Deciphering differential biomarkers for anti-interleukin-6 receptor and anti-tumour necrosis factor-α treatment response in rheumatoid arthritis by multiomics analysis.

Objective: To identify blood-based predictive and pharmacodynamic biomarkers at different timepoints in patients with active rheumatoid arthritis (RA) treated with anti-interleukin-6 receptor (anti-IL-6R) and anti-tumour necrosis factor-α (anti-TNF-α).

Methods: This study used blood samples from the MONARCH trial (NCT02332590), a randomised, double-blind, phase III trial that compared the safety and efficacy of sarilumab (anti-IL-6R) and adalimumab (anti-TNF-α) monotherapy in patients with RA who were intolerant/inadequate responders to methotrexate. The study evaluated predictive biomarkers to anti-IL-6R and anti-TNF-α treatments at baseline and week 2 and pharmacodynamic biomarkers at week 2 and week 24 using Olink proteomics analysis (n=804 serum samples from 268 patients).

Neoadjuvant immune checkpoint inhibitors for patients with resectable stage III/IV melanoma: A nationwide real-life study in France (NEOMEL).

Background: Despite the clear therapeutic benefits of neoadjuvant treatment (NT) with immune checkpoint inhibitors (ICIs) in clinical trials, the efficacy of NT ICIs (NT-ICI) and the optimal regimen for patients (pts) with resectable metastatic melanoma (RMM) remain to be confirmed in real life.

Objective: To assess the efficacy and safety of NT-ICI among pts with RMM in real life.

Methods: NEOMEL is a French retrospective multicentric cohort study.

Management of cardiac metastases of melanoma in the era of immunotherapy: a case series.

Cardiac metastasis from melanoma is a rare but clinically significant condition often underdiagnosed because of its asymptomatic nature. This retrospective case series examines six patients with metastatic melanoma treated at the University Hospital of Bordeaux who were incidentally found to have cardiac metastases during follow-up. The patients were treated with immune checkpoint inhibitors (ICIs) either alone or combined with surgical excision of cardiac lesions.

Directed Evolution's Selective Use of Quantum Tunneling in Designed Enzymes─A Combined Theoretical and Experimental Study.

Natural enzymes are powerful catalysts, reducing the apparent activation energy for reactions and enabling chemistry to proceed as much as 10 times faster than the corresponding solution reaction. It has been suggested for some time that, in some cases, quantum tunneling can contribute to this rate enhancement by offering pathways through a barrier inaccessible to activated events. A central question of interest to both physical chemists and biochemists is the extent to which evolution introduces mechanisms below the barrier, or tunneling mechanisms.

Resolution of immune checkpoint inhibitors-induced inflammatory arthritis while maintaining active treatment with checkpoint inhibitors and after its discontinuation: An observational study.

Introduction: Immune checkpoint inhibitors-induced inflammatory arthritis (ICI-IA) affects about 5% of ICI recipients. We aimed (1) to characterize the resolution of ICI-IA during ICI treatment and after ICI discontinuation and (2) to assess how ICI-IA influences ICI management across time.

Methods: All ICI-treated patients referred to rheumatology at Bordeaux University Hospital were identified and patients with ICI-IA with a follow-up of≥6months after ICI-IA onset were included.

Probing Ferryl Reactivity in a Nonheme Iron Oxygenase Using an Expanded Genetic Code.

The ability to introduce noncanonical amino acids as axial ligands in heme enzymes has provided a powerful experimental tool for studying the structure and reactivity of their Fe=O ("ferryl") intermediates. Here, we show that a similar approach can be used to perturb the conserved Fe coordination environment of 2-oxoglutarate (2OG) dependent oxygenases, a versatile class of enzymes that employ highly-reactive ferryl intermediates to mediate challenging C-H functionalizations. Replacement of one of the cis-disposed histidine ligands in the oxygenase VioC with a less electron donating -methyl-histidine (MeHis) preserves both catalytic function and reaction selectivity.

Safety of immune checkpoint inhibitor rechallenge after severe immune-related adverse events: a retrospective analysis.

Immune checkpoint inhibitors (ICIs) present clinicians with the challenge of managing immune-related adverse events (irAEs), which can range from mild to severe due to immune system activation . While guidelines recommend discontinuing ICIs for grade 3 partial and all grade 4 irAEs, there is growing interest in rechallenging patients based on oncological outcomes, particularly for cardiovascular and neurological irAEs where data remains scarce . We retrospectively evaluated the safety of ICI rechallenge following grade 3-4 irAEs, specifically focusing on cardiovascular and neurological events, in patients discussed at our multidisciplinary immunotoxicity assessment board between 2019 and 2021.

Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée).

Background: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population.

Improved survival over time with immunotherapy in locally advanced and metastatic cutaneous squamous cell carcinomas.

Purpose: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in white-skinned populations. There is little information on the epidemiology of cSCC, and even less on advanced cases (acSCC). Therefore, we analyzed acSCC patients to describe their characteristics, management, and outcomes over time.

A non-canonical nucleophile unlocks a new mechanistic pathway in a designed enzyme.

Directed evolution of computationally designed enzymes has provided new insights into the emergence of sophisticated catalytic sites in proteins. In this regard, we have recently shown that a histidine nucleophile and a flexible arginine can work in synergy to accelerate the Morita-Baylis-Hillman (MBH) reaction with unrivalled efficiency. Here, we show that replacing the catalytic histidine with a non-canonical N-methylhistidine (MeHis23) nucleophile leads to a substantially altered evolutionary outcome in which the catalytic Arg124 has been abandoned.

Clinical impact of proton pump inhibitors and other co-medications on advanced melanoma patients treated with BRAF/MEK inhibitors.

Purpose: While several studies reported the influence of co-medications on immune checkpoint therapy and chemotherapy, it remains poorly studied with targeted therapy. Targeted therapies inhibiting BRAF and MEK had significantly improved management of advanced melanoma with BRAFV600 mutation over the last decade, we aimed to investigate the possible influence of co-mediations on the efficacy and toxicity of these targeted therapies (TT).

Methods: We conducted an observational study identifying patients with advanced melanoma treated with BRAF/MEK inhibitors between 2013 and 2020 in the Bordeaux University Hospital.

Immune checkpoint inhibitor rechallenge in patients who previously experienced immune-related inflammatory arthritis: a multicentre observational study.

Objective: Another course of immune checkpoint inhibitors (ICIs) is often considered in patients with cancer progression and previous immune-related adverse events, including inflammatory arthritis (ICI-IA), but there are limited data regarding safety of ICI rechallenge in this setting. We aimed to assess the rate and clinical features associated with ICI-IA flare/recurrence on ICI rechallenge.

Methods: We conducted a multicentre observational study including cancer patients with ICI-IA who started a second course of ICI more than 3 months after ICI discontinuation in four French university hospitals.

How Is Substrate Halogenation Triggered by the Vanadium Haloperoxidase from ?

Vanadium haloperoxidases (VHPOs) are unique enzymes in biology that catalyze a challenging halogen transfer reaction and convert a strong aromatic C-H bond into C-X (X = Cl, Br, I) with the use of a vanadium cofactor and HO. The VHPO catalytic cycle starts with the conversion of hydrogen peroxide and halide (X = Cl, Br, I) into hypohalide on the vanadate cofactor, and the hypohalide subsequently reacts with a substrate. However, it is unclear whether the hypohalide is released from the enzyme or otherwise trapped within the enzyme structure for the halogenation of organic substrates.

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Introduction: The starting point of our article is the observation that the target group of Afro-Latin-Caribbean men, who have sex with men, is not reached by sexual health promotion programs for MSM, nor by those aimed at Afro-Latino-Caribbean audiences. Indeed, it seems to be in a blind spot of prevention programs designed by key audiences.

Purpose Of Research: The objective of our article is to understand the vulnerabilities of this group, the impacts of its invisibility and the intersectoral discrimination (homophobia, racism, …) of which itis victim on the management of his sexual health, in order to highlight ways to improve prevention programs towards this group.

Brief Communication: Lambert-Eaton Myasthenic Paraneoplastic Syndrome Associated With Merkel Cell Carcinoma Successfully Treated by Immune Checkpoint Inhibitors: 2 Cases.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous tumor with high metastatic potential. In rare cases, it can be associated with paraneoplastic syndromes (PNS), which result from an antitumor immunity against antigens produced by the tumor itself. Lambert-Eaton Myasthenic Syndrome (LEMS) is a neurological autoimmune PNS characterized by an impairment of the neuromuscular junction, leading to proximal muscle weakness and fatigability.

The Construction of Pre-exposure Prophylaxis (PrEP) by Prevention Professionals as a Tool for Black African Migrant Women … or Not?

While sub-Saharan African migrants are recognized as a key population in the HIV epidemics, they are absent from the PrEP delivery system and in particular women. The central argument of this article is that PrEP for Black African migrant women is an ambivalent offer that makes it necessary to understand how migration, gender, sexuality, and origin interact. Bringing together a sociologist and a prevention project manager, this article looks at how Belgian prevention professionals navigate with this ambivalent offer.

What Drives Radical Halogenation versus Hydroxylation in Mononuclear Nonheme Iron Complexes? A Combined Experimental and Computational Study.

Nonheme iron halogenases are unique enzymes in nature that selectively activate an aliphatic C-H bond of a substrate to convert it into C-X (X = Cl/Br, but not F/I). It is proposed that they generate an Fe(OH)(X) intermediate in their catalytic cycle. The analogous Fe(OH) intermediate in nonheme iron hydroxylases transfers OH to give alcohol product, whereas the halogenases transfer X to the carbon radical substrate.

Harmonization of programmed death-ligand 1 immunohistochemistry and mRNA expression scoring in metastatic melanoma: a multicentre analysis.

Aims: The aim of this multicentre study was to harmonize programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and melanoma scoring. To provide a reference for PD-L1 expression independently of the IHC protocol, PD-L1 mRNA expression was compared with IHC.

Methods And Results: Standardized PD-L1 assays (22C3, 28-8, SP142, SP263) and laboratory-developed tests (QR1, 22C3) were evaluated on three IHC platforms with a training set (seven cases).

Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation.

Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT).