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Immune checkpoint (IC) blockade and adoptive transfer of tumor-specific T-cells (ACT) are two major strategies to treat metastatic melanoma. Their combination can potentiate T-cell activation in the suppressive tumor microenvironment, but the autoimmune adverse effects associated with systemic injection of IC blockers persist with this strategy. ACT of tumor-reactive T-cells defective for IC expression would overcome this issue. For this purpose, PD-1 and TIGIT appear to be relevant candidates, because their co-expression on highly tumor-reactive lymphocytes limits their therapeutic efficacy within the tumor microenvironme,nt. Our study compares the consequences of PDCD1 or TIGIT genetic deletion on anti-tumor properties and T-cell fitness of melanoma-specific T lymphocytes. Transcriptomic analyses revealed down-regulation of cell cycle-related genes in PD-1 KO T-cells, consistent with biological observations, whereas proliferative pathways were preserved in TIGIT KO T-cells. Functional analyses showed that PD-1 KO and TIGIT KO T-cells displayed superior antitumor reactivity than their wild-type counterpart in vitro and in a preclinical melanoma model using immunodeficient mice. Interestingly, it appears that TIGIT KO T-cells were more effective at inhibiting tumor cell proliferation in vivo , and persist longer within tumors than PD-1 KO T-cells, consistent with the absence of impact of TIGIT deletion on T-cell fitness. Taken together, these results suggest that TIGIT deletion, over PD-1 deletion, in melanoma-specific T-cells is a compelling option for future immunotherapeutic strategies., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Male C57BL/6N mice exposed to the chronic subordinate colony housing (CSC; 19 days) paradigm, a preclinically validated model of chronic psychosocial stress, are characterized by unaffected basal morning plasma corticosterone (CORT) concentrations despite adrenal and pituitary hyperplasia and increased adrenocorticotropic hormone (ACTH) plasma concentrations, compared with single-housed control (SHC) mice. However, as CSC mice are still able to show an increased CORT secretion towards novel heterotypic stressors, these effects might reflect an adaptation rather than a functional breakdown of general hypothalamus-pituitary-adrenal (HPA) axis functionality. In the present study we used male mice of a genetically modified mouse line, to investigate whether genetically-driven ACTH overexpression compromises adaptational processes occurring at the level of the adrenals during CSC exposure. Experimental mice carried a point mutation in the DNA binding domain of the glucocorticoid (GC) receptor (GR), attenuating dimerization of GR (GR dim ), resulting in a congenially compromised negative feedback inhibition at the level of the pituitary. In line with previous studies, CSC mice in both the wild type (WT; GR +/+ ) and GR dim group developed adrenal enlargement. Moreover, compared with respective SHC and WT mice, CSC GR dim mice show increased basal morning plasma ACTH and CORT concentrations. Quantitative polymerase chain reaction (qPCR) analysis revealed neither a genotype effect, nor a CSC effect on pituitary mRNA expression of the ACTH precursor proopiomelanocortin (POMC). Finally, CSC increased anxiety-related behavior, active coping and splenocyte in vitro (re)activity in both WT and GR dim mice, while a CSC-induced increase in adrenal lipid vesicles and splenic GC resistance was detectable only in WT mice. Of note, lipopolysaccharide (LPS)-stimulated splenocytes of GR dim mice were resistant to the inhibitory effects of CORT. Together our findings support the hypothesis that pituitary ACTH protein concentration is negatively controlled by GR dimerization under conditions of chronic psychosocial stress, while POMC gene transcription is not dependent on intact GR dimerization under both basal and chronic stress conditions. Finally, our data suggest that adrenal adaptations during chronic psychosocial stress (i.e., ACTH desensitization), aiming at the prevention of prolonged hypercorticism, are protective only to a certain threshold of plasma ACTH levels., Competing Interests: DL, MK, SK, LG, LK, MT, MNH, SV, JT and SOR have nothing to declare and do not have any conflict of interest., (© 2023 The Authors.)

Background: Methylation at 5 CpG sites was previously shown to classify chronic lymphocytic leukemia (CLL) into 3 prognostic subgroups. Here, we aimed to validate the marker set in an additional cohort and to evaluate its clinical utility for CLL patient stratification., Methods: We evaluated this epigenetic marker set in 79 German patients using bisulfite treatment followed by pyrosequencing and classification using a support vector machine-learning tool., Results: The n-CLL, i-CLL, and m-CLL classification was detected in 28 (35%), 10 (13%), and 41 (51%) patients, respectively. Epigenetic grouping was associated with IGHV mutational status ( P  = 2 × 10 -12 ), isolated del13q ( P  = 9 × 10 -6 ), del17p ( P  = .015), complex karyotype ( P  = .005), VH-usage, and clinical outcome as time to first treatment ( P  = 1.4 × 10 -12 ) and overall survival ( P  = .003). Multivariate Cox regression analysis identified n-CLL as a factor for earlier treatment hazard ratio (HR), 6.3 (95% confidence interval [CI] 2.4-16.4; P  = .0002) compared to IGHV mutational status (HR 4.6, 95% CI 1.9-11.3, P  = .0008). In addition, when comparing the prognostic value of the epigenetic classification system with the IGHV classification, epigenetic grouping performed better compared to IGHV mutational status using Kaplan-Meier estimation and allowed the identification of a third, intermediate (i-CLL) group. Thus, our study confirmed the prognostic value of the epigenetic marker set for patient stratification in routine clinical diagnostics., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M. Ha. received research funding, consulting, and lecture fees from Roche, Abbvie, Gilead, Janssen, Celgene, and Astra Zeneca. The remaining authors declare no competing interests., (© The Author(s) 2022.)

Background: Thus far, most researchers on genocide and transgenerational transmissions have focused on the National Socialist Holocaust as the most abhorrent example of this severe human rights violation. Few data have been published on other ethnic or religious groups affected by genocidal actions in this context., Methodology: Using a mixed-method approach integrating qualitative interviews with standardized instruments (SCID and PDS), this study examines how individual and collective trauma have been handed down across three generations in an Alevi Kurd community whose members (have) suffered genocidal perpetrations over a longer time period (a "genocidal environment"). Qualitative, open-ended interviews with members of three generations answering questions yielded information on (a) how their lives are shaped by the genocidal experiences from the previous generation and related victim experiences, (b) how the genocidal events were communicated in family narratives, and (c) coping strategies used. The first generation is the generation which directly suffered the genocidal actions. The second generation consists of children of those parents who survived the genocidal actions. Together with their family (children, partner, relatives), this generation suffered forced displacement. Members of the third generation were born in the diaspora where they also grew up., Results: Participants reported traumatic memories, presented in examples in this publication. The most severe traumatic memories included the Dersim massacre in 1937-1938 in Turkey, with 70,000-80,000 victims killed, and the enforced resettlement in western Turkey. A content analysis revealed that the transgenerational transmission of trauma continued across three generations. SCID and PDS data indicated high rates of distress in all generations., Conclusions: Genocidal environments such as that of the Kurdish Alevis lead to transgenerational transmission mediated by complex factors.

Background: Childhood melanocytic tumors represent a diagnostic and therapeutic challenge, and additional research is needed to better define the natural history of these tumors., Methods: The authors developed a comprehensive, prospective registry called Molecular Analysis of Childhood Melanocytic Tumors for children and adolescents with an atypical Spitz tumor/Spitz melanoma (AST/SM), conventional or adult-type melanoma (CM), melanoma arising in a giant congenital nevus (MCM), or atypical melanocytic proliferation of other types (OT) to better define the clinical behavior of these lesions by incorporating an integrated clinicopathologic and molecular analysis using centralized pathology review and various platforms, including fluorescence in situ hybridization; array comparative genomic hybridization; and whole genome, exome, and capture targeted panels., Results: From May 2016 to November 2019, 70 children were enrolled with a median age at diagnosis of 9.1 years. Thirty-seven had AST/SM, 17 had CM, 4 had MCM, and 12 had OT. Patients with AST/SM were younger (median age, 7 years), and their tumor most commonly arose in the extremities and trunk. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT promoter mutation analysis had a mutation, and all patients were alive. Among the CM patients, the median age was 13 years; 11 had a BRAFV600E mutation, and 7 had a TERT promoter mutation. Three patients died of their disease. All 4 patients with MCM harbored an NRASQ61 mutation and died of their disease. The OT group was heterogenous, and all patients survived., Conclusions: The incorporation of an integrated clinicopathologic and genomic analysis identifies distinct subgroups of pediatric melanocytic lesions that have different clinical behaviors. The integration of this combined diagnostic modality can help to individualize diagnoses and treatments for these patients., (© 2021 American Cancer Society.)

Recent fMRI studies on specific animal phobias, particularly spider phobia (arachnophobia), have identified a large variety of specific brain regions involved in normal and disturbed fear processing. Both functional and structural brain abnormalities have been identified among phobic patients. Current research suggests that both conscious and subconscious fear processing play a crucial role in phobic disorders. Cognitive behavioral therapy has been identified as an effective treatment for specific phobias and has been associated with neuroplastic effects which can be evaluated using current neuroimaging techniques. Recent research suggests that new approaches using virtual (VR) or augmented reality (AR) tend to be similarly effective as traditional " in vivo " therapy methods and could expand treatment options for different medical or individual scenarios. This narrative review elaborates on neural structures and particularities of arachnophobia. Current treatment options are discussed and future research questions are highlighted., Competing Interests: KD is a member of Janssen Pharmaceuticals Steering Committee Neurosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hinze, Röder, Menzie, Müller, Domschke, Riemenschneider and Noll-Hussong.)

Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity.

We report programmable receptors for the imaging-based analysis of 5-methylcytosine (5mC) in user-defined DNA sequences of single cells. Using fluorescent transcription-activator-like effectors (TALEs) that can recognize sequences of canonical and epigenetic nucleobases through selective repeats, we imaged cellular SATIII DNA, the origin of nuclear stress bodies (nSB). We achieve high nucleobase selectivity of natural repeats in imaging and demonstrate universal nucleobase binding by an engineered repeat. We use TALE pairs differing in only one such repeat in co-stains to detect 5mC in SATIII sequences with nucleotide resolution independently of differences in target accessibility. Further, we directly correlate the presence of heat shock factor 1 with 5mC at its recognition sequence, revealing a potential function of 5mC in its recruitment as initial step of nSB formation. This opens a new avenue for studying 5mC functions in chromatin regulation in situ with nucleotide, locus, and cell resolution., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)