Cerebellar Transcranial Direct Current Stimulation (tDCS), Leaves Virtual Navigation Performance Unchanged

Spatial cognition is an umbrella term used to refer to the complex set of abilities necessary to encode, categorize, and use spatial information from the surrounding environment to move effectively and orient within it. Experimental studies indicate that the cerebellum belongs to the neural network involved in spatial cognition, although its exact role in this function remains unclear. Our aim was to investigate in a pilot study using a virtual reality navigation task in healthy subjects whether cerebellar transcranial direct current stimulation (tDCS), a non-invasive technique, influences spatial navigation. Forty healthy volunteers (24 women; age range = 20–42 years; years of education range 13–18) were recruited. The virtual reality spatial navigation task comprised two phases: encoding, in which participants actively navigated the environment and learned the spatial locations for one object, and retrieval, in which they retrieved the position of the object they had discovered and memorized in the previous encoding phase, starting from another starting point. Participants received tDCS stimulation (anodal or sham according to the experimental condition they were assigned to) for 20 min before beginning the retrieval phase. Our results showed that cerebellar tDCS left the accuracy of the three indexes used to measure effective navigational abilities unchanged. Hence, cerebellar tDCS had no influence on the retrieval phase for the spatial maps stored. Further studies, enrolling a larger sample and testing a different stimulation protocol, may give a greater insight into the role of the cerebellum in spatial navigation

Comments on Anomaly Cancellations by Pole Subtractions and Ghost Instabilities with Gravity

We investigate some aspects of anomaly cancellation realized by the subtraction of an anomaly pole, stressing on some of its properties in superspace. In a local formulation these subtractions can be described in terms of a physical scalar, an axion and related ghosts. They appear to be necessary for the unitarization of the theory in the ultraviolet, but they may generate an infrared instability of the corresponding effective action, signalled by ghost condensation. In particular the subtraction of the superanomaly multiplet by a pole in superspace is of dubious significance, due to the different nature of the chiral and conformal anomalies. In turn, this may set more stringent constraints on the coupling of supersymmetric theories to gravity.Comment: 18 pages. Revised version. To appear in "Classical and Quantum Gravity

KIT/PDGFRA Variant Allele Frequency as Prognostic Factor in Gastrointestinal Stromal Tumors (GISTs): Results From a Multi-Institutional Cohort Study

Background: The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA-mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. Patients and methods: This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA-VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. Results: Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF > 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P = .003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT-mutated GIST, the presence of nVAF >50% was statistically associated with higher disease recurrence. Conclusion: In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib

APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research

Introduction: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). Methods and objectives: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. Conclusion: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project

Underweight subjects with anorexia nervosa have an enhanced salivary cortisol response not seen in weight restored subjects with anorexia nervosa

The cortisol response to awakening (CAR) has been reported to be enhanced in symptomatic patients with anorexia nervosa (AN). However, it has been not established whether the dysregulation of CAR was a primary phenomenon or a change secondary to malnutrition. Therefore, we aimed to explore the salivary CAR in both underweight and weigh-restored women with AN. Fifty-nine women volunteered for the study. They were 18 underweight AN women, 15 weight-restored AN women and 26 normal-weight healthy women. Saliva samples were collected in the morning, immediately on awakening and after 15, 30 and 60 min to measure saliva levels of cortisol. Participants' anxiety levels in the morning of sampling were measured by the State-Trait Anxiety Inventory. As compared to control women, underweight AN patients showed an enhanced CAR whereas weight-restored patients had a normal CAR. These results could be not explained by group differences in body mass index or levels of anxiety. These findings show, for the first time, that the enhanced CAR occurring in the acute phase of AN is not seen in weight-recovered patients, suggesting that the dysregulated activity of the hypothalamus-pituitary-adrenal axis of symptomatic AN patients is a state-dependent phenomenon

An immersive virtual reality system for ecological assessment of peripersonal and extrapersonal unilateral spatial neglect

Background Unilateral spatial neglect (USN) is a debilitating neuropsychological syndrome that often follows brain injury, in particular a stroke affecting the right hemisphere. In current clinical practice, the assessment of neglect is based on old-fashioned paper-and-pencil and behavioral tasks, and sometimes relies on the examiner’s subjective judgment. Therefore, there is a need for more exhaustive, objective and ecological assessments of USN. Methods In this paper, we present two tasks in immersive virtual reality to assess peripersonal and extrapersonal USN. The tasks are designed with several levels of difficulty to increase sensitivity of the assessment. We then validate the feasibility of both assessments in a group of healthy adult participants. Results We report data from a study with a group of neurologically unimpaired participants (N = 39). The results yield positive feedback on comfort, usability and design of the tasks. We propose new objective scores based on participant’s performance captured by head gaze and hand position information, including, for instance, time of exploration, moving time towards left/right and time-to-reach, which could be used for the evaluation of the attentional spatial bias with neurological patients. Together with the number of omissions, the new proposed parameters can result in lateralized index ratios as a measure of asymmetry in space exploration. Conclusions We presented two innovative assessments for USN based on immersive virtual reality, evaluating the far and the near space, using ecological tasks in multimodal, realistic environments. The proposed protocols and objective scores can help distinguish neurological patients with and without USN.</p

Real-time fMRI and EEG neurofeedback: A perspective on applications for the rehabilitation of spatial neglect

Spatial neglect is a neuropsychological syndrome characterized by a failure to orient, perceive, and act toward the contralesional side of the space after brain injury. Neglect is one of the most frequent and disabling neuropsychological syndromes following right-hemisphere damage, often persisting in the chronic phase and responsible for a poor functional outcome at hospital discharge. Different rehabilitation approaches have been proposed over the past 60 years, with a variable degree of effectiveness. In this point-of-view article, we describe a new rehabilitation technique for spatial neglect that directly targets brain activity and pathological physiological processes: namely, neurofeedback (NFB) with real-time brain imaging methodologies. In recent proof-of-principle studies, we have demonstrated the potential of this rehabilitation technique. Using real-time functional MRI (rt-fMRI) NFB in chronic neglect, we demonstrated that patients are able to upregulate their right visual cortex activity, a response that is otherwise reduced due to losses in top-down attentional signals. Using real-time electroencephalography NFB in patients with acute or chronic condition, we showed successful regulation with partial restoration of brain rhythm dynamics over the damaged hemisphere. Both approaches were followed by mild, but encouraging, improvement in neglect symptoms. NFB techniques, by training endogenous top-down modulation of attentional control on sensory processing, might induce sustained changes at both the neural and behavioral levels, while being non-invasive and safe. However, more properly powered clinical studies with control groups and longer follow-up are needed to fully establish the effectiveness of the techniques, identify the most suitable candidates, and determine how the techniques can be optimized or combined in the context of rehabilitation

An immersive virtual reality tool for assessing left and right unilateral spatial neglect

The reported rate of the occurrence of unilateral spatial neglect (USN) is highly variable likely due to the lack of validity and low sensitivity of classical tools used to assess it. Virtual reality (VR) assessments try to overcome these limitations by proposing immersive and complex environments. Nevertheless, existing VR‐based tasks are mostly focused only on near space and lack analysis of psychometric properties and/or clinical validation. The present study evaluates the clinical validity and sensitivity of a new immersive VR‐based task to assess USN in the extra‐personal space and examines the neuronal correlates of deficits of far space exploration. The task was administrated to two groups of patients with right ( N = 28) or left ( N = 11) hemispheric brain lesions, also undergoing classical paper‐and‐pencil assessment, as well as a group of healthy participants. Our VR‐based task detected 44% of neglect cases compared to 31% by paper‐and‐pencil tests in the total sample. Importantly, 30% of the patients (with right or left brain lesions) with no clear sign of USN on the paper‐and‐pencil tests performed outside the normal range in the VR‐based task. Voxel lesion‐symptom mapping revealed that deficits detected in VR were associated with lesions in insular and temporal cortex, part of the neural network involved in spatial processing. These results show that our immersive VR‐based task is efficient and sensitive in detecting mild to strong manifestations of USN affecting the extra‐personal space, which may be undetected using standard tools

Identification of <em>SLC15A4/PHT1</em> Gene Products Upregulation Marking the Intestinal Epithelial Monolayer of Ulcerative Colitis Patients

SLC15A4/PHT1 is an endolysosome-resident carrier of oligopeptides and histidine recently come into view as a key path marker of immune/autoimmune/inflammatory pathways in immune cells. Yet, its emerging role in inflammatory processes directly targeting the gastrointestinal epithelial layer, as in the multifactorial pathophysiology of inflammatory bowel disease (IBD), is poorly investigated. Here, the first identification of SLC15A4/PHT1 gene products in human colonic epithelium of ulcerative colitis (UC) patients is reported, showing protein primarily localized in intracellular vesicle-like compartments. Qualitative and quantitative immunohistochemical analyses of colon biopsies revealed overexpression of SLC15A4/PHT1 protein product in the epithelial layer of UC patients. Results were successfully mirrored in vitro, in spontaneously differentiated enterocyte-like monolayers of Caco-2 cells specifically exposed to DSS (dextran sodium sulphate) to mimic IBD inflammatory onsets. SLC15A4/PHT1 expression and cellular localization were characterized confirming its (dys)regulation traits in inflamed vs. healthy epithelia, strongly hinting the hypothesis of SLC15A4/PHT1 increased function associated with epithelial inflammation in IBD patients

A newly identified flower-specific splice variant of AUXIN RESPONSE FACTOR8 regulates stamen elongation and endothecium lignification in arabidopsis

In addition to the full-length transcript ARF8.1, a splice variant (ARF8.2) of the auxin response factor gene ARF8 has been reported. Here, we identified an intron-retaining variant of ARF8.2, ARF8.4, whose translated product is imported into the nucleus and has tissue-specific localization in Arabidopsis thaliana. By inducibly expressing each variant in arf8-7 flowers, we show that ARF8.4 fully complements the short-stamen phenotype of the mutant and restores the expression of AUX/IAA19, encoding a key regulator of stamen elongation. By contrast, the expression of ARF8.2 and ARF8.1 had minor or no effects on arf8-7 stamen elongation and AUX/IAA19 expression. Coexpression of ARF8.2 and ARF8.4 in both the wild type and arf8-7 caused premature anther dehiscence: We show that ARF8.2 is responsible for increased expression of the jasmonic acid biosynthetic gene DAD1 and that ARF8.4 is responsible for premature endothecium lignification due to precocious expression of transcription factor gene MYB26. Finally, we show that ARF8.4 binds to specific auxin-related sequences in both the AUX/IAA19 and MYB26 promoters and activates their transcription more efficiently than ARF8.2. Our data suggest that ARF8.4 is a tissue-specific functional splice variant that controls filament elongation and endothecium lignification by directly regulating key genes involved in these processes