The 'Is' and the 'Ought' of the Animal Organism: Hegel's Account of Biological Normativity.

This paper investigates Hegel's account of the animal organism as it is presented in the Philosophy of Nature, with a special focus on its normative implications. I argue that the notion of "organisation" is fundamental to Hegel's theory of animal normativity. The paper starts by showing how a Hegelian approach takes up the scientific image of organism and assigns a basic explanatory role to the notion of "organisation" in its understanding living beings. Moving from this premise, the paper turns to the group of accounts in contemporary theoretical biology known as "organisational accounts" (OA), which offer a widely debated strategy for naturalizing teleology and normativity in organisms. As recent scholarship recognizes, these accounts explicitly rely on insights from Kant and Post-Kantianism. I make the historical and conceptual argument that Hegel's view of the organism shares several basic commitments with OAs, especially regarding the notion of "organisational closure". I assess the account of normativity that such accounts advance and its implications for how we approach Hegel. Finally, I argue that the notion of "organisation" is more fundamental to Hegel's theory of animal normativity than the Aristotelian notion of "Gattung" or "species", which by contrast appears derivative - at least in the Philosophy of Nature and the Lectures - and does not play the central role in his account maintained by some scholars.

Minor head injury in the elderly at very low risk: a retrospective study of 6 years in an Emergency Department (ED).

INTRODUCTION: Mild head injury (MHI) is a common clinical problem in emergency departments (EDs). Long-standing debate is still going on about MHI in the elderly: current guidelines recommend to perform a CT scan on this group. MATERIALS AND METHODS: We performed a retrospective study by reviewing patients older than 65 years, evaluated in our ED for which a CT scan of the head was performed for MHI, between 2004 and 2010. According to Italian Guidelines, we considered only patients with low-risk MHI. RESULTS: We considered 2149 eligible patients: we recorded 47 pathological acute findings on CT scan (2.18%), but only 3 patients (0.14%) underwent neurosurgery. We analysed our patients according to different age groups: in patients in the 65- to 79-year-old group, we documented pathological findings on CT in 0.66% of cases, with a significant increase in the group older than 80 years, with a rate of 3.33% of acute findings on CT (OR 5.22, P < .001); 617 patients were on antiplatelet therapy: 22 of these patients (3.72%) had a pathological finding on CT scan (OR 2.23, P < .005). DISCUSSION: Our retrospective analyses demonstrated that the incidence of intracranial complications after MHI is not different from that of the general population, and based on this finding, a CT does not seem to be necessary, at least up to 80 years old. Our data suggest that antiplatelet therapy could be a significant risk factor. Our results suggest that elderly patients between 65 and 79 years old without risk factors could be managed as younger patients.

Social media analysis of Twitter tweets related to ASD in 2019-2020, with particular attention to COVID-19: topic modelling and sentiment analysis.

Background: Social media contains an overabundance of health information relating to people living with different type of diseases. Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts and reported trends have revealed a considerable increase in prevalence and incidence. Research had shown that the ASD community provides significant support to its members through Twitter, providing information about their values and perceptions through their use of words and emotional stance. Our purpose was to analyze all the messages posted on Twitter platform regarding ASD and analyze the topics covered within the tweets, to understand the attitude of the various people interested in the topic. In particular, we focused on the discussion of ASD and COVID-19. Methods: The data collection process was based on the search for tweets through hashtags and keywords. After bots screening, the NMF (Non-Negative Matrix Factorization) method was used for topic modeling because it produces more coherent topics compared to other solutions. Sentiment scores were calculated using AFiNN for each tweet to represent its negative to positive emotion. Results: From the 2.458.929 tweets produced in 2020, 691.582 users were extracted (188 bots which generated 59.104 tweets), while from the 2.393.236 total tweets from 2019, the number of identified users was 684.032 (230 bots which generated 50.057 tweets). The total number of COVID-ASD tweets is only a small part of the total dataset. Often, the negative sentiment identified in the sentiment analysis referred to anger towards COVID-19 and its management, while the positive sentiment reflected the necessity to provide constant support to people with ASD. Conclusions: Social media contributes to a great discussion on topics related to autism, especially with regards to focus on family, community, and therapies. The COVID-19 pandemic increased the use of social media, especially during the lockdown period. It is important to help develop and distribute appropriate, evidence-based ASD-related information.

Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.

Optimization of diarylthiazole B-raf inhibitors: identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect.

Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R(1) and R(2) groups of the scaffold. This effort ultimately led to N-(4-{2-(1-cyclopropylpiperidin-4-yl)-4-[3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl]thiazol-5-yl}-pyridin-2-yl)acetamide (20), which maintains favorable in vitro and in vivo properties, but lacks hERG liability. Besides exhibiting potent antiproliferative activity against only cell lines bearing B-Raf V600E or V600D mutations, compound 20 also intriguingly shows a weaker "paradoxical" activation of MEK in non-mutant B-Raf cells than other known B-Raf inhibitors. It also demonstrates very good efficacy in vivo against the A375 xenograft melanoma model (tumor volume inhibition >90% at 10 mg kg(-1) ); it is therefore a suitable candidate for preclinical development.

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

6-Substituted pyrrolo[3,4-c]pyrazoles: an improved class of CDK2 inhibitors.

We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma.