Direct Photocatalyzed Hydrogen Atom Transfer (HAT) for Aliphatic C-H Bonds Elaboration

[Image: see text] Direct photocatalyzed hydrogen atom transfer (d-HAT) can be considered a method of choice for the elaboration of aliphatic C–H bonds. In this manifold, a photocatalyst (PC(HAT)) exploits the energy of a photon to trigger the homolytic cleavage of such bonds in organic compounds. Selective C–H bond elaboration may be achieved by a judicious choice of the hydrogen abstractor (key parameters are the electronic character and the molecular structure), as well as reaction additives. Different are the classes of PCs(HAT) available, including aromatic ketones, xanthene dyes (Eosin Y), polyoxometalates, uranyl salts, a metal-oxo porphyrin and a tris(amino)cyclopropenium radical dication. The processes (mainly C–C bond formation) are in most cases carried out under mild conditions with the help of visible light. The aim of this review is to offer a comprehensive survey of the synthetic applications of photocatalyzed d-HAT

More Chips to Nitroolefins: Decatungstate Photocatalysed Hydroalkylation Under Batch and Flow Conditions

The hydroalkylation of nitroalkenes and β-nitroacrylates via a photocatalytic strategy has been optimised under both batch and continuous flow conditions. This target has been achieved by exploiting the potentialities of the decatungstate anion as a versatile hydrogen atom transfer (HAT) photocatalyst for the generation of alkyl radicals from aliphatic heterocycles, amides and cycloalkanes

Efficacy of adalimumab as second-line therapy in a pediatric cohort of crohn’s disease patients who failed infliximab therapy: The Italian society of pediatric gastroenterology, hepatology, and nutrition experience

Background: Adalimumab (Ada) treatment is an available option for pediatric Crohn’s disease (CD) and the published experience as rescue therapy is limited. Objectives: We investigated Ada efficacy in a retrospective, pediatric CD cohort who had failed previous infliximab treatment, with a minimum follow-up of 6 months. Methods: In this multicenter study, data on demographics, clinical activity, growth, laboratory values (CRP) and adverse events were collected from CD patients during follow-up. Clinical remission (CR) and response were defined with Pediatric CD Activity Index (PCDAI) score ≤10 and a decrease in PCDAI score of ≥12.5 from baseline, respectively. Results: A total of 44 patients were consecutively recruited (mean age 14.8 years): 34 of 44 (77%) had active disease (mean PCDAI score 24.5) at the time of Ada administration, with a mean disease duration of 3.4 (range 0.3–11.2) years. At 6, 12, and 18 months, out of the total of the enrolled population, CR rates were 55%, 78%, and 52%, respectively, with a significant decrease in PCDAI scores (P<0.01) and mean CRP values (mean CRP 5.7 and 2.4 mL/dL, respectively; P<0.01) at the end of follow-up. Steroid-free remission rates, considered as the total number of patients in CR who were not using steroids at the end of this study, were 93%, 95%, and 96% in 44 patients at 6, 12, and 18 months, respectively. No significant differences in growth parameters were detected. In univariate analysis of variables related to Ada efficacy, we found that only a disease duration >2 years was negatively correlated with final PCDAI score (P<0.01). Two serious adverse events were recorded: 1 meningitis and 1 medulloblastoma. Conclusion: Our data confirm Ada efficacy in pediatric patients as second-line biological therapy after infliximab failure. Longer-term prospective data are warranted to define general effectiveness and safety in pediatric CD patients

A protocol for co-creating research project lay summaries with stakeholders:Guideline development for Canada's AGE-WELL Network

Background Funding bodies increasingly require researchers to write lay summaries to communicate projects’ real-world relevance to the public in an accessible way. However, research proposals and findings are generally not easily readable or understandable by non-specialist readers. Many researchers find writing lay summaries difficult because they typically write for fellow subject specialists or academics rather than the general public or a non-specialist audience. The primary objective of our project is to develop guidelines for researchers in Canada’s AGE-WELL Network of Centres of Excellence, and ultimately various other disciplines, sectors, and institutions, to co-create lay summaries of research projects with stakeholders. To begin, we produced a protocol for co-creating a lay summary based on workshops we organized and facilitated for an AGE-WELL researcher. This paper presents the lay summary co-creation protocol that AGE-WELL researchers will be invited to use. Methods Eligible participants in this project will be 24 AgeTech project researchers who are funded by the AGE-WELL network in its Core Research Program 2020. If they agree to participate in this project, we will invite them to use our protocol to co-produce a lay summary of their respective projects with stakeholders. The protocol comprises six steps: Investigate principles of writing a good lay summary, identify the target readership, identify stakeholders to collaborate with, recruit the identified stakeholders to work on a lay summary, prepare for workshop sessions, and execute the sessions. To help participants through the process, we will provide them with a guide to developing an accessible, readable research lay summary, help them make decisions, and host, and facilitate if needed, their lay summary co-creation workshops. Discussion Public-facing research outputs, including lay summaries, are increasingly important knowledge translation strategies to promote the impact of research on real-world issues. To produce lay summaries that include information that will interest a non-specialist readership and that are written in accessible language, stakeholder engagement is key. Furthermore, both researchers and stakeholders benefit by participating in the co-creation process. We hope the protocol helps researchers collaborate with stakeholders effectively to co-produce lay summaries that meet the needs of both the public and project funders

Photoinduced Halogen-Atom Transfer by N-Heterocyclic Carbene-Ligated Boryl Radicals for C(sp³)-C(sp³) Bond Formation

Herein, we present a comprehensive study on the use of N-heterocyclic carbene (NHC)-ligated boryl radicals to enable C(sp3)–C(sp3) bond formation under visible-light irradiation via Halogen-Atom Transfer (XAT). The methodology relies on the use of an acridinium dye to generate the boron-centered radicals from the corresponding NHC-ligated boranes via single-electron transfer (SET) and deprotonation. These boryl radicals subsequently engage with alkyl halides in an XAT step, delivering the desired nucleophilic alkyl radicals. The present XAT strategy is very mild and accommodates a broad scope of alkyl halides, including medicinally relevant compounds and biologically active molecules. The key role of NHC-ligated boryl radicals in the operative reaction mechanism has been elucidated through a combination of experimental, spectroscopic, and computational studies. This methodology stands as a significant advancement in the chemistry of NHC-ligated boryl radicals, which had long been restricted to radical reductions, enabling C–C bond formation under visible-light photoredox conditions

Gremlin is a novel agonist of the major pro-angiogenic receptor VEGFR2

The bone morphogenic protein antagonist gremlin is expressed during embryonic development and under different pathologic conditions, including cancer. Gremlin is a proangiogenic protein belonging to the cystine-knot superfamily that includes transforming growth factor-β proteins and the angiogenic vascular endothelial growth factors (VEGFs). Here, we demonstrate that gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals, in a bone morphogenic protein-independent manner. Similar to VEGF-A, gremlin activates VEGFR2 in endothelial cells, leading to VEGFR2-dependent angiogenic responses in vitro and in vivo. Gremlin thus represents a novel proangiogenic VEGFR2 agonist distinct from the VEGF family ligands with implications in vascular development, angiogenesis-dependent diseases, and tumor neovascularization

18F-choline PET/CT and PET/MRI in primary and recurrent hyperparathyroidism: a systematic review of the literature

The aims of the present systematic review were to: (1) assess the role of 18F-fluorocholine (FCH) positron emission tomography (PET) with computed tomography (CT) and PET with magnetic resonance imaging (MRI) in patients with biochemically known hyperparathyroidism; (2) compare the diagnostic performance of FCH PET/CT or PET/MRI with conventional morphological and functional imaging. A literature search until December 2019 was performed in the PubMed, Scopus and Web of Science databases, using the terms “choline” AND “PET” AND “hyperparathyroidism”. The search was conducted with and without the addition of filters (e.g., language: English only; type of article: original article; subjects: humans only) and selecting only articles published in the last 5 years. Twenty-three articles and 1112 patients were considered. Different FCH PET/CT acquisition protocols were adopted across the studies, using dynamic, early or delayed scans. FCH PET/CT proved more accurate than ultrasonography (US) or 99mTc-sestamibi single-photon emission tomography (SPET). PET/MRI also seemed to be more accurate than MRI alone in detecting benign parathyroid lesions. FCH PET/CT is more accurate than conventional morphological and functional imaging modalities (US or SPET) for the detection of benign parathyroid lesions. It could, therefore, be a reliable tool in both primary and recurrent hyperparathyroidism

The D647N mutation of FGFR1 induces ligand-independent receptor activation

The activation loop (A-loop) of kinases, a key regulatory region, is recurrently mutated in several kinase proteins in cancer resulting in dysregulated kinase activity and response to kinase inhibitors. FGFR1 receptor tyrosine kinase represents an important oncogene and therapeutic target for solid and hematological tumors. Here we investigate the biochemical and molecular effects of D647N mutation lying in the A-loop of FGFR1.When expressed in normal and tumoral in vitro cell models, FGFR1D647N is phosphorylated also in the absence of ligands, and this is accompanied by the activation of intracellular signaling. The expression of FGFR1D647N significantly increases single and collective migration of cancer cells in vitro and in vivo, when compared to FGFR1WT. FGFR1D647N expression exacerbates the aggressiveness of cancer cells, increasing their invasiveness in vitro and augmenting their pro-angiogenic capacity in vivo.Remarkably, the D647N mutation significantly increases the sensitivity of FGFR1 to the ATP-competitive inhibitor Erdafitinib suggesting the possibility that this mutation could become a specific target for the development of new inhibitors. Although further efforts are warranted for an exhaustive description of the activation mechanisms, for the identification of more specific inhibitors and for confirming the clinical significance of mutated FGFR1D647N, overall our data demonstrate that the D647N substitution of FGFR1 is a novel pro-oncogenic activating mutation of the receptor that, when found in cancer patients, may anticipate good response to erdafitinib treatment