Adenovirus-Mediated Sensitization to the Cytotoxic Drugs Docetaxel and Mitoxantrone Is Dependent on Regulatory Domains in the E1ACR1 Gene-Region

Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdΔΔ and dl922–947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1AΔCR2 mutants (AdE1A1108, dl922–947) and AdE1A1102 or dl1102 enhance cell killing to the same degree as wild type virus. In PC-3 xenografts in vivo the dl1102 mutant significantly prolongs time to tumor progression that is further enhanced in combination with docetaxel. Neither dl1102 nor dl1104 replicates in normal human epithelial cells (NHBE). These findings suggest that additional E1A-deletions might be included when developing more potent replication-selective oncolytic viruses, such as the AdΔCR2-mutants, to further enhance potency through synergistic cell killing in combination with current chemotherapeutics

Decreasing Differences in Expert Advice : Evidence from Chess Players

We study the impact of external advice on the relative performance of chess players. We asked players in chess tournaments to evaluate positions in past games and allowed them to revise their evaluation following advice from a high or a low ability player. While our data confirms the theoretical prediction that high-quality advice has the potential to act as a “great equalizer,” reducing the difference between high and low ability players, this is not what happens in practice. This is in part because our subjects ignore too much of the advice they receive, but also because low ability players pay – either due to overconfidence or intrinsic preference – a higher premium than high ability ones by following their initial idea instead of high-quality advice

Dopaminergic modulation of cortical motor network lateralization

Introduction Unilateral movements are primarily processed in contralateral cortical and subcortical areas and additionally in ipsilateral cerebellum, leading to an asymmetric pattern of neural activation. Decrease of lateralization is characteristic of aging (Naccarato et al., 2006; Wu et al., 2005), and disease, for example, in unilateral brain lesions or stroke (Carr et al., 1993; Rehme et al., 2011) and Parkinson's disease (PD; Wu et al., 2015). The explanation for imbalanced lateralization in drug-naive PD is an adaptive compensation, compatible with the finding that PD-associated deficient input from cortico-subcortical circuits is compensated by reduced cortical inhibition and increased cortical facilitation (Blesa et al., 2017). Here, we investigated the effect of dopamine depletion and substitution on cortical motor lateralization, with the hypothesis that lateralization decreases in advanced PD and that administration of levodopa, at least to a certain extent, reinstates lateralization. Methods We used fMRI to study motor activation in advanced PD patients and in healthy controls (HC) during unilateral upper and lower limb movements. Ten right-handed, left side symptom-dominant PD patients were tested in pseudo-randomized order after intake of their usual dopaminergic medication – 'ON' state – and after withdrawal of medication – 'OFF' state. Eighteen right-handed age-matched HC participated in a single session. We quantified activation lateralization using the average laterality index (AveLI; Matsuo et al., 2012) in three cortical motor regions of interest (ROIs): primary motor cortex (M1), supplementary motor area (SMA) and premotor cortex (PMC), during the four movement conditions. We compared AveLI between group pairs (PD OFF vs. HC, PD ON vs. HC, PD OFF vs. PD ON) within each ROI and movement condition. We estimated the effective connectivity between ROIs using bilinear dynamic causal modeling (DCM; Friston et al., 2003) and developed a measure to quantify the lateralization of the resulting connectivity networks to compare between groups. By constructing a group level parametric empirical Bayes (PEB) model (Friston et al., 2016) over all the subjects and conducting a search over nested models, we compared DCM parameter estimates between groups, thus providing the potential link between changes in motor lateralization and connectivity. Results In line with our predictions, motor activation lateralization as estimated with the AveLI showed a trend towards decrease in the PD OFF group compared to HC, in all three ROIs during left hand movement and in M1 during left foot movement (Fig. 1). Between-group differences were observed solely in conditions corresponding to movement of the more affected body side. Contrary to our hypothesis, dopamine substitution did not reinstate lateralization – in fact, AveLI in the PD ON group closely resembled that of the PD OFF group. Connectivity lateralization of input-specific modulation (DCM.B) networks was significantly lower in all conditions in the PD group as compared to HC. While on the body side more affected by PD, differences were found for both PD OFF and PD ON, input-specific modulation related to the less affected side was more altered in PD ON. PEB analysis revealed qualitatively more between-group differences in input-specific modulation on the more affected PD side and included many interhemispheric connections (Fig. 2). Conclusions Decreased lateralization is not only present in drug-naïve PD patients (Wu et al., 2015) but also in dopa-treated patients. Acute dopamine modulation does not alter lateralization. Decreased lateralization is evident in both fMRI activation amplitudes (as estimated with AveLI) and effective connectivity (as demonstrated through the DCM analysis)

Network anatomy in logopenic variant of primary progressive aphasia

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis

Sea level rise risks and societal adaptation benefits in low-lying coastal areas

Sea level rise (SLR) will increase adaptation needs along low-lying coasts worldwide. Despite centuries of experience with coastal risk, knowledge about the effectiveness and feasibility of societal adaptation on the scale required in a warmer world remains limited. This paper contrasts end-century SLR risks under two warming and two adaptation scenarios, for four coastal settlement archetypes (Urban Atoll Islands, Arctic Communities, Large Tropical Agricultural Deltas, Resource-Rich Cities). We show that adaptation will be substantially beneficial to the continued habitability of most low-lying settlements over this century, at least until the RCP8.5 median SLR level is reached. However, diverse locations worldwide will experience adaptation limits over the course of this century, indicating situations where even ambitious adaptation cannot sufficiently offset a failure to effectively mitigate greenhouse-gas emissions

Molecular Imaging of Pulmonary Tuberculosis in an Ex-Vivo Mouse Model Using Spectral Photon-Counting Computed Tomography and Micro-CT

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm(3) and 2.83 mm(3), respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Pathways to care for people for dementia: an international multi-centre study

Objective: the aim of the present study was to characterize the clinical pathways that people with dementia (PwD) in different countries follow to reach specialized dementia care. Methods: we recruited 548 consecutive clinical attendees with a standardized diagnosis of dementia, in 19 specialized public centers for dementia care in 15 countries. The WHO “Encounter Form”, a standardized schedule that enables data concerning basic socio-demographic, clinical and pathways data to be gathered, was completed for each participant. Results: the median time from the appearance of the first symptoms to the first contact with specialist dementia care was 56 weeks. The primary point of access to care was the general practitioners (55.8%). Psychiatrists, geriatricians and neurologists represented the most important second point of access. In about a third of cases, PwD were prescribed psychotropic drugs (mostly antidepressants and tranquillizers). Psychosocial interventions (such as psychological counselling, psychotherapy and practical advice) were delivered in less than 3% of situations. The analyses of the ‘pathways diagram’ revealed that the path of PwD to receiving care is complex, diverse across countries, and that there are important barriers to clinical care. Conclusions: the study of pathways followed by PwD to reach specialized care has implications for the subsequent course and the outcome of dementia. Insights into local differences in the clinical presentations and the implementation of currently available dementia care are essential to develop more tailored strategies for these patients, locally, nationally and internationally