Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=–0·744, p=0·0035). The proportion of patients with p16+/HPV– oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5–82·7) for p16+/HPV+, 40·4% (38·6–42·4) for p16–/HPV–, 53·2% (46·6–60·8) for p16–/HPV+, and 54·7% (49·2–60·9) for p16+/HPV–. 5-year disease-free survival was 84·3% (95% CI 82·9–85·7) for p16+/HPV+, 60·8% (58·8–62·9) for p16–/HPV–; 71·1% (64·7–78·2) for p16–/HPV+, and 67·9% (62·5–73·7) for p16+/HPV–. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation: Patients with discordant oropharyngeal cancer (p16–/HPV+ or p16+/HPV–) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16–/HPV– oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions

Genome-Wide Analysis of Factors Affecting Transcription Elongation and DNA Repair: A New Role for PAF and Ccr4-Not in Transcription-Coupled Repair

RNA polymerases frequently deal with a number of obstacles during transcription elongation that need to be removed for transcription resumption. One important type of hindrance consists of DNA lesions, which are removed by transcription-coupled repair (TC-NER), a specific sub-pathway of nucleotide excision repair. To improve our knowledge of transcription elongation and its coupling to TC-NER, we used the yeast library of non-essential knock-out mutations to screen for genes conferring resistance to the transcription-elongation inhibitor mycophenolic acid and the DNA-damaging agent 4-nitroquinoline-N-oxide. Our data provide evidence that subunits of the SAGA and Ccr4-Not complexes, Mediator, Bre1, Bur2, and Fun12 affect transcription elongation to different extents. Given the dependency of TC-NER on RNA Polymerase II transcription and the fact that the few proteins known to be involved in TC-NER are related to transcription, we performed an in-depth TC-NER analysis of a selection of mutants. We found that mutants of the PAF and Ccr4-Not complexes are impaired in TC-NER. This study provides evidence that PAF and Ccr4-Not are required for efficient TC-NER in yeast, unraveling a novel function for these transcription complexes and opening new perspectives for the understanding of TC-NER and its functional interconnection with transcription elongation

Exploiting spatial correlation for pilot reuse in single-cell mMTC

Abstract As a key enabler for massive machine-type communications (mMTC), spatial multiplexing relies on massive multiple-input multiple-output (mMIMO) technology to serve the massive number of user equipments (UEs). To exploit spatial multiplexing, accurate channel estimation through pilot signals is needed. In mMTC systems, it is impractical to allocate a unique orthogonal pilot sequence to each UE as it would require too long pilot sequences, degrading the spectral efficiency. This work addresses the design of channel features from correlated fading channels to assist the pilot assignment in multi-sector mMTC systems under pilot reuse of orthogonal sequences. In order to reduce pilot collisions and to enable pilot reuse, we propose to extract features from the channel covariance matrices that reflect the level of orthogonality between the UEs channels. Two features are investigated: covariance matrix distance (CMD) feature and CMD-aided channel charting (CC) feature. In terms of symbol error rate and achievable rate, the CC-based feature shows superior performance than the CMD-based feature and baseline pilot assignment algorithms

Channel charting aided pilot reuse for massive MIMO systems with spatially correlated channels

Abstract Massive multiple-input multiple-output (mMIMO) technology is a way to increase spectral efficiency and provide access to the Internet of things (IoT) and machine-type communication (MTC) devices. To exploit the benefits of large antenna arrays, accurate channel estimation through pilot signals is needed. Massive IoT and MTC systems cannot avoid pilot reuse because of the enormous numbers of connected devices. We propose a pilot reuse algorithm based on channel charting (CC) to mitigate pilot contamination in a multi-sector single-cell mMIMO system having spatially correlated channels. We show that after creating an interference map via CC, a simple strategy to allocate the pilot sequences can be implemented. The simulation results show that the CC-based pilot reuse strategy improves channel estimation accuracy, which subsequently improves the symbol detection performance and increases the spectral efficiency compared to other existing schemes. Moreover, the performance of the CC pilot assignment method approaches that of exhaustive search pilot assignment for small network setups

Channel charting aided pilot allocation in multi-cell massive MIMO mMTC networks

Abstract Serving a plethora of devices in massive machinetype communications (mMTC) can rely on spatial multiplexing enabled by massive multiple-input multiple-output (mMIMO) technology. To release the full potential, accurate channel estimation is needed. Due to the large numbers of devices it necessitates pilot reuse. We propose a pilot allocation algorithm based on multi-point channel charting (CC) to mitigate inevitable pilot contamination in a multi-cell multi-sector mMTC network with spatially correlated mMIMO channels. The generated CC represents an effective interference map from channel covariance matrices to capture the degree of pilot contamination caused by sharing the same pilot sequence among multiple users. The map is then fed into a greedy algorithm that aims at optimizing the reuse pattern of orthogonal pilot sequences to minimize the performance degradation caused by pilot contamination. The proposed CC-based method is empirically shown to obtain notable gains over a reuse-factor-aware random pilot allocation, yet leaving room for further improvements

Organic Acids, Sugars, and Anthocyanins Contents in Juices of Tunisian Pomegranate Fruits

peer reviewedJuices made from fruits of 30 Tunisian accessions of pomegranate were studied for their organic acids, sugars, and anthocyanin contents, using high performance liquid chromatography. Among the detected organic acids, malic acid was the major one (>50%) followed by citric acid (>22%), while among sugars, fructose and glucose were most present in pomegranate juice contributing 53.9 and 43.4% of the total sugar content, respectively. The total anthocyanin content ranged from 9-115 mg per litre of juice with the following ranges of the six compounds found: cyanidin-3,5-diglucoside (3.1-74.4 mg/L), delphinidin-3-glucoside (0.7-22.0 mg/L), cyanidin-3-glucoside (0.8-21.0 mg/L), pelargonidin-3-glucoside (0.5-16.1 mg/L), pelargonidin-3,5-diglucoside (0.0-11.8 mg/L), and delphinidin-3,5-diglucoside (0.0-5.4 mg/L). Based on the analyzed parameters, cluster analysis allowed grouping cultivars into two main clusters. One was made of sour cultivars and the second of the sweet ones. Principle component and cluster analyses suggested that the composition of the pomegranate fruits is determined by cultivar rather than cultivation location

BCL-6 a possible missing link for anti-inflammatory PPAR-delta signalling in pancreatic beta cells

AIMS/HYPOTHESIS: Inflammatory mediators contribute to pancreatic beta cell death in type 1 diabetes. Beta cells respond to cytokine exposure by activating gene networks that alter cellular metabolism, induce chemokine release (thereby increasing insulitis), and cause apoptosis. We have previously shown by microarray analysis that exposure of INS-1E cells to IL-1beta + IFN-gamma induces the transcription factor peroxisome proliferator-activated receptor (Ppar)-delta and several of its target genes. PPAR-delta controls cellular lipid metabolism and is a major regulator of inflammatory responses. We therefore examined the role of PPAR-delta in cytokine-treated beta cells. MATERIALS AND METHODS: Primary beta cells that had been purified by fluorescence-activated cell sorting and INS-1E cells were cultured in the presence of the cytokines TNF-alpha, IL-1beta, or IL-1beta + IFN-gamma, or the synthetic PPAR-delta agonist GW501516. Gene expression was analysed by real-time PCR. PPAR-delta, monocyte chemoattractant protein (MCP-1, now known as CCL2) promoter and NF-kappaB activity were determined by luciferase reporter assays. RESULTS: Exposure of primary beta cells or INS-1E cells to cytokines induced Ppar-delta mRNA expression and PPAR-delta-dependent CD36, lipoprotein lipase, acyl CoA synthetase and adipophilin mRNAs. Cytokines and the PPAR-delta agonist GW501516 also activated a PPAR-delta response element reporter in beta cells. Unlike immune cells, neither INS-1E nor beta cells expressed the transcriptional repressor B-cell lymphoma-6 (BCL-6). As a consequence, PPAR-delta activation by GW501516 did not decrease cytokine-induced Mcp-1 promoter activation or mRNA expression, as reported for macrophages. Transient transfection with a BCL-6 expression vector markedly reduced Mcp-1 promoter and NF-kappaB activities in beta cells. CONCLUSIONS/INTERPRETATION: Cytokines activate the PPAR-delta gene network in beta cells. This network does not, however, regulate the pro-inflammatory response to cytokines because beta cells lack constitutive BCL-6 expression. This may render beta cells particularly susceptible to propagating inflammation in type 1 diabetes.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe