scholarly journals Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19

2021 ◽  
Vol 11 (7) ◽  
pp. 668
Author(s):  
Michail Papapanou ◽  
Eleni Papoutsi ◽  
Timoleon Giannakas ◽  
Paraskevi Katsaounou
Keyword(s):  
Clinical Evidence ◽  
Current Knowledge ◽  
Ex Vivo ◽  
Elongation Factor ◽  
Antiviral Agent ◽  
Antiviral Effect ◽  
Clinical Profile ◽  
Phase Iii ◽  
Current Standard ◽  
Exact Integration

Current standard treatment of COVID-19 lacks in effective antiviral options. Plitidepsin, a cyclic depsipeptide authorized in Australia for patients with refractory multiple myeloma, has recently emerged as a candidate anti-SARS-CoV-2 agent. The aim of this review was to summarize current knowledge on plitidepsin’s clinical profile, anti-tumour and anti-SARS-CoV-2 mechanisms and correlate this with available or anticipated, preclinical or clinical evidence on the drug’s potential for COVID-19 treatment.PubMed, Scopus, CENTRAL, clinicaltrials.gov, medRxiv and bioRxiv databases were searched.Plitidepsinexerts its anti-tumour and antiviral properties primarily through acting on isoforms of the host cell’s eukaryotic-translation-elongation-factor-1-alpha (eEF1A). Through inhibiting eEF1A and therefore translation of necessary viral proteins, it behaves as a “host-directed” anti-SARS-CoV-2 agent. In respect to its potent anti-SARS-CoV-2 properties, the drug has demonstrated superior ex vivo efficacy compared to other host-directed agents and remdesivir, and it might retain its antiviral effect against the more transmittable B.1.1.7 variant. Its well-studied safety profile, also in combination with dexamethasone, may accelerate its repurposing chances for COVID-19 treatment. Preliminary findings in hospitalized COVID-19 patients, have suggested potential safety and efficacy of plitidepsin, in terms of viral load reduction and clinical resolution. However, the still incomplete understanding of its exact integration into host cell–SARS-CoV-2 interactions, its intravenous administration exclusively purposing it for hospital settings the and precocity of clinical data are currently considered its chief deficits. A phase III trial is being planned to compare the plitidepsin–dexamethasone regimen to the current standard of care only in moderately affected hospitalized patients. Despite plitidepsin’s preclinical efficacy, current clinical evidence is inadequate for its registration in COVID-19 patients.Therefore, multicentre trials on the drug’s efficacy, potentially also studying populations of emerging SARS-CoV-2 lineages, are warranted.

Cancer Immunology and CAR-T Cells: A Turning Point Therapeutic Approach in Colorectal Carcinoma with clinical insight

2020 ◽  
Vol 20 ◽  
Author(s):  
Suman K Ray ◽  
Yamini Meshram ◽  
Sukhes Mukherjee
Keyword(s):  
T Cells ◽  
Colorectal Carcinoma ◽  
Cancer Immunotherapy ◽  
Clinical Evidence ◽  
Ex Vivo ◽  
Clinical Success ◽  
Recent Decade ◽  
Molecular Immunology ◽  
Car T ◽  
Engineered T Cells

: Cancer immunotherapy endeavours in harnessing delicate strength and specificity of immune system for therapy of different malignancies including colorectal carcinoma. The recent challenge for cancer immunotherapy is to practice and develop molecular immunology tools to create tactics that efficiently and securely boost antitumor reactions. After several attempts of deceptive outcomes, the wave has lastly altered and immunotherapy has become a clinically confirmed treatment for several cancers. Immunotherapeutic methods include administration of antibodies or modified proteins that either block cellular activity or co-stimulate cells through immune control pathways, cancer vaccines, oncolytic bacteria, ex vivo activated adoptive transfer of T cells and natural killer cells. Engineered T cells are used to produce a chimeric antigen receptor (CAR) to treat different malignancies including colorectal carcinoma in a recent decade. Despite considerable early clinical success, CAR-T therapies are associated with some side effects and sometimes display minimal efficacy. It gives special emphasis on the latest clinical evidence with CAR-T technology and also other related immunotherapeutic methods with promising performance, and highlighted how this therapy can affect therapeutic outcome and next upsurge as a key clinical aspect of colorectal carcinoma. In this review we recapitulate the current developments produced to improve the efficacy and specificity of CAR-T therapies in colon cancer.

scholarly journals Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

2021 ◽  
Vol 22 (8) ◽  
pp. 3860
Author(s):  
Elisa Ren ◽  
Giulia Curia
Keyword(s):  
Animal Models ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Current Knowledge ◽  
Focal Epilepsy ◽  
Ex Vivo ◽  
Hippocampal Sclerosis ◽  
Control Group ◽  
Epileptogenic Zone ◽  
Epileptiform Discharges

Temporal lobe epilepsy (TLE) is one of the most common types of focal epilepsy, characterized by recurrent spontaneous seizures originating in the temporal lobe(s), with mesial TLE (mTLE) as the worst form of TLE, often associated with hippocampal sclerosis. Abnormal epileptiform discharges are the result, among others, of altered cell-to-cell communication in both chemical and electrical transmissions. Current knowledge about the neurobiology of TLE in human patients emerges from pathological studies of biopsy specimens isolated from the epileptogenic zone or, in a few more recent investigations, from living subjects using positron emission tomography (PET). To overcome limitations related to the use of human tissue, animal models are of great help as they allow the selection of homogeneous samples still presenting a more various scenario of the epileptic syndrome, the presence of a comparable control group, and the availability of a greater amount of tissue for in vitro/ex vivo investigations. This review provides an overview of the structural and functional alterations of synaptic connections in the brain of TLE/mTLE patients and animal models.

scholarly journals Cardiac Cell Therapy: Insights into the Mechanisms of Tissue Repair

2021 ◽  
Vol 22 (3) ◽  
pp. 1201
Author(s):  
Hsuan Peng ◽  
Kazuhiro Shindo ◽  
Renée R. Donahue ◽  
Ahmed Abdel-Latif
Keyword(s):  
Stem Cell ◽  
Immune Responses ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Cell Delivery ◽  
Cardiac Cell Therapy ◽  
Stem Cell Treatment

Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.

scholarly journals Antiviral Activities of a Medicinal Plant Extract Against Sacbrood Virus in Honeybees

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Liping Sun ◽  
Xueqi Zhang ◽  
Shufa Xu ◽  
Chunsheng Hou ◽  
Jin Xu ◽  
...  
Keyword(s):  
Honey Bees ◽  
Apis Cerana ◽  
Larval Growth ◽  
Antiviral Agent ◽  
Antiviral Effect ◽  
Absolute Quantification ◽  
Chinese Medicinal Herb ◽  
Sacbrood Virus ◽  
Antiviral Activities ◽  
Potential Strategy

Abstract Background Sacbrood is an infectious disease of the honey bee caused by Scbrood virus (SBV) which belongs to the family Iflaviridae and is especially lethal for Asian honeybee Apis cerana. Chinese Sacbrood virus (CSBV) is a geographic strain of SBV. Currently, there is a lack of an effective antiviral agent for controlling CSBV infection in honey bees. Methods Here, we explored the antiviral effect of a Chinese medicinal herb Radix isatidis on CSBV infection in A. cerana by inoculating the 3rd instar larvae with purified CSBV and treating the infected bee larvae with R. isatidis extract at the same time. The growth, development, and survival of larvae between the control and treatment groups were compared. The CSBV copy number at the 4th instar, 5th instar, and 6th instar larvae was measured by the absolute quantification PCR method. Results Bioassays revealed that R. isatidis extract significantly inhibited the replication of CSBV, mitigated the impacts of CSBV on larval growth and development, reduced the mortality of CSBV-infected A. cerana larvae, and modulated the expression of immune transcripts in infected bees. Conclusion Although the mechanism underlying the inhibition of CSBV replication by the medicine plant will require further investigation, this study demonstrated the antiviral activity of R. isatidis extract and provides a potential strategy for controlling SBV infection in honey bees.

scholarly journals Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jean-Sélim Driouich ◽  
Maxime Cochin ◽  
Guillaume Lingas ◽  
Grégory Moureau ◽  
Franck Touret ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Exposure ◽  
Clinical Evidence ◽  
Antiviral Effect ◽  
Dose Effect ◽  
Plasma Drug ◽  
Hamster Model ◽  
Viral Genomes ◽  
Antiviral Efficacy ◽  
Repurposed Drugs

AbstractDespite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2. Here we use a Syrian hamster model to assess the antiviral efficacy of favipiravir, understand its mechanism of action and determine its pharmacokinetics. When treatment is initiated before or simultaneously to infection, favipiravir has a strong dose effect, leading to reduction of infectious titers in lungs and clinical alleviation of the disease. Antiviral effect of favipiravir correlates with incorporation of a large number of mutations into viral genomes and decrease of viral infectivity. Antiviral efficacy is achieved with plasma drug exposure comparable with those previously found during human clinical trials. Notably, the highest dose of favipiravir tested is associated with signs of toxicity in animals. Thereby, pharmacokinetic and tolerance studies are required to determine whether similar effects can be safely achieved in humans.

scholarly journals Suicidal Erythrocyte Death in Metabolic Syndrome

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 154
Author(s):  
Ignazio Restivo ◽  
Alessandro Attanzio ◽  
Luisa Tesoriere ◽  
Mario Allegra
Keyword(s):  
Metabolic Syndrome ◽  
Cell Death ◽  
Endothelial Dysfunction ◽  
Cell Membrane ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Inflammatory Milieu ◽  
Cardiometabolic Factors

Eryptosis is a coordinated, programmed cell death culminating with the disposal of cells without disruption of the cell membrane and the release of endocellular oxidative and pro-inflammatory milieu. While providing a convenient form of death for erythrocytes, dysregulated eryptosis may result in a series of detrimental and harmful pathological consequences highly related to the endothelial dysfunction (ED). Metabolic syndrome (MetS) is described as a cluster of cardiometabolic factors (hyperglycemia, dyslipidemia, hypertension and obesity) that increases the risk of cardiovascular complications such as those related to diabetes and atherosclerosis. In the light of the crucial role exerted by the eryptotic process in the ED, the focus of the present review is to report and discuss the involvement of eryptosis within MetS, where vascular complications are utterly relevant. Current knowledge on the mechanisms leading to eryptosis in MetS-related conditions (hyperglycemia, dyslipidemia, hypertension and obesity) will be analyzed. Moreover, clinical evidence supporting or proposing a role for eryptosis in the ED, associated to MetS cardiovascular complications, will be discussed.

scholarly journals Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

2011 ◽  
pp. 141-151
Author(s):  
Daniele Santini ◽  
Maria Elisabetta Fratto ◽  
Bruno Vincenzi ◽  
Silvia Angeletti ◽  
Giordano Dicuonzo ◽  
...  
Keyword(s):  
Clinical Data ◽  
Survival Data ◽  
Clinical Evidence ◽  
Bisphosphonate Therapy ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Phase Iii Trial ◽  
Skeletal Disease

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

AMELIORATE: early intensification in FLT3-mutated acute myeloid leukemia based on peripheral blast clearance – MYNERVA-GIMEMA AML1919 trial

2021 ◽  
Author(s):  
Francesco Mannelli ◽  
Giacomo Gianfaldoni ◽  
Paola Guglielmelli ◽  
Francesco Buccisano ◽  
Roberto Caporale ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Status ◽  
Phase Iii ◽  
Multiparameter Flow Cytometry ◽  
Current Standard ◽  
Disease Category ◽  
Measurable Residual Disease ◽  
Acute Myeloid

AMELIORATE is a Phase III, randomized trial aiming to personalize treatment intensity in FLT3-mutated acute myeloid leukemia. The current study provides an early appraisal of chemosensitivity based on peripheral blasts clearance, as assessed by multiparameter flow cytometry, from baseline to day 4 of induction. This biomarker was previously demonstrated to predict complete remission achievement and measurable residual disease status. For patients experiencing low peripheral blast cells (i.e., ≤2.0 logs), two major adjustments of treatment as compared with current standard of care are envisioned in the experimental arm: the immediate switch to intensified induction with high-doses cytarabine (1500 mg/m2 b.i.d. on days 5–7 of induction); and the early allocation of the patient to high-risk disease category, to be further refined later based on postinduction measurable residual disease status.

PPARβ/δ Priming Enhances the Anti-Apoptotic and Therapeutic Properties of Mesenchymal Stromal Cells in Myocardial Ischemia-Reperfusion Injury

2021 ◽  
Author(s):  
Charlotte Sarre ◽  
Rafael Contreras Lopez ◽  
Nitirut Nerpernpisooth ◽  
Christian Barrere ◽  
Sarah Bahraoui ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Phase Iii ◽  
Therapeutic Properties ◽  
Cardioprotective Effects

Abstract Background: Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. Objectives: The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction.Methods and results: Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H202. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on co-cultured cardiomyocytes. When injected during reperfusion in an ex vivo heart model of myocardial infarction, PPARβ/δ-primed MSC at a dose of 3.75x105 MSC/heart provided the same cardioprotective efficiency than 7.5x105 naïve MSC, identified as the optimal dose in our model. These enhanced short-term cardioprotective effects were associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 hour of reperfusion. By contrast, inhibition of PPARβ/δ before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. Conclusion: Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.

5 Cold stored platelets correct cardiac surgery induced platelet dysfunction

2021 ◽  
Vol 167 (3) ◽  
pp. e1.5-e1
Author(s):  
Tom Scorer ◽  
Andrew Mumford
Keyword(s):  
Cardiac Surgery ◽  
Shelf Life ◽  
Platelet Function ◽  
Platelet Transfusion ◽  
Ex Vivo ◽  
Flow Chamber ◽  
Platelet Dysfunction ◽  
Current Standard ◽  
Blood Samples

IntroductionPlatelet dysfunction (thrombocytopathy) is a major problem in the bleeding patient and increases morbidity and healthcare costs. The thrombocytopathy resulting from cardiopulmonary bypass (CPB) can be used to study therapies targeted to improve outcomes in other scenarios, such as trauma. Platelet transfusion is used widely to correct thrombocytopathy. However, the current standard, room temperature stored platelets (RTP) have several disadvantages including; short shelf life, risk of bacterial contamination and deterioration in platelet function during storage. Cold stored platelets (CSP) are a potential alternative product with longer shelf life, reduced contamination risk and better-preserved platelet function.MethodsUsing ex vivo mixing studies, we investigated whether CSP were better able to reverse the thrombocytopathy associated with cardiac surgery than RTP. Blood samples were collected from 20 cardiac surgery patients. Donor platelets were split into two bags and stored at either 4°C (CSP), or 22°C (RTP) for up to seven days. The donor platelets were mixed with the patient blood samples to simulate platelet transfusion. The mixed samples were analysed using the TEG 5000 and using a collagen coated flow chamber at arterial shear. Patient samples were analysed alongside healthy controls (n = 20).ResultsAfter mixing the patient samples with CSP, the TEG R times were shorter than in samples mixed with RTP (p<0.0001), indicating more rapid initiation of clot formation. In the flow chamber experiments, the clot volume was greater in the patient samples mixed with CSP compared with samples mixed with RTP (p<0.0001).ConclusionsThese findings suggest that CSP, but not RTP can partially reverse the thrombocytopathy associated with cardiac surgery ex vivo, at clinically relevant mixing volumes. Reversal of thrombocytopathy by mixing CSP was greatest in the arterial shear model, which may indicate superior in vivo efficacy that requires confirmation in clinical trials.* this abstract presentation was awarded First Place.

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