Search

International audience; An improvement in the catalytic enantioselective allylboration of isatins with 2-allyl-1,3,2-dioxaborolane in the presence of chiral BINOL derivatives is reported, offering an efficient one-step access to enantioenriched N-unprotected 3-allyl-3-hydroxy-2-oxindoles. This catalytic process is also effective for the crotylboration reaction with enantiomeric ratios (er) up to 97:3, as well as for the asymmetric synthesis of homopropargylic alcohols via an allenyl addition to indoline-2,3-diones. Origins of the high enantioselectivity in chiral BINOL-catalyzed allylboration of isatins were examined by DFT calculations. A hypothetical scenario suggested a crucial internal hydrogen bonding between the amide group (C═O···H-O) and the ethylene hydroxyl of the transient chiral mixed boronate ester, generating a rigid and stabilized system that favors the addition of the allylboron species to the Re face of the ketone function. The key role of the alcohol additive (t-BuOH or t-AmOH) in the enantioselective allylboration reaction of isatins has also been shown on the basis of a kinetics study and computational calculations by favoring the transesterification of the 2-allyl-1,3,2-dioxaborolane with BINOL via proton transfer processes.

Liquid biopsy and circulating tumor cell (CTC) screening has gained interest over the last two decades for detecting almost all solid malignancies. To date, the major limitation in terms of the applicability of CTC screening in daily clinical practice is the lack of reproducibility due to the high number of platforms available that use various technologies (e.g., label-dependent versus label-free detection). Only a few studies have compared different CTC platforms. The aim of this study was to compare the efficiency of four commercially available CTC platforms (Vortex (VTX-1), ClearCell FX, ISET, and Cellsearch) for the detection and identification of uveal melanoma cells (OMM 2.3 cell line). Tumor cells were seeded in RPMI medium and venous blood from healthy donors, and then processed similarly using these four platforms. Melan-A immunochemistry was performed to identify tumor cells, except when the Cellsearch device was used (automated identification). The mean overall recovery rates (with mean recovered cells) were 39.2% (19.92), 22.2% (11.31), 8.9% (4.85), and 1.1% (0.20) for the ISET, Vortex (VTX-1), ClearCell FX, and CellSearch platforms, respectively. Although paramount, the recovery rate is not sufficient to assess a CTC platform. Other parameters, such as the purpose for using a platform (diagnosis, genetics, drug sensitivity, or patient-derived xenograft models), reproducibility, purity, user-friendliness, cost-effectiveness, and ergonomics, should also be considered before they can be used in daily clinical practice and are discussed in this article.

Reconstruction of the posterior lamella after eyelid tumor removal is challenging and not consensual. Tarsus is the most suitable graft, but is only available in small amounts. Herein, we aim to determine the most appropriate way to replace the tarsus by comparing the biomechanical, histological, and optical properties of five commonly used grafts.This study was conducted at the University hospital of Nice between June 2019 and June 2020. Five posterior lamella grafts (tarsus, conchal cartilage, sclera, hard palate, and dermis) were harvested in five fresh frozen cadavers. Biomechanical properties were assessed by tractometry. Collagen and elastin fibers were analyzed by using histological analysis and optical characterization with the second harmonic generation imaging.The mean Young's modulus was 8.92 MPa (range, 2.90-22.90 MPa), 1.05 MPa (range, 0.39-1.76 MPa), 8.72 MPa (range, 2.0-23.50 MPa), 2.57 MPa (range, 0.41-4.35 MPa), and 1.44 MPa (range, 0.71-2.30 MPa) for the tarsus, the conchal cartilage, the sclera, the hard palate mucosa, and the dermis, respectively. The mean tensile strength was 3 MPa (range, 1.70-6.88 MPa), 0.54 MPa (range, 0.13-0.79 MPa), 2.87 MPa (range, 1.23-5.40 MPa), 1.4 MPa (range, 0.21-2.40 MPa) and 1.0 MPa (range, 0.46-1.43 MPa) for the tarsus, the conchal cartilage, the sclera, the hard palate mucosa, and the dermis, respectively. Hard palate mucosa was the closest to the tarsus regarding the ratio of elastin and collagen fibers. The average second harmonic generation intensity was 221 arbitrary units (a.u.) (range, 165-362 a.u.), 182 a.u. (range, 35-259 a.u.), 369 a.u. (range, 206-533 a.u.), 108 a.u. (range, 34-208 a.u.), and 244 a.u. (range, 195-388 a.u.) for the tarsus, the conchal cartilage, the sclera, the hard palate mucosa, and the dermis, respectively. The hard palate mucosa and the dermis were the closest to the tarsus regarding the collagen fiber size and orientation, respectively.By attributing 2 points for each characteristic (biomechanical, histological, and optical), the hard palate mucosa and the sclera seem to be the most suitable grafts to replace the tarsus.The aim of this article was to assess the biomechanical, histological and optical characteristics of five of the most commonly used tarsal grafts; this may be helpful in decisions for clinical practice.

Purpose To compare the effect of antiseptics and antibiotics on the occurrence of Infectious Keratitis (IK) secondary to Corneal Foreign Body (CFB) removal. Methods Multicenter retrospective study conducted between June 2020 and June 2022 in patients referred for CFBs and treated with Picloxydine (Group 1) or Tobramycin (Group 2) for 7 days. A follow-up visit was scheduled on Day 3 (D3) and a phone call on D30. The primary outcome measure was the occurrence of IK. Results 307 patients (300 men) with a mean age of 42.8 (14.8) years were included. The mean (SD) time to consultation was 43.1 (45.6) hours. Picloxydine and Tobramycin were given to 155 and 152 patients. Half of patients (n = 154, 50.2%) were building workers and 209 (68.1%) did not wear eye protections. CFBs were mainly metallic (n = 292, 95.1%). Upon referral, rust was found in 220 patients (72.1%). A burr was used in 119 (38.9%) patients. IK occurred in 15 (4.9%) patients, 8 (5.3%) in Group 1 and 7 (4.5%) in Group 2 (p = 0.797). IK was successfully treated in all cases. Persistent rust was found in 113 patients (36.9%) on D3 without difference between burr or needle use (p = 0.278). On D3, corneal healing was delayed in 154 patients (47.2%), mainly in burr-treated patients (p = 0.003). The mean (SD) work stoppage duration was 0.32 (0.98) days. Conclusion IK rate was 4.9%. The efficacy of antibiotics and antiseptics was similar on CFB removal. Using a burr was associated with a longer healing time. CFBs had a limited social impact.

International audience

Aldol addition of α-triisopropylsilyl-α-diazoacetone (TIPS-diazoacetone), promoted by excess lithium diisopropylamide (LDA), was developed and applied to the synthesis of original C-TIPS diazoaldols, C-TIPS diazoketols, and a related Mannich-type product. An unprecedented mechanistic pathway has been proposed, involving a lithiated triazene intermediate resulting from the nucleophilic addition of LDA on the diazo moiety, supported by experimental results and DFT calculations.

Ophthalmic malignancies include various rare neoplasms involving the conjunctiva, the uvea, or the periocular area. These tumors are characterized by their scarcity as well as their histological, and sometimes genetic, diversity. Uveal melanoma (UM) is the most common primary intraocular malignancy. UM raises three main challenges highlighting the specificity of ophthalmic malignancies. First, UM is a very rare malignancy with an estimated incidence of 6 cases per million inhabitants. Second, tissue biopsy is not routinely recommended due to the risk of extraocular dissemination. Third, UM is an aggressive cancer because it is estimated that about 50% of patients will experience metastatic spread without any curative treatment available at this stage. These challenges better explain the two main objectives in the creation of a dedicated UM biobank. First, collecting UM samples is essential due to tissue scarcity. Second, large-scale translational research programs based on stored human samples will help to better determine UM pathogenesis with the aim of identifying new biomarkers, allowing for early diagnosis and new targeted treatment modalities. Other periocular malignancies, such as conjunctival melanomas or orbital malignancies, also raise specific concerns. In this context, the number of biobanks worldwide dedicated to ocular malignancies is very limited. The aims of this article were (i) to describe the specific challenges raised by a dedicated ocular malignancy biobank, (ii) to report our experience in setting up such a biobank, and (iii) to discuss future perspectives in this field.

Resume Les lymphomes sont les pathologies orbitaires malignes de l’adulte les plus frequentes. Parmi eux, le lymphome du manteau est une forme particulierement agressive, souvent decouverte par une atteinte systemique, et dont le pronostic est sombre du fait de recidives frequentes. Cette pathologie decoule d’une translocation chromosomique t(11 ;14)(q13 ;q32) aboutissant a un signal anti-apoptotique via une surexpression de Bcl-2. Son traitement repose actuellement sur une poly-chimiotherapie a base de cytarabine. Nous decrivons ici le cas d’un patient presentant une recidive orbitaire d’un lymphome du manteau traite avec succes par inhibiteur de Bcl-2 par voie orale en monotherapie. Un homme de 58 ans ayant ete traite pour un lymphome du manteau par R-CHOP il y a 8 ans et en remission depuis 5 ans a presente une baisse d’acuite rapidement progressive gauche associee a une diplopie binoculaire. L’examen clinique montrait une baisse d’acuite visuelle gauche a 1/20 Parinaud 20, un deficit pupillaire afferent relatif gauche. L’examen orbito-palpebral montrait une paralysie du VI gauche, une exophtalmie axile de 2 mm indolore ainsi qu’une hypoesthesie dans le territoire du V1 gauche permettant de diagnostiquer un syndrome de l’apex orbitaire gauche. Le champ visuel montrait un elargissement de la tâche aveugle gauche. Un scanner et une IRM realises en urgence montraient une masse tissulaire extra-conique apicale infiltrant le muscle droit median, s’etendant a la fissure orbitaire superieure, au canal optique et au sinus caverneux gauche, en hyper signal T2 et iso signal T1. L’aspect morphologique etait fortement evocateur d’un processus infiltratif lymphomateux. Une tomodensitometrie par emission de positon au 18 FDG (PET FDG) permettait d’identifier la lesion orbitaire mais egalement des hyperfixations pathologiques axillaires et coliques ; compte tenu du tableau clinique et para clinique, le diagnostic de recidive de lymphome du manteau etait pose sans recours a la biopsie. Un traitement par Venetoclax (inhibiteur du Bcl-2), etait debute. A un mois de traitement on constatait une disparition clinique complete du syndrome de l’apex avec remontee de l’acuite visuelle a 8/10 Parinaud 4 et une reponse metabolique complete au PET-Scanner. Le TEP scanner de controle ainsi que l’examen clinique a 3 mois etaient strictement normaux. Lors de la consultation de suivi a un an, le patient etait toujours sous Venetoclax, l’examen clinique etait inchange et le PET-scanner decrivait toujours une reponse metabolique complete.

The NOTCH signaling system regulates a variety of cellular processes during embryonic development and homeostasis maintenance in different tissues and contexts. Hence, dysregulation of NOTCH signaling is associated with a plethora of human cancers, and there have been multiple efforts to target key components of this pathway. In this review, we briefly highlight the latest research advances in understanding HES6, a poorly studied component of the NOTCH pathway. We summarize the role of HES6 in cancers with a focus on uveal melanoma. Finally, we discuss the ongoing efforts to target the NOTCH-HES6 axis in cancers.

Purpose To report our 14-year experience with orbital exenteration and assess risk factors for poor prognosis by focusing on conjunctival melanoma. Patients and method A retrospective study was conducted in our tertiary care centre (Jules Gonin Eye Hospital, Lausanne, Switzerland) between 2003 and 2017. Inclusion criteria were patients aged ≥18 years with a follow-up >12 months, without metastatic spread at the time of surgery. Data recorded were age, gender, tumour histology, surgical technique, postoperative complications, surgical margin status, local recurrence, postoperative radiation beam therapy and metastatic status. Results Twenty-five patients with a mean age of 63.2 years (38–92) were included. Conjunctival melanoma was the most frequently identified tumour (n = 14, 56%) followed by conjunctival squamous cell carcinoma (n = 4, 16%), sebaceous carcinoma (n = 3, 12%), choroidal melanoma (n = 2, 8%) and basal cell carcinoma (n = 2, 8%). Eighteen tumours (72%) originated from the conjunctival tissue. Clear surgical margins were achieved in 21 (84%) patients. Fourteen (56%) patients experienced distant metastases and died from metastatic spread after a mean follow-up of 52.3 months (6–120). The 1-, 3- and 5-year overall survival (OS) was 96%, 72% and 60%, respectively. In the univariate analysis, positive surgical margins, local recurrence and metachronous metastases were associated with a decreased OS (p = 0.002, p = 0.005 and p = 0.007, respectively). In the multivariate analysis, positive surgical margins and metachronous metastases were also associated with a decreased OS (p = 0.02 and p = 0.042, respectively). Conjunctival melanoma was not associated with a poorer prognosis (p = 0.280). Conclusion Free surgical margins are needed to increase OS. To achieve clearer surgical margins, neoadjuvant targeted therapies/immunotherapies may be considered.

Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM., N.J.L. would like to thank all members of the Laboratory of Clinical and Experi-mental Pathology (LPCE), Centre Hospitalier Universitaire de Nice, Nice, France; and all members of the Anatomic Pathology Service, Pathology Department, Centro Hospitalar e Universitario do Porto,Porto, Portugal, especially to JoseRamon Vizcaino (Head of Service), Joana Raposo Alves (Advisor ofPathology Training), Andre Coelho, David Tente and Francisca Emanuel Costa for their continuous support and help in the development

Immune checkpoint inhibitors (ICIs) have dramatically changed the prognosis of advanced melanoma patients, but also exposed them to immune-related adverse events (irAEs).1 Furthermore, with the combination ipilimumab (IPI) plus nivolumab (NIVO) some rare irAEs, such as myositis and neuromuscular diseases, are increasingly emerging.2 Similar manifestations have been reported during coronavirus disease 2019 (COVID-19)3 and more rarely with the vaccination.4 Because cancer patients exhibit severe and fatal forms of the COVID-19 disease, vaccination is recommended.

Purpose. To determine the course and outcomes of cataract surgery in one-eyed patients. Methods. This retrospective cohort study was conducted at the University Hospital of Nice, France. All one-eyed patients who underwent cataract surgery in their functional eye between January 2014 and December 2018 were included. A one-eyed patient was defined as having a visual acuity (VA) ≤20/200 in the other eye. Data were collected from the medical records and included the sociodemographic factors, the past medical history, data from the preoperative and postoperative clinical examinations, the surgical course, and the visual outcomes. Results. One hundred one-eyed patients with a mean age of 74.01 years were included (48 men/52 women). The mean preoperative VA was 20/100 (+0.74 logMAR). The VA ranged between 20/200 and 20/40 in 75 (75%) patients, was >20/40 in 8 (8%), and was p < 0.001 ). Conclusion. A low rate of intraoperative complications was observed in one-eyed patients during cataract surgery. In most cases, a good visual recovery was achieved after cataract surgery, even in patients who experienced a surgical complication.

Simple Summary Managing locally advanced periocular malignant tumours, especially those invading the orbit, is challenging. Orbital exenteration has long been considered the gold standard. The development of conservative surgical techniques in the early 2000s, followed by the emergence of new targeted therapies and immunotherapies over the past decade, has led to a paradigm shift towards the use of ‘eye-sparing’ strategies. Abstract The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly disfiguring and traumatic surgery. The last two decades have been marked by the emergence of a new paradigm shift towards the use of ‘eye-sparing’ strategies. In the early 2000s, the first step consisted of performing wide conservative eyelid and orbital excisions. Multiple flaps and grafts were needed, as well as adjuvant radiotherapy in selected cases. Although being incredibly attractive, several limitations such as the inability to treat the more posteriorly located orbital lesions, as well as unbearable diplopia, eye pain and even secondary eye loss were identified. Therefore, surgeons should distinguish ‘eye-sparing’ from ‘sight-sparing’ strategies. The second step emerged over the last decade and was based on the development of targeted therapies and immunotherapies. Their advantages include their potential ability to treat almost all tumours, regardless of their locations, without performing complex surgeries. However, several limitations have been reported, including their side effects, the appearance of primary or secondary resistances, their price and the lack of consensus on treatment regimen and exact duration. The aim of this article was to review the evolution of the management of locally advanced periocular malignant tumours over the last three decades and highlight the new paradigm shift towards the use of ‘eye-sparing’ strategies.

International audience; This review provides an overview of the applications of α-halogenoacetamides in domino and cycloaddition reactions. α-Halogenoacetamides are versatile building blocks that can lead to a wide variety of complex aza-heterocycles of biological interest when engaged in domino and/or cycloaddition reactions. The reactivity and the reaction conditions involved for these species (solvent, base, etc.) are closely related to the substituent onto the nitrogen atom of the amide: N-alkyl α-halogenoacetamides usually act as formal 1,3-dipoles in domino processes whereas N-alkoxy derivatives often react as real 1,3-dipoles via the formation of aza-oxyallyl cation species. This important modulation of the reactivity of these compounds opens the way to a large panel of reactions and therefore to a large diversity of aza-heterocycles.

Introduction L’association ipilimumab (IPI) + nivolumab (NIVO) offre un taux de réponse et de guérison supérieur aux anti-PD1 en monothérapie mais expose à des événements indésirables immunitaires (EII) plus fréquents. La COVID-19 a tué plus de 3 M de personnes. Comme les patients atteints de cancers sont particulièrement exposés aux formes sévères/mortelles, la vaccination est recommandée. Il n’existe pas de données testant la relation entre vaccination et développement/exacerbation des EII au cours du traitement par ICI. Nous rapportons un cas de myopathie nécrosante survenue 10 jours après la vaccination contre la COVID-19 chez un patient atteint d’un mélanome avancé traité par IPI + NIVO. Matériel et méthodes Un homme de 43 ans était inclus en 2015 dans l’essai adjuvant EORTC MK-3475 (pembrolizumab vs. placebo) pour un mélanome stade IIIb. E n 02/2021 une récidive ganglionnaire lombo-aortique, non opérable survenait. Malgré un statut BRAF (+) et une levée d’aveugle révélant qu’il avait reçu le pembrolizumab (sans EII à l’époque), un traitement par IPI + NIVO était alors débuté. Il recevait sa 1ère et 2e injection les 25/02 et 19/03/21. Le 12/03, il recevait sa 1ère dose de vaccin COVID-19 (Pfizer/BioNTech), sans réaction immédiate. Le 22/03 il développait un tableau associant: myalgies, faiblesse musculaire des membres, dysphagie, dyspnée, dysphonie et diplopie bilatérale avec rhabdomyolyse (CK 12647 U/L). Le bilan immunologique revenait négatif. L’ENMG décrivait un syndrome myogène. L’IRM musculaire révélait un aspect de myosite (muscles rotateurs du cou/de la cuisse) et l’histologie retrouvait un aspect de myopathie inflammatoire avec nécrose multifocale de myocytes et infiltrat inflammatoire à prédominance macrophagique. Le diagnostic de myopathie nécrosante grade IV était retenu. L’immunothérapie était arrêtée et une corticothérapie (bolus puis per os) permettait une amélioration progressive. Le patient est toujours sous corticothérapie orale, la surveillance oncologique montre à ce jour une réponse partielle. La 2e injection du vaccin n’a pas été faite d’autant plus que les IgG étaient fortement positives. Discussion Des myosites secondaires aux ICI, au COVID-19 et de façon plus anecdotique à la vaccination ont été rapportées. Ici, l’association temporelle étroite de la bi-ICI et du diagnostic de myopathie suggère que la myopathie est un EII et que la vaccination a contribué au développement de la myopathie par un effet de boost immunitaire. Le scénario inverse ne peut être exclu. Parce que de plus en plus de patients traités par ICI seront vaccinés dans les prochains mois, les cliniciens doivent être conscients de cette association potentielle du vaccin COVID-19 et de l’exacerbation des EII. Des données prospectives de pharmacovigilance sont nécessaires.

International audience; Enantiopure (R) and (S) cyclic α,α-disubstituted amino acid derivatives displaying a δ-valerolactam side chain were prepared from a common isoxazolidine precursor. The (R)-configured δ-valerolactam 11 was converted into diastereoisomeric pseudopeptides to investigate its ability to induce secondary structures in peptidomimetics. Conformational studies of these pseudopeptides were carried out in the solid state (X-ray diffraction), in solution (NMR analyses), and in silico (computer-aided conformational analysis), which demonstrated that such quaternary amino acids induce β-turn conformations stable enough to be retained in polar media (DMSO). Incorporation of this new type of α,α-disubstituted amino acid into a representative pseudopeptidic sequence by N- then C-elongation and N-debenzylation is also described herein and could serve for the synthesis of various structured peptidomimetics

International audience; No abstract available

International audience; An efficient two-step strategy for the synthesis of constrained C-glycosyl amino acid derivatives from C-vinylglycosides involving a 1,3-dipolar cycloaddition using L-(-)menthone-derived nitrone as the key step is described. After optimization of 1,3-dipolar cycloaddition conditions, various C-vinylglycosides were tested leading exclusively to one dia-[a]

PURPOSE Phantom eye syndrome (PES) is an underestimated complication of eye amputation (EA) characterized by phantom eye pain (PEP), phantom visions and/or phantom sensations. The aim of this study was to assess PEP prevalence, features, risk factors, social and psychological consequences and associated quality of life. METHODS A questionnaire study was conducted in three oculoplastic departments between April 2016 and July 2017. Patients >18 years who had undergone EA ≥3 months earlier were included and asked to complete a prestamped questionnaire. Patient's characteristics, preoperative, surgical and postoperative data were collected. RESULTS Of the 185 questionnaires given, 115 (62%) were returned for analysis. Hundred patients with a mean age of 65.1 years (29-92; SD = 13.0) were included. Eye amputation (EA) indications were uveal melanoma (n = 24, 24%), trauma (n = 20, 20%), retinal detachment (n = 20, 20%), glaucoma (n = 14, 14%) and endophthalmitis (n = 12, 12%). Forty-seven (47%), 30 (30%) and 38 (38%) patients experienced PEP, phantom visions and phantom sensations, respectively. Anxiety and depression [Hospital Anxiety Depression scale (HADS) score ≥8 for both] were diagnosed in 34 (34%) and 42 (42%) patients, respectively. The mean EQ-5D-3L and EQ-5D visual analogue scale scores were 0.8 (0.06-1; SD = 0.2) and 68 (0-100; SD = 22), respectively. Preoperative eye pain (p = 0.031), glaucoma (p = 0.027), postoperative anxiety with HADS score ≥8 (p = 0.012) and ≥11 (p = 0.014), aesthetic discomfort (p = 0.002) and EQ-5D-3L score

Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression.

Resume Objectif Decrire les rapports anatomiques de la voie d’abord retro-caronculaire ainsi que des ses applications cliniques en oculoplastique a partir d’une etude conduite au laboratoire d’anatomie. Patients et methode Huit orbites provenant de 4 cadavres frais ont ete dissequees au laboratoire d’anatomie de la faculte de medecine de Nice entre octobre 2018 et janvier 2019. Resultats Les principaux rapports anatomiques rencontres sont le muscle de Duverney-Horner et le sac lacrymal en avant, les arteres ethmoidales anterieures, posterieures et l’ethmoide en arriere, la poulie du muscle oblique superieur vers le haut, le canal lacrymo-nasal et le tendon d’insertion du muscle oblique inferieur vers le bas. La voie d’abord retro-caronculaire permet d’aborder l’orbite posterieurement au sac lacrymal et au muscle de Duverney-Horner permettant une meilleure protection de ces derniers. La voie d’abord retro-caronculaire permet la realisation de plusieurs procedures oculoplastiques : la dacryocystorhinostomie, la reparation des fractures orbitaires mediales, la decompression de la paroi mediale de l’orbite, la biopsie de tumeurs extraconiques mediales et la pexie periostee du globe oculaire en cas de paralysie complete du III. Conclusion La voie d’abord retro-caronculaire est une voie fiable permettant de s’affranchir d’une cicatrice cutanee. Elle permet un abord large de la portion mediale de l’orbite meme si le champ operatoire est plus reduit que celui obtenu en cas d’abord cutane. Elle necessite une connaissance anatomique precise et une courbe d’apprentissage accrue.

The eye is an exemplarily challenging organ to treat when considering ocular tumors. It is at the crossroads of several major aims in oncology: tumor control, organ preservation, and functional outcomes including vision and quality of life. The proximity between the tumor and organs that are susceptible to radiation damage explain these challenges. Given a high enough dose of radiation, virtually any cancer will be destroyed with radiotherapy. Yet, the doses inevitably absorbed by normal tissues may lead to complications, the likelihood of which increases with the radiation dose and volume of normal tissues irradiated. Precision radiotherapy allows personalized decision-making algorithms based on patient and tumor characteristics by exploiting the full knowledge of the physics, radiobiology, and the modifications made to the radiotherapy equipment to adapt to the various ocular tumors. Anticipation of the spectrum and severity of radiation-induced complications is crucial to the decision of which technique to use for a given tumor. Radiation can damage the lacrimal gland, eyelashes/eyelids, cornea, lens, macula/retina, optic nerves and chiasma, each having specific dose–response characteristics. The present review is a report of non-cancer effects that may occur following ionizing irradiation involving the eye and orbit and their specific patterns of toxicity for a given radiotherapy modality.

Simple Summary Conjunctival melanoma (CM) is a small but highly aggressive and infiltrative periocular malignancy. Despite wide surgical excision followed by adjuvant therapy, about one third and one quarter of patients will experience local recurrence and metastatic spread, respectively. The management of locally advanced (≥T2) tumours may require mutilating surgeries such as orbital exenteration to achieve local control. The last decade has been marked by the emergence of eye-sparing strategies based on wide surgical excision followed by adjuvant proton beam therapy. More recently, new genetic and immunological insights have incriminated several signalling pathways (MAPK, PI3K-AKT) and immune cells, making CM a “targetable” malignancy. Anti-BRAF and anti-MEK targeted therapies and immunotherapies have revolutionized the current management of CM through the use of new eye-sparing strategies and treatment of metastases. Abstract Although its incidence has increased over the last decades, conjunctival melanoma (CM) remains a rare but challenging periocular malignancy. While there is currently no recognized standard of care, “no-touch” surgical excision followed by adjuvant treatments is usually recommended. Despite its small size, managing CM is challenging for clinicians. The first challenge is the high risk of tumour local recurrence that occurs in about one third of the patients. The management of locally advanced CM (≥T2) or multiple recurrences may require mutilating surgeries such as orbital exenteration (OE). The second challenge is the metastatic spread of CM that occurs in about one quarter of patients, regardless of whether complete surgical excision is performed or not. This highlights the infiltrative and highly aggressive behaviour of CM. Recently, attention has been directed towards the use of eye-sparing strategies to avoid OE. Initially, wide conservative surgeries followed by customized brachytherapy or radiotherapy have appeared as viable strategies. Nowadays, new biological insights into CM have revealed similarities with cutaneous melanoma. These new findings have allowed clinicians to reconsider the management of locally advanced CM with “medical” eye-sparing treatment as well as the management of metastatic spread. The aim of this review was to summarize the current and future perspectives of treatment for CM based on recent biological findings.

Resume Objectif Decrire de maniere didactique la dissemination locoregionale et systemique du melanome choroidien. Patients et methodes Deux patients ayant beneficie d’une enucleation primaire pour melanome choroidien en 2018 au CHU de Nice ont ete inclus. La frequence de l’extension extrasclerale et de l’envahissement vortiqueux ainsi que la survenue de metastases synchrones et metachrones ont retrospectivement ete evalues dans notre base de donnees. Resultats le patient N°1 presentait un volumineux melanome choroidien avec envahissement scleral non transfixiant et envahissement des veines vortiqueuses. L’analyse cytogenetique retrouvait une perte du chromosome 3 et un gain 8q. Le bilan d’extension etait negatif. Le second patient presentait un volumineux melanome choroidien avec extension extrasclerale et envahissement vortiqueux. L’analyse cytogenetique retrouvait une perte du chromosome 3 et un gain 8q. Le bilan d’extension retrouvait des metastases hepatiques multiples. Notre serie comportait 1762 patients: 85 patients (4,8 %) et 46 patients (2,6 %) presentaient un envahissement vortiqueux et une extension extrasclerale respectivement. Les patients presentant un envahissement vortiqueux presentaient au moins une metastase hepatique synchrone et metachrone dans 1,2 % et 18,8 % des cas respectivement. Les patients presentant une extension extrasclerale presentaient au moins une metastase hepatique synchrone et metachrone dans 6,5 % et 30,4 % des cas respectivement. Le suivi moyen de 49,4 mois (1–180). Conclusion L’extension extrasclerale et l’envahissement des veines vortiqueuses permettent d’illustrer la dissemination locoregionale et systemique du melanome choroidien. Ces derniers sont generalement associes a des tumeurs genetiquement agressives et greves d’un haut risque metastatique.

Simple Summary To date, there is no treatment for metastatic uveal melanoma. Identifying its metastatic spread is essential. Liquid biopsy can identify patients at risk of metastatic spread early. Here, we aim to summarize the current knowledge of liquid biopsy in ophthalmic malignant tumors, including uveal melanoma. Our objective is to establish the current state of liquid biopsy in the ophthalmic field, as well as its perspectives and limitations. Abstract Tissue biopsy is considered the gold standard when establishing a diagnosis of cancer. However, tissue biopsies of intraocular ophthalmic malignancies are hard to collect and are thought to be associated with a non-negligible risk of extraocular dissemination. Recently, the liquid biopsy (LB) has emerged as a viable, non-invasive, repeatable, and promising way of obtaining a diagnosis, prognosis, and theragnosis of patients with solid tumors. LB refers to blood, as well as any human liquid. The natural history of uveal melanoma (UM) and retinoblastoma (RB) are radically opposed. On the one hand, UM is known to disseminate through the bloodstream, and is, therefore, more accessible to systemic venous liquid biopsy. On the other hand, RB rarely disseminates hematogenous, and is, therefore, more accessible to local liquid biopsy by performing an anterior chamber puncture. In this review, we summarize the current knowledge concerning LB in UM, RB, conjunctival tumors, and choroidal metastases. We also develop the current limitations encountered, as well as the perspectives.

International audience; A stereospecific Mizoroki-Heck cross-coupling of differently substituted glycals with haloarenes resulting in the exclusive formation of either α- or β-aryl-C-glycosides depending solely on the configuration at C3 was achieved. The reaction was easy to set up because no specific precautions were required concerning moisture or oxygen, and it proceeded by a chirality transfer from C3 to C1. After optimization of cross-coupling conditions, various prepared glycals (7 examples) and arenes (10 examples) were tested, leading stereospecifically to the corresponding aryl-C-glycosides with a carbonyl group at C3, thus opening up new horizons for the total synthesis of glycosylated natural products.

International audience; In this paper, a new access to several chiral 3-aminoglycals as potential precursors for glycosylated natural products is reported from a common starting material, (-)-methyl-L-lactate. The stereodivergent strategy is based on the implementation of a ring-closing metathesis of vinyl ethers as key step of reaction sequences developed.

The access to new oxazolo[3,2-d][1,4]oxazepin-5(3H)-ones starting from α-bromoamido alcohols and Michael acceptors under mild conditions is presented. This domino process proved to be chemo-, regio-, and stereoselective and allows the formation of a large diversity of highly functional 7-membered rings in good yields up to 95%. The complete shift of the regioselectivity of the intermediate enolate from a C–C to a C–O bond formation, contrary to the already known alkylations of such ambident nucleophiles, is mostly triggered by steric effects. The last step of the sequence was modeled by DFT giving some important insights for this C–C vs C–O bond shift.

International audience; A catalytic 1,3-dipolar cycloaddition between carboalkoxy ketonitrones and methacrolein under the effect of chiral ruthenium Lewis acid (R,R-1) was developed with high regio-, diastereo-, and enantiocontrol. The diastereochemical outcome of the cycloaddition reaction is marked by a significant solvent effect, and a divergent endo or exo control can be tuned by an appropriate choice of both the solvent and the N- and O-substituents of the ketonitrone. A rationale of the solvent effect, based on the computational study of the interactions between the methacrolein–Ru complex and its counteranion (SbF6–), is proposed to explain the selectivities obtained.

Small and large scale proteomic technologies are providing a wealth of potential interactions between proteins bearing phospho-recognition modules and their substrates. Resulting interaction maps reveal such a dense network of interactions that the functional dissection and understanding of these networks often require to break specific interactions while keeping the rest intact. Here, we developed a computational strategy, called STRIP, to predict the precise interaction site involved in an interaction with a phospho-recognition module. The method was validated by a two-hybrid screen carried out using the ForkHead Associated (FHA) 1 domain of Rad53, a key protein of Saccharomyces cerevisiae DNA checkpoint, as a bait. In this screen we detected 11 partners, including Cdc7 and Cdc45, essential components of the DNA replication machinery. FHA domains are phospho-threonine binding modules and the threonines involved in both interactions could be predicted using the STRIP strategy. The threonines T484 and T189 in Cdc7 and Cdc45, respectively, were mutated and loss of binding could be monitored experimentally with the full-length proteins. The method was further tested for the analysis of 63 known Rad53 binding partners and provided several key insights regarding the threonines likely involved in these interactions. The STRIP method relies on a combination of conservation, phosphorylation likelihood, and binding specificity criteria and can be accessed via a web interface at http://biodev.extra.cea.fr/strip/.

Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensation of alpha-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with different alkenes were investigated under thermal solvent-free conditions. Considering conversions, yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this transformation, which creates a tetrafunctionalized stereogenic quaternary center. From the adducts derived from vinyl ethers, a three-step access to highly functionalized alpha-substituted amino acid derivatives is described.

Detection of structural motif of residues in protein structures allows identification of structural or functional similarity between proteins. In the field of protein engineering, structural motif identification is essential to select protein scaffolds on which a motif of residues can be transferred to design a new protein with a given function. We describe here the RASMOT-3D PRO webserver (http://biodev.extra.cea.fr/rasmot3d/) that performs a systematic search in 3D structures of protein for a set of residues exhibiting a particular topology. Comparison is based on Calpha and Cbeta atoms in two steps: inter-atomic distances and RMSD. RASMOT-3D PRO takes in input a PDB file containing the 3D coordinates of the searched motif and provides an interactive list of identified protein structures exhibiting residues of similar topology as the motif searched. Each solution can be graphically examined on the website. The topological search can be conducted in structures described in PDB files uploaded by the user or in those deposited in the PDB. This characteristic as well as the possibility to reject scaffolds sterically incompatible with the target, makes RASMOT-3D PRO a unique webtool in the field of protein engineering.

Two new bisflavan-3-ols, named colletinin A (1) and 2,2″-diepicolletinin A (2) have been isolated from Rhododendron collettianum. Their structures were determined by means of 1D and 2D NMR analysis, aided by HREIMS data. The relative configuration was determined by means of 1H-1H NOESY correlation but the absolute configuration could not be established.

International audience; The [4+2] heterocycloaddition reaction between (E)‐γ‐substituted β‐unsaturated α‐oxo esters 1a−d and cyclic and acyclic ketone enol ethers 2a−l afforded heteroadducts 3−5 in high yields when either [Eu(fod)3] or SnCl4 were used as the catalyst. With methyl (E)‐benzylidenepyruvate (1a), the two catalytic modes displayed divergent stereoselectivities. In the case of the heterocycloaddition of silyl enol ether 2h, X‐ray investigations established the relative configurations of the bicyclic adducts 3h and 5h, each obtained as the major isomer with [Eu(fod)3] and with SnCl4, respectively. These assignments provided valuable information concerning the concerted vs. nonconcerted mechanism of these acid‐catalysed reactions. With methyl (E)‐tert‐butoxymethylenepyruvate (1d), the scope of the reaction proved to be restricted to alkyl enol ethers as the dienophiles. In this case, the stereochemical process followed a different pathway, exemplified by the X‐ray structure of the adduct 4q, obtained with total stereoselectivity from 1d and 1‐methoxycyclohexene (2f) when SnCl4 was the catalyst.

New isoxazolidines were synthesized in good to excellent yields by 1,3-dipolar cycloaddition of N-vinylamide dipolarophiles and nitrones. Strikingly, solvent-free conditions gave high conversion and yields, shortened reaction time, and minimized degradation products. N-Vinyloxazolidin-2-one and its analogues used in these cycloaddition reactions were conveniently prepared in excellent yields by a modified version of Buchwald's one-step copper-catalyzed vinylation using vinyl bromide. From the adducts, a two-step access to various unsymmetric aspartate derivatives was also described.

International audience; CRISPR (clustered regularly interspaced short palin-dromic repeats) arrays and their associated (Cas) proteins confer bacteria and archaea adaptive immunity against exogenous mobile genetic elements, such as phages or plasmids. CRISPRCasFinder allows the identification of both CRISPR arrays and Cas proteins. The program includes: (i) an improved CRISPR array detection tool facilitating expert validation based on a rating system, (ii) prediction of CRISPR orientation and (iii) a Cas protein detection and typing tool updated to match the latest classification scheme of these systems. CRISPRCasFinder can either be used online or as a standalone tool compatible with Linux operating system. All third-party software packages employed by the program are freely available. CRISPRCasFinder is available at https://crisprcas.i2bc.paris-saclay.fr.

In the field of molecular machines, systems producing an oriented motion have been intensely looked for. Results, obtained toward this goal, do not exploit Brownian motion whereas it happens in natural systems such as myosin. Hereby we propose the synthesis of a molecular ratchet aiming to mimic this phenomenon or to be able to act as a molecular motor through low energy activation.The first part of this work consisted in the design by modelisation of a synthetic equivalent of a ratchet, basically consisting of a toothed wheel and a pawl. This study aim at determining if such a molecule could produce an oriented motion by simple Brownian motion. This system is consisting of a functionalized bishomoinositol moiety as the wheel and a cycloadduct of anthracene as the pawl, linked by spacers allowing the adjustment of the energy barriers.The synthesis of a model where a bicyclo[2.2.2]octane moiety plays the role of a simplified wheel has been conducted in order to validate various synthetic strategies. This gave the opportunity to develop an alternative method of the synthesis of the bicyclo[2.2.2]octanedicarboxylic diacid as well as an esterification methodology compatible with the bulkiness or low solubility of both partners. The macrolactonization product could be obtained and opens some possible applications as nanovehicle wheels.The synthesis of the model was the occasion to highlight synthetic limitations concerning the spacers (ethers) in the original system. A new series of targets taking into account the synthetic restrictions while keeping the ratchet behavior were designed. The discovery of another synthetic difficulties (amides, triazoles, tetrazoles and alkenes) yielded a single refined target. Toward this goal, the synthesis of the bishomoinositol functionalized in the bridgehead position was engaged in a first pathway including these functions at the beginning of the synthesis, the second way introducing them on the bishomoinositol at the end of the sequence., Dans le domaine des machines moléculaires, la recherche d'un système produisant un mouvement orienté fait l'objet d'intenses recherches. Des résultats ont déjà été obtenus en ce sens mais n'exploitant pas le mouvement brownien comme le font les systèmes trouvés dans la nature comme la myosine. Nous proposons donc la synthèse d'une roue à rochet avec pour but de mimer ce phénomène, si besoin avec une activation de faible énergie.La première partie de ce travail a consisté en la conception par modélisation de l'équivalent synthétique d'une roue à rochet, basiquement constituée d'une roue crantée et d'un cliquet en vue d'étudier si une telle molécule pourrait produire une rotation orientée. Ce système est constitué d'un motif bishomoinositol fonctionnalisé en tant que roue et d'un cycloadduit de l'anthracène comme cliquet, liés par des bras espaceurs.La synthèse d'un système modèle dans lequel un motif bicyclo[2.2.2]octane joue le rôle de roue simplifiée a été menée afin de valider les différentes stratégies de synthèse. A cette occasion, une méthode alternative de la synthèse du diacide bicyclo[2.2.2]octanoïque a été mise au point ainsi qu'une méthodologie d'estérification compatible avec cet acide ainsi que le diacide 9,10-anthracènedioïque. Nous sommes ainsi parvenus à obtenir le produit de macrolactonisation, avec de possibles application comme roue de nanovéhicules.La synthèse du modèle a été l'occasion de pointer certaines impossibilités synthétiques au niveau des espaceurs (éthers, amides, triazoles, tétrazoles, alcènes) dans le système original. Un nouveau travail de modélisation a permis d'aboutir à une cible accessible synthétiquement conservant le comportement de roue à rochet. Dans cette optique, la synthèse du bishomoinositol fonctionnalisé par des acides en tête de pont a été entreprise par une première voie incluant ces groupements au départ de la synthèse, une seconde voie introduisant ces groupements en fin de séquence.