Chiral and herringbone symmetry breaking in water-surface monolayers

We report the observation from monolayers of eicosanoic acid in the L′2 phase of three distinct out-of-plane first-order diffraction peaks, indicating molecular tilt in a nonsymmetry direction and hence the absence of mirror symmetry. At lower pressures the molecules tilt in the direction of their nearest neighbors. In this region we find a structural transition, which we tentatively identify as the rotator-herringbone transition L2d−L2h

Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer

Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) or mutations (both driver and passenger mutations), recent results have shown that noncanonical transcripts including long noncoding RNAs and transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation and immunogenicity of tumor antigens derived from noncanonical mRNA splicing events between coding exons and TEs. Comparing human non-small cell lung cancer (NSCLC) and diverse healthy tissues, we identified a subset of splicing junctions that is both tumor specific and shared across patients. We used HLA-I peptidomics to identify peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides were immunogenic in vitro, and CD8+ T cells specific for junction-encoded epitopes were present in tumors and tumor-draining lymph nodes from patients with NSCLC. We conclude that noncanonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in patients with NSCLC

Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements

Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction-derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3-lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer

Building a successful minimally invasive mitral valve repair program before introducing the robotic approach: The Massachusetts General Hospital experience

BackgroundPatients with mitral valve prolapse (MVP) requiring surgical repair (MVr) are increasingly operated using minimally invasive strategies. Skill acquisition may be facilitated by a dedicated MVr program. We present here our institutional experience in establishing minimally invasive MVr (starting in 2014), laying the foundation to introduce robotic MVr.MethodsWe reviewed all patients that had undergone MVr for MVP via sternotomy or mini-thoracotomy between January 2013 and December 2020 at our institution. In addition, all cases of robotic MVr between January 2021 and August 2022 were analyzed. Case complexity, repair techniques, and outcomes are presented for the conventional sternotomy, right mini-thoracotomy and robotic approaches. A subgroup analysis comparing only isolated MVr cases via sternotomy vs. right mini-thoracotomy was conducted using propensity score matching.ResultsBetween 2013 and 2020, 799 patients were operated for native MVP at our institution, of which 761 (95.2%) received planned MVr (263 [34.6%] via mini-thoracotomy) and 38 (4.8%) received planned MV replacement. With increasing proportions of minimally invasive procedures (2014: 14.8%, 2020: 46.5%), we observed a continuous growth in overall institutional volume of MVP (n = 69 in 2013; n = 127 in 2020) and markedly improved institutional rates of successful MVr, with 95.4% in 2013 vs. 99.2% in 2020. Over this period, a higher complexity of cases were treated minimally-invasively and increased use of neochord implantation ± limited leaflet resection was observed. Patients operated minimally invasively had longer aortic cross-clamp times (94 vs. 88 min, p = 0.001) but shorter ventilation times (4.4 vs. 4.8 h, p = 0.002) and hospital stays (5 vs. 6 days, p < 0.001) than those operated via sternotomy, with no significant differences in other outcome variables. A total of 16 patients underwent robotically assisted MVr with successful repair in all cases.ConclusionA focused approach towards minimally invasive MVr has transformed the overall MVr strategy (incision; repair techniques) at our institution, leading to a growth in MVr volume and improved repair rates without significant complications. On this foundation, robotic MVr was first introduced at our institution in 2021 with excellent outcomes. This emphasizes the importance of building a competent team to perform these challenging operations, especially during the initial learning curve

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study

Background and ObjectivesTo report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.MethodsWe retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.ResultsWe identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.DiscussionGFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome

Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter = 4.0 cm in adults, or a Z-score = 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Psychological aspects of ortho-surgical protocols

By the results of an exploratory research, we were able to put forward the specificity of the request in ortho-surgical protocol. Even if many studies evaluated correlations between psychological profiles and postoperative dissatisfaction, no one asked for the link between initial request and postoperative dissatisfaction. We suggest setting up an observation and forwardlooking research’s protocol: 100 patients must been followed in a longitudinal way during 3 years (medium time between the first consultation and 6 months after the surgery). The whole duration of the study is about 4 years. It’s divided in three times: treatment’s proposal, preoperative hospitalization’s day, postoperative hospitalization’s day (three psychological interviews after the auto-administration of a clinical questionnaire, the Rathus Scale, the Hamilton depression and anxiety scale and the SF-36 quality of life scale. The research’s main objective is to study the correlation between initial request and the satisfaction level. The second objectives are the evaluation of self-respect, anxiety, depression, and quality of life scales at the three times of the research, and the evaluation of the psychological following’s impact on the results. Thirdly, we want to set up a questionnaire upon the initial request to help the practitioners

La dimension psychique dans les protocoles chirurgico-orthodontiques

Si de nombreuses études ont évalué les corrélations entre profil psychologique et insatisfaction post-opératoire, aucune n’a cherché à étudier en quoi la demande initiale pouvait être le vecteur majeur de l’insatisfaction post-opératoire. Les résultats d’une étude exploratoire ont permis de dégager la spécificité de la demande de protocole chirurgico-orthodontique. Nous proposons la mise en place d’un protocole de recherche observationnel et prospectif : 100 patients inclus seront suivis de manière longitudinale sur trois ans (temps moyen entre la première consultation et six mois en post-opératoire). La durée totale de l’étude est de quatre ans et se découpe en trois temps : proposition de traitement, HDJ pré- opératoire, HDJ post-opératoire (trois entretiens psychologiques après l’administration d’un questionnaire clinique, de l’échelle d’affirmation de soi de Rathus, de l’échelle de dépression et d’anxiété d’Hamilton et de l’échelle de qualité de vie SF-36). L’objectif principal de la recherche est d’étudier la corrélation entre la demande initiale et le degré de satisfaction. Les objectifs secondaires sont l’évaluation de l’évolution des scores d’estime de soi, d’anxiété et de dépression, et de qualité de vie aux trois temps de la recherche; l’impact du suivi psychologique sur cette évolution; la mise en place d’un questionnaire portant sur la demande initiale susceptible d’orienter le praticien sur l’adéquation du traitement