Algorithm for multi-curve-fitting with shared parameters and a possible application in evoked compound action potential measurements

BACKGROUND: Experimental results are commonly fitted by determining parameter values of suitable mathematical expressions. In case a relation exists between different data sets, the accuracy of the parameters obtained can be increased by incorporating this relationship in the fitting process instead of fitting the recordings separately. METHODS: An algorithm to fit multiple measured curves simultaneously was developed. The method accounts for parameters that are shared by some curves. It can be applied to either linear or nonlinear equations. Simulated noisy "measurement results" were created to compare the introduced method to the "straight forward" way of fitting the curves separately. RESULTS: The analysis of the simulated measurements confirm, that the introduced method yields more accurate parameters compared to the ones gained by fitting the measurements separately. Therefore it needs more computer time. As an example, the new fitting algorithm is applied to the measurements of the evoked compound action potentials (ECAP) of the auditory nerve: This leads to promising ideas to reduce artefacts generated by the measuring process. CONCLUSION: The introduced fitting algorithm uses the relationship between multiple measurement results to increase the accuracy of the parameters. Its application in the field of ECAP measurements is promising and should be further investigated

Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98

Tau is a neuronal protein that stabilizes axonal microtubules (MTs) in the central nervous system. In Alzheimer’s disease (AD) and other tauopathies, phosphorylated Tau accumulates in intracellular aggregates, a pathological hallmark of these diseases. However, the chronological order of pathological changes in Tau prior to its cytosolic aggregation remains unresolved. These include its phosphorylation and detachment from MTs, mislocalization into the somatodendritic compartment, and oligomerization in the cytosol. Recently, we showed that Tau can interact with phenylalanine-glycine (FG)-rich nucleoporins (Nups), including Nup98, that form a diffusion barrier inside nuclear pore complexes (NPCs), leading to defects in nucleocytoplasmic transport. Here, we used surface plasmon resonance (SPR) and bio-layer interferometry (BLI) to investigate the molecular details of Tau:Nup98 interactions and determined how Tau phosphorylation and oligomerization impact the interactions. Importantly, phosphorylation, but not acetylation, strongly facilitates the accumulation of Tau with Nup98. Oligomerization, however, seems to inhibit Tau:Nup98 interactions, suggesting that Tau-FG Nup interactions occur prior to oligomerization. Overall, these results provide fundamental insights into the molecular mechanisms of Tau-FG Nup interactions within NPCs, which might explain how stress-and disease-associated posttranslational modifications (PTMs) may lead to Tau-induced nucleocytoplasmic transport (NCT) failure. Intervention strategies that could rescue Tau-induced NCT failure in AD and tauopathies will be further discussed

Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and to produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, their synergy enhances bundling and spatial arrangement of microtubules. We further show that different Tau condensates efficiently induce pathological Tau aggregates in cells, including accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations and a condensate-like density for nuclear-envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations

ASTRIS: A real world treatment study of osimertinib in patients (pts) with EGFR T790M-positive non-small cell lung cancer (NSCLC) - European subset

n/

Brigatinib (BRG) vs crizotinib (CRZ) in the phase III ALTA-1L trial

n/

973MO KEYNOTE-189 5-year update: First-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC

Background: Pembro + pem-platinum significantly improved survival vs pbo + pem-platinum in patients (pts) with previously untreated, metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, regardless of PD-L1 TPS, in the phase III KEYNOTE-189 study (NCT02578680). We report updated results with ∼5 y of follow-up. Methods: Pts were randomized 2:1 to receive pembro 200 mg or pbo Q3W for up to 35 cycles (2y). All pts also received pem and investigator’s choice of carboplatin/cisplatin for 4 cycles, followed by maintenance pem until PD/unacceptable toxicity. Crossover from the pbo + pem-platinum group to pembro monotherapy was permitted after PD. Primary endpoints were OS and PFS. Results: Among 616 pts randomized (pembro + pem-platinum, n = 410; pbo + pem-platinum, n = 206), median time from randomization to data cutoff (Mar 8, 2022) was 64.6 (range, 60.1–72.4) mo. 116/202 (57.4%) treated pts crossed over from pbo + pem-platinum to anti–PD-(L)1 therapy during/outside the study. Median (95% CI) OS was 22.0 (19.5‒24.5) mo vs 10.6 (8.7‒13.6) mo with pembro + pem-platinum vs pbo + pem-platinum (HR, 0.60; 95% CI, 0.50‒0.72) and 5-y OS rates were 19.4% vs 11.3%, respectively. Median (95% CI) PFS was 9.0 (8.1‒10.4) mo vs 4.9 (4.7‒5.5) mo (HR, 0.50; 95% CI, 0.42‒0.60). Additional efficacy results are in the table. Among pts with ≥1 dose of assigned treatment, grade 3‒5 AEs occurred in 295/405 (72.8%) vs 136/202 (67.3%) of pts. Among 57 pts who completed 35 cycles of pembro, ORR was 86.0% (CR, n = 8; PR, n = 41); 3-y OS rate after completion of 35 cycles of pembro was 71.9%. Conclusions: First-line pembro + pem-platinum continued to show OS and PFS benefits with manageable toxicity vs pbo + pem-platinum, irrespective of PD-L1 expression. Pts who completed 35 cycles of pembro experienced durable responses. These data further support pembro + pem-platinum as a standard of care for metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

Introduction: In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. Methods: Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. Results: A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. Conclusions: In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study

Evaluating Metaphor Reification in Tangible Interfaces

International audienceMetaphors are a powerful conceptual device to reason about human actions. As such, they have been heavily used in designing and describing human computer interaction. Since they can address scripted text, verbal expression, imaging, sound, and gestures, they can also be considered in the design and analysis of multimodal interfaces. In this paper we discuss the description and evaluation of the relations between metaphors and their implementation in human computer interaction with a focus on tangible user interfaces (TUIs), a form of multimodal interface. The objective of this paper is to define how metaphors appear in a tangible context in order to support their evaluation. Relying on matching entities and operations between the domain of interaction and the domain of the digital application, we propose a conceptual framework based on three components: a structured representation of the mappings holding between the metaphor source, the metaphor target, the interface and the digital system; a conceptual model for describing metaphorical TUIs; three relevant properties, coherence, coverage and compliance, which define at what extent the implementation of a metaphorical tangible interface matches the metaphor. The conceptual framework is then validated and applied on a tangible prototype in an educational application

Interactive Assistance for Tour Planning

Abstract. It is often difficult for individual tourists to make a sightseeing tour plan because they do not have prior knowledge about the destination. Although several systems have been developed for assisting the user’s tour planning, these systems lack interactivity, while demanding a lot of data input from the user. In this paper, we introduce a new computer-aided tour planning system, called CT-Planner, which realizes collaborative tour planning. The system provides several tour plans with different characters and asks the user to give feedback. The feedback is utilized by the system for inferring the user’s preferences and then revising the tour plans. This cycle is repeated until the user is satisfied with the final plan. Thanks to this cycle the user does not have to register his profiles in advance. In addition, the system allows the user to specify his special requests, which leads to a more satisfying experience of computer-aided tour planning

Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN

Background: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years. Patients and methods: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP. Results: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P ¼ 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P ¼ 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off. Conclusions: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC