Tumour-associated antigenic peptides are present in the HLA class I ligandome of cancer cell line derived extracellular vesicles

Funding: Breast Cancer Now (Grant Number(s): 2018JulPR1086), Wellcome Trust (GrantNumber(s): 105621/Z/14/Z), Melville Charitable Trust.The recent success of monoclonal antibody checkpoint inhibitor therapies that enhance the ability of CD8+ T cells to detect cancer-related antigenic peptides has refocused the need to fully understand the repertoire of peptides being presented to the immune system. Whilst the peptide ligandome presented by cell surface human leucocyte antigen class I (HLA-I) molecules on cancer cells has been studied extensively, the ligandome of extracellular vesicles (EVs) remains poorly defined. Here we report the HLA-I ligandome of both the cell surface and EVs from eight breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-361, MDA-MB-415, MDA-MB-453, HCC 1806, HCC 1395, and HCC 1954), and additionally the melanoma cell line ESTDAB-056 and the multiple myeloma line RPMI 8226. Utilising HLA-I immunoisolation and mass spectrometry, we detected a total of 6574 peptides from the cell surface and 2461 peptides from the EVs of the cell lines studied. Within the EV HLA-I ligandome, we identified 150 peptides derived from tumour associated antigenic proteins, of which 19 peptides have been shown to elicit T cell responses in previous studies. Our data thus shows the prevalence of clinically relevant tumour-associated antigenic peptides in the HLA-I ligandome presented on EV.Publisher PDFPeer reviewe

Concert recording 2018-04-20a

[Track 1]. Caro mio ben / Giuseppe Giordani -- [Track 2]. Alma del core / Antonio Caldara -- [Track 3]. A little bit in love from Wonderful town / Bernstein -- [Track 4]. Im Abendrot / Franz Schubert -- [Track 5]. Something\u27s coming from West side story / Bernstein -- [Track 6]. Che far senza Euridice from Orfeo e Euridice / Christoph Willibald Gluck -- [Track 7]. What a movie from Trouble in Tahiti / Bernstein -- [Track 8]. Simple song from Mass / Bernstein -- [Track 9]. Round midnight / Thelonius Monk -- [Track 10]. My house from Peter Pan / Bernstein -- [Track 11]. Heaven help my heart from Chess / Andersson & Ulvaeus -- [Track 12]. L\u27heure exquise / Reynaldo Hahn -- [Track 13]. Captain Hook\u27s soliloquy from Peter Pan / Bernstein -- [Track 14]. Two love songs. Extinguish my eyes [Track 15]. When my soul touches yours / Bernstein -- [Track 16]. Go on from Mass / Bernstein -- [Track 17]. Wanderers Nachtlied / Schubert -- [Track 18]. Peter, Peter from Peter Pan / Bernstein -- [Track 19]. L\u27escalve / Édouard Lalo -- [Track 20]. Allerseelen / Richard Strauss -- [Track 21]. Nothing more than this from Candide / Bernstein -- [Track 22]. O del mio dolce ardor / Gluck -- [Track 23]. Governer\u27s serenade from Candide / Bernstein -- [Track 24]. Sogno d\u27or / Giacomo Puccini -- [Track 25]. I understand from On the town / Bernstein -- [Track 26]. Dream with me from Peter Pan / Bernstein -- [Track 27]. Il est doux, il est bon from Herodiade / Jules Massenet -- [Track 28]. Easter from Five mystical songs / Ralph Vaughan Williams -- [Track 29]. One hand, one heart from West side story / Bernstein -- [Track 30]. Porgi amor from Les Nozze di Figaro / Wolfgang Amadeus Mozart -- [Track 31]. Glitter and be gay from Candide / Bernstein

Concert recording 2017-11-06

[Track 1]. Sebben crudele / Antonio Caldara -- [Track 2]. Orpheus with his lute / William Schuman -- [Track 3]. Heaven help my heart -- [Track 4]. Little elegy / John Duke -- [Track 5]. Bel piacere / G.F. Handel -- [Track 6]. I dreamed a dream from Les Miserables / Claude-Michel Schönberg -- [Track 7]. In questa tomba oscura / Ludwig van Beethoven -- [Track 8]. Lasst mich nur auf meinem Sattel gelten! from Freisinn / Robert Shumann -- [Track 9]. Für Musik / Robert Franz -- [Track 10]. Edelweiss from The sound of music / Rodgers & Hammerstein -- [Track 11]. Tu lo sai / Giuseppe Torelli -- [Track 12]. Glück / Max Reger -- [Track 13] Le colibri / Ernest Chausson -- [Track 14] Der Der Schäfer / Hugo Wolf -- [Track 15]. A route to the sky / Jake Heggie -- [Track 16]. Ich liebe dich / Edvard Grieg -- [Track 17]. When it all fall down from Chaplin / Christopher Curtis -- [Track 18]. Voyage a Paris / Francis Poulenc -- [Track 19]. Crucifixion / arr. Hall Johnson -- [Track 20]. Bright is the ring of words / Ralph Vaughan Williams -- [Track 21]. Non t\u27amo piu / Francesco Paolo Tosti -- [Track 22]. Se tu m\u27ami / Alessandro Parisotti -- [Track 23]. I love the way from Something\u27s rotten / Kirkpatrick & Kirkpatrick -- [Track 24]. A madrigal / Herbert Howells -- [Track 25]. El majo discrete / Enrique Granados -- [Track 26]. The roadside fire / Ralph Vaughan Williams -- [Track 27]. Che fiero costume / Giovanni Legrenzi -- [Track 28]. An die Musik / Franz Shubert -- [Track 29]. I will sing new songs of gladness / Anton Dvorak -- [Track 30]. Full fathom five from The tempest / Henry Purcell -- [Track 31]. Nimmerstate Libe / Hugo Wolf -- [Track 32]. Deposuit potentes from Magnificat / Johann Sebastian Bach -- [Track 33]. Vaghissima sembiante / Stefano Donaudy -- [Track 34]. Tormani a vaghegghiar from Alcina / G.F. Handel -- [Track 35]. Nobody knows this little rose / John Duke -- [Track 36]. Let beauty awake / Ralph Vaughan Williams -- [Track 37]. Steal away / arr. Hall Johnson -- [Track 38]. Come paride vezzoso from L\u27elisir d\u27amore / Kirkpatrick & Kirkpatrick -- [Track 39]. Dich, teure Halle from Tannhaüser / Richard Wagner -- [Track 40]. Non t\u27accotare all\u27urna / Giuseppe Verdi -- [Track 41]. Zur Rosenzeit / Edvard Grieg

Concert recording 2017-04-29

[Track 1]. When the children are asleep from Carousel / Richard Rogers & Oscar Hammerstein -- [Track 2]. Quartet from The secret garden / Lucy Simon -- [Track 3]. Agony from Into the woods / Stephen Sondheim -- [Track 4]. Stepsister\u27s lament from Cinderella / Rogers & Hammerstein -- [Track 5]. Only love from The scarlet pimpernel / Frank Wildhorn -- [Track 6]. Schroeder from You\u27re a good man Charlie Brown / Clark Gesner -- [Track 7]. Where in the world from The secret garden [Track 8]. How could I ever know from The secret garden / Lucy Simon -- [Track 9]. Who am I from Peter Pan / Leonard Bernstein -- [Track 10]. Some things are meant to be from Little Women / Jason Howland -- [Track 11]. With you from Ghost / Bruce Joel Rubin -- [Track 12]. When he sees me from Waitress [Track 13]. Never ever getting rid of me from Waitress / Sara Bareilles -- [Track 14]. Sepia life from Grateful / John Bucchino -- [Track 15]. Thank you for the music from Mamma mia / Benny Andersson & Björn Ulvaeus -- [Track 16]. Agony reprise from Into the woods / Stephen Sondheim -- [Track 17]. If I loved you from Carousel / Rodgers & Hammerstein

Attention bias to emotional faces varies by IQ and anxiety in Williams syndrome

Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N=46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570