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A central challenge in developing personalized cancer cell immunotherapy is the identification of tumor-reactive T cell receptors (TCRs). By exploiting the distinct transcriptomic profile of tumor-reactive T cells relative to bystander cells, we build and benchmark TRTpred, an antigen-agnostic in silico predictor of tumor-reactive TCRs. We integrate TRTpred with an avidity predictor to derive a combinatorial algorithm of clinically relevant TCRs for personalized T cell therapy and benchmark it in patient-derived xenografts., (© 2024. The Author(s).)

Background: Despite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear., Methods: To better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8 + and CD4 + EC - resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8 + and CD4 + TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8 + and CD4 + tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival., Results: We found that CD8 + TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1 - and PD-1 dim , respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8 + PD-1 dim CD39 + and PD-1 hi CD39 + T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4 + T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1 hi compared with PD-1 - or PD-1 dim T cells, and in fact, it was the CD4 + PD-1 hi subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8 + PD-1 hi CD39+ and CD4 + PD-1 hi tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1 hi , CD39, CXCL13 and CD103 by CD8 + TILs and PD-1 hi and CXCL13 by CD4 + Tconv TILs, correlated with prolonged survival of patients with EC., Conclusions: Our results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1 hi and CD39 or PD-1 hi can be used to select and expand CD8 + and CD4 + tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3 + , CD8 + and CD4 + lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity., Competing Interests: Competing interests: AG is a member of the scientific advisory board (SAB) of Achilles Therapeutics, SingulaBIO, RootPath, and BioNTech SE, and consults for PACT Pharma, and Instil BIo. AG is co-inventor of patents licensed and with royalties related to this work E-059-2013/0, E-085-2013/0, E-149-2015/0. IM reports grants from Roche, BMS, AstraZeneca and Genmab, as well as consultancy activities for Roche, BMS, AZ, Phamamar, F-sar, Merus, Amunix, Pieris, Numab, Third Rock and Highlight therapeutics. The authors declare that no other conflict of interest exists., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

T-cell receptor β analysis can be exploited to monitor changes in the clonotypic composition of tumor-infiltrating lymphocyte (TIL) during ex vivo expansion in IL2. Oligoclonal TILs are often outgrown by infrequent clonotypes with greater proliferative capacity, and this could impact the antitumor reactivity of the expanded TILs. See related article by Poschke et al., p. 4289 ., (©2020 American Association for Cancer Research.)

Deep brain stimulation (DBS) has been found to be effective in treatment resistant neurological and psychiatric disorders. So far there has been only one completed trial in schizophrenia, in which seven treatment resistant patients received DBS in the subgenual anterior cingulate cortex (sgACC, N = 4) or the nucleus accumbens (NAc, N = 3); four met symptomatic response criteria over the trial period. Six patients underwent 18 F-FDG PET at baseline and after at least 6 months of stimulation. Individual patient analysis indicated that DBS to both the sgACC and NAc was associated with local and distant changes in glucose metabolism. Increments and decrements of brain activity were observed in regions that included the medial prefrontal cortex, the dorsolateral prefrontal cortex, the anterior cingulate cortex, the caudate nucleus, the NAc, the hippocampus and the thalamus. Increased activity appeared to be associated with clinical improvement. These preliminary findings suggest that DBS acts by modulating cerebral activity in the cortico-basal-thalamic-cortical circuit in patients with schizophrenia who show improvement in psychotic symptoms., Competing Interests: Declaration of competing interest All authors report no biomedical financial interest or potential conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly., Methods: Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed)., Findings: One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively)., Interpretation: These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The need for early detection, prevention and intervention in psychosis has prompted the study of prodromal and threshold syndromes. One strategy involves the assessment of schizotypy, a personality construct involving unusual perceptual experiences, magical thinking or bizarre behavior. Sensitive measurement instruments could potentially allow detection of signs heralding transition to psychosis in high-risk individuals, or risk of relapse in patients after a first psychotic episode. The Schizotypal Personality Questionnaire (SPQ) is a self-report scale, originally developed for English speakers, that covers the nine DSM-IV criteria for schizotypal personality disorder (SPD). Our aim was to validate a Spanish version of the SPQ and assess its psychometric properties., Methods: The original SPQ was back-translated and administered to university students (n=250). We assessed the internal consistency, the convergent, discriminant and criterion validity of the instrument, and analyzed its factor structure., Results: Our version of the SPQ showed good internal consistency, and convergent (O-LIFE), discriminant (P-scale of EPQ) and criterion validity (SCID-II). Factor analyses supported a four-factor structure in fitting SPQ data., Conclusions: Our Spanish version of the SPQ questionnaire preserved the psychometric properties of the original questionnaire. This adaptation will provide a useful tool for the early detection of prodromal schizophrenia symptoms and clinical relapse in Spanish-speaking populations.

Background: Despite the theoretical potential of m-health solutions in the treatment of patients with schizophrenia, there remains a lack of technological solutions in daily practice. The aim of this study was to measure the receptivity of patients, informal carers, and clinicians to an integral intervention model focused on patients with persistent positive symptoms: Mobile Therapeutic Attention for Patients with Treatment Resistant Schizophrenia (m-RESIST)., Methods: A qualitative study of the needs and acceptability of outpatients with treatment-resistant schizophrenia was carried out in Parc Sanitari Sant Joan de Déu (Barcelona). We analyzed the opinions of patients, informal carers, and clinicians concerning the services initially thought to be part of the solution. Five focus groups and eight interviews were carried out, using discourse analysis as the analytical approach., Results: A webpage and a virtual forum were perceived as suitable to get reliable information on both the disease and support. Data transmission service, online visits, and instant messages were evaluated as ways to improve contact with clinicians. Alerts were appreciated as reminders of daily tasks and medical appointments. Avoiding stressful situations for outpatients, promoting an active role in the management of the disease, and maintaining human contact with clinicians were the main suggestions for improving the effectiveness of the solution., Conclusions: Positive acceptance of m-RESIST services is related to its usefulness in meeting user needs, its capacity to empower them, and the possibility of maintaining human contact.

The aim of this study is to analyze the differences in low frequency fluctuation (LFF) values between schizophrenia patients with and without auditory verbal hallucinations (AVH). Nineteen schizophrenia patients with persistent AVH (HP), fourteen non-hallucinating schizophrenia patients (nHP) and twenty healthy controls (HC) underwent R-fMRI. LFF values were calculated in the slow frequency band (0.01-0.08Hz). By means of group level contrasts, we performed direct voxel-wise group comparisons. Both groups of patients showed decreased amplitude LFF (ALFF) values in the occipital pole and lingual gyrus compared to HC, whereas increased ALFF values were found in the temporal pole and fusifom gyrus. Schizophrenia patients exhibited decreased fractional ALFF (fALFF) values in the precuneus, occipital pole and bilateral occipital cortex, and increased fALFF in the insula compared to HC. There were also differences between patients with and without AVH. (Ok to start with lower case?) fALFF values were higher in the putamen and insular cortex and lower in the frontal pole in HP compared to nHP and HC. ALFF increased in HP patients in the bilateral thalamus and bilateral parahippocampal gyrus, compared to nHP patients and HC. Our results suggest that altered dynamics in low-frequency fluctuations may play a key role in the neurophysiology of auditory hallucinations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Background: Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder characterized by odd or bizarre behavior, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. Schizophrenia proper has been associated with anomalies in dopaminergic neurotransmission and deficits in neurophysiological markers of self-monitoring, such as low amplitude in cognitive event-related brain potentials (ERPs) like the error-related negativity (ERN), and the error positivity (Pe). These components occur after performance errors, rely on adequate fronto-striatal function, and are sensitive to dopaminergic modulation. Here we postulated that analogous to observations in schizophrenia, SPD individuals would show deficits in self-monitoring, as measured by the ERN and the Pe. We also assessed the capacity of dopaminergic antagonists to reverse these postulated deficits., Methods: We recorded the electroencephalogram (EEG) from 9 SPD individuals and 12 healthy controls in two separate experimental sessions while they performed the Eriksen Flanker Task, a classical task recruiting behavioral monitoring. Participants received a placebo or 1 mg risperidone according to a double-blind randomized design., Results: After placebo, SPD individuals showed slower reaction times to hits, longer correction times following errors and reduced ERN and Pe amplitudes. While risperidone impaired performance and decreased ERN and Pe in the control group, it led to behavioral improvements and ERN amplitude increases in the SPD individuals., Conclusions: These results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

To understand the neural mechanism that underlies treatment resistant auditory verbal hallucinations (AVH), is still an important issue in psychiatric research. Alterations in functional connectivity during rest have been frequently reported in patients with schizophrenia. Though the default mode network (DN) appears to be abnormal in schizophrenia patients, little is known about its role in resistant AVH. We collected resting-state functional magnetic resonance imaging (R-fMRI) data with a 3T scanner from 19 schizophrenia patients with chronic AVH resistant to pharmacological treatment, 14 schizophrenia patients without AVH and 20 healthy controls. Using seed-based correlation analysis, we created spherical seed regions of interest (ROI) to examine functional connectivity of the two DN hub regions (posterior cingulate cortex and anteromedial prefrontal cortex) and the two DN subsystems: dorsomedial prefrontal cortex subsystem and medial temporal lobe subsystem (p<0.0045 corrected). Patients with hallucinations exhibited higher FC between dMPFC ROI and bilateral central opercular cortex, bilateral insular cortex and bilateral precentral gyrus compared to non hallucinating patients and healthy controls. Additionally, patients with hallucinations also exhibited lower FC between vMPFC ROI and bilateral paracingulate and dorsal anterior cingulate cortex. As the anterior cingulate cortex and the insula are two hubs of the salience network, our results suggest cross-network abnormalities between DN and salience system in patients with persistent hallucinations., (Copyright © 2014 Elsevier B.V. All rights reserved.)