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Dual blockade of BRAF and MEK kinases is a standard of care for metastatic V600E/K BRAF mutant melanoma. This study reports the first systematic description of colitis due to BRAF and MEK inhibitors.We studied consecutive patients with melanoma, treated with BRAF and MEK inhibitors, who had colitis requiring hospitalisation. Electronic files were studied; endoscopic biopsies and colectomy specimens were read centrally.Between January 2021 and March 2022, nine women and one man, aged 50-90 years, were studied. Nine patients received encorafenib and binimetinib; one patient received dabrafenib and trametinib. The main symptoms were diarrhoea, haematochezia, abdominal pain and intestinal obstruction. Blood tests showed anaemia, increased CRP and low serum albumin levels in most patients. All patients had ulcerations of the right colon with (2/10) or without (8/10) stenosis of the ileocecal valve, and 4/10 patients also had ulcerations distal to the right colon. Histopathological findings were suggestive of ischaemia and mild inflammation. Nine of the 10 patients discontinued BRAF/MEK inhibitors. Drugs were reintroduced in four patients, three of whom had a severe relapse of diarrhoea. Two patients required surgery and underwent intestinal resection. One patient died of enterocolitis.BRAF/MEK inhibitors can induce severe colitis characterised by ulcerations of the right colon.

International audience; Gold-(I) catalysis was used for the intramolecular cyclization of tertiary alcohols with terminal alkynes to form diverse aza-spirocycles. The reaction was carried out with low catalyst loading under microwave irradiation to give both sulfonylated and acylated spirocyclic nitrogen derivatives. Gram scale spirocyclization was carried out and demonstrates the robustness of the reaction. An intramolecular Mizoroki-Heck reaction was performed to give several tetracyclic spirocycles. Double bond reduction and selective protecting group manipulation gave spiropiperazine and spiromorpholine derivatives. These compounds were incorporated into biologically relevant scaffolds to give the first selective spirocyclic inhibitors of LIMK.

Keratoacanthoma (KA) and well-differentiated cutaneous squamous cell carcinoma (cSCC) are hardly distinguishable clinically and histologically. They both can be seen in patients with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome, corresponding to DNA microsatellite instability. In our case, a young man had the excision of two rapidly growing skin tumours for which distinction between KA and cSCC was initially clinically and pathologically challenging. The diagnosis of well-differentiated cSCCs was made and the patient was treated with surgery. Ten years after the first cSCC, he was diagnosed with Muir-Torre syndrome, a variant of Lynch syndrome, with an heterozygote mutation of the MSH2 gene. This later diagnosis allowed to screen his family members for the same mutation and to adopt an appropriate follow-up regarding the risk of digestive tumours for him and his family. Furthermore, it is important to know that, in case of non-resectable cSCC occurring in this patient, immunotherapy using anti-PD1 antibody would probably be effective due to the known increased immunogenicity of MMR deficient tumours.

We synthesized 5-[18 F]-fluoro-1H-indol-2-yl)(4-methyl-1-piperazinyl)methanone ([18 F]5) via a Suzuki approach starting from a protected pinacol borane precursor followed by acidic hydrolysis of the t-Boc protecting group. The non-optimized radiochemical yield was 5.7 ± 1.35%, radiochemical purity was over 99%, and molar activity was 100.7 ± 34.5 GBq/μmol (n = 3). [18 F]5 was stable in rat plasma for at least 4 h and was evaluated by μPET imaging and biodistribution using a unilateral quinolinic acid rat model of neuroinflammation. The time-activity curve showed that [18 F]5 entered the brain immediately after intravenous injection and then left it progressively with a very low level reached from 30 min after injection. The biodistribution study showed no difference in the accumulation of [18 F]5 between the lesioned and intact side of the brain and between control rats and animals pretreated with a saturating dose of JNJ-7777120 as a specific H4R antagonist. Hence, despite its in vitro nanomolar affinity for H4R, and its ability to cross the blood-brain barrier in rats, [18 F]5 does not appear suitable to image in vivo the receptor by PET.

The convenient preparation of 1,4-dideoxy-1,4-imino-L-arabinitol derivatives carrying a propargyl group by way of the addition of TMS-propargyl Grignard reagent to a N-sulfinylglycosylamine is reported. This compound was coupled via a triazole-tether to various aromatic and heteroaromatic groups, thus providing structures that can be considered as simplified mimics of UDP-Galf, the substrate of GlfT2, a galactofuranosyltransferase present in mycobacteria. These new compounds were evaluated as inhibitors of this enzyme and found to have significant activity (IC50 values in the high M to low mM range) in spite of the absence of the diphospho linkage present in the parent sugar nucleotide.

Temporal theta slow-wave activity (TTA-SW) in premature infants is a specific signature of the early development of temporal networks, as it is observed at the turning point between non-sensory driven spontaneous local processing and cortical network functioning. The role in development and the precise location of TTA-SW remain unknown. Previous studies have demonstrated that preterms from 28 weeks of gestational age (wGA) are able to discriminate phonemes and voice, supporting the idea of a prior genetic structural or activity-dependent fingerprint that would prepare the auditory network to compute auditory information at the onset of thalamocortical connectivity. They recorded TTA-SW in 26-32 wGA preterms. The rate of TTA-SW in response to click stimuli was evaluated using low-density EEG in 30 preterms. The sources of TTA-SW were localized by high-density EEG using different tissues conductivities, head models and mathematical models. They observed that TTA-SW is not sensory driven. Regardless of age, conductivities, head models and mathematical models, sources of TTA-SW were located adjacent to auditory and temporal junction areas. These sources become situated closer to the surface during development. TTA-SW corresponds to spontaneous transient endogenous activities independent of sensory information at this period which might participate in the implementation of auditory, language, memory, attention and or social cognition convergent and does not simply represent a general interaction between the subplate and the cortical plate. Hum Brain Mapp 38:2345-2358, 2017. © 2017 Wiley Periodicals, Inc.

Highly substituted pyrido[4,3-b]indole derivatives were synthesized through a straightforward one-pot silver-catalyzed process involving 2-alkynylindole-3-carbaldehyde oximes. The tandem cyclization/nucleophilic addition sequence was optimized and applied to a wide range of nucleophiles, which reacted regioselectively at the pyrido[4,3-b]indole C4 position. The scope and limitations of the methodology were evaluated and the final compounds were obtained in fair to very good yields. This versatile method proved to be compatible with various chemical functionalities or (hetero)cycles.

The synthesis and regioselective functionalization of rare 2,4-disubstituted-pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. C-4 aminations were performed by chlorine nucleophilic substitution SNAr reactions, and their efficiencies were compared with those for direct one-pot amide C–O activation with bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) as a reagent. The latter method was used to perform palladium-catalyzed C-4 (het)arylation. Finally, two C-4 amino and aryl derivatives were prepared on a large scale and engaged in desulfurative Liebeskind–Srogl-type reactions under microwave irradiation to afford the envisioned compound library. Each step was optimized, and the results are discussed.

A new and efficient palladium-catalyzed amination of imidazo[2,1-b][1,3,4]thiadiazole at the C-5 position under microwave irradiation is reported. The reactivity toward bromine release at the C-5 position was investigated, and palladium-catalyzed cross-coupling conditions were optimized. A wide range of amines was employed to examine the scope and limitations of the method. To complete this methodological study, the influence of the nature and the positions of additional imidazo[2,1-b][1,3,4]thiadiazole substitutions was investigated.

The use of flow chemistry to obtain (7-aza)indole derivatives was investigated in three steps (C-3 iodination followed by N-Boc protection). Excellent yields were achieved after very short reaction times. The challenge of using a continuous flow process was incremented by performing a novel copper-free Sonogashira cross coupling in C-3 (7-Aza)indolic position using a recyclable supported palladium catalyst. A library of polyfunctionalized (7-aza)indoles was obtained in high yield with a very efficient process (< 3 min.). Scale-up was studied and the preparation of significant amounts of final alkynyl and Boc protected (aza)indoles can be immediately extended to a pilot scale in optimum security conditions.

The development of electronics adept at interfacing with the nervous system is an ever-growing effort, leading to discoveries in fundamental neuroscience applied in clinical setting. Highly capacitive and electrochemically stable electronic materials are paramount for these advances. A systematic study is presented where copolymers based on 3,4-ethylenedioxythiophene (EDOT) and its hydroxyl-terminated counterpart (EDOTOH) are electropolymerized in an aqueous solution in the presence of various counter anions and additives. Amongst the conducting materials developed, the copolymer p(EDOT-ran-EDOTOH) doped with perchlorate in the presence of ethylene glycol shows high specific capacitance (105 F g-1 ), and capacitance retention (85%) over 1000 galvanostatic charge-discharge cycles. A microelectrode array-based on this material is fabricated and primary cortical neurons are cultured therein for several days. The microelectrodes electrically stimulate targeted neuronal networks and record their activity with high signal-to-noise ratio. The stability of charge injection capacity of the material is validated via long-term pulsing experiments. While providing insights on the effect of additives and dopants on the electrochemical performance and operational stability of electropolymerized conducting polymers, this study highlights the importance of high capacitance accompanied with stability to achieve high performance electrodes for biological interfacing.

An original and efficient palladium-catalyzed amination of imidazo[2,1-b][1,3,4]thiadiazole is reported. The SNAr and Buchwald–Hartwig cross-coupling reactions were investigated to access C-2 aminated imidazo[1,2-b][1,3,4]thiadiazole derivatives. The reaction conditions were optimized under microwave irradiation, and a wide range of amines were used to determine the scope and limitations of the method. To complete this study, the palladium-catalyzed and SNAr amination reactions were compared to determine the best strategy. The X-ray crystallographic data of imidazo[2,1-b][1,3,4]thiadiazole derivative 20 was used to formally establish the structures of the products.

The first efficient synthesis of various 1,4-disubstituted pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyridazines is reported. The reactivity toward chlorine release at the C-1 and C-4 positions was investigated. SNAr and palladium-catalysed cross-coupling reactions were carried out, and conditions were optimised for each procedure. 1,4-Bis(het)aryl derivatives were obtained under a Suzuki cross-coupling procedure whereas SNAr substitution was achieved mainly at C-1 in preference to C-4. The monosubstituted C-4 morpholino derivative was used as a starting material to provide dissymmetrical 1,4-diaminated or 1-(het)aryl-4-morpholino products.

A photochemical catalytic reduction of CO2 was performed in an organic solvent with iron(0) porphyrins as homogeneous molecular catalysts under visible light irradiation. With modified tetraphenylporphyrins consisting of internal phenolic groups, the photochemical process led to the production of CO, with H2 as a minor product. High catalytic selectivity for CO formation and turnover numbers up to 30 were obtained. Degradation of the catalyst occurred at longer irradiation times, along with decreased selectivity. Furthermore, addition of a weak acid, which increased the reduction efficiency under electrochemical conditions, led to rapid deactivation of the catalyst. With the unmodified tetraphenylporphyrin as catalyst, we observed lower performance and higher proportion of H2, which highlighted differences in the reduction pathways followed. A combination of a spectroscopic study and product analysis performed under various conditions led to detailed reduction mechanisms and helped pave the way for designing durable photocatalytic systems.

An efficient and convenient method was developed for the formation of polysubstituted thiazolo[3,2-b][1,2,4]triazoles through C-5 (het)arylation. The direct C–H activation protocol giving access to di- and trisubstituted derivatives in excellent yields was optimized. The method is suitable for use with a wide range of (hetero)aryl bromides, and allows access to a collection of C-5,6 bis(het)aryl derivatives with full regioselectivity. The results are supported by a full description of all final compounds, and X-ray crystallographic data confirmed that the spectroscopic analyses were interpreted correctly.

An efficient and convenient method was developed for the formation of S-substituted thiotriazoles through an unprecedented organometallic addition and subsequent ring-opening sequence of 3-substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The method is applicable to a wide range of substrates containing different functional groups and furnishes excellent yields of the corresponding N-unsubstituted 3- or 5-alkyl, aryl, alkynyl and alkenyl sulfanyl-1,2,4-triazole products.

The synthesis and regioselective functionalization of rare 2,4-disubstituted-pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. C-4 aminations were performed by chlorine nucleophilic substitution SNAr reactions, and their efficiencies were compared with those for direct one-pot amide C–O activation with bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) as a reagent. The latter method was used to perform palladium-catalyzed C-4 (het)arylation. Finally, two C-4 amino and aryl derivatives were prepared on a large scale and engaged in desulfurative Liebeskind–Srogl-type reactions under microwave irradiation to afford the envisioned compound library. Each step was optimized, and the results are discussed.

A new and efficient palladium-catalyzed amination of imidazo[2,1-b][1,3,4]thiadiazole at the C-5 position under microwave irradiation is reported. The reactivity toward bromine release at the C-5 position was investigated, and palladium-catalyzed cross-coupling conditions were optimized. A wide range of amines was employed to examine the scope and limitations of the method. To complete this methodological study, the influence of the nature and the positions of additional imidazo[2,1-b][1,3,4]thiadiazole substitutions was investigated.

This work reports the original synthesis of trisarylimidazo[2,1- b ][1,3,4]thiadiazole derivatives using a C–H arylation process. The scope of the reaction demonstrated the critical importance of the electronic effects of each substituent on the efficiency of the reaction. In addition, a double efficient ‘one-pot’ functionalization at the C-2 and then at the C-5 positions of 2-bromo-6-arylimidazo[2,1- b ][1,3,4]thiadiazole derivatives was achieved using a sequential Suzuki–Miyaura–C–H arylation cascade procedure.

The use of flow chemistry to obtain (7-aza)indole derivatives was investigated in three steps (C-3 iodination followed by N-Boc protection). Excellent yields were achieved after very short reaction times. The challenge of using a continuous flow process was incremented by performing a novel copper-free Sonogashira cross coupling in C-3 (7-Aza)indolic position using a recyclable supported palladium catalyst. A library of polyfunctionalized (7-aza)indoles was obtained in high yield with a very efficient process (< 3 min.). Scale-up was studied and the preparation of significant amounts of final alkynyl and Boc protected (aza)indoles can be immediately extended to a pilot scale in optimum security conditions.

An original and efficient palladium-catalyzed amination of imidazo[2,1-b][1,3,4]thiadiazole is reported. The SNAr and Buchwald–Hartwig cross-coupling reactions were investigated to access C-2 aminated imidazo[1,2-b][1,3,4]thiadiazole derivatives. The reaction conditions were optimized under microwave irradiation, and a wide range of amines were used to determine the scope and limitations of the method. To complete this study, the palladium-catalyzed and SNAr amination reactions were compared to determine the best strategy. The X-ray crystallographic data of imidazo[2,1-b][1,3,4]thiadiazole derivative 20 was used to formally establish the structures of the products.

An efficient and original synthesis of various 2,4,7-trisubstituted pyrido[3,2-d]pyrimidines is reported. The first access to and the chemical interest of 2,4,7-trichloropyrido[3,2-d]pyrimidine is described. Double arylations and SNAr reactions occurred selectively at the C4 and C2 positions of 2,4,7-trichloropyrido[3,2-d]pyrimidine. The reactions at the C7 position were achieved under microwave irradiation in a few minutes. A one-step synthesis of a 2,4,7-tris(aminated) derivative was achieved as a highly efficient alternative.

Highly substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized through successive cyclization and Suzuki–Miyaura cross-coupling reactions. The palladium-catalyzed coupling reaction was optimized and a wide range of boronic acids was used to evaluate the scope and limitations of the methodology. The final compounds were obtained in fair to very good yields and high compatibility with various chemical functions or (hetero)cycles was observed.

The article explores the process of "sportification"--i.e., processing physical activity in a sport regulated by a set of rules and standards, legitimized by supervisory institutions--from two originals practices, parkour and urban golf. To study these practices, we crossed the contributions of urban sociology and of the contemporary sociology of sport while respecting the methodological principles of qualitative sociology. A first point concerns the process of"sport" itself, its definition, its various stages, and the role played by communication of stakeholders on public space. The cultural mediation shows us how to institutionalize the movement that represents the "sports" resulted in the same time reconfiguration of physical practices themselves. Recent events illustrate the ongoing reconfiguration, we will detail them. Finally, we show the effects produced by the process on the definition of urban culture and sports: setting sight of activities, enhanced cooperation with the media-cultural, polarization between different types of practical in the case of parkour, around a confrontation between two of the founders.

Summary Farnesol is known for inducing apoptosis in some fungi and mammalian cells. To evaluate its potential role as an antifungal agent, we studied its impact on the human pathogen Aspergillus fumigatus. We found that growth of A. fumigatus wild type is inhibited, but two cell wall mutants, Δmnt1 andΔglfA, are much more susceptible to farnesol. This susceptibility is partially rescued by osmotic stabilization, suggesting that farnesol is a cell wall perturbing agent. However, farnesol does not activate but inhibit the cell wall integrity (CWI) pathway. Remarkably, mutants lacking AfMkk2 or AfMpkA, two kinases essential for CWI signalling, are also highly susceptible to farnesol, suggesting that its mode of action goes beyond inhibition of CWI signalling. Farnesyl derivatives are known for interfering with the function of prenylated proteins. We analysed the subcellular localization of two prenylated Rho family GTPases, AfRho1 and AfRho3, which are implicated in controlling CWI and the cytoskeleton. We found that under normal growth conditions AfRho1 and AfRho3 predominantly localize to the hyphal tip. After farnesol treatment this localization is rapidly lost, which is accompanied by swelling of the hyphal tips. Parallel displacement of tropomyosin from the tips suggests a concomitant disorganization of the apical actin cytoskeleton.