Multisensory Congruency as a Mechanism for Attentional Control over Perceptual Selection

The neural mechanisms underlying attentional selection of competing neural signals for awareness remains an unresolved issue. We studied attentional selection, using perceptually ambiguous stimuli in a novel multisensory paradigm that combined competing auditory and competing visual stimuli. We demonstrate that the ability to select, and attentively hold, one of the competing alternatives in either sensory modality is greatly enhanced when there is a matching cross-modal stimulus. Intriguingly, this multimodal enhancement of attentional selection seems to require a conscious act of attention, as passively experiencing the multisensory stimuli did not enhance control over the stimulus. We also demonstrate that congruent auditory or tactile information, and combined auditory–tactile information, aids attentional control over competing visual stimuli and visa versa. Our data suggest a functional role for recently found neurons that combine voluntarily initiated attentional functions across sensory modalities. We argue that these units provide a mechanism for structuring multisensory inputs that are then used to selectively modulate early (unimodal) cortical processing, boosting the gain of task-relevant features for willful control over perceptual awareness

A Platform of Porous Biomaterials as 3D Culture Systems for Cancer Biology

Background: The role of stem cells in tissue development and repair is beginning to be unravelled and will open remarkable opportunities to improve current medical treatments. Yet, the cascade of events that enable us to distinguish between abnormal and functional tissue morphogenesis is not well known and the potential involvement of stem cells in cancer initiation or tissue regeneration is still at an embryonic stage. Most biological studies rely on culturing cells onto two-dimensional (2D) substrates, which poorly reflect the three-dimensional (3D) environment that governs the physical, chemical, and biological processes at the heart of tissue development. Here, we introduce a library of 3D culture systems − scaffolds − with enhanced cell-material interactions. Materials and Methods: 3D scaffolds made of biodegradable synthetic polymers were fabricated by either rapid prototyping, eletrospinning and their combination. Mesenchymal stem cells derived from bone marrow were isolated from patients after informed consent, seeded on the scaffolds and cultured for up to 35 days. Cell morphology was observed by scanning electron microscopy. Cell number and metabolic activity were quantified by DNA and alamar blue assays. Differentiation was assessed by gene expression, while extrfacellular matrix (ECM) formation by biochemical assays. Results: 3D scaffolds with tailored mechanical and physichochemical properties could be fabricated by different processing technologies. While rapid prototyping resulted in the fabrication of scaffolds with controlled porosity at the macro scale, electrospinning enabled the creation of fibrillar meshes mimicking the physical micro and nano scale dimensions of native ECM. Nutrient availability had a profound effect on tissue formation in 2D and 3D. Despite steep nutrient concentration gradients in 3D scaffolds, stem cells proliferated while avoiding significant death. Cell migration into millimeter-size circular patterns in the scaffold’s pores was supported by ECM organization. Higher concentrations of nutrients controlled the rates of proliferation and did not induce differentiation markers. Furthermore, scaffolds with customized physicochemical and surface properties influenced stem cell morphology and activity. Conclusions: These 3D scaffolds offer a new platform to study the mechanisms behind stem cell driven tissue morphogenesis and may play a role in cancer biology research to create organotypic 3D models to study cancer initiation and development, as well as the potential involvement of stem cells in these processes

Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer

AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC. PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included. RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively. CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297

Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer

Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C min at steady-state. The geometric mean (GM) C min at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C min at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P <.001) for SGC and RCC patients, respectively. When dose-normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (C min 971 μg/L [95% CI: 790-1193] vs 669 μg/L [95% CI: 568-788]) (P =.005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM C min at BTD were comparable between the SGC and the RCC group, 694 μg/L (95% CI: 584-824) vs 583 μg/L (95% CI: 496-671) (P =.1). The observed cabozantinib exposure at BTD of approximately 600 μg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity

Morphosyntactic processing in late second-language learners

The goal of the present study was to investigate the electro- physiological correlates of second-language (L2) morphosyn- tactic processing in highly proficient late learners of an L2 with long exposure to the L2 environment. ERPs were col- lected from 22 English–Spanish late learners while they read sentences in which morphosyntactic features of the L2 present or not present in the first language (number and gender agree- ment, respectively) were manipulated at two different sentence positions—within and across phrases. The results for a control group of age-matched native-speaker Spanish participants in- cluded an ERP pattern of LAN-type early negativity followed by P600 effect in response to both agreement violations and for both sentence positions. The late L2 learner results included a similar pattern, consisting of early negativity followed by P600, in the first sentence position (within-phrase agreement viola- tions) but only P600 effects in the second sentence position (across-phrase agreement violation), as well as significant am- plitude and onset latency differences between the gender and the number violation effects in both sentence positions. These results reveal that highly proficient learners can show electro- physiological correlates during L2 processing that are qualita- tively similar to those of native speakers, but the results also indicate the contribution of factors such as age of acquisition and transfer processes from first language to L

Specifying computer-supported collaboration scripts

Collaboration scripts are activity programs which aim to foster collaborative learning by structuring interaction between learners. Computer-supported collaboration scripts generally suffer from the problem of being restrained to a specific learning platform and learning context. A standardization of collaboration scripts first requires a specification of collaboration scripts that integrates multiple perspectives from computer science, education and psychology. So far, only few and limited attempts at such specifications have been made. This paper aims to consolidate and expand these approaches in light of recent findings and to propose a generic framework for the specification of collaboration scripts. The framework enables a description of collaboration scripts using a small number of components (participants, activities, roles, resources and groups) and mechanisms (task distribution, group formation and sequencing)

Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study

Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who participated in a 3-year randomized, placebo-controlled double-blind trial examining the effects of folic acid on carotid intima-media thickness. All participants had slightly elevated homocysteine levels and were vitamin B12 replete. Cognitive functioning was assessed at baseline and after 3 years by means of a neuropsychological test battery. At baseline, increased serum ferritin was associated with decreased sensorimotor speed, complex speed, and information-processing speed and increased serum iron was associated with decreased sensorimotor speed. Cognitive performance over 3 years was not associated with HFE C282Y genotype or iron parameters. In conclusion, serum iron parameters do not show a straightforward relationship with cognitive functioning, although elevated iron levels may decrease cognitive speed in older individuals susceptible to cognitive impairmen