Molecular Subtypes of Extra-pulmonary Neuroendocrine Carcinomas Identified by the Expression of Neuroendocrine Lineage-Specific Transcription Factors

Extra-pulmonary neuroendocrine carcinomas (EPNEC) represent a group of rare and heterogenous neoplasms with adverse clinical outcome. Their molecular profile is largely unexplored. Our aim was to investigate if the major transcriptional drivers recently described in high-grade pulmonary neuroendocrine carcinomas characterize distinct molecular and clinical subgroups of EPNEC. Gene expression of ASCL1, NEUROD1, DLL3, NOTCH1, INSM1, MYCL1, POU2F3, and YAP1 was investigated in a series of 54 EPNEC (including 10 cases with mixed components analyzed separately) and in a group of 48 pulmonary large cell neuroendocrine carcinomas (P-LCNEC). Unsupervised hierarchical cluster analysis classified the whole series into four major clusters. P-LCNEC were classified into two major clusters, the first ASCL1/DLL3/INSM1-high and the second (including four EPNEC) ASCL1/DLL3-low but INSM1-high. The remaining EPNEC cases were sub-classified into two other clusters. The first showed INSM1-high and alternative ASCL1/DLL3 or NEUROD1 high expression. The second was characterized mainly by MYCL1 and YAP1 overexpression. In the ten cases with mixed histology, ASCL1, DLL3, INSM1, and NEUROD1 genes were significantly upregulated in the neuroendocrine component. Higher gene-expression levels of NOTCH1 and INSM1 were associated with lower pT stage and negative nodal status. Low INSM1 gene expression was associated with shorter overall survival in the entire case series (p = 0.0017) and with a trend towards significance in EPNEC, only (p = 0.06). In conclusion, our results show that EPNEC possess distinct neuroendocrine-lineage-specific transcriptional profiles; moreover, low INSM1 gene expression represents a novel potential unfavorable prognostic marker in high-grade NECs including those in extra-pulmonary location

The influence of footwear on the modular organization of running

For most of our history, we predominantly ran barefoot or in minimalist shoes. The advent of modern footwear, however, might have introduced alterations in the motor control of running. The present study investigated shod and barefoot running under the perspective of the modular organization of muscle activation, in order to help addressing the neurophysiological factors underlying human locomotion. On a treadmill, 20 young and healthy inexperienced barefoot runners ran shod and barefoot at preferred speed (2.8 ± 0.4 m/s). Fundamental synergies, containing the time-dependent activation coefficients (motor primitives) and the time-invariant muscle weightings (motor modules), were extracted from 24 ipsilateral electromyographic activities using non-negative matrix factorization. In shod running, the average foot strike pattern was a rearfoot strike, while in barefoot running it was a mid-forefoot strike. In both conditions, five fundamental synergies were enough to describe as many gait cycle phases: weight acceptance, propulsion, arm swing, early swing and late swing. We found the motor primitives to be generally shifted earlier in time during the stance-related phases and later in the swing-related ones in barefoot running. The motor primitive describing the propulsion phase was significantly of shorter duration (peculiarity confirmed by the analysis of the spinal motor output). The arm swing primitive, instead, was significantly wider in the barefoot condition. The motor modules demonstrated analogous organization with some significant differences in the propulsion, arm swing and late swing synergies. Other than to the trivial absence of shoes, the differences might be deputed to the lower ankle gear ratio (and the consequent increased system instability) and to the higher recoil capabilities of the longitudinal foot arch during barefoot compared to shod running. © 2017 Santuz, Ekizos, Janshen, Baltzopoulos and Arampatzis

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Computational models and motor learning paradigms: Could they provide insights for neuroplasticity after stroke? An overview

Computational approaches for modelling the central nervous system (CNS) aim to develop theories on processes occurring in the brain that allow the transformation of all information needed for the execution of motor acts. Computational models have been proposed in several fields, to interpret not only the CNS functioning, but also its efferent behaviour. Computational model theories can provide insights into neuromuscular and brain function allowing us to reach a deeper understanding of neuroplasticity. Neuroplasticity is the process occurring in the CNS that is able to permanently change both structure and function due to interaction with the external environment. To understand such a complex process several paradigms related to motor learning and computational modeling have been put forward. These paradigms have been explained through several internal model concepts, and supported by neurophysiological and neuroimaging studies. Therefore, it has been possible to make theories about the basis of different learning paradigms according to known computational models. Here we review the computational models and motor learning paradigms used to describe the CNS and neuromuscular functions, as well as their role in the recovery process. These theories have the potential to provide a way to rigorously explain all the potential of CNS learning, providing a basis for future clinical studies

Unfolding dermatologic spectrum of Behçet’s disease in Italy: real-life data from the International AIDA Network Behçet’s disease Registry

Behçet’s disease (BD) is a heterogeneous multifactorial autoinflammatory disease characterized by a plethora of clinical manifestations. Cutaneous lesions are considered hallmarks of the disease. However, their evolution over time and a thorough description are scarcely reported in non-endemic regions. The aim of this study was to detail BD skin manifestations and their evolution over time in Italy, as well as the dermatological prognostic impact of specific cutaneous features in long-standing disease. Data were collected in a double fashion, both retrospectively and prospectively, from the AutoInflammatory Disease Alliance (AIDA) international registry dedicated to BD, between January 2022 and December 2022. A total of 458 Italian patients were included. When assessing skin manifestations course, the constant or sporadic presence or absence of cutaneous involvement between onset and follow-up was considered. Oral ulcers (OU) (88.4%) and genital ulcers (GU) (52.6%), followed by skin involvement (53.7%) represented the most common presenting mucocutaneous manifestations at disease onset. Up to the time of enrolment into the AIDA registry, 411 (93.8%) patients had suffered from OU and 252 (57.9%) from GU; pseudofolliculitis (PF) accounted for the most common skin manifestation (170 patients, 37.1%), followed by erythema nodosum (EN) (102 patients, 22.3%), skin ulcers (9 patients, 2%) and pyoderma gangrenosum (4 patients, 0.9%). A prospective follow-up visit was reported in 261/458 patients; 24/148 (16.2%) subjects with skin involvement as early as BD onset maintained cutaneous lesions for the entire period of observation, while 120 (44.1%) patients suffered from sporadic skin involvement. Conversely, 94/113 (83.2%) with no skin involvement at disease onset did not develop skin lesions thereafter. At follow-up visits, cutaneous involvement was observed in 52 (20%) patients, with a statistically significant association between PF and constant skin involvement (p = 0.031). BD in Italy is characterized by a wide spectrum of clinical presentations and skin manifestations in line with what is described in endemic countries. Patients with skin disease at the onset are likely to present persistent cutaneous involvement thereafter; mucocutaneous lesions observed at the onset, especially PF, could represent a warning sign for future persistent skin involvement requiring closer dermatological care