SARS-CoV-2 RBD protein enhances the oncolytic activity of the vesicular stomatitis virus

Despite recent advances in the research on oncolytic viruses (OVs), a better understanding of how to enhance their replication is key to improving their therapeutic index. Understanding viral replication is important to improve treatment outcomes based on enhanced viral spreading within the tumor milieu. The VSV-Δ51 oncolytic virus has been widely used as an anticancer agent with a high selectivity profile. In this study, we examined the role of the SARS-CoV-2 spike protein receptor-binding domain (RBD) in enhancing VSV-Δ51 viral production and oncolytic activity. To test this hypothesis, we first generated a novel VSV-Δ51 mutant that encoded the SARS-COV-2 RBD and compared viral spreading and viral yield between VSV-Δ51-RBD and VSV-Δ51 in vitro. Using the viral plaque assay, we demonstrated that the presence of the SARS-CoV-2 RBD in the VSV-Δ51 genome is associated with a significantly larger viral plaque surface area and significantly higher virus titers. Subsequently, using an ATP release-based assay, we demonstrated that the SARS-CoV-2 RBD could enhance VSV-Δ51 oncolytic activity in vitro. This observation was further supported using the B16F10 tumor model. These findings highlighted a novel use of the SARS-CoV-2 RBD as an anticancer agent.Instituto de BiotecnologíaFil: Alkayyal, Almohanad A. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Alkayyal, Almohanad A. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Ajina, Reham. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Ajina, Reham. King Saud bin Abdulaziz University for Health Sciences. College of Applied Medical Sciences. Department of Clinical Laboratory Sciences; Arabia SauditaFil: Cacciabue, Marco Polo Domingo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Cacciabue, Marco Polo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cacciabue, Marco Polo Domingo. Universidad Nacional de Luján. Departamento de Ciencias Básicas; ArgentinaFil: Alkayyal, Aaesha A. Taibah University. College of Medicine; Arabia SauditaFil: Saeedi, Nizar H. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Hussain Alshehry, Taofik. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Kaboha, Feras. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Alotaibi, Mohammed A. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Alotaibi, Mohammed A. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Zaidan, Nada. King Abdulaziz City for Science and Technology. Joint Centers of Excellence Program. 8King Abdulaziz City for Science and Technology-Brigham and Women's Hospital (KACST-BWH) Centre of Excellence for Biomedicine; Arabia SauditaFil: Shah, Khalid. Harvard Medical School. Brigham and Women’s Hospital. Center for Stem Cell and Translational Immunotherapy (CSTI); Estados UnidosFil: Shah, Khalid. Harvard Medical School. Brigham and Women’s Hospital. Department of Neurosurgery; Estados UnidosFil: Shah, Khalid. Harvard University. Harvard Stem Cell Institute; Estados UnidosFil: Alroqi, Fayhan. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Alroqi, Fayhan. Ministry of the National Guard. Department of Immunology; Arabia SauditaFil: Alroqi, Fayhan. King Saud bin Abdulaziz University for Health Sciences. Faculty of Medicine; Arabia SauditaFil: Bakur Mahmoud, Ahmad. Taibah University. College of Applied Medical Sciences; Arabia SauditaFil: Bakur Mahmoud, Ahmad. Taibah University. Strategic Research and Innovation Laboratories; Arabia SauditaFil: Bakur Mahmoud, Ahmad. King Abdullah International Medical Research Center. Immunology Research Program; Arabia Saudit

Repurposing the oncolytic virus VSV∆51M as a COVID-19 vaccine

The coronavirus disease 2019 (COVID-19) pandemic imposes an urgent and continued need for the development of safe and cost-effective vaccines to induce preventive responses for limiting major outbreaks around the world. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we repurposed the VSV∆51M oncolytic virus platform to express the spike receptor-binding domain (RBD) antigen. In this study, we report the development and characterization of the VSV∆51M-RBD vaccine. Our findings demonstrate successful expression of the RBD gene by the VSV∆51M-RBD virus, inducing anti-RBD responses without attenuating the virus. Moreover, the VSV∆51M-RBD vaccine exhibited safety, immunogenicity, and the potential to serve as a safe and effective alternative or complementary platform to current COVID-19 vaccines

Phage display derived monoclonal antibodies: from bench to bedside

Monoclonal antibodies (mAbs) have become one of the most important classes of biopharmaceutical products, and they continue to dominate the universe of biopharmaceutical markets in terms of approval and sales. They are the most profitable single product class, where they represent six of the top ten selling drugs. At the beginning of the 1990s, an in vitro antibody selection technology known as antibody phage display was developed by John McCafferty and Sir. Gregory Winter that enabled the discovery of human antibodies for diverse applications, particularly antibody-based drugs. They created combinatorial antibody libraries on filamentous phage to be utilized for generating antigen specific antibodies in a matter of weeks. Since then, more than 70 phage–derived antibodies entered clinical studies and 14 of them have been approved. These antibodies are indicated for cancer, and non-cancer medical conditions, such as inflammatory, optical, infectious, or immunological diseases. This review will illustrate the utility of phage display as a powerful platform for therapeutic antibodies discovery and describe in detail all the approved mAbs derived from phage display

SARS-CoV-2 RBD protein enhances the oncolytic activity of the vesicular stomatitis virus

Despite recent advances in the research on oncolytic viruses (OVs), a better understanding of how to enhance their replication is key to improving their therapeutic index. Understanding viral replication is important to improve treatment outcomes based on enhanced viral spreading within the tumor milieu. The VSV-Δ51 oncolytic virus has been widely used as an anticancer agent with a high selectivity profile. In this study, we examined the role of the SARS-CoV-2 spike protein receptor-binding domain (RBD) in enhancing VSV-Δ51 viral production and oncolytic activity. To test this hypothesis, we first generated a novel VSV-Δ51 mutant that encoded the SARS-COV-2 RBD and compared viral spreading and viral yield between VSV-Δ51-RBD and VSV-Δ51 in vitro. Using the viral plaque assay, we demonstrated that the presence of the SARS-CoV-2 RBD in the VSV-Δ51 genome is associated with a significantly larger viral plaque surface area and significantly higher virus titers. Subsequently, using an ATP release-based assay, we demonstrated that the SARS-CoV-2 RBD could enhance VSV-Δ51 oncolytic activity in vitro. This observation was further supported using the B16F10 tumor model. These findings highlighted a novel use of the SARS-CoV-2 RBD as an anticancer agent.Fil: Alkayyal, Almohanad A.. King Abdullah International Medical Research Center, Riyadh; Arabia Saudita. University of Tabuk; Arabia SauditaFil: Ajina, Reham. Abdulaziz University; Arabia Saudita. King Abdullah International Medical Research Center, Riyadh; Arabia SauditaFil: Cacciabue, Marco Polo Domingo. Universidad Nacional de Luján; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Alkayyal, Aaesha A.. Taibah University; Arabia SauditaFil: Saeedi, Nizar H.. University of Tabuk; Arabia SauditaFil: Hussain Alshehry, Taofik. King Saud University; Arabia SauditaFil: Kaboha, Feras. King Saud University; Arabia SauditaFil: Alotaibi, Mohammed A.. University of Tabuk; Arabia Saudita. King Saud University; Arabia SauditaFil: Zaidan, Nada. King Abdulaziz City For Science And Technology; Arabia SauditaFil: Shah, Khalid. Harvard Medical School; Estados UnidosFil: Alroqi, Fayhan. National Guard Health Affairs; Arabia Saudita. King Saud Bin Abdulaziz University For Health Sciences; Arabia SauditaFil: Bakur Mahmoud, Ahmad. Taibah University; Arabia Saudita. King Saud Bin Abdulaziz University For Health Sciences; Arabia Saudit

Correction to: Sepsis increases perioperative metastases in a murine model

It has been highlighted that the original manuscript [1] contains a typesetting error in Fig. 1 and the Fig. 1c panel gas been inadvertently duplicated in panel Fig. 1d. This does not affect the results and conclusions of the article. The correct version of Fig. 1 is included with this Correction. The original article has been updated

Sepsis increases perioperative metastases in a murine model

Abstract Background Cancer surgery can promote tumour metastases and worsen prognosis, however, the effect of perioperative complications on metastatic disease remains unclear. In this study we sought to evaluate the effect of common perioperative complications including perioperative blood loss, hypothermia, and sepsis on tumour metastases in a murine model. Methods Prior to surgery, pulmonary metastases were established by intravenous challenge of CT26LacZ colon cancer cells in BALB/c mice. Surgical stress was generated through partial hepatectomy (PH) or left nephrectomy (LN). Sepsis was induced by puncturing the cecum to express stool into the abdomen. Hemorrhagic shock was induced by removal of 30% of total blood volume (i.e. stage 3 hemorrhage) via the saphenous vein. Hypothermia was induced by removing the heating apparatus during surgery and lowering core body temperatures to 30 °C. Lung tumour burden was quantified 3 days following surgery. Results Surgically stressed mice subjected to stage 3 hemorrhage or hypothermia did not show an additional increase in lung tumour burden. In contrast, surgically stressed mice subjected to intraoperative sepsis demonstrated an additional 2-fold increase in the number of tumour metastases. Furthermore, natural killer (NK) cell function, as assessed by YAC-1 tumour cell lysis, was significantly attenuated in surgically stressed mice subjected to intraoperative sepsis. Both NK cell-mediated cytotoxic function and lung tumour burden were improved with perioperative administration of polyI:C, which is a toll-like receptor (TLR)-3 ligand. Conclusions Perioperative sepsis alone, but not hemorrhage or hypothermia, enhances the prometastatic effect of surgery in murine models of cancer. Understanding the cellular mechanisms underlying perioperative immune suppression will facilitate the development of immunomodulation strategies that can attenuate metastatic disease

Current Insights into Diagnosis, Prevention Strategies, Treatment, Therapeutic Targets, and Challenges of Monkeypox (Mpox) Infections in Human Populations

In the wake of the emergence and worldwide respread of a viral infection called Monkeypox (Mpox), there is a serious threat to the health and safety of the global population. This viral infection was endemic to the western and central parts of Africa, but has recently spread out of this endemic area to various countries, including the United Kingdom (UK), Portugal, Spain, the United States of America (USA), Canada, Sweden, Belgium, Italy, Australia, Germany, France, the Netherlands, Israel, and Mexico. This is a timely review focusing on recent findings and developments in the epidemiology, clinical features, therapeutic targets, diagnosis, prevention mechanisms, research challenges and possible treatment for Mpox. To date (29 November 2022), there have been around 81,225 reported cases of Mpox. In most cases, this illness is mild; however, there is a fatality rate ranging from 1 to 10%, which might be increased due to associated complications and/or secondary infections. There is a real challenge in the diagnosis of Mpox, since its symptoms are very similar to those of other infections, including smallpox and chickenpox. Generally, to prevent/limit the risk and transmission of Mpox, the detection and isolation of infected individuals, as well as hand hygiene and cleanliness, are essential and effective approaches to control/combat this viral infection. Nevertheless, updated information about Mpox from different angles is lacking. Thus, this review provides updated and comprehensive information about the Mpox illness, which should highlight the global burden, pathogenicity, symptoms, diagnosis, prevention measures and possible treatment of this emerging disease

Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular Docking

Overexpression of the thymidine phosphorylase (TP) enzyme induces angiogenesis, which eventually leads to metastasis and tumor growth. The crucial role of TP in cancer development makes it an important target for anticancer drug discovery. Currently, there is only one US-FDA-approved drug, i.e., Lonsurf, a combination of trifluridine and tipiracil, for the treatment of metastatic colorectal cancer. Unfortunately, numerous adverse effects are associated with its use, such as myelosuppression, anemia, and neutropenia. Since the last few decades, the discovery of new, safe, and effective TP inhibitory agents has been rigorously pursued. In the present study, we evaluated a series of previously synthesized dihydropyrimidone derivatives 1–40 for their TP inhibitory potential. Compounds 1, 12, and 33 showed a good activity with IC50 = 314.0 ± 0.90, 303.5 ± 0.40, and 322.6 ± 1.60 µM, respectively. The results of mechanistic studies revealed that compounds 1, 12, and 33 were the non-competitive inhibitors. These compounds were also evaluated for cytotoxicity against 3T3 (mouse fibroblast) cells and were found to be non-cytotoxic. Finally, the molecular docking suggested the plausible mechanism of non-competitive inhibition of TP. The current study thus identifies some dihydropyrimidone derivatives as potential inhibitors of TP, which can be further optimized as leads for cancer treatment