Service Platform for Converged Interactive Broadband Broadcast and Cellular Wireless

A converged broadcast and telecommunication service platform is presented that is able to create, deliver, and manage interactive, multimedia content and services for consumption on three different terminal types. The motivations of service providers for designing converged interactive multimedia services, which are crafted for their individual requirements, are investigated. The overall design of the system is presented with particular emphasis placed on the operational features of each of the sub-systems, the flows of media and metadata through the sub-systems and the formats and protocols required for inter-communication between them. The key features of tools required for creating converged interactive multimedia content for a range of different end-user terminal types are examined. Finally possible enhancements to this system are discussed. This study is of particular interest to those organizations currently conducting trials and commercial launches of DVB-H services because it provides them with an insight of the various additional functions required in the service provisioning platforms to provide fully interactive services to a range of different mobile terminal types

Epigenetic regulation of RhoB loss of expression in lung cancer

<p>Abstract</p> <p>Background</p> <p>RhoB is down-regulated in most lung cancer cell lines and tumor tissues when compared with their normal counterparts. The mechanism of this loss of expression is not yet deciphered.</p> <p>Methods</p> <p>Since no mutation has been reported in the RhoB sequence, we investigated the epigenetic regulation of RhoB expression by analyzing the effect of HDAC inhibitors and methyltransferase inhibitors, by direct sequencing after bisulfite treatment and by methylation specific PCR.</p> <p>Results</p> <p>We first showed that histone deacetylase (HDAC) inhibitors induce a significant RhoB re-expression in lung cancer cell lines whereas only a slight effect was observed with methyl transferase inhibitors. As promoter methylation is the most common epigenetic process in lung cancer, we performed methylation specific PCR and sequence analysis after bisulfite treatment and demonstrated that RhoB was methylated neither in lung cancer cell lines nor in tumor tissues. We also showed that a variable number of tandem repeats sequences in the 5' region of the RhoB gene was involved in HDAC response.</p> <p>Conclusion</p> <p>We thus propose that RhoB regulation of expression occurs mainly by histone deacetylation rather than by promoter hypermethylation and that this process can be modulated by specific 5' sequences within the promoter.</p

Genome-wide analysis of Corsican population reveals a close affinity with Northern and Central Italy

Despite being the fourth largest island in the Mediterranean basin, the genetic variation of Corsica has not been explored as exhaustively as Sardinia, which is situated only 11 km South. However, it is likely that the populations of the two islands shared, at least in part, similar demographic histories. Moreover, the relative small size of the Corsica may have caused genetic isolation, which, in turn, might be relevant under medical and translational perspectives. Here we analysed genome wide data of 16 Corsicans, and integrated with newly (33 individuals) and previously generated samples from West Eurasia and North Africa. Allele frequency, haplotype-based, and ancient genome analyses suggest that although Sardinia and Corsica may have witnessed similar isolation and migration events, the latter is genetically closer to populations from continental Europe, such as Northern and Central Italians

Relationship between RET fusion partner and treatment outcomes in patients (pts) with non-small cell lung cancer (NSCLC) from the phase I/II ARROW study and real-world data (RWD)

Background: The ARROW study is assessing the anti-tumour activity of pralsetinib, a highly-selective RET inhibitor in advanced solid tumours, including RET fusion+ NSCLC. Prolonged overall survival (OS) was reported with RET inhibitor therapy in NSCLC pts with CCDC6 vs KIF5B RET fusions (Tan AC, et al. JTO 2020). We examined the relationship between RET fusion partner and treatment outcomes in pts with RET fusion+ NSCLC from ARROW and RWD. Methods: In phase 2 of ARROW, 233 pts with RET fusion+ NSCLC (KIF5B n=164, CCDC6 n=41, Other n=28) received 400mg/day pralsetinib until progression, intolerance or withdrawal. Primary endpoints: overall response rate (ORR) and safety. In Q4 2021, 67 pts with RET fusion+ NSCLC (KIF5B n=46, CCDC6 n=8, Other n=13) met eligibility criteria from the nationwide (US-based) de-identified Flatiron Health-FMI NSCLC clinico-genomic database. Cox regression analyses are reported. Results: Baseline characteristics by RET fusion partner were balanced across subgroups within ARROW. ORR was similar with KIF5B and CCDC6, but lower with Other RET fusions (Table); the same trend was seen in treatment-naïve and prior treatment subgroups. Disease control rate (DCR) was high in all pts, but lowest in the Other RET fusions subgroup. Median duration of response (DOR) and progression-free survival (PFS) were higher with CCDC6 vs KIF5B RET fusions irrespective of prior treatment. OS data are immature. In the RWD cohort, median OS was numerically longer in CCDC6 and Other RET fusions vs KIF5B RET-driven disease (52.8 and 38.5 vs 19.1 months); when adjusted for covariates including RET inhibitor usage (KIF5B n=12, CCDC6 n=5, Other n=5), OS HRs for CCDC6 and Other RET fusions vs KIF5B were 0.49 (95% CI: 0.08–3.11) and 0.41 (95% CI: 0.13–1.30), respectively. Conclusions: Pralsetinib is active in RET fusion+ NSCLC, regardless of fusion partner or prior treatment. CCDC6 RET-driven disease may have a better prognosis vs KIF5B

Clinical Outcomes With Dabrafenib Plus Trametinib in a Clinical Trial Versus Real-World Standard of Care in Patients With BRAF-Mutated Advanced NSCLC

INTRODUCTION: BRAF mutations are rare in patients with NSCLC, and treatment options are limited. Dabrafenib plus trametinib (dab-tram) was approved for BRAF(V600)-mutated advanced NSCLC (aNSCLC), based on results from a phase 2 study (NCT01336634). This retrospective analysis compared the effectiveness of dab-tram, based on previously reported clinical trial data, versus real-world standard of care in patients with BRAF-mutated aNSCLC. METHODS: Real-world cohorts were derived from a deidentified real-world database (2011–2020) and included patients with BRAF-mutated aNSCLC receiving first-line platinum-based chemotherapy (PBC), first-line immune checkpoint inhibitors (ICIs) plus PBC, or second-line ICIs. Weighting by odds was used to estimate the average treatment effect of the treated. RESULTS: For first-line dab-tram versus PBC, the hazard ratio (HR; 95% confidence interval) for death in unweighted and weighted analyses was 0.65 (0.39–1.1) and 0.51 (0.29–0.92; p = 0.03), respectively; unweighted and weighted median overall survival was 17.3 (12.3–40.2) versus 14.5 (9.2–19.6) months and 17.3 (14.6-not reached) versus 9.7 (6.4–19.6) months, respectively. Hazard ratio of death in unweighted and weighted analyses was 0.56 (0.29–1.1) and 0.57 (0.28–1.17), respectively, with first-line dab-tram versus PBC plus ICI, and 0.65 (0.39–1.07) and not reported (Cox proportional-hazards assumption violated), respectively, with second-line dab-tram versus ICI. CONCLUSIONS: In this indirect comparison in patients with BRAF-mutated aNSCLC, the risk of death was lower and median overall survival was longer with first-line dab-tram versus PBC. In analyses of dab-tram versus first-line PBC plus ICI or second-line ICI, sample sizes were small and findings were inconclusive with overlapping confidence intervals. Despite some limitations, the study provides useful data for this rare patient population

Examination of effects of GSK3β phosphorylation, β-catenin phosphorylation, and β-catenin degradation on kinetics of Wnt signaling pathway using computational method

<p>Abstract</p> <p>Background</p> <p>Recent experiments have explored effects of activities of kinases other than the well-studied GSK3β, in wnt pathway signaling, particularly at the level of β-catenin. It has also been found that the kinase PKA attenuates β-catenin degradation. However, the effects of these kinases on the level and degradation of β-catenin and the resulting downstream transcription activity remain to be clarified. Furthermore, the effect of GSK3β phosphorylation on the β-catenin level has not been examined computationally. In the present study, the effects of phosphorylation of GSK3β and of phosphorylations and degradation of β-catenin on the kinetics of the wnt signaling pathway were examined computationally.</p> <p>Methods</p> <p>The well-known computational Lee-Heinrich kinetic model of the wnt pathway was modified to include these effects. The rate laws of reactions in the modified model were solved numerically to examine these effects on β-catenin level.</p> <p>Results</p> <p>The computations showed that the β-catenin level is almost linearly proportional to the phosphorylation activity of GSK3β. The dependence of β-catenin level on the phosphorylation and degradation of free β-catenin and downstream TCF activity can be analyzed with an approximate, simple function of kinetic parameters for added reaction steps associated with effects examined, rationalizing the experimental results.</p> <p>Conclusion</p> <p>The phosphorylations of β-catenin by kinases other than GSK3β involve free unphorphorylated β-catenin rather than GSK3β-phosphorylated β-catenin*. In order to account for the observed enhancement of TCF activity, the β-catenin dephosphorylation step is essential, and the kinetic parameters of β-catenin phosphorylation and degradation need to meet a condition described in the main text. These findings should be useful for future experiments.</p