HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favorable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; CDDP: cisplatin (CDDP); FFPE: formalin-fixed paraffin-embedded (FFPE); HNC: head and neck cancers (HNC); HPV: human papillomavirus (HPV); hrHPV: high risk human papillomavirus (hrHPV); OCSCC: oral cavity squamous carcinomas (OCSSC); OPSCC: oropharyngeal squamous cell carcinoma (OPSCC); OS: overall survival (OS); qPCR: quantitative polymerase chain reaction; RB1: RB transcriptional corepressor 1; ROC: receiver operating characteristic curve (ROC)

Intravoxel incoherent motion diffusion-weighted imaging for oropharyngeal squamous cell carcinoma: Correlation with human papillomavirus Status

Purpose: To investigate the relationships between imaging parameters derived from intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and HPV status in oropharyngeal squamous cell carcinoma (OPSCC). Materials and Methods: 73 patients with a new diagnosis of OPSCC were enrolled in the present study. MRI including IVIM-DWI with nine b value (range 0–800 s/mm2) was acquired in all patients. Primary tumor (PT) and the largest metastatic lymph node (LN), if present, were volumetrically contoured and the tissue diffusion coefficient Dt, perfusion fraction f and perfusion-related diffusion coefficient D* were estimated by a bi-exponential fit. The apparent diffusion coefficient (ADC) was also estimated by a mono-exponential fit. The predictive power of the most relevant patient/tumor characteristics and image-based features in determining the HPV status was assessed. Results: 67 PTs and 67 metastatic LNs were analyzed. Significant differences in ADC and Dt values among HPV-positive and HPV-negative patients were found for PTs (p = 0.003 and p < 0.001, respectively), while a trend toward significance in Dt was reported for LNs (p = 0.066). The perfusion-related parameters, f, D* and D*× f, were not related to HPV status. The best predictive model for HPV positivity was obtained combining alcohol intake and smoke habits with Dt values of PTs (accuracy = 80.8%, sensitivity = 85.7%, specificity = 64.7%). Conclusion: Significant correlations were found between IVIM-DWI and HPV status in OPSCCs. The perfusion-free diffusion coefficient, Dt, may better reflect the HPV-related tumor differences compared to ADC, whereas the perfusion-related parameters were not able to reliably discriminate HPV-positive from HPV-negative OPSCC

Correlation between histogram-based DCEMRI parameters and 18F-FDG PET values in oropharyngeal squamous cell carcinoma: Evaluation in primary tumors and metastatic nodes

Objectives To investigate the correlation between histogram-based Dynamic Contrast-Enhanced magnetic resonance imaging (DCE-MRI) parameters and positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG-PET) values in oropharyngeal squamous cell carcinoma (OPSCC), both in primary tumors (PTs) and in metastatic lymph nodes (LNs). Methods 52 patients with a new pathologically-confirmed OPSCC were included in the present retrospective cohort study. Imaging including DCE-MRI and 18F-FDG PET/CT scans were acquired in all patients. Both PTs and the largest LN, if present, were volumetrically contoured. Quantitative parameters, including the transfer constants, Ktrans and Kep, and the volume of extravascular extracellular space, ve, were calculated from DCE-MRI. The percentiles (P), P10, P25, P50, P75, P90, and skewness, kurtosis and entropy were obtained from the histogram-based analysis of each perfusion parameter. Standardized uptake values (SUV), SUVmax, SUVpeak, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated applying a SUV threshold of 40%. The correlations between all variables were investigated with the Spearman-rank correlation test. To exclude false positive results under multiple testing, the Benjamini-Hockberg procedure was applied. Results No significant correlations were found between any parameters in PTs, while significant associations emerged between Ktrans and 18F-FDG PET parameters in LNs. Conclusions Evident relationships emerged between DCE-MRI and 18F-FDG PET parameters in OPSCC LNs, while no association was found in PTs. The complex relationships between perfusion and metabolic biomarkers should be interpreted separately for primary tumors and lymph-nodes. A multiparametric approach to analyze PTs and LNs before treatment is advisable in head and neck squamous cell carcinoma (HNSCC)

Multiparametric mri evaluation of oropharyngeal squamous cell carcinoma. A mono-institutional study

The aim of this paper is to define the pre-treatment radiological characteristics of oropha-ryngeal squamous cell carcinoma (OPSCC) using morphological and non-morphological magnetic resonance imaging (MRI), based on HPV status, in a single-institution cohort. In total, 100 patients affected by OPSCC were prospectively enrolled in the present study. All patients underwent 1.5T MR with standard sequences, including diffusion-weighted imaging with and intravoxel incoherent motion (IVIM-DWI) technique and a dynamic contrast-enhanced (DCE) MRI. For all patients, human papillomavirus (HPV) status was available. No statistically significant differences in the vol-ume of primary tumors (PTs) and lymph nodes (LNs) were observed based on HPV status. When comparing the two patient groups, no significant differences were found for the PT radiologic characteristics (presence of well-defined borders, exophytic growth, ulceration, and necrosis) and LN morphology (solid/cystic/necrotic). Tumor subsite, smoking status, and alcohol intake significantly differed based on HPV status, as well as ADC and Dt values of both PTs and LNs. We detected no significant difference in DCE-MRI parameters by HPV status. Based on a multivariate logistic re-gression model, the combination of clinical factors, such as tumor subsite and alcohol habits, with the perfusion-free diffusion coefficient Dt of LNs, may help to accurately discriminate OPSCC by HPV status

Smart mobility: a mobile approach

The Internet of Things (IoT) is one of the key ingredients for the realization of Smart Cities. IoT devices are essential components of the Smart Cities infrastructure, as they can provide information collected from the environment through sensors or allow other systems to reach out and act on the world through actuators. IoT data collection, however, is not limited to sensors and machines, but to data from social networks, and the web. Social networks have a huge impact on the amount of data being produced daily, becoming an increasingly central and important data source. The exploitation of these data sources, combined with the growing popularity of mobile devices, can lead to the development of better solutions to improve people’s quality of life. This paper discusses how to take advantage of the benefits of mobile devices and the vast range of information sources and services, such as traffic conditions, and narrow, closed or conditioned roads data. The proposed system uses a real-time collection, organization, and transmission of traffic and road conditions data to provide efficient and accurate information to drivers. With the purpose of supporting and improving traffic data collection and distribution, an Android application was developed to collect information about extraordinary events that take place in a city, providing warnings and alternative routes to drivers and helping them to improve their time management. The developed solution also exploits the existing gaps in other applications, implementing a more specific solution for the Madeira Island traffic condition problems.info:eu-repo/semantics/acceptedVersio

Carfilzomib, cyclophosphamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: A pooled analysis of two studies

Despite remarkable advances in the treatment of multiple myeloma (MM) in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors have been demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with MM receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard-risk versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard-risk versus high-risk patients, we observed similar progression-free survival (PFS) (3-year PFS: 52% vs. 43%, respectively; P=0.50), overall survival (OS) (3-year OS: 78% vs. 73%; P=0.38), and overall response rate (88% vs. 95%; P=0.47), with no statistical differences between the two groups. No difference in terms of PFS was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed MM patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted in similar PFS and OS as in standard-risk patients

Carfilzomib, cyclophosphamide and dexamethasone for newly diagnosed, high-risk myeloma patients not eligible for transplant: A pooled analysis of two studies

open20noFunding: The IST-CAR-561 (NCT01857115) study was sponsored by Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON, the Netherlands), in collaboration with Fondazione Neoplasie Sangue ONLUS (Italy). The IST-CAR-506 (NCT01346787) study was sponsored by the HOVON Foundation and co-sponsored by Fondazione Neoplasie Sangue ONLUS. Both trials were supported by funding from AMGEN (Onyx Pharmaceuticals), which had no role in study design, data collection, data analysis, data interpretation, writing of the report or publication of this article. The corresponding author had full access to all the data in the two studies, and had final responsibility for the decision to prepare and submit this manuscript for publication, together with the other authors.Despite remarkable advances in the treatment of multiple myeloma (MM) in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors have been demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with MM receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard-risk versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard-risk versus high-risk patients, we observed similar progression-free survival (PFS) (3-year PFS: 52% vs. 43%, respectively; P=0.50), overall survival (OS) (3-year OS: 78% vs. 73%; P=0.38), and overall response rate (88% vs. 95%; P=0.47), with no statistical differences between the two groups. No difference in terms of PFS was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed MM patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted in similar PFS and OS as in standard-risk patients.noneMina R.; Bonello F.; Petrucci M.T.; Liberati A.M.; Conticello C.; Ballanti S.; Musto P.; Olivieri A.; Benevolo G.; Capra A.; Gilestro M.; Galieni P.; Cavo M.; Siniscalchi A.; Palumbo A.; Montefusco V.; Gaidano G.; Omede P.; Boccadoro M.; Bringhen S.Mina R.; Bonello F.; Petrucci M.T.; Liberati A.M.; Conticello C.; Ballanti S.; Musto P.; Olivieri A.; Benevolo G.; Capra A.; Gilestro M.; Galieni P.; Cavo M.; Siniscalchi A.; Palumbo A.; Montefusco V.; Gaidano G.; Omede P.; Boccadoro M.; Bringhen S

Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma

Lenalidomide-dexamethasone improved outcome in newly diagnosed elderly multiple myeloma patients. We randomly assigned 662 patients who were age \u202165 years or transplantation-ineligible to receive induction with melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus lowdose dexamethasone (Rd). The primary end point was progression-free survival (PFS) in triplet (MPR and CPR) vs doublet (Rd) lenalidomide-containing regimens. After a median follow-up of 39 months, the medianPFSwas22 months for the triplet combinations and 21 months for the doublet (P 5 .284). The median overall survival (OS) was not reached in either arms, and the 4-year OS was 67% for the triplet and 58% for the doublet arms (P 5 .709). By considering the 3 treatment arms separately, no difference in outcome was detected among MPR, CPR, and Rd. The most common grade \u20213 toxicity was neutropenia: 64% in MPR, 29% in CPR, and 25% in Rd patients (P < .0001). Grade \u20213 nonhematologic toxicities were similar among arms and were mainly infections (6.5% to 11%), constitutional (3.5% to 9.5%), and cardiac (4.5% to 6%), with no difference among the arms. In conclusion, in the overall population, the alkylator-containing tripletsMPRandCPRwere not superior to the alkylator-free doublet Rd, which was associated with lower toxicit