

Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells characteristics that promote the growth of malignant tumours, including genomic instability and mutations, the ability to evade cellular death and the capacity of sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) is a protein that plays key roles in cellular regulation, namely in DNA damage repair and cell survival. The inhibition of PARP1 promotes cellular death in cells with homologous recombination deficiency, and therefore, the interest in PARP protein has been rising as a target for anticancer therapies. There are already some PARP1 inhibitors approved by Food and Drug Administration (FDA), such as Olaparib and Niraparib. The last compound presents in its structure an indazole core. In fact, pyrazoles and indazoles have been raising interest due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as inhibitors of PARP1 and presented promising results. Therefore, this review aims to address the importance of PARP1 in cell regulation and its role in cancer. Moreover, it intends to report a comprehensive literature review of PARP1 inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PARP1 inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The mitochondrial pyruvate carrier (MPC) is a protein complex composed of two subunits, MPC1 and MPC2. This carrier is at the interface between glycolysis and mitochondrial metabolism and plays an essential role in hepatic glucose production., Methods: Here we describe an in vitro screen for small molecule inhibitors of the MPC using a strain of Lactococcus lactis that has been engineered to co-express the two subunits of the human MPC and is able to import exogenous 14C-pyruvate. We then tested the top candidates for potential antidiabetic effects through the repression of gluconeogenesis., Results: By screening the Prestwick compound library of 1'200 drugs approved by the Food and Drug Administration for inhibitors of pyruvate uptake, twelve hit molecules were identified. In a secondary screen, the most potent inhibitors were found to inhibit pyruvate-driven oxygen consumption in mouse C2C12 muscle cells. Assessment of gluconeogenesis showed that Zaprinast, as well as the established MPC inhibitor UK5099, inhibited in vitro and in vivo hepatic glucose production. However, when tested acutely in mice without the administration of gluconeogenic substrates, MPC inhibitors raised blood glucose levels, pointing to liver-independent effects. Furthermore, chronic treatment with Zaprinast failed to correct hyperglycemia in both lean and obese diabetic mouse models., Conclusions: New MPC inhibitors have been identified, showing inhibitory effects on hepatic glucose production., General Significance: For potential antidiabetic applications, MPC inhibitors should target the liver without undesired inhibition of mitochondrial pyruvate metabolism in the skeletal muscles or pancreatic beta-cells in order to avoid dual effects on glycemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the present work., (Copyright © 2023. Published by Elsevier B.V.)

[Display omitted] Protein kinases constitute the largest group within the kinase family, and mutations and translocations of protein kinases due to genetic alterations are intimately linked to the pathogenesis of numerous diseases. Bruton's tyrosine kinase (BTK) is a member of the protein kinases and plays a pivotal role in the development and function of B cells. BTK belongs to the tyrosine TEC family. The aberrant activation of BTK is closely associated with the pathogenesis of B-cell lymphoma. Consequently, BTK has always been a critical target for treating hematological malignancies. To date, two generations of small-molecule covalent irreversible BTK inhibitors have been employed to treat malignant B-cell tumors, and have exhibited clinical efficacy in hitherto refractory diseases. However, these drugs are covalent BTK inhibitors, which inevitably lead to drug resistance after prolonged use, resulting in poor tolerance in patients. The third-generation non-covalent BTK inhibitor Pirtobrutinib has obtained approval for marketing in the United States, thereby circumventing drug resistance caused by C481 mutation. Currently, enhancing safety and tolerance constitutes the primary issue in developing novel BTK inhibitors. This article systematically summarizes recently discovered covalent and non-covalent BTK inhibitors and classifies them according to their structures. This article also provides a detailed discussion of binding modes, structural features, pharmacological activities, advantages and limitations of typical compounds within each structure type, providing valuable references and insights for developing safer, more effective and more targeted BTK inhibitors in future studies. [ABSTRACT FROM AUTHOR]

Purpose: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. Patients and methods: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. Results: Patients had AML ( n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. Conclusion: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed. [ABSTRACT FROM AUTHOR]

Abstract: The site specific functionalization of phosphate groups with amino acid side chains of substrate proteins represents one of the most important regulatory mechanisms of biological systems. Phosphorylation and dephosphorylation are reversibly catalyzed by protein kinases and protein phosphatases, and the aberrant regulation of these enzymes is associated with the onset and progression of various disease states such as cancer, diabetes, neurodegenerative and autoimmune disorders, making these proteins attractive targets for drug discovery. Here we report on strategies currently explored for the identification and development of various inhibitors directed against clinically relevant phosphatases. While over the last years, inhibition of phosphorylation has evolved into a key strategy in targeted therapies, the development of clinically relevant phosphatase inhibitors still faces major bottlenecks and is often plagued by limited selectivity and unfavorable pharmacokinetics. The reader will gain a better understanding of the importance of the field and its current limitations. [Copyright &y& Elsevier]

Introduction: Patients with haemophilia can develop inhibitors to exogenous coagulation factors. Some patients are tolerant to factor, while those who develop inhibitors do so early in life. Genetics and environmental factors are known to contribute to inhibitor risk. However, it is not yet possible to predict inhibitor formation or treatment responsiveness in individuals. We hypothesize that factors in the antenatal/neonatal period inform inhibitor risk development., Aim: To consider the design of longitudinal studies beginning in the antenatal/neonatal period and the use of new technologies to better understand haemophilia inhibitors., Methods: A working group was formed for the NHLBI State of the Science Workshop: Factor VIII Inhibitors: Generating a National Blueprint for Future Research to solicit input from the US haemophilia community and international collaborators to consider design of pregnancy/birth longitudinal cohorts that leverage -omics, existing phenotypic data, and in silico modelling to study inhibitors., Results: An antenatal/neonatal longitudinal cohort should begin with enrolment of pregnant genetic carriers of haemophilia and span the at-risk period for inhibitor development in the child. Data and samples from the mother, placenta, neonate and young child can be obtained that are amenable to existing assays, genomics and other -omics studies. Data can inform in silico prediction and mathematical models., Conclusion: A longitudinal study beginning before birth offers the unique opportunity to study factors that influence inhibitor development prior to exposure. Advances in -omics and computational biology can study complex phenotypes in this rare disease. This study could be accomplished through interdisciplinary efforts and patient community engagement., (© 2019 John Wiley & Sons Ltd.)

Introduction: Inhibitor formation against coagulation factor VIII (FVIII) is an unresolved serious problem in replacement therapy for the X-linked bleeding disorder haemophilia A. Although FVIII inhibitors have been extensively studied, much of the basic mechanism of this immune response remains to be uncovered., Aim: Within the NHLBI State of the Science Workshop on Factor VIII Inhibitors, Working Group 3 identified three scientific priorities for basic and translational research on FVIII inhibitor formation., Methods: A larger list of potential areas of research was initially developed as a basis for subsequent prioritization. Each scientific goal was further evaluated based on required effort, potential impact, approach, methods, technologies and models., Results: The three priorities include the following: activation signals and immune regulation that shape the response to FVIII (including innate immunity, microbiome, adaptive immunity and regulatory T cell studies in humans); utility of animal models and non-animal approaches (in silico, genetic, single-cell/sorted population "omics," in vitro) to help predict inhibitor formation and identify novel therapeutics; and impact of the source of FVIII, its structure and von Willebrand factor on immunogenicity and tolerance., Conclusions: Early interactions between FVIII and the immune system, biomarker development and studies in different patient groups (previously treated or untreated, with or without inhibitor formation, patients undergoing immune tolerance induction or gene therapy) deserve particular emphasis. Finally, linking basic to clinical studies, development of a repository for biospecimens and opportunities for interdisciplinary research training are important components to solving the urgent problem of inhibitor formation., (© 2019 John Wiley & Sons Ltd.)

The 5-year overall survival rate of AML patients remains 25-40%. The prognosis is even more dismal for older patients who are ineligible for intensive chemotherapy and patients with secondary or relapsed/refractory AML. In 2017, 4 new drugs were approved by the US Food and Drug Administration for AML treatment: The FLT3 inhibitor midostaurin, the isocitrate dehydrogenase ( IDH )-2 inhibitor enasidenib, a liposomal formulation of cytarabine and daunorubicin (CPX-351), and the anti-CD33 antibody gemtuzumab ozogamicin. Additionally, the IDH 1 inhibitor ivosidenib has received FDA approval in July 2018. However, all these drugs were approved in certain settings and/or for certain subsets of AML patients. Herein, we review the mechanisms of actions and preclinical data, highlight pivotal clinical trial data, and discuss future directions and challenges for further development of these 5 novel therapeutics. Finally, we briefly overview some of the highly promising agents that are currently in advanced stages of clinical development.

Background: Inhibitor development to factor VIII (FVIII) hemophilia therapy results in increased complications and substantial economic costs. The SIPPET study, the first randomized controlled trial to compare the immunogenicity of plasma-derived FVIII (pdFVIII)/von Willebrand factor (VWF) and recombinant-DNA-derived FVIII (rFVIII), demonstrated higher inhibitor rates in previously untreated patients (PUPs) treated with rFVIII than in PUPs treated with pdFVIII/VWF., Objective: To quantify the economic impact of treating PUPs with pdFVIII/VWF vs rFVIII., Methods: An Excel-based clinical and economic model was developed from a US healthcare payer perspective and run over a 5-year period. The analysis utilized a cohort approach to model patient treatment and outcomes over a monthly cycle to quantify differences in costs of FVIII, bypassing agents, and hospitalizations for serious bleeds. Rates of high-titer inhibitor development were obtained from the SIPPET study. Patients developing high-titer inhibitors were treated with immune tolerance induction (ITI). Patients who developed low-titer inhibitors and those who did not develop inhibitors continued their usual FVIII treatment. Patients who were successfully treated with ITI returned to FVIII treatment, while unsuccessfully treated patients received bypassing agents. Total costs per treated patient were estimated and a one-way sensitivity analysis was conducted to quantify the impact of parameter uncertainty on the model outcomes., Results: Total cumulative costs per patient over 5 years were $834,621 for pdFVIII/VWF patients and $1,237,163 for rFVIII patients, representing a total saving of $402,542 per patient over the 5-year period, for an average annual saving of $80,508 per patient., Conclusions: Based on data from the SIPPET study, this analysis found that initiating FVIII treatment in severe hemophilia A PUPs with pdFVIII/VWF has the potential to offer substantial cost savings to healthcare payers, amounting to a one-third reduction in costs.

Essentials Immunologic methods detect factor VIII (FVIII) antibodies in some inhibitor-negative specimens. Specimens were tested by modified Nijmegen-Bethesda assay (NBA) and fluorescence immunoassay. The NBA with preanalytical heat inactivation detects FVIII inhibitors down to 0.2 NBU. IgG 4 frequency validates the established threshold for positivity of ≥ 0.5 NBU for this NBA., Summary: Background The Bethesda assay for measurement of factor VIII inhibitors called for quantification of positive inhibitors by using dilutions producing 25-75% residual activity (RA), corresponding to 0.4-2.0 Bethesda units, with the use of 'more sensitive methods' for samples with RA closer to 100% being recommended. The Nijmegen modification (Nijmegen-Bethesda assay [NBA]) changed the reagents used but not these calculations. Some specimens negative by the NBA have been shown to have FVIII antibodies detectable with sensitive immunologic methods. Objective To examine the performance at very low inhibitor titers of the Centers for Disease Control and Prevention (CDC)-modified NBA (CDC-NBA), which includes preanalytic heat inactivation to liberate bound anti-FVIII antibodies. Methods Specimens with known inhibitors were tested with the CDC-NBA. IgG 4 anti-FVIII antibodies were measured by fluorescence immunoassay (FLI). Results Diluted inhibitors showed linearity below 0.4 Nijmegen-Bethesda units (NBU). With four statistical methods, the limit of detection of the CDC-NBA was determined to be 0.2 NBU. IgG 4 anti-FVIII antibodies, which correlate most strongly with functional inhibitors, were present at rates above the background rate of healthy controls in specimens with titers ≥ 0.2 NBU and showed an increase in frequency from 14.3% at 0.4 NBU to 67% at the established threshold for positivity of 0.5 NBU. Conclusions The CDC-NBA can detect inhibitors down to 0.2 NBU. The FLI, which is more sensitive, demonstrates anti-FVIII IgG 4 in some patients with negative (< 0.5) NBU. The sharp increase in IgG 4 frequency between 0.4 and 0.5 NBU validates the established threshold for positivity of ≥ 0.5 NBU for the CDC-NBA, supporting the need for method-specific thresholds., (© 2017 International Society on Thrombosis and Haemostasis.)

The current therapy for the human immunodeficiency virus (HIV) infection is a combination of anti-HIV drugs targeting multiple steps of virus replication. The drugs for the acquired immunodeficiency syndrome (AIDS) treatment include reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, co-receptor inhibitor and the newly added integrase inhibitors. Raltegravir, elvitegravir and dolutegravir are the three Food and Drug Administration (FDA) approved integrase strand transfer inhibitors for clinical treatment of HIV infection. The addition of these integrase inhibitors benefits a lot to HIV infected patients. Although it is only seven years from the first integrase inhibitor, which was approved by FDA to now, multiple drug resistant HIV strains have emerged in clinical treatment. Most of the drug resistant virus strains are against raltegravir. Some are cross-resistant to elvitegravir. Dolutegravir is effective for suppression of the current drug resistant viruses. A number of clinical trials have been performed on the three integrase inhibitors. In this study, the application of the three integrase inhibitors in clinical treatment and the findings of drug resistance to integrase inhibitors are summarized., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Infection with influenza A virus is still a global concern since it causes significant mortality, morbidity and economic loss. New burst pandemics and rapid emergence of drug-resistance strains in recent years call for novel antiviral therapies. One promising way to overcome this problem is searching new inhibitors among thousands of drugs approved in the clinic for the treatment of different diseases or approved to be safe by clinical trials. In the present work, a collection of 1280 compounds, most of which have been clinically used in human or animal, were screened for anti-influenza activity and 41 hits (SI>4.0) were obtained. Next the 18 hit compounds with SI >10.0 were tested for antiviral activity against 7 other influenza virus strains in canine-originated MDCK cells, 9 compounds exhibited broad antiviral spectrum. The antiviral effects of the 9 compounds were also confirmed in human-originated A549 cells and chicken-originated DF1 cells, by infectious virus yield reduction assay and indirect immunofluorescent assay. Results from the time of addition assay showed that the 9 candidates impaired different stages of influenza virus life cycle, indicating they are novel inhibitors with different mechanisms compared with the existing M2 ion-channel blockers or neuraminidase (NA) inhibitors. Taken together, our findings provide 9 novel drug candidates for the treatment of influenza virus infection. Further mechanism of action study of these inhibitors may lead to the discovery of new anti-influenza targets and structure-activity relationship (SAR) study can be initiated to improve the efficacy of these new classes of influenza inhibitors., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We report the discovery of an inhibitor of NEDD8-activating enzyme (NAE) by an integrated virtual screening approach. Piperacillin 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity. Furthermore, piperacillin 1 was able to inhibit the degradation of the NAE downstream protein substrate p27(kip1). Our molecular modeling and kinetic studies suggested that this compound may act as a non-covalent ATP-competitive inhibitor of NAE., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Vascular endothelial growth factor-C (VEGF-C) is a secreted growth factor essential for lymphangiogenesis. VEGF-C functions in both physiological and pathological lymphangiogenesis, particularly in tumor metastasis, making it an attractive therapeutic target. Members of two families of cell surface receptors transduce VEGF-C signals: neuropilin-2 (Nrp2) and VEGF-receptor (VEGFR)-2/3. Nrp2 is a promising target for inhibition because it is highly expressed in lymphatic vessels. Here we describe a microplate-based assay for discovery of VEGF-C/Nrp2 inhibitors. We optimize this assay for use in screening an inhibitor library and identify three novel Nrp2/VEGF-C binding inhibitors from the National Institutes of Health (NIH) Clinical Collection small molecule library., (Copyright © 2014 Elsevier Inc. All rights reserved.)