Biomed Pharmacother. 2022 Dec;156:113850. doi: 10.1016/j.biopha.2022.113850. Epub 2022 Oct 28.

ABSTRACT

As diseases caused by new and emerging viruses continue to be a major threat to humans and animals worldwide the need for new therapeutic options intensifies. A wide variety of viruses including Influenza A virus, Human immunodeficiency virus, Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus require ion channels for efficient replication. Thus, targeting host ion channels may serve as an effective means to attenuate virus replication and help treat viral diseases. Targeting host ion channels is an attractive therapeutic option because a range of ion channel-blocking compounds already exist for the treatment of other human diseases and some of these possess in vitro and sometimes in vivo antiviral activity. Therefore, identifying the specific ion channels involved in replicative cycles could provide opportunities to repurpose these ion channel inhibitors for treating viral diseases. Furthermore, optimised methodologies for identifying effective ion channel targeting drugs and their mechanisms of action could enable rapid responses to newly emerged viruses. This review discusses the potential of ion channels as suitable drug targets to treat diseases caused by viruses by describing known ion channel targeting drugs including their antiviral activity; by summarising prior research demonstrating the requirement for host ion channels for efficient replication of some viruses; and by hypothesising about the role these drugs might play in our ongoing fight against viral diseases.

PMID:36411658 | DOI:10.1016/j.biopha.2022.113850

Biomed Pharmacother. 2022 Dec;156:113944. doi: 10.1016/j.biopha.2022.113944. Epub 2022 Nov 3.

ABSTRACT

BACKGROUND: Inflammatory Bowel Disease (IBD) is recognized as a group of chronic inflammatory disorders, localized in the gastrointestinal tract, which does not have a cure known. Indeed, the pharmacological approaches, commonly used, demonstrate significant toxicity, which highlights the need of investigating new possible treatments. Erythropoietin (EPO) is clinically used in anemic patients, with chronic renal insufficiency, due to its erythropoietic effect. However, it has also been described other non-erythropoietic effects, such as an anti-inflammatory role. There is already preclinical evidence about its anti-inflammatory effect in the IBD context, namely in an acute model of colitis in mice. Therefore, it is relevant to ascertain its anti-inflammatory effect in a chronic model, but mainly its hematopoietic side effect, during chronic treatment.

AIM: This experiment aims to evaluate the efficacy and safety of EPO treatment in a chronic 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents.

METHODS: The induction of chronic colitis consistedofn five weekly intrarectal administrations of 1% TNBS, and then mice were treated daily with 500 IU/Kg or 1000 IU/Kg of EPO, through intraperitoneal injections, for 14 days.

RESULTS: EPO demonstrated a significant anti-inflammatory effect, translated by a significant reduction of the concentration oftumorr necrosis factor-α, fecal calprotectin, and fecal hemoglobin. Moreover, it has also been demonstrated to be safe, considering the cardiovascular system, in terms of extraintestinal manifestations, namely at renal and hepatic functions.

CONCLUSIONS: EPO demonstrated to be a promising pharmacological approach to be considered in the management of IBD, being an interesting target for drug repositioning.

PMID:36411630 | DOI:10.1016/j.biopha.2022.113944

Nat Genet. 2022 Nov 21. doi: 10.1038/s41588-022-01221-w. Online ahead of print.

ABSTRACT

Osteoarthritis is a common progressive joint disease. As no effective medical interventions are available, osteoarthritis often progresses to the end stage, in which only surgical options such as total joint replacement are available. A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached. To date, there have been no large multiancestry genetic studies of osteoarthritis. Here, we leveraged the unique resources of 484,374 participants in the Million Veteran Program and UK Biobank to address this gap. Analyses included participants of European, African, Asian and Hispanic descent. We discovered osteoarthritis-associated genetic variation at 10 loci and replicated findings from previous osteoarthritis studies. We also present evidence that some osteoarthritis-associated regions are robust to population ancestry. Drug repurposing analyses revealed enrichment of targets of several medication classes and provide potential insight into the etiology of beneficial effects of antiepileptics on osteoarthritis pain.

PMID:36411363 | DOI:10.1038/s41588-022-01221-w

Mol Inform. 2022 Nov 21. doi: 10.1002/minf.202200077. Online ahead of print.

ABSTRACT

Computational drug repurposing aims to discover new treatment regimens by analyzing approved drugs on the market. This study proposes previously approved compounds that can change the expression profile of disease-causing proteins by developing a network theory-based drug repurposing approach. The novelty of the proposed approach is an exploration of module similarity between a disease-causing network and a compound-specific interaction network; thus, such an association leads to more realistic modeling of molecular cell responses at a system biology level. The overlap of the disease network and each compound-specific network is calculated based on a shortest-path similarity of networks by accounting for all protein pairs between networks. A higher similarity score indicates a significant potential of a compound. The approach was validated for breast and lung cancers. When all compounds are sorted by their normalized-similarity scores, 36 and 16 drugs are proposed as new candidates for breast and lung cancer treatment, respectively. A literature survey on candidate compounds revealed that some of our predictions have been clinically investigated in phase II/III trials for the treatment of two cancer types. As a summary, the proposed approach has provided promising initial results by modeling biochemical cell responses in a network-level data representation.

PMID:36411244 | DOI:10.1002/minf.202200077

Front Mol Biosci. 2022 Nov 3;9:1062346. doi: 10.3389/fmolb.2022.1062346. eCollection 2022.

ABSTRACT

I was fortunate to do my military service during the Vietnam era as a medical officer at the National Institutes of Health (NIH) in Bethesda, Maryland. My first research at NIH was concerned with making a variety of optical measurements on nucleic acid bases and proteins, including single crystal spectra in linearly polarized light and near infrared circular dichroism, interpreting the spectra using molecular orbital and crystal field theories. What I do now is drug discovery, a field at the opposite end of the scientific spectrum. This article gives a brief account of my transition from spectroscopy to sickle cell hemoglobin polymerization to protein folding to drug discovery for treating sickle cell disease. My lab recently developed a high throughput assay to screen the 12,657 compounds of the California Institute of Biomedical Research ReFrame drug repurposing library. This is a precious library because the compounds have either been FDA approved or have been tested in clinical trials. Since the 1970s numerous agents have been reported in the literature to inhibit HbS polymerization and/or sickling with only one successful drug, hydroxyurea, and another of dubious value, voxelotor, even though it has been approved by the FDA. Our screen has discovered 106 anti-sickling agents in the ReFrame compound library. We estimate that as many as 21 of these compounds could become oral drugs for treating sickle cell disease because they inhibit at concentrations typical of the free concentrations of oral drugs in human serum.

PMID:36406264 | PMC:PMC9669753 | DOI:10.3389/fmolb.2022.1062346

Front Genet. 2022 Nov 4;13:1019940. doi: 10.3389/fgene.2022.1019940. eCollection 2022.

ABSTRACT

Given the considerable cost of drug discovery, drug repurposing is becoming attractive as it can effectively shorten the development timeline and reduce the development cost. However, most existing drug-repurposing methods omitted the heterogeneous health conditions of different COVID-19 patients. In this study, we evaluated the adverse effect (AE) profiles of 106 COVID-19 drugs. We extracted four AE signatures to characterize the AE distribution of 106 COVID-19 drugs by non-negative matrix factorization (NMF). By integrating the information from four distinct databases (AE, bioassay, chemical structure, and gene expression information), we predicted the AE profiles of 91 drugs with inadequate AE feedback. For each of the drug clusters, discriminant genes accounting for mechanisms of different AE signatures were identified by sparse linear discriminant analysis. Our findings can be divided into three parts. First, drugs abundant with AE-signature 1 (for example, remdesivir) should be taken with caution for patients with poor liver, renal, or cardiac functions, where the functional genes accumulate in the RHO GTPases Activate NADPH Oxidases pathway. Second, drugs featuring AE-signature 2 (for example, hydroxychloroquine) are unsuitable for patients with vascular disorders, with relevant genes enriched in signal transduction pathways. Third, drugs characterized by AE signatures 3 and 4 have relatively mild AEs. Our study showed that NMF and network-based frameworks contribute to more precise drug recommendations.

PMID:36406131 | PMC:PMC9673014 | DOI:10.3389/fgene.2022.1019940

J Neural Transm (Vienna). 2022 Nov 19. doi: 10.1007/s00702-022-02566-6. Online ahead of print.

ABSTRACT

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The "Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)" is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration: http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044.

PMID:36401749 | DOI:10.1007/s00702-022-02566-6

Cardiovasc Drugs Ther. 2022 Nov 19. doi: 10.1007/s10557-022-07406-z. Online ahead of print.

ABSTRACT

PURPOSE: As of July 2022, the COVID-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the D-dimer levels were increased in non-survivors compared to survivors and heparin treatment has begun to be administered to the patients in severe clinics. As we knew that the entrance of SARS-CoV-2 to the host cell needs to be facilitated by host proteases; we published our hypothesis that heparin as a serine protease inhibitor may block the interaction between spike protein receptor-binding domain and host proteases. In our study, we aimed to investigate the interactions between not only heparins but also other antiplatelet and anticoagulant drugs including fondaparinux.

METHODS: In this study, docking studies were carried out to evaluate the interactions between low molecular weight heparins (LMWHs) (enoxaparin, dalteparin, tinzaparin), direct oral anticoagulant, and antiplatelet drugs with host proteases. Molecular docking studies were performed by using Schrödinger molecular modeling software. 3D structures of the ligands were obtained from the 2D structures by assigning the OPLS-2005 force field using the Maestro 12.7. The 3D crystal structure of the furin complexed with an inhibitor, 2,5-dideoksistreptamin derivative, was extracted from the Protein Data Bank (PDB ID: 5MIM). Docking studies were carried out using the Grid-based Ligand Docking with Energetics module of the Schrödinger Software.

RESULTS: The docking studies revealed that fondaparinux was the most relevant molecule to interact with furin with a docking score of - 12.74. It showed better interaction than the natural ligand of furin with an increased score compared to the docking score of - 8.155 of the natural ligand. AnaGA*IsA structure representing LMWH structure has shown a docking score of - 11.562 which was also better than the score of the natural ligand of furin.

CONCLUSION: Our findings have shown that LMWHs and fondaparinux can be used for their possible antiviral effects in COVID-19 patients. Our results have shown that in accordance with heparin and LMWH, fondaparinux can also be a candidate for "drug repurposing" in COVID-19 therapy, not only because of their anticoagulant but also possible antiviral effects.

PMID:36401727 | DOI:10.1007/s10557-022-07406-z

Appl Biochem Biotechnol. 2022 Nov 19. doi: 10.1007/s12010-022-04231-w. Online ahead of print.

ABSTRACT

Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein-protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR-SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein-protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens.

PMID:36401726 | DOI:10.1007/s12010-022-04231-w

Appl Biochem Biotechnol. 2022 Nov 19. doi: 10.1007/s12010-022-04207-w. Online ahead of print.

ABSTRACT

In recent years, candidiasis attains major clinical importance due to its unique pathogenic strategy, which distinguishes it from other nosocomial infections. Secreted aspartyl proteinases (SAPs) is a hydrolytic enzyme secreted by Candida species that mediate versatile biological activity including hyphal formation, adherence, biofilm formation, phenotypic adaptation, etc. Emerging clinical evidence strongly suggested that conventional anti-fungal agent's are often prone to high level of resistance upon repeated exposure. Drug repurposing is an ideal strategy that shall impose the additional clinical benefits of the already approved molecules. Hence, through this realistic pathway, the potential of the suitable lead candidates will be explored in order to prolong the life span of existing molecules thereby need for newer therapeutics shall be avoided. The main aim of the present investigation is to determine the enzyme inhibitory potential of certain FDA-approved antibiotics and to validate its efficacy against the virulent enzyme secreted aspartyl proteinase (SAP) of Candida albicans via the AutoDock simulation program. The outcome of in silico dynamic simulations depicts that the drugs such as gentamicin, clindamycin, meropenem, metronidazole, and aztreonam emphasize superior binding affinity in terms of demonstrating considerable interaction with the core catalytic residues (Asp 32, Asp86, Asp 218, Gly220, Thr 221, and Thr 222). Data further indicates that the drug gentamicin exhibited best binding affinity of - 14.16 kcal/mol followed by meropenem (- 9.20 kcal/mol), clindamycin (- 9.00 kcal/mol), ciprofloxacin (- 8.95 kcal/mol), and imipenem (- 8.00 kcal/mol). In conclusion, repurposed antibiotics like gentamicin, clindamycin, meropenem, metronidazole, and aztreonam shall be considered an alternate drug of choice for the clinical management of drug resistant candida infections in the near future.

PMID:36401722 | DOI:10.1007/s12010-022-04207-w

Eur Neuropsychopharmacol. 2022 Oct 20;66:30-44. doi: 10.1016/j.euroneuro.2022.10.004. Online ahead of print.

ABSTRACT

Several psychotropic drugs, including antidepressants (AD), mood stabilizers, and antipsychotics (AP) have been suggested to have favorable effects in the treatment of COVID-19. The aim of this systematic review and meta-analysis was to collect evidence from studies concerning the scientific evidence for the repurposing of psychotropic drugs in COVID-19 treatment. Two independent authors searched PubMed-MEDLINE, Scopus, PsycINFO, and ClinicalTrials.gov databases, and reviewed the reference lists of articles for eligible articles published up to 13th December 2021. All computational, preclinical and clinical (observational and/or RCTs) studies on the effect of any psychotropic drug on Sars-CoV-2 or patients with COVID-19 were considered for inclusion. We conducted random effect meta-analyses on clinical studies reporting the effect of AD or AP on COVID-19 outcomes. 29 studies were included in the synthesis: 15 clinical, 9 preclinical, and 5 computational studies. 9 clinical studies could be included in the quantitative analyses. AD did not increase the risk of severe COVID-19 (RR= 1.71; CI 0.65-4.51) or mortality (RR=0.94; CI 0.81-1.09). Fluvoxamine was associated with a reduced risk of mortality for COVID-19 (OR=0.15; CI 0.02-0.95). AP increased the risk of severe COVID-19 (RR=3.66; CI 2.76-4.85) and mortality (OR=1.53; CI 1.15-2.03). Fluvoxamine might be a possible candidate for psychotropic drug repurposing in COVID-19 due to its anti-inflammatory and antiviral potential, while evidence on other AD is still controversial. Although AP are associated with worse COVID-19 outcomes, their use should be evaluated case to case and ongoing treatment with antipsychotics should be not discontinued in psychiatric patients.

PMID:36399837 | DOI:10.1016/j.euroneuro.2022.10.004

J Biomol Struct Dyn. 2022 Nov 18:1-15. doi: 10.1080/07391102.2022.2148000. Online ahead of print.

ABSTRACT

The global and rapid spread of the novel human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has brought immediate urgency to the discovery of favorable targets for COVID-19 treatment. Here, we consider drug reuse as an attractive methodology for drug discovery by reusing existing drugs to treat diseases other than their initial indications. Here, we review current information concerning the global health issue of COVID-19 including VEGFR-2 inhibitors. Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2. The present study suggests the potential anti-SARS-CoV-2 activities of 35 reported VEGFR-2 inhibitors containing the amide and urea linkers. Nineteen members revealed the best in silico results and hence, were subjected to further molecular dynamics (MD) simulation for their inhibitory activities against SARS-CoV-2 Mpro across 100 ns. Furthermore, MD simulations followed by calculations of the free energy of binding were also carried out for the most promising ligand-pocket complexes from docking studies to clarify some information on their dynamic and thermodynamic properties and approve the docking results. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19.Communicated by Ramaswamy H. Sarma.

PMID:36399002 | DOI:10.1080/07391102.2022.2148000

Medicine (Baltimore). 2022 Nov 11;101(45):e31635. doi: 10.1097/MD.0000000000031635.

ABSTRACT

Bladder cancer (BC) is a common type of cancer worldwide. Currently, the gold standard treatment is transurethral resection of bladder tumor (TUR-Bt) accompanied by intravesical Bacillus Calmette-Guérin (BCG) instillation for patients with middle-to-high-risk non-muscle-invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in almost 50% of high risk cases, leading to NMIBC persistence or early recurrence. In these patients, the gold standard remains radical cystectomy; however, it can seriously affect the patients' quality of life. Moreover, for patients with muscle-invasive bladder cancer (MIBC), the 5-year survival rate after radical cystectomy with neoadjuvant chemotherapy remains low. Recent discoveries have paved the way for a new era in BC treatment. Metformin is the most widely used oral hypoglycemic drug in clinical practice, being mostly used in the treatment of type 2 diabetes. Epidemiological studies have demonstrated that metformin exerts a potentially positive effect on reducing the incidence and mortality of cancer; therefore, a increasing number of studies have investigated the potential anticancer effects of metformin and its mechanisms of action. This review aims to summarize the evidence for the role of metformin in bladder cancer therapy, including how metformin mediates bladder cancer cell apoptosis.

PMID:36397350 | DOI:10.1097/MD.0000000000031635

Trends Pharmacol Sci. 2022 Nov 5:S0165-6147(22)00228-0. doi: 10.1016/j.tips.2022.10.002. Online ahead of print.

ABSTRACT

The cardiac glycoside (CG) digoxin is a generic drug approved for the treatment of heart failure and supraventricular arrhythmias. Over the past few decades, substantial strides have been made toward repurposing digoxin to treat various noncardiac diseases. Here, we evaluate recent insights into basic and clinical work related to noncardiac use of digoxin.

PMID:36396496 | DOI:10.1016/j.tips.2022.10.002

Cell Syst. 2022 Nov 16;13(11):911-923.e9. doi: 10.1016/j.cels.2022.10.001. Epub 2022 Oct 28.

ABSTRACT

Morphological and gene expression profiling can cost-effectively capture thousands of features in thousands of samples across perturbations by disease, mutation, or drug treatments, but it is unclear to what extent the two modalities capture overlapping versus complementary information. Here, using both the L1000 and Cell Painting assays to profile gene expression and cell morphology, respectively, we perturb human A549 lung cancer cells with 1,327 small molecules from the Drug Repurposing Hub across six doses, providing a data resource including dose-response data from both assays. The two assays capture both shared and complementary information for mapping cell state. Cell Painting profiles from compound perturbations are more reproducible and show more diversity but measure fewer distinct groups of features. Applying unsupervised and supervised methods to predict compound mechanisms of action (MOAs) and gene targets, we find that the two assays not only provide a partially shared but also a complementary view of drug mechanisms. Given the numerous applications of profiling in biology, our analyses provide guidance for planning experiments that profile cells for detecting distinct cell types, disease phenotypes, and response to chemical or genetic perturbations.

PMID:36395727 | DOI:10.1016/j.cels.2022.10.001

Bioinformatics. 2022 Nov 17:btac735. doi: 10.1093/bioinformatics/btac735. Online ahead of print.

ABSTRACT

MOTIVATION: Gene set analysis methods rely on knowledge-based representations of genetic interactions in the form of both gene set collections and protein-protein interaction (PPI) networks. However, explicit representations of genetic interactions often fail to capture complex interdependencies among genes, limiting the analytic power of such methods.

RESULTS: We propose an extension of gene set enrichment analysis to a latent embedding space reflecting PPI network topology, called gene set proximity analysis (GSPA). Compared with existing methods, GSPA provides improved ability to identify disease-associated pathways in disease-matched gene expression datasets, while improving reproducibility of enrichment statistics for similar gene sets. GSPA is statistically straightforward, reducing to a version of traditional gene set enrichment analysis through a single user-defined parameter. We apply our method to identify novel drug associations with SARS-CoV-2 viral entry. Finally, we validate our drug association predictions through retrospective clinical analysis of claims data from 8 million patients, supporting a role for gabapentin as a risk factor and metformin as a protective factor for severe COVID-19.

AVAILABILITY: GSPA is available for download as a command-line Python package at https://github.com/henrycousins/gspa.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36394254 | DOI:10.1093/bioinformatics/btac735

Front Immunol. 2022 Oct 27;13:1022104. doi: 10.3389/fimmu.2022.1022104. eCollection 2022.

ABSTRACT

BACKGROUND: Bronchopulmonary dysplasia (BPD), its complication pulmonary hypertension (BPD-PH) and preterm brain and gut injury lead to significant morbidity and mortality in infants born extremely prematurely. There is extensive evidence that the pro-inflammatory cytokine interleukin 1 (IL-1) plays a key role in the pathophysiology of these illnesses. Two decades of clinical use in paediatric and adult medicine have established an excellent safety and efficacy record for IL-1 blockade with IL-1 receptor antagonist (IL-1Ra, medication name anakinra). Building on robust pre-clinical evidence, the Anakinra Pilot trial aims to demonstrate safety and feasibility of administering anakinra to preterm infants, and to establish pharmacokinetics in this population. Its ultimate goal is to facilitate large studies that will test whether anakinra can ameliorate early-life inflammation, thus alleviating multiple complications of prematurity.

METHODS AND ANALYSIS: Anakinra Pilot is an investigator-initiated, single arm, safety and feasibility dose-escalation trial in extremely preterm infants born between 24 weeks 0 days (240) and 276 weeks of gestational age (GA). Enrolled infants will receive anakinra intravenously over the first 21 days after birth, starting in the first 24 h after birth. In the first phase, dosing is 1 mg/kg every 48 h, and dosage will increase to 1.5 mg/kg every 24 h in the second phase. Initial anakinra dosing was determined through population pharmacokinetic model simulations. During the study, there will be a interim analysis to confirm predictions before undertaking dose assessment. Anakinra therapy will be considered safe if the frequency of adverse outcomes/events does not exceed that expected in infants born at 240-276 weeks GA.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT05280340.

PMID:36389766 | PMC:PMC9647081 | DOI:10.3389/fimmu.2022.1022104

Front Immunol. 2022 Oct 26;13:989972. doi: 10.3389/fimmu.2022.989972. eCollection 2022.

ABSTRACT

Metastatic castration-resistant prostate cancer (CRPC) has long been considered to be associated with patient mortality. Among metastatic organs, bone is the most common metastatic site, with more than 90% of advanced patients developing bone metastases (BMs) before 24 months of death. Although patients were recommended to use bone-targeted drugs represented by bisphosphonates to treat BMs of CRPC, there was no significant improvement in patient survival. In addition, the use of immunotherapy and androgen deprivation therapy is limited due to the immunosuppressed state and resistance to antiandrogen agents in patients with bone metastases. Therefore, it is still essential to develop a safe and effective therapeutic schedule for CRPC patients with BMs. To this end, we propose a multiplex drug repurposing scheme targeting differences in patient immune cell composition. The identified drug candidates were ranked from the perspective of M2 macrophages by integrating transcriptome and network-based analysis. Meanwhile, computational chemistry and clinical trials were used to generate a comprehensive drug candidate list for the BMs of CRPC by drug redundancy structure filtering. In addition to docetaxel, which has been approved for clinical trials, the list includes norethindrone, testosterone, menthol and foretinib. This study provides a new scheme for BMs of CRPC from the perspective of M2 macrophages. It is undeniable that this multiplex drug repurposing scheme specifically for immune cell-related bone metastases can be used for drug screening of any immune-related disease, helping clinicians find promising therapeutic schedules more quickly, and providing reference information for drug R&D and clinical trials.

PMID:36389722 | PMC:PMC9643318 | DOI:10.3389/fimmu.2022.989972

Front Immunol. 2022 Oct 27;13:962079. doi: 10.3389/fimmu.2022.962079. eCollection 2022.

ABSTRACT

Despite the efficacy of antiviral drug repositioning, convalescent plasma (CP), and the currently available vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the worldwide coronavirus disease 2019 (COVID-19) pandemic is still challenging because of the ongoing emergence of certain new SARS-CoV-2 strains known as variants of concern (VOCs). Mutations occurring within the viral genome, characterized by these new emerging VOCs, confer on them the ability to efficiently resist and escape natural and vaccine-induced humoral and cellular immune responses. Consequently, these VOCs have enhanced infectivity, increasing their stable spread in a given population with an important fatality rate. While the humoral immune escape process is well documented, the evasion mechanisms of VOCs from cellular immunity are not well elaborated. In this review, we discussed how SARS-CoV-2 VOCs adapt inside host cells and escape anti-COVID-19 cellular immunity, focusing on the effect of specific SARS-CoV-2 mutations in hampering the activation of CD8+ T-cell immunity.

PMID:36389664 | PMC:PMC9647062 | DOI:10.3389/fimmu.2022.962079

Front Oncol. 2022 Oct 27;12:1009193. doi: 10.3389/fonc.2022.1009193. eCollection 2022.

ABSTRACT

The development of effective and personalized treatment options for patients with rare cancers like chordoma is hampered by numerous challenges. Biomarker-guided repurposing of therapies approved in other indications remains the fastest path to redefining the treatment paradigm, but chordoma's low mutation burden limits the impact of genomics in target discovery and precision oncology efforts. As our knowledge of oncogenic mechanisms across various malignancies has matured, it's become increasingly clear that numerous properties of tumors transcend their genomes - leading to new and uncharted frontiers of therapeutic opportunity. In this review, we discuss how the implementation of cutting-edge tools and approaches is opening new windows into chordoma's vulnerabilities. We also note how a convergence of emerging observations in chordoma and other cancers is leading to the identification and evaluation of new therapeutic hypotheses for this rare cancer.

PMID:36387127 | PMC:PMC9647139 | DOI:10.3389/fonc.2022.1009193