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Journal of Virology Aug 2023With increasing resistance of SARS-CoV-2 variants to antibodies, there is interest in developing entry inhibitors that target essential receptor-binding regions of the...
With increasing resistance of SARS-CoV-2 variants to antibodies, there is interest in developing entry inhibitors that target essential receptor-binding regions of the viral Spike protein and thereby present a high bar for viral resistance. Such inhibitors could be derivatives of the viral receptor, ACE2, or peptides engineered to interact specifically with the Spike receptor-binding pocket. We compared the efficacy of a series of both types of entry inhibitors, constructed as fusions to an antibody Fc domain. Such a design can increase protein stability and act to both neutralize free virus and recruit effector functions to clear infected cells. We tested the reagents against prototype variants of SARS-CoV-2, using both Spike pseudotyped vesicular stomatitis virus vectors and replication-competent viruses. These analyses revealed that an optimized ACE2 derivative could neutralize all variants we tested with high efficacy. In contrast, the Spike-binding peptides had varying activities against different variants, with resistance observed in the Spike proteins from Beta, Gamma, and Omicron (BA.1 and BA.5). The resistance mapped to mutations at Spike residues K417 and N501 and could be overcome for one of the peptides by linking two copies in tandem, effectively creating a tetrameric reagent in the Fc fusion. Finally, both the optimized ACE2 and tetrameric peptide inhibitors provided some protection to human ACE2 transgenic mice challenged with the SARS-CoV-2 Delta variant, which typically causes death in this model within 7-9 days. IMPORTANCE The increasing resistance of SARS-CoV-2 variants to therapeutic antibodies has highlighted the need for new treatment options, especially in individuals who do not respond to vaccination. Receptor decoys that block viral entry are an attractive approach because of the presumed high bar to developing viral resistance. Here, we compare two entry inhibitors based on derivatives of the ACE2 receptor, or engineered peptides that bind to the receptor-binding pocket of the SARS-CoV-2 Spike protein. In each case, the inhibitors were fused to immunoglobulin Fc domains, which can further enhance therapeutic properties, and compared for activity against different SARS-CoV-2 variants. Potent inhibition against multiple SARS-CoV-2 variants was demonstrated , and even relatively low single doses of optimized reagents provided some protection in a mouse model, confirming their potential as an alternative to antibody therapies.
Topics: Animals; Mice; Humans; SARS-CoV-2; Angiotensin-Converting Enzyme 2; COVID-19; Spike Glycoprotein, Coronavirus; HIV Fusion Inhibitors; Mice, Transgenic; Peptides
PubMed: 37555663
DOI: 10.1128/jvi.00684-23 -
Molecular Therapy Oncolytics Sep 2023Unraveling the complexities of the tumor microenvironment (TME) and its correlation with responsiveness to immunotherapy has become a main focus in overcoming resistance...
Unraveling the complexities of the tumor microenvironment (TME) and its correlation with responsiveness to immunotherapy has become a main focus in overcoming resistance to such treatments. Targeting tumor-intrinsic retinoic acid-inducible gene-I (RIG-I), a sensor for viral RNA, was shown to transform the TME from an immunogenically "cold" state to an inflamed, "hot" lesion, which we demonstrated previously to be a crucial mediator of the efficacy of immune checkpoint inhibition with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4). In this study, we focus on the chimeric oncolytic virus vesicular stomatitis virus (VSV)-Newcastle disease virus (NDV), comprised of genetic components of VSV and NDV, and we investigate its utility to support tumor-intrinsic RIG-I-dependent therapy with anti-CTLA-4. Overall, we demonstrate that treatment with VSV-NDV efficiently delays tumor growth and significantly prolongs survival in a murine model of malignant melanoma, which was further enhanced in combination with anti-CTLA-4. Although the direct oncolytic and pro-inflammatory effects of VSV-NDV therapy were independent of RIG-I activation, the synergism with anti-CTLA-4 therapy and associated activation of tumor-specific T cells was critically dependent on active RIG-I signaling in tumor cells. This work highlights the therapeutic value of utilizing an immune-stimulatory oncolytic virus to sensitize tumors to immune checkpoint inhibition.
PubMed: 37654972
DOI: 10.1016/j.omto.2023.08.001 -
International Journal of Molecular... Dec 2023Anti-cancer therapy based on oncolytic viruses (OVs) is a targeted approach that takes advantage of OVs' ability to selectively infect and replicate in tumor cells,...
Anti-cancer therapy based on oncolytic viruses (OVs) is a targeted approach that takes advantage of OVs' ability to selectively infect and replicate in tumor cells, activate the host immune response, and destroy malignant cells over healthy ones. Vesicular stomatitis virus (VSV) is known for its wide range of advantages: a lack of pre-existing immunity, a genome that is easily amenable to manipulation, and rapid growth to high titers in a broad range of cell lines, to name a few. VSV-induced tumor immunity can be enhanced by the delivery of immunostimulatory cytokines. The targeted cytokine delivery to tumors avoids the significant toxicity associated with systemic delivery while also boosting the immune response. To demonstrate this enhanced effect on both tumor growth and survival, a novel recombinant VSV (rVSV)-mIL12-mGMCSF, co-expressing mouse IL-12 (interleukin-12) and GM-CSF (granulocyte-macrophage colony-stimulating factor), was tested alongside rVSV-dM51-GFP (rVSV-GFP) that was injected intratumorally in a syngeneic in vivo C57BL/6 mouse model infused subcutaneously with B16-F10 melanoma cells. The pilot study tested the effect of two viral injections 4 days apart and demonstrated that treatment with the two rVSVs resulted in partial inhibition of tumor growth (TGII of around 40%) and an increased survival rate in animals from the treatment groups. The effect of the two VSVs on immune cell populations will be investigated in future in vivo studies with an optimized experimental design with multiple higher viral doses, as a lack of this information presents a limitation of this study.
Topics: Animals; Mice; Mice, Inbred C57BL; Pilot Projects; Immunotherapy; Immunization; Cytokines; Interleukin-12; Melanoma, Experimental
PubMed: 38203382
DOI: 10.3390/ijms25010211 -
Italian Journal of Dermatology and... Oct 2023The oral mucosa can be involved in a wide variety of mucocutaneous conditions that may present primarily in the mouth or affect other cutaneous or mucosal sites. Many of... (Review)
Review
The oral mucosa can be involved in a wide variety of mucocutaneous conditions that may present primarily in the mouth or affect other cutaneous or mucosal sites. Many of these conditions are immune mediated and typically present as inflammatory mucosal pathology. Patients experiencing such conditions usually seek medical evaluation and treatment due to the associated pain and discomfort and occasionally taste disturbance or dysphagia and the overall deterioration in the oral health-related quality of life. These conditions share some common features and there could be some overlapping in their clinical presentation, which can lead to delays in diagnosis and proper management of patients. Clinicians dealing with such disorders, including dermatologists, need to be aware of the oral manifestations of mucocutaneous conditions, their clinical features, underlying mechanisms, diagnostic approaches, and treatment options, as well as the recent advances in the research on these conditions. This review provides a comprehensive, evidence-based reference for clinicians, with updated insights into a group of immune mediated conditions known to cause oral mucosal pathology. Part one will cover oral lichen planus, erythema multiforme and systemic lupus erythematosus, while part two will cover pemphigus vulgaris and mucous membrane pemphigoid, recurrent aphthous stomatitis, in addition to the less common disorders linear IgA disease, dermatitis herpetiformis and epidermolysis bullosa.
Topics: Humans; Mouth Mucosa; Mouth Diseases; Quality of Life; Stomatitis, Aphthous; Pemphigus
PubMed: 37916401
DOI: 10.23736/S2784-8671.23.07676-4 -
Antiviral Research Dec 2023Apoptosis signal-regulating kinase 1 (ASK1)/MAP3K5 is a stress response kinase that is activated by various stimuli. It is known as an upstream activator of p38-...
Apoptosis signal-regulating kinase 1 (ASK1)/MAP3K5 is a stress response kinase that is activated by various stimuli. It is known as an upstream activator of p38- Mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) that are reactive oxygen species (ROS)-induced kinases. Accumulating evidence show that ROS accumulate in virus-infected cells. Here, we investigated the relationship between viruses and ASK1/p38MAPK or ASK1/JNK pathways. Our findings suggest that virus infection activates ASK1 related pathways. In parallel, ASK1 inhibition led to a remarkable reduction in the replication of a broad range of viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccinia virus (VV), vesicular stomatitis virus (VSV), Herpes Simplex Virus (HSV), and Human Immunodeficiency virus (HIV) in different human cell lines. Our work demonstrates the potential therapeutic use of Selonsertib, an ASK1 inhibitor, as a pan-antiviral drug in humans. Surprisingly, we observed differential effects of Selonsertib in in vitro and in vivo hamster models, suggesting caution in using rodent models to predict clinical and therapeutic outcomes in humans.
Topics: Humans; Signal Transduction; RNA, Viral; MAP Kinase Kinase Kinase 5; Reactive Oxygen Species; Antiviral Agents; COVID-19; SARS-CoV-2; p38 Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases; Apoptosis
PubMed: 37863359
DOI: 10.1016/j.antiviral.2023.105736 -
Drug Design, Development and Therapy 2024Recurrent aphthous stomatitis (RAS) refers to a sore and frequently recurring inflammation of the oral tissues, distinguished by the presence of small ulcers that cause... (Review)
Review
Recurrent aphthous stomatitis (RAS) refers to a sore and frequently recurring inflammation of the oral tissues, distinguished by the presence of small ulcers that cause significant discomfort and cannot be attributed to any underlying disease. Different treatments have been used for RAS. This review aims to provide a comprehensive overview of the treatment options over the past decade for recurrent aphthous stomatitis (RAS), encompassing both natural and synthetic treatments. It will utilize clinical efficacy studies conducted in vivo and in vitro, along with a focus on the pharmaceutical approach through advancements in drug delivery development. We conducted a thorough literature search from 2013 to 2023 in prominent databases such as PubMed, Scopus, and Cochrane, utilizing appropriate keywords of recurrent aphthous stomatitis, and treatment. A total of 53 clinical trials with 3022 patients were included, with 35 using natural materials in their research and a total of 16 articles discussing RAS treatment using synthetic materials. All the clinical trials showed that natural and synthetic medicines seemed to benefit RAS patients by reducing pain score, ulcer size, and number of ulcers and shortening the healing duration.
Topics: Stomatitis, Aphthous; Humans; Biological Products; Synthetic Drugs
PubMed: 38681204
DOI: 10.2147/DDDT.S449370 -
BioRxiv : the Preprint Server For... Oct 2023Nirmatrelvir was the first protease inhibitor (PI) specifically developed against the SARS-CoV-2 main protease (3CL/M) and licensed for clinical use. As SARS-CoV-2...
Nirmatrelvir was the first protease inhibitor (PI) specifically developed against the SARS-CoV-2 main protease (3CL/M) and licensed for clinical use. As SARS-CoV-2 continues to spread, variants resistant to nirmatrelvir and other currently available treatments are likely to arise. This study aimed to identify and characterize mutations that confer resistance to nirmatrelvir. To safely generate M resistance mutations, we passaged a previously developed, chimeric vesicular stomatitis virus (VSV-M) with increasing, yet suboptimal concentrations of nirmatrelvir. Using Wuhan-1 and Omicron M variants, we selected a large set of mutants. Some mutations are frequently present in GISAID, suggesting their relevance in SARS-CoV-2. The resistance phenotype of a subset of mutations was characterized against clinically available PIs (nirmatrelvir and ensitrelvir) with cell-based and biochemical assays. Moreover, we showed the putative molecular mechanism of resistance based on in silico molecular modelling. These findings have implications on the development of future generation M inhibitors, will help to understand SARS-CoV-2 protease-inhibitor-resistance mechanisms and show the relevance of specific mutations in the clinic, thereby informing treatment decisions.
PubMed: 37808638
DOI: 10.1101/2023.09.22.558628 -
JAMA Network Open Oct 2023Oral mucositis (OM) is a common and debilitating adverse effect observed in patients with head and neck cancer (HNC) receiving radiation therapy (RT). Previous studies...
IMPORTANCE
Oral mucositis (OM) is a common and debilitating adverse effect observed in patients with head and neck cancer (HNC) receiving radiation therapy (RT). Previous studies examining associations between OM and clinical outcomes were performed in the era of 3-dimensional conformal RT planning with low rates of concurrent chemotherapy, and thus may not reflect current practice.
OBJECTIVE
To prospectively assess patient-reported OM and identify its associations with clinical outcomes and quality of life.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study performed at a single institution included 702 consecutive patients who underwent definitive or adjuvant intensity-modulated RT (IMRT) for primary HNC from February 9, 2015, to May 27, 2022. Data were analyzed from November 28, 2022, to August 18, 2023.
MAIN OUTCOMES AND MEASURES
Severity of OM was assessed based on highest reported mouth and throat soreness (MTS) score during radiotherapy according to the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer survey, which was administered weekly during IMRT. Linear mixed models were used to compare mean MTS scores grouped by disease site and chemotherapy regimen. Fisher exact tests and 1-way analysis of variance tests were performed to identify associations between severity of OM and clinical outcomes.
RESULTS
Among 576 eligible patients, the median age was 62.5 (IQR, 56.3-69.1) years, and 451 patients (78.3%) were men. In terms of race and ethnicity, 6 patients (1.0%) were American Indian or Alaska Native; 2 (0.3%), Asian; 31 (5.4%), Black; 8 (1.4%), Hispanic or Latino; 509 (88.4%), White; and 28 (4.9%), unknown. The most common treatment site was oropharynx (268 [46.5%]), and most patients received concurrent chemotherapy (464 [80.6%]). By the end of treatment, 360 patients (62.5%) developed severe OM and 568 (98.6%) developed some degree of OM. Linear mixed models found no significant differences in OM between HNC disease sites. Groups with greater highest severity of OM reported had higher rates of measured outcomes (listed respectively by MTS score 0, 1, 2, 3, and 4): feeding tube placement (0%, 3.6% [2 of 56], 6.6% [10 of 152], 14.7% [40 of 272], and 21.6% [19 of 88]; P = .001), hospitalization (12.5% [1 of 8], 10.7% [6 of 56], 15.1% [23 of 152], 23.9% [65 of 272], and 28.4% [25 of 88]; P = .02), opiate use (0%, 19.6% [11 of 56], 42.8%[65 of 152], 61.4% [167 of 272], and 64.8% [57 of 88]; P < .001) and experienced greater weight loss (median, -0.7 [IQR, -1.7 to -0.4] kg; median, 3.9 [IQR, 1.1 to 6.1] kg; median, 5.0 [IQR, 2.2 to 7.7] kg; median, 4.7 [IQR, 2.1 to 7.7] kg; and median, 7.7 [IQR, 2.8 to 10.6] kg; P < .001).
CONCLUSIONS AND RELEVANCE
In this cohort study of patients with HNC, 62.5% developed severe OM. Higher severity of OM was associated with feeding tube placement, hospitalization, opiate use, and weight loss. Improvements in OM prevention and management are needed.
Topics: Male; Humans; Middle Aged; Female; Radiotherapy, Intensity-Modulated; Cohort Studies; Quality of Life; Head and Neck Neoplasms; Stomatitis; Opiate Alkaloids; Weight Loss
PubMed: 37819659
DOI: 10.1001/jamanetworkopen.2023.37265 -
Clinical and Experimental Rheumatology Oct 2023To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour...
OBJECTIVES
To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF).
METHODS
Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients.
RESULTS
In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients.
CONCLUSIONS
Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.
Topics: Humans; Retrospective Studies; Fever; Hereditary Autoinflammatory Diseases; Pharyngitis; Lymphadenitis; Stomatitis, Aphthous; Receptors, Tumor Necrosis Factor, Type I
PubMed: 37470237
DOI: 10.55563/clinexprheumatol/am4phc -
Pediatric Rheumatology Online Journal Sep 2023Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children; by definition, episodes...
OBJECTIVE
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children; by definition, episodes occur every 2 to 8 weeks. However, in a subset of our patients, we noticed a higher frequency of attacks, of less than 2 weeks, which we refer to as extreme PFAPA (ePFAPA). This group consisted of patients who were extreme upon presentation of PFAPA, and those who became extreme after initiation of abortive corticosteroid treatment. We aimed to characterize demographic and clinical features of ePFAPA, including the two groups, and to compare them to patients with non-extreme PFAPA (nPFAPA).
STUDY DESIGN
The medical records of 365 patients with PFAPA who attended Schneider Children's Medical Center of Israel from March 2014 to April 2021 were reviewed. Patients with concomitant familial Mediterranean fever were excluded. Characteristics of the ePFAPA (including subgroups) and nPFAPA groups were compared using Wilcoxon rank sum, Pearson's chi-squared, and Fisher's exact tests.
RESULTS
Forty-seven patients (12.9%) were identified as having ePFAPA. Among patients with ePFAPA, compared to patients with nPFAPA, the median (interquartile range) age at disease onset was earlier: 1.5 years (0.7-2.5) vs. 2.5 years (1.5-4.0), P < 0.001; and diagnosis was younger: 2.6 years (2.0-3.6) vs. 4.5 years (3.0-6.2), P < 0.001. A higher proportion of patients with ePFAPA than nPFAPA were treated with colchicine prophylaxis (53% vs. 19%, P < 0.001), but symptoms and signs during flares did not differ significantly between these groups. Demographic and clinical characteristics were similar between patients with ePFAPA from presentation of PFAPA (22, 47% of those with ePFAPA) and ePFAPA from after corticosteroid treatment.
CONCLUSION
About half the patients categorized with ePFAPA syndrome already had extreme features upon presentation. Patients with ePFAPA compared to nPFAPA presented and were diagnosed at an earlier age.
Topics: Child; Humans; Infant; Stomatitis, Aphthous; Lymphadenitis; Lymphadenopathy; Familial Mediterranean Fever; Pharyngitis; Syndrome
PubMed: 37658370
DOI: 10.1186/s12969-023-00880-1