1,720,994 research outputs found
Accumulation of Host Cell Genetic Errors following High-Risk HPV Infection
Full text linkAPOBEC3 cytidine deaminases convert deoxycytidine to deoxyuridine in single-stranded DNA, forming part of the innate immune response to HPV infection but also contributing to mutagenesis of the host genome of infected cells during HPV-associated carcinogenesis. Of the seven human APOBEC3 genes, two (APOBEC3A and APOBEC3B) have been implicated in both processes, with evidence increasingly pointing to APOBEC3A as the main culprit in somatic mutagenesis. This review discusses recent developments in host and viral genome sequencing that suggests viral editing by one or more APOBEC3 enzymes plays an important role in viral clearance, while bursts of APOBEC3A activity may drive carcinogenesis in persistently infected cells. Progress in our understanding of HPV replication is also discussed and a model is presented in which chronic activation of the DNA damage response by HPV, together with suppression of p53 function acts to create a perfect storm for APOBEC3 activity against the host cell genome
HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management
Full text linkHuman papillomavirus (HPV)-positive (HPV
+) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV
+ OPSCC from its HPV-negative (HPV
−) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV
+ OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV
+ OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes.
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Large inherent variability in data derived from highly standardised cell culture experiments.
Full text linkCancer drug development is hindered by high clinical attrition rates, which are blamed on weak predictive power by preclinical models and limited replicability of preclinical findings. However, the technically feasible level of replicability remains unknown. To fill this gap, we conducted an analysis of data from the NCI60 cancer cell line screen (2.8 million compound/cell line experiments), which is to our knowledge the largest depository of experiments that have been repeatedly performed over decades. The findings revealed profound intra-laboratory data variability, although all experiments were executed following highly standardised protocols that avoid all known confounders of data quality. All compound/ cell line combinations with > 100 independent biological replicates displayed maximum GI50 (50% growth inhibition) fold changes (highest/ lowest GI50) > 5% and 70.5% displayed maximum fold changes > 1000. The highest maximum fold change was 3.16 × 10 (lowest GI50: 7.93 ×10 µM, highest GI50: 25.0 µM). FDA-approved drugs and experimental agents displayed similar variation. Variability remained high after outlier removal, when only considering experiments that tested drugs at the same concentration range, and when only considering NCI60-provided quality-controlled data. In conclusion, high variability is an intrinsic feature of anti-cancer drug testing, even among standardised experiments in a world-leading research environment. Awareness of this inherent variability will support realistic data interpretation and inspire research to improve data robustness. Further research will have to show whether the inclusion of a wider variety of model systems, such as animal and/ or patient-derived models, may improve data robustness. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
Molecular landscape of proliferative verrucous leukoplakia: a systematic review
No full textProliferative verrucous leukoplakia (PVL) is a rare oral potentially malignant disorder characterised by multifocal origin and unpredictable long-term evolution to oral squamous cell carcinoma (OSCC) or oral verrucous carcinoma (OVC). Currently no predictive biomarkers are in clinical use. We aimed to explore the genomic profile of PVL. A total of 685 cases in 26 studies were included in this review. Genomic data were presented in 15% of studies and biomarker analysis was reported in 85% of studies. At first clinical presentation, PVL is characterised by a high loss of heterozygosity (LOH), similar to OSCC, and low copy number alterations (CNA). As these progress, more CNAs and mutations in CDKN2A and alterations to ELAVL1 expression are noted, but no TP53 mutations are identified. There is significantly lower LOH at 17p in early PVL compared with OSCC (p = 0.037). Deletions in chromosomal loci 17q12, 5q31.1 and amplifications in 7q11.2, 7q22 are shared between early lesions and OVC. PVL shows CNAs at 11q31. WNT signalling pathway genes (SUZ12, CTTN and FOLR3) are enriched in CN-altered regions. PVL stroma shows significantly lower α-SMA and higher CD34 expression than OVC and OSCC. The exact genomic landscape is currently unclear, and further studies are necessary to unravel this mystery.</p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Investigating the Expression of SYCP2 in HPV associated Cancers
Full text linkHigh risk Human papillomavirus infections are linked to highly prevalent cancers; a consequence of aborted viral cycles and deregulation of HPV oncogenes E6 and E7. In many cases of cancer, meiotic genes can be seen upregulated, activation of meiotic genes in normal tissue can have detrimental effects due to the unique characteristics of gametogenesis that if observed in normal cells can be oncogenic. The gene of interest investigated in this project is SYCP2; it is a meiosis specific gene that is a part of the synaptonemal complex that links homologous chromosomes and facilitates synapsis. Recent studies showed it is strongly upregulated in HPV associated cancers when it’s normal expression should be restricted to testis, it has been linked to what is called Cancer Testis Antigens (CTA) which are a group of genes that has been associated to tumours of different histological origins whose normal expression is restricted to testes. This gene is of interest because CTAs hold unique therapeutic potential as biomarkers or immunotherapeutics. It has been documented that SYCP2 is upregulated, however, existing data thus far only shows the mRNA level. In order to explore any therapeutic potential of this gene its expression profile needs to be investigated, and its possible correlation to viral infection or oncogenesis. In this project we aim to investigate if the large increase in SYCP2 transcript levels in HPV16+ cancers is paralleled by a similar increase in SYCP2 protein levels. This study has looked into the protein expression of SYCP2 that if further investigated, could form a useful model in understanding HPV infection and the possible role SYCP2 has in aiding oncogenesis
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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