scholarly journals A virus-free cellular model recapitulates several features of severe COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giovanni Lavorgna ◽  
Giulio Cavalli ◽  
Lorenzo Dagna ◽  
Silvia Gregori ◽  
Alessandro Larcher ◽  
...  
Keyword(s):  
Cell Lines ◽  
Disease Model ◽  
Clinical Information ◽  
Experimental Models ◽  
Interferon Response ◽  
Relative Paucity ◽  
Molecular Features ◽  
Mrna Content ◽  
Risk Patients ◽  
Clinically Significant

AbstractAs for all newly-emergent pathogens, SARS-CoV-2 presents with a relative paucity of clinical information and experimental models, a situation hampering both the development of new effective treatments and the prediction of future outbreaks. Here, we find that a simple virus-free model, based on publicly available transcriptional data from human cell lines, is surprisingly able to recapitulate several features of the clinically relevant infections. By segregating cell lines (n = 1305) from the CCLE project on the base of their sole angiotensin-converting enzyme 2 (ACE2) mRNA content, we found that overexpressing cells present with molecular features resembling those of at-risk patients, including senescence, impairment of antibody production, epigenetic regulation, DNA repair and apoptosis, neutralization of the interferon response, proneness to an overemphasized innate immune activity, hyperinflammation by IL-1, diabetes, hypercoagulation and hypogonadism. Likewise, several pathways were found to display a differential expression between sexes, with males being in the least advantageous position, thus suggesting that the model could reproduce even the sex-related disparities observed in the clinical outcome of patients with COVID-19. Overall, besides validating a new disease model, our data suggest that, in patients with severe COVID-19, a baseline ground could be already present and, as a consequence, the viral infection might simply exacerbate a variety of latent (or inherent) pre-existing conditions, representing therefore a tipping point at which they become clinically significant.

scholarly journals Experimental Models for Studying HPV-Positive and HPV-Negative Penile Cancer: New Tools for An Old Disease

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 460
Author(s):  
Beatriz Medeiros-Fonseca ◽  
Antonio Cubilla ◽  
Haissa Brito ◽  
Tânia Martins ◽  
Rui Medeiros ◽  
...  
Keyword(s):  
Mouse Models ◽  
Cell Lines ◽  
Penile Cancer ◽  
Hpv Infection ◽  
Experimental Models ◽  
In Vivo Models ◽  
Recent Developments ◽  
Key Aspects

Penile cancer is an uncommon malignancy that occurs most frequently in developing countries. Two pathways for penile carcinogenesis are currently recognized: one driven by human papillomavirus (HPV) infection and another HPV-independent route, associated with chronic inflammation. Progress on the clinical management of this disease has been slow, partly due to the lack of preclinical models for translational research. However, exciting recent developments are changing this landscape, with new in vitro and in vivo models becoming available. These include mouse models for HPV+ and HPV− penile cancer and multiple cell lines representing HPV− lesions. The present review addresses these new advances, summarizing available models, comparing their characteristics and potential uses and discussing areas that require further improvement. Recent breakthroughs achieved using these models are also discussed, particularly those developments pertaining to HPV-driven cancer. Two key aspects that still require improvement are the establishment of cell lines that can represent HPV+ penile carcinomas and the development of mouse models to study metastatic disease. Overall, the growing array of in vitro and in vivo models for penile cancer provides new and useful tools for researchers in the field and is expected to accelerate pre-clinical research on this disease.

A Novel Noninvasive Technique for Pulse-Wave Imaging and Characterization of Clinically-Significant Vascular Mechanical Properties In Vivo

2007 ◽  
Vol 29 (3) ◽  
pp. 137-154 ◽  
Author(s):  
Kana Fujikura ◽  
Jianwen Luo ◽  
Viktor Gamarnik ◽  
Mathieu Pernot ◽  
Royd Fukumoto ◽  
...  
Keyword(s):  
Aortic Wall ◽  
Pulse Wave ◽  
Distal Region ◽  
Noninvasive Technique ◽  
Abdominal Aortic ◽  
Wave Imaging ◽  
Risk Patients ◽  
Noninvasive Mapping ◽  
Clinically Significant

The pulse-wave velocity (PWV) has been used as an indicator of vascular stiffness, which can be an early predictor of cardiovascular mortality. A noninvasive, easily applicable method for detecting the regional pulse wave (PW) may contribute as a future modality for risk assessment. The purpose of this study was to demonstrate the feasibility and reproducibility of PW imaging (PWI) during propagation along the abdominal aortic wall by acquiring electrocardiography-gated (ECG-gated) radiofrequency (rf) signals noninvasively. An abdominal aortic aneurysm (AAA) was induced using a CaCl2 model in order to investigate the utility of this novel method for detecting disease. The abdominal aortas of twelve normal and five CaCl2, mice were scanned at 30 MHz and electrocardiography (ECG) was acquired simultaneously. The radial wall velocities were mapped with 8000 frames/s. Propagation of the PW was demonstrated in a color-coded ciné-loop format in all cases. In the normal mice, the wave propagated in linear fashion from a proximal to a distal region. However, in CaCl2 mice, multiple waves were initiated from several regions (i.e., most likely initiated from various calcified regions within the aortic wall). The regional PWV in normal aortas was 2.70 ± 0.54 m/s ( r2 = 0.85 ± 0.06, n = 12), which was in agreement with previous reports using conventional techniques. Although there was no statistical difference in the regional PWV between the normal and CaCl2-treated aortas (2.95 ± 0.90 m/s ( r2 = 0.51 ± 0.22, n = 5)), the correlation coefficient was found to be significantly lower in the CaCl2-treated aortas ( p<0.01). This state-of-the-art technique allows noninvasive mapping of vascular disease in vivo. In future clinical applications, it may contribute to the detection of early stages of cardiovascular disease, which may decrease mortality among high-risk patients.

scholarly journals Quantitative analysis of tumour spheroid structure

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alexander P Browning ◽  
Jesse A Sharp ◽  
Ryan J Murphy ◽  
Gency Gunasingh ◽  
Brodie Lawson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tumour Microenvironment ◽  
Culture Conditions ◽  
Experimental Models ◽  
Seeding Density ◽  
Modelling Framework ◽  
Tumour Spheroid ◽  
Tumour Spheroids ◽  
Wide Range

Tumour spheroids are common in vitro experimental models of avascular tumour growth. Compared with traditional two-dimensional culture, tumour spheroids more closely mimic the avascular tumour microenvironment where spatial differences in nutrient availability strongly influence growth. We show that spheroids initiated using significantly different numbers of cells grow to similar limiting sizes, suggesting that avascular tumours have a limiting structure; in agreement with untested predictions of classical mathematical models of tumour spheroids. We develop a novel mathematical and statistical framework to study the structure of tumour spheroids seeded from cells transduced with fluorescent cell cycle indicators, enabling us to discriminate between arrested and cycling cells and identify an arrested region. Our analysis shows that transient spheroid structure is independent of initial spheroid size, and the limiting structure can be independent of seeding density. Standard experimental protocols compare spheroid size as a function of time; however, our analysis suggests that comparing spheroid structure as a function of overall size produces results that are relatively insensitive to variability in spheroid size. Our experimental observations are made using two melanoma cell lines, but our modelling framework applies across a wide range of spheroid culture conditions and cell lines.

scholarly journals A Novel Autophagy-Related lncRNA Gene Signature to Improve the Prognosis of Patients with Melanoma

2020 ◽  
Author(s):  
Yi Ding ◽  
Tian Li ◽  
Min Li ◽  
Tuersong Tayier ◽  
MeiLin Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Model ◽  
Risk Group ◽  
Clinical Information ◽  
Low Risk ◽  
Gene Set Enrichment Analysis ◽  
Positive Regulation ◽  
Risk Patients ◽  
Cox Analysis

Abstract Background: Autophagy and long non-coding RNAs (lncRNAs) have been the focus of research on the pathogenesis of melanoma. However, the autophagy network of lncRNAs in melanoma has not been reported. The purpose of this study was to investigate the lncRNA prognostic markers related to melanoma autophagy and predict the prognosis of patients with melanoma.Methods: We downloaded RNA-sequencing data and clinical information of melanoma from The Cancer Genome Atlas. The co-expression of autophagy-related genes (ARGs) and lncRNAs was analyzed. The risk model of autophagy-related lncRNAs was established by univariate and multivariate COX regression analyses, and the best prognostic index was evaluated combined with clinical data. Finally, gene set enrichment analysis was performed on patients in the high- and low-risk groups.Results: According to the results of the univariate COX analysis, only the overexpression of LINC00520 was associated with poor overall survival, unlike HLA-DQB1-AS1, USP30-AS1, AL645929, AL365361, LINC00324, and AC055822. The results of the multivariate COX analysis showed that the overall survival of patients in the high-risk group was shorter than that recorded in the low-risk group (p<0.001). Moreover, in the receiver operating characteristic curve of the risk model we constructed, the area under the curve (AUC) was 0.734, while the AUC of T and N was 0.707 and 0.658, respectively. The Gene Ontology was mainly enriched with the positive regulation of autophagy and the activation of the immune system. The results of the Kyoto Encyclopedia of Genes and Genomes enrichment were mostly related to autophagy, immunity, and melanin metabolism.Conclusion: The positive regulation of autophagy may slow the transition from low-risk patients to high-risk patients in melanoma. Furthermore, compared with clinical information, the autophagy-related lncRNAs risk model may better predict the prognosis of patients with melanoma and provide new treatment ideas.

Embryonal Tumours

2020 ◽  
pp. 188-197
Author(s):  
Maura Massimino ◽  
Eric Bouffet ◽  
Vijay Ramaswamy
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Genomic Analysis ◽  
Large Cell ◽  
Biological Risk ◽  
High Risk Patients ◽  
Molecular Features ◽  
Risk Patients ◽  
Embryonal Tumours ◽  
Health Organization

Paediatric embryonal tumours are highly heterogeneous entities which account for 15–20% of all childhood tumours of the central nervous system (CNS). Although historically considered one entity, integrated genomic analysis has unveiled this is no longer the case, and in fact CNS-PNET (primitive neuroectodermal tumour) has been removed from the World Health Organization (WHO) classification of CNS tumours. Patients are risk-stratified based on residual disease after surgery, metastatic dissemination, and, with the medulloblastoma subgroup, specific molecular features. In patients with medulloblastoma, 60–70% of patients over three years old are classified as standard-risk cases, while high-risk patients include those with disseminated and/or residual disease, large-cell and/or anaplastic histotypes, and MYC gene amplification in some protocols. Atypical teratoid rhabdoid tumours (ATRTs) are risk-stratified in a similar manner; however, recently integrated genomics has revealed the presence of three distinct molecular variants which seem to have distinct clinical features and outcomes. Clinical trials already underway or currently being planned will (1) examine the feasibility of reducing the dose of craniospinal irradiation and the volume of posterior fossa radiotherapy (RT) for patients generally considered at low biological risk (i.e. those with the WNT subgroup of medulloblastomas; (2) ascertain whether intensifying chemotherapy or RT can improve outcomes in high-risk patients; and (3) seek therapeutic targets that will enable tailored therapies, especially for relapsing patients and those at higher biological risk.

scholarly journals Frequent Screening With Serial Neck Ultrasound Is More Likely to Identify False-Positive Abnormalities Than Clinically Significant Disease in the Surveillance of Intermediate Risk Papillary Thyroid Cancer Patients Without Suspicious Findings on Follow-Up Ultrasound Evaluation

2015 ◽  
Vol 100 (4) ◽  
pp. 1561-1567 ◽  
Author(s):  
Samantha Peiling Yang ◽  
Ariadne M. Bach ◽  
R. Michael Tuttle ◽  
Stephanie A. Fish
Keyword(s):  
False Positive ◽  
Disease Recurrence ◽  
Intermediate Risk ◽  
Papillary Thyroid ◽  
Neck Ultrasound ◽  
Risk Patients ◽  
Clinically Significant ◽  
Structural Disease ◽  
Significant Disease

Context: American Thyroid Association (ATA) intermediate-risk thyroid cancer patients who achieve an excellent treatment response demonstrate a low risk of structural disease recurrence. Despite this fact, most patients undergo frequent surveillance neck ultrasound (US) during follow-up. Objective: The objective of the study was to evaluate the clinical utility of routine screening neck US in ATA intermediate-risk patients documented to have a nonstimulated thyroglobulin less than 1.0 ng/mL and a neck US without suspicious findings after therapy. Patients and Design: Retrospective review of 90 ATA intermediate-risk papillary thyroid carcinoma patients treated with total thyroidectomy and radioactive iodine ablation in a tertiary referral center. Main Outcome Measures: A comparison between the frequency of finding false-positive US abnormalities and the frequency of identifying structural disease recurrence in the study cohort was measured. Results: Over a median of 10 years, 90 patients had a median of six US (range 2–16). Structural disease recurrence was identified in 10% (9 of 90) at a median of 6.3 years. Recurrence was associated with other clinical indicators of disease in 5 of the 90 patients (5.6%, 5 of 90) and was detected without other signs of recurrence in four patients (4.8%, 4 of 84). False-positive US abnormalities were identified in 57% (51 of 90), leading to additional testing, which failed to identify clinically significant disease. Conclusions: In ATA intermediate-risk patients who have a nonstimulated thyroglobulin less than 1.0 ng/mL and a neck US without suspicious findings after therapy, frequent US screening during follow-up is more likely to identify false-positive abnormalities than clinically significant structural disease recurrence.

scholarly journals Knockout of IRF7 Highlights its Modulator Function of Host Response Against Avian Influenza Virus and the Involvement of MAPK and TOR Signaling Pathways in Chicken

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 385
Author(s):  
Tae Hyun Kim ◽  
Colin Kern ◽  
Huaijun Zhou
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Host Response ◽  
Antiviral Response ◽  
Influenza Viruses ◽  
Interferon Response ◽  
Type I

Interferon regulatory factor 7 (IRF7) is known as the master transcription factor of the type I interferon response in mammalian species along with IRF3. Yet birds only have IRF7, while they are missing IRF3, with a smaller repertoire of immune-related genes, which leads to a distinctive immune response in chickens compared to in mammals. In order to understand the functional role of IRF7 in the regulation of the antiviral response against avian influenza virus in chickens, we generated IRF7-/- chicken embryonic fibroblast (DF-1) cell lines and respective controls (IRF7wt) by utilizing the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system. IRF7 knockout resulted in increased viral titers of low pathogenic avian influenza viruses. Further RNA-sequencing performed on H6N2-infected IRF7-/- and IRF7wt cell lines revealed that the deletion of IRF7 resulted in the significant down-regulation of antiviral effectors and the differential expression of genes in the MAPK (mitogen-activated protein kinase) and mTOR (mechanistic target of rapamycin) signaling pathways. Dynamic gene expression profiling of the host response between the wildtype and IRF7 knockout revealed potential signaling pathways involving AP1 (activator protein 1), NF-κB (nuclear factor kappa B) and inflammatory cytokines that may complement chicken IRF7. Our findings in this study provide novel insights that have not been reported previously, and lay a solid foundation for enhancing our understanding of the host antiviral response against the avian influenza virus in chickens.

Endometrial cancer: experimental models useful for studies on molecular aspects of endometrial cancer and carcinogenesis.

2003 ◽  
pp. 23-42 ◽  
Author(s):  
G Vollmer
Keyword(s):  
Endometrial Cancer ◽  
Tumor Cell ◽  
Cell Lines ◽  
Hormone Replacement ◽  
Endometrial Adenocarcinoma ◽  
Experimental Models ◽  
New Drugs ◽  
Tumor Cell Lines ◽  
Endometrial Cancers

There is definitely a need for the development of new drugs for the treatment and cure of endometrial cancer. In addition there are various new drugs or phyto-remedies under development which are intended for use in the treatment and prevention of breast cancer, for the treatment of menopausal symptoms and for hormone replacement therapy. The efficacy of novel drugs targeting steroid receptors in endometrial cancers has to be evaluated and the safety of other endocrine measures on endometrial cancers or on endometrial carcinogenesis has to be assessed. For these experimental purposes five main classes of experimental models are available: spontaneous endometrial tumorigenesis models in inbred animals (Donryu rats, DA/Han rats, BDII/Han rats), inoculation tumors from chunks of tumors (rat EnDA-tumor, human EnCa 101 tumor) or from inoculated tumor cell lines (rat RUCA-I cells, human Ishikawa and ECC-1 cells), developmental estrogenic exposure or chemical carcinogen exposure of CD-1 and ICR mice, transgenic approaches such as mice heterozygous regarding the tumor suppressor gene PTEN (pten(+/-)-mice) and endometrial tumor cell lines cultured under conditions promoting in vivo-like morphology and functions e.g. cell culture on reconstituted basement membrane. Although the number of models is comparatively small, most aspects related to functions of estrogenic or gestagenic substances are assessable, particularly if various experimental models are combined. Whereas models based on human endometrial adenocarcinoma cells are widely used, the properties and advantages of animal-derived models have mainly been ignored so far.

scholarly journals Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1)

Leukemia ◽  
2019 ◽  
Vol 34 (2) ◽  
pp. 404-415 ◽  
Author(s):  
Tatjana Meyer ◽  
Nikolaus Jahn ◽  
Stefanie Lindner ◽  
Linda Röhner ◽  
Anna Dolnik ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Lines ◽  
De Novo ◽  
Functional Characterization ◽  
Interferon Response ◽  
Excellent Outcome ◽  
Recurrent Mutations ◽  
Primary Mouse ◽  
Inflammasome Activity

Abstract BRCA1/BRCA2-containing complex 3 (BRCC3) is a Lysine 63-specific deubiquitinating enzyme (DUB) involved in inflammasome activity, interferon signaling, and DNA damage repair. Recurrent mutations in BRCC3 have been reported in myelodysplastic syndromes (MDS) but not in de novo AML. In one of our recent studies, we found BRCC3 mutations selectively in 9/191 (4.7%) cases with t(8;21)(q22;q22.1) AML but not in 160 cases of inv(16)(p13.1q22) AML. Clinically, AML patients with BRCC3 mutations had an excellent outcome with an event-free survival of 100%. Inactivation of BRCC3 by CRISPR/Cas9 resulted in improved proliferation in t(8;21)(q22;q22.1) positive AML cell lines and together with expression of AML1-ETO induced unlimited self-renewal in mouse hematopoietic progenitor cells in vitro. Mutations in BRCC3 abrogated its deubiquitinating activity on IFNAR1 resulting in an impaired interferon response and led to diminished inflammasome activity. In addition, BRCC3 inactivation increased release of several cytokines including G-CSF which enhanced proliferation of AML cell lines with t(8;21)(q22;q22.1). Cell lines and primary mouse cells with inactivation of BRCC3 had a higher sensitivity to doxorubicin due to an impaired DNA damage response providing a possible explanation for the favorable outcome of BRCC3 mutated AML patients.

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