scholarly journals Defining Efficacy of Chikungunya Virus Candidate Vaccines: Different Endpoints Derived From the Virus—Cytokine—Ferritin (VCF) Model

2021 ◽  
Vol 1 ◽  
Author(s):  
Stephanie M. Lim ◽  
Sudip K. Dutta ◽  
Byron E. E. Martina
Keyword(s):  
Chikungunya Virus ◽  
Current Knowledge ◽  
Effective Vaccine ◽  
Preclinical Model ◽  
Preclinical Models ◽  
Efficacy Data ◽  
Proper Understanding ◽  
Prevention Of Infection ◽  
Correlates Of Protection ◽  
The Indian Ocean

Following the disruptive epidemics throughout the Indian Ocean, Southeast Asia and the Americas, efforts have been deployed to develop an effective vaccine against chikungunya virus (CHIKV). The continuous threat of CHIKV (re-)emergence and the huge public health and economic impact of the epidemics, makes the development of a safe and effective vaccine a priority. Several platforms have been used to develop candidate vaccines, but there is no consensus about how to translate results from preclinical models to predict efficacy in humans. This paper outlines a concept of what constitutes an effective vaccine against CHIKV, which may be applied to other viral vaccines as well. Defining endpoints for an effective vaccine is dependent on a proper understanding of the pathogenesis and immune response triggered during infection. The preclinical model adopted to evaluate experimental vaccines is imperative for the translation of preclinical efficacy data to humans. Several CHIKV animal models exist; however, not all provide suitable endpoints for measuring vaccine efficacy. This review summarizes the current knowledge related to CHIKV pathogenesis and the correlates of protection. We then define what would constitute an effective CHIKV vaccine in humans using four key endpoints, namely: (i) prevention of chronic disease, (ii) prevention of acute disease, (iii) prevention of transmission to mosquitoes, and (iv) complete prevention of infection. Lastly, we address some of the gaps that prevent translation of immunogenicity and efficacy findings from preclinical models to humans, and we propose to use the combination of virus–cytokine–ferritin levels as a read-out for measuring vaccine-induced protection.

scholarly journals Circulating tumor cells in precision oncology: clinical applications in liquid biopsy and 3D organoid model

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chang Yang ◽  
Bai-Rong Xia ◽  
Wei-Lin Jin ◽  
Ge Lou
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Liquid Biopsy ◽  
Disease Modeling ◽  
Current Knowledge ◽  
Response To Therapy ◽  
Preclinical Model ◽  
Precision Oncology ◽  
Preclinical Models ◽  
Tumor Patient

AbstractCirculating tumor cells (CTCs) are a rare subset of cells found in the blood of patients with solid tumors, which function as a seed for metastases. Cancer cells metastasize through the bloodstream either as single migratory CTCs or as multicellular groupings—CTC clusters. The CTCs preserve primary tumor heterogeneity and mimic tumor properties, and may be considered as clinical biomarker, preclinical model, and therapeutic target. The potential clinical application of CTCs is being a component of liquid biopsy. CTCs are also good candidates for generating preclinical models, especially 3D organoid cultures, which could be applied in drug screening, disease modeling, genome editing, tumor immunity, and organoid biobanks. In this review, we summarize current knowledge on the value and promise of evolving CTC technologies and highlight cutting-edge research on CTCs in liquid biopsy, tumor metastasis, and organoid preclinical models. The study of CTCs offers broad pathways to develop new biomarkers for tumor patient diagnosis, prognosis, and response to therapy, as well as translational models accelerating oncologic drug development.

scholarly journals Epitope-Specific Serological Assays for RSV: Conformation Matters

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 23 ◽  
Author(s):  
Emily Phung ◽  
Lauren Chang ◽  
Kaitlyn Morabito ◽  
Masaru Kanekiyo ◽  
Man Chen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Antigenic Site ◽  
Immune Monitoring ◽  
Effective Vaccine ◽  
F Protein ◽  
Correlates Of Protection ◽  
Vaccine Trials ◽  
Antigenic Sites ◽  
Syncytial Virus ◽  
The Impact

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in children and older adults. An effective vaccine must elicit neutralizing antibodies targeting the RSV fusion (F) protein, which exists in two major conformations, pre-fusion (pre-F) and post-fusion (post-F). Although 50% of the surface is shared, pre-F contains highly neutralization-sensitive antigenic sites not present on post-F. Recent advancement of several subunit F-based vaccine trials has spurred interest in quantifying and understanding the protective potential of antibodies directed to individual antigenic sites. Monoclonal antibody competition ELISAs are being used to measure these endpoints, but the impact of F conformation and competition from antibodies binding to adjacent antigenic sites has not been thoroughly investigated. Since this information is critical for interpreting clinical trial outcomes and defining serological correlates of protection, we optimized assays to evaluate D25-competing antibodies (DCA) to antigenic site Ø on pre-F, and compared readouts of palivizumab-competing antibodies (PCA) to site II on both pre-F and post-F. We show that antibodies to adjacent antigenic sites can contribute to DCA and PCA readouts, and that cross-competition from non-targeted sites is especially confounding when PCA is measured using a post-F substrate. While measuring DCA and PCA levels may be useful to delineate the role of antibodies targeting the apex and side of the F protein, respectively, the assay limitations and caveats should be considered when conducting immune monitoring during vaccine trials and defining correlates of protection.

scholarly journals Complete Coding Sequence of a Chikungunya Virus Strain Imported into Slovenia from Thailand in Late 2018

2019 ◽  
Vol 8 (37) ◽  
Author(s):  
Samo Zakotnik ◽  
Misa Korva ◽  
Nataša Knap ◽  
Barbara Robnik ◽  
Nina Gorišek Miksić ◽  
...  
Keyword(s):  
Cell Culture ◽  
Phylogenetic Analysis ◽  
Envelope Protein ◽  
Viral Genome ◽  
Chikungunya Virus ◽  
Whole Genome ◽  
Reverse Transcription Pcr ◽  
The Indian Ocean ◽  
Complete Viral Genome ◽  
A226v Mutation

A case of chikungunya virus infection was imported from Thailand into Slovenia in late 2018. The infection was diagnosed using real-time reverse transcription-PCR, the virus was isolated in cell culture, and the whole genome was sequenced. Phylogenetic analysis of the nearly complete viral genome indicated that the virus belongs to the Indian Ocean lineage but does not possess the A226V mutation in the envelope protein E1.

Recent Atmospheric Variability at Kibo Summit, Kilimanjaro, and Its Relation to Climate Mode Activity

2018 ◽  
Vol 31 (10) ◽  
pp. 3875-3891 ◽  
Author(s):  
Emily Collier ◽  
Thomas Mölg ◽  
Tobias Sauter
Keyword(s):  
Indian Ocean ◽  
Current Knowledge ◽  
Southern Oscillation ◽  
Strong Association ◽  
Atmospheric Modeling ◽  
High Mountain ◽  
Atmospheric Variability ◽  
Rain Season ◽  
The Indian Ocean ◽  
The Impact

Abstract Accurate knowledge of the impact of internal atmospheric variability is required for the detection and attribution of climate change and for interpreting glacier records. However, current knowledge of such impacts in high-mountain regions is largely based on statistical methods, as the observational data required for process-based assessments are often spatially or temporally deficient. Using a case study of Kilimanjaro, 12 years of convection-permitting atmospheric modeling are combined with an 8-yr observational record to evaluate the impact of climate oscillations on recent high-altitude atmospheric variability during the short rains (the secondary rain season in the region). The focus is on two modes that have a well-established relationship with precipitation during this season, El Niño–Southern Oscillation and the Indian Ocean zonal mode, and demonstrate their strong association with local and mesoscale conditions at Kilimanjaro. Both oscillations correlate positively with humidity fluctuations, but the association is strongest with the Indian Ocean zonal mode in the air layers near and above the glaciers because of changes in zonal circulation and moisture transport, emphasizing the importance of the moisture signal from this basin. However, the most anomalous conditions are found during co-occurring positive events because of the combined effects of the (i) extended positive sea surface temperature anomalies, (ii) enhanced atmospheric moisture capacity from higher tropospheric temperatures, (iii) most pronounced weakening of the subsiding branch of the Indian Ocean Walker circulation over East Africa, and (iv) stronger monsoonal moisture fluxes upstream from Kilimanjaro. This study lays the foundation for unraveling the contribution of climate modes to observed changes in Kilimanjaro’s glaciers.

scholarly journals Arthritogenic Alphaviruses: A Worldwide Emerging Threat?

2019 ◽  
Vol 7 (5) ◽  
pp. 133 ◽  
Author(s):  
Laura I. Levi ◽  
Marco Vignuzzi
Keyword(s):  
Chikungunya Virus ◽  
Neglected Tropical Diseases ◽  
Current Knowledge ◽  
Life Quality ◽  
Sub Saharan Africa ◽  
Ross River Virus ◽  
Pacific Island ◽  
The Pacific ◽  
Sub Saharan ◽  
Mayaro Virus

Arthritogenic alphaviruses are responsible for a dengue-like syndrome associated with severe debilitating polyarthralgia that can persist for months or years and impact life quality. Chikungunya virus is the most well-known member of this family since it was responsible for two worldwide epidemics with millions of cases in the last 15 years. However, other arthritogenic alphaviruses that are as of yet restrained to specific territories are the cause of neglected tropical diseases: O’nyong’nyong virus in Sub-Saharan Africa, Mayaro virus in Latin America, and Ross River virus in Australia and the Pacific island countries and territories. This review evaluates their emerging potential in light of the current knowledge for each of them and in comparison to chikungunya virus.

Development of a novel patient-derived preclinical model from malignant effusions in patients with tyrosine kinase inhibitor resistant clear cell renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 445-445
Author(s):  
Jung Hun Kang ◽  
Mi Hwa Heo ◽  
Hee Kyung Kim ◽  
Jinhyun Cho ◽  
Youjin Kim ◽  
...  
Keyword(s):  
Clear Cell ◽  
Drug Effects ◽  
Preclinical Model ◽  
Targeted Agents ◽  
Preclinical Models ◽  
Cell Renal Cell Carcinoma ◽  
Genomic Features ◽  
Pdx Model ◽  
Malignant Effusions ◽  
Pdx Models

445 Background: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood and there is a need to develop new therapeutic options overcoming them. Methods: To develop a preclinical model that predicts clinical activity of novel agents.We established patient-derived cell (PDC) and xenograft (PDX) models from malignant effusions (n = 15) or surgical specimen (n = 4).Genomic features of the PDX model were compared with those of the primary tumor. Drug effects of cell viability were then tested with PDC and PDX models. Results: Successful PDCs, defined as cells that maintained growth following 2 passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. Conclusions: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations. We show that novel preclinical models are developed using malignant effusions derived from patients with kidney cancer. The preclinical models can be used to test anti-tumor activity of novel therapeutics. The preclinical model we developed can be used to interrogate sensitivity to targeted agents based on genomic alterations. The PDC model from malignant effusions of patients was successfully converted to a PDX model, and represents an important and feasible platform for future cancer research.

Genomic characterization of preclinical models derived from primary and metastatic sites from rapid autopsy patients in PDMR.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13506-e13506
Author(s):  
Li Chen ◽  
Rajesh Patidar ◽  
Biswajit Das ◽  
Yvonne A Evrard ◽  
Chris Alan Karlovich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Preclinical Model ◽  
Expression Data ◽  
Preclinical Models ◽  
Rapid Autopsy ◽  
Metastatic Sites ◽  
Pdx Models

e13506 Background: The National Cancer Institute has developed a repository of preclinical models [Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov )] including patient derived xenografts (PDXs), organoids (PDOrgs) and in vitro tumor cultures (PDCs) from patients with solid tumor cancer histologies. A subset of these preclinical models is derived from post-mortem collections from rapid autopsies representing the end point in disease progression. Clinical annotations and genomic datasets associated with these models provide a unique opportunity to study tumor evolution, mechanistic insights into the metastatic process, and treatment resistance. Methods: To date, 43 PDXs, 21 PDCs, and 23 PDOrgs using rapid autopsy specimens from 8 primary and 35 metastatic sites of 18 patients have been developed by the Biological Testing Branch (DTP, DCTD, NCI Frederick, MD) for the PDMR. Whole exome (WES) and total transcriptome (RNASeq) data were processed to generate mutation, copy number alteration (CNA) and gene expression data. Multi-model lineage trees were reconstructed based on putative somatic variants for all the models derived from all patients. The fraction of the genome affected by CNA was compared both within and across PDX models. Results: Most of the rapid autopsy PDX models (32/43) are derived from pancreatic adenocarcinoma (PAAD) patients (13/18), with metastatic specimens originating from sites including liver, colon, omentum, and lung. Driver mutations are present in all preclinical model specimens derived from the same patient. For instance, KRAS p.G12D is present in all patient-derived model specimens derived from PAAD patient 521955. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n = 24, mean = 6.39%, sd = 5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n = 19, mean = 16.92%, sd = 10.46%). This indicates presence of tumor heterogeneity between metastatic and primary sites. The lineage tree for models from patient 521955 indicates that one liver metastasis has a unique seeding event compared to the other 4 metastatic sites. Unsupervised clustering analysis on gene expression data also confirms the observed tumor site relationships. Conclusions: Our data demonstrate the potential use of these preclinical models available from the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance.

scholarly journals Chikungunya: an emerging and spreading arthropod-borne viral disease.

2009 ◽  
Vol 3 (10) ◽  
pp. 744-752 ◽  
Author(s):  
Francesca Cavrini ◽  
Paolo Gaibani ◽  
Anna Maria Pierro ◽  
Giada Rossini ◽  
Maria Paola Landini ◽  
...  
Keyword(s):  
Developing Countries ◽  
Indian Ocean ◽  
Chikungunya Virus ◽  
Research Work ◽  
Viral Disease ◽  
La Réunion ◽  
Viremic Patient ◽  
The Indian Ocean ◽  
Clinical Pictures ◽  
Local Transmission

The infection caused by the virus Chikungunya is known since the last 50 years, but since the disease was mainly diffuse in geographical areas located in developing countries, a few research work have been made available until the appearance of an important epidemiological outbreak in 2005 in the island of La Reunion, that is part of metropolitan France even if located in the Southern Eastern part of the Indian Ocean. In 2007, a smaller outbreak of Chikungunya developed in the Northern Eastern part of Italy, where the local transmission has been made possible by the enormous population of Aedes albopictus and the presence of a viremic patient coming from the Indian Ocean area. Nowadays, Chikungunya is spreading in Southeast Asia countries, including Indonesia, Malaysia, Thailand and Singapore. This paper reviews different aspects of the disease caused by Chikungunya virus, including: history, epidemiology, biological and pathogenetic aspects, clinical pictures, diagnosis and treatment.

scholarly journals Virtual Model for Legg-Clavé-Perthes: Preliminary Work to Develop a Minimally Invasive Preclinical Model

2019 ◽  
Author(s):  
Bethany Juhnke ◽  
Susan A. Novotny ◽  
Jennifer C. Laine ◽  
Ferenc Toth ◽  
Arthur Erdman
Keyword(s):  
Blood Flow ◽  
Femoral Head ◽  
Minimally Invasive ◽  
Perthes Disease ◽  
Preclinical Model ◽  
Virtual Model ◽  
Preclinical Models ◽  
Long Term Outcomes ◽  
New Methods

Legg-Calvé-Perthes disease (LCPD) is a painful pediatric hip condition caused by an idiopathic disruption of blood flow to the femoral head. The bone subsequently becomes necrotic and fragile. This can result in significant femoral head deformity, leading to pain and early degeneration of the hip. Severity of avascular involvement of the femoral head correlates with long-term outcomes, including hip arthritis and replacement. Preclinical models present extreme cases of the disease and do not represent the spectrum of LCPD seen clinically. A virtual model was developed to explore advancing the preclinical model through new methods of visualizing the data. Overall, three opportunities to advance the preclinical model and our understanding of LCPD are presented.

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