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Objective: To differentiate clinical and non‐clinical depression via a set of symptoms. Methods: A sample of 140 patients attending a clinical service for those with mood disorders together with 40 subjects denying ever experiencing a clinical episode of depression were compared, with participants completing a questionnaire capturing many symptoms of depression as well as illness correlates. Results: A latent class analysis of symptom data identified two classes and with class assignment corresponding strongly with initial clinical vs. non‐clinical assignment. Univariate analyses identified the extent to which individual symptoms contributed to differentiation. Study data suggested DSM criteria that would benefit from re‐writing or of reassignment. Two models for classifying clinical depression were generated. The first involved individuals feeling hopeless and also being suicidal or at risk of self‐harm. The second involved a symptom set corresponding to DSM‐5 criteria but with only five making significant independent contributions to diagnostic differentiation. Conclusion: The study is heuristic in offering a strategy for more precisely differentiating clinical and non‐clinical depression in more representative samples, so allowing resolution of key features, and determining whether a monothetic or polythetic diagnostic symptom criterion model is optimal. [ABSTRACT FROM AUTHOR]

We introduce a multi-species chemotaxis type system admitting an arbitrarily large number of population species, all of which are attracted versus repelled by a single chemical substance. The production versus destruction rates of the chemotactic substance by the species is described by a probability measure. For such a model, we investigate the variational structures, in particular, we prove the existence of Lyapunov functionals, we establish duality properties as well as a logarithmic Hardy–Littlewood–Sobolev type inequality for the associated free energy. The latter inequality provides the optimal critical value for the conserved total population mass. [ABSTRACT FROM AUTHOR]

For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer., Competing Interests: Declaration of interests S.L.: consulting fees, honoraria, travel/accommodation or research funding (Sanofi, GLG Consulting, Rejuversen, Eisai, Prosigna, Roche, Pfizer, Novartis, Shionogi, Synthon, CRUK, Boehringer Ingelheim, Piqur Therapeutics, AstraZeneca, Carrick Therapeutics, Merck KGaA) and previous employment by Pfizer. A.R.: stock ownership (Amgen, Immunogen). I.K: honoraria, travel/accommodation (BMS , Delcath Inc, Immunocore, Pierre Fabre, Genentech, Merck Serono, Takeda Pharmaceuticals Int.). B.J.V.D.E.: consulting and ownership interests (iTeos Therapeutics, Oncorus, Amgen, Vaccitech). M.R.M.: grants or personal fees (AstraZeneca, Roche, G.S.K., Novartis, Immunocore, BMS, Pfizer, Merck/MSD, Regeneron, BiolineRx, Replimune, Kineta, Silicon Therapeutics and GRAIL). T.M.C.: founder, employee, and shareholder (Cleancard). X.L.: consulting (SimCell). A provisional patent related to applications of the INCITE signature has been filed. No other authors declare competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers., Patients and Methods: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS)., Results: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome., Conclusions: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective., (©2022 American Association for Cancer Research.)

Cupressaceae pollen causes allergic reactions worldwide with long-lasting symptomatic periods. Currently, no cypress polcalcin is available for diagnostic purposes. With the aim to investigate the pattern of sensitization to a cypress polcalcin, a synthetic gene of Jun o 4, the Juniperus oxycedrus 4EF-hand polcalcin, was cloned and expressed in Escherichia coli. Its features were investigated in comparison with the grass 2EF-hand Phl p 7. Rhinitis was the symptom most frequently reported in a cohort of Italian patients sensitized to rJun o 4 and/or rPhl p 7. The detection of many pollen allergic patients sensitized to the cypress polcalcin, but negative to Phl p 7, indicates that Phl p 7 cannot be further considered a marker of sensitization towards all the polcalcins. A 4EF-hand cypress polcalcin claims the inclusion in allergy diagnostic tests. In addition, the sensitivity of polcalcins to gastrointestinal digestion is reported and discussed for the first time., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To demonstrate that there can be distinctive differences in information generated by standard interval measures as against using daily monitoring for evaluating progress in those with a bipolar disorder., Method: We undertook a 20-week study of individuals with a bipolar II disorder randomly assigned to receive either lamotrigine or lithium. Patients were rated on standard measures of depression and hypomania at monthly intervals, and they also completed a daily rating measure of their mood swings. We sought to demonstrate the potential for differing interpretations that emerge from these measurement strategies., Results: We graphed data for one subject who showed distinct improvement but demonstrated distinctly differing trajectories provided by monthly and daily data. In a second analysis, we considered sets of those who were judged as improving distinctly with lithium or lamotrigine to determine whether the drugs differed in speed of action, and again observed differing patterns between monthly and daily rating measures., Conclusions: A daily rating strategy appeared to provide additional and differing data compared to standard monthly measures. We therefore argue for the inclusion of daily mood ratings in clinical trials evaluating mood stabilisers and their use by clinicians in managing those with a bipolar II disorder.

Purpose/background: No study to date has compared lithium and lamotrigine as maintenance mood stabilizers for bipolar II disorder. The aim of this study was to evaluate and compare these two medications in terms of their maintenance efficacy and side effect profile, thus evaluating their comparative cost/benefit profile., Methods/procedures: Forty-four subjects with a newly diagnosed bipolar II disorder were randomly assigned to receive either lithium or lamotrigine treatment in a 20-week single-blinded study. Subjects received either slow-release lithium progressively up-titrated to achieve a serum level of 0.8 mEq/L, or lamotrigine increased progressively to a maintenance dose of 200 mg/d. Our primary outcome measure examined daily data on hypomanic and depressive symptoms. Secondary measures evaluated hypomanic and depressive symptom severity, global functioning, and global improvement in hypomanic and depressive symptoms., Findings/results: We terminated the trial principally because of severe ongoing side effects experienced by many of those receiving lithium, and with additional concerns about initial severe side effects (including psychosis) experienced by several assigned to lamotrigine. Analyses of study completer data for 28 participants suggested comparable efficacy of both medications; however, lamotrigine had a distinctly lower rate of severe side effects across the study. We calculated that if study trends on outcome measures were valid, then an extremely large sample would be required to demonstrate superiority of either drug, thus making it unlikely that any such adequately powered study will be mounted in the future., Implications/conclusions: The small sample size limits any definitive conclusions, but our data suggest that lithium and lamotrigine are likely to have equal efficacy as mood stabilizers for those with a bipolar II condition but that, as maintenance treatments, lithium has more distinctive side effects., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1 + tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC. Clinical responses were assessed by irRC. T cell and Ab responses were assessed by ex vivo IFN-gamma ELIspot and ELISA. Tumor biopsies pre- and post-treatment were evaluated for immune infiltrates. Eight patients were enrolled: 5, 2, and 1 in Arms A-C, respectively. There were no DLTs. Best clinical responses were SD (4) and PD (4). T-cell and antibody (Ab) responses to NY-ESO-1 were detected in 6 (75%) and 7 (88%) patients, respectively, and were associated with SD. The breadth of Ab responses was greater for patients with SD than PD ( p = .036). For five patients evaluable in the TME, treatment was associated with increases in proliferating (Ki67 + ) CD8 + T cells and decreases in RORγt + CD4 + T cells. T cell densities increased for those with SD. Detection of T cell responses to NY-ESO-1 ex vivo in most patients suggests that IPI may have enhanced those responses. Proliferating intratumoral CD8 + T cells increased after vaccination plus IPI suggesting favorable impact of IPI plus NY-ESO-1 vaccines on the TME. List of Abbreviations : Ab = antibody; CTCAE = NCI Common Terminology Criteria for Adverse Events; DHFR/DHRP = dihydrofolate reductase; DLT = Dose-limiting toxicity; ELISA = enzyme-linked immunosorbent assay; IFA = incomplete Freund's adjuvant (Montanide ISA-51); IFNγ = Interferon gamma; IPI = Ipilimumab; irRC = immune-related response criteria; mIFH = multispectral immunofluorescence histology; OLP = NY-ESO-1 overlapping long peptides; PBMC = peripheral blood mononuclear cells; PD = Progressive disease; pICLC = poly-ICLC (Hiltonol), a TLR3/MDA-5 agonist; RLT = Regimen-limiting Toxicity; ROI = regions of interest; RT = room temperature; SAE = serious adverse event; SD = stable disease; TEAE = treatment-emergent adverse events; TLR = toll-like receptor; TME = tumor microenvironment; TRAE = treatment-related adverse events., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab., Patients and Methods: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety., Results: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients., Conclusions: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab., (©2020 American Association for Cancer Research.)

Oral allergy syndrome (OAS) is one of the most common IgE-mediated allergic reactions. It is characterized by a number of symptoms induced by the exposure of the oral and pharyngeal mucosa to allergenic proteins belonging to class 1 or to class 2 food allergens. OAS occurring when patients sensitized to pollens are exposed to some fresh plant foods has been called pollen food allergy syndrome (PFAS). In the wake of PFAS, several different associations of allergenic sources have been progressively proposed and called syndromes. Molecular allergology has shown that these associations are based on IgE co-recognition taking place between homologous allergens present in different allergenic sources. In addition, the molecular approach reveals that some allergens involved in OAS are also responsible for systemic reactions, as in the case of some food Bet v 1-related proteins, lipid transfer proteins and gibberellin regulated proteins. Therefore, in the presence of a convincing history of OAS, it becomes crucial to perform a patient's tailored molecule-based diagnosis in order to identify the individual IgE sensitization profile. This information allows the prediction of possible cross-reactions with homologous molecules contained in other sources. In addition, it allows the assessment of the risk of developing more severe symptoms on the basis of the features of the allergenic proteins to which the patient is sensitized. In this context, we aimed to provide an overview of the features of relevant plant allergenic molecules and their involvement in the clinical onset of OAS. The value of a personalized molecule-based approach to OAS diagnosis is also analyzed and discussed., Competing Interests: Competing interestsCA, MLB, RF, DZ and AM as ADL stakeholder, develop, manufacture, and distribute the FABER test as a diagnostic service. LT, TR and IG as employees of ADL contribute to develop, manufacture and perform the FABER test. MAC and MT receive funding from ADL., (© The Author(s) 2020.)