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Abstract Cancer curing immune responses against heterogeneous solid cancers require that a coordinated immune activation is initiated in the antigen avid but immunosuppressive tumor microenvironment (TME). The plastic TME, and the poor systemic tolerability of immune activating drugs are, however, fundamental barriers to generating curative anticancer immune responses. Here, we introduce the CarboCell technology to overcome these barriers by forming an intratumoral sustained drug release depot that provides high payloads of immune stimulatory drugs selectively within the TME. The CarboCell thereby induces a hot spot for immune cell training and polarization and further drives and maintains the tumor-draining lymph nodes in an anticancer and immune activated state. Mechanistically, this transforms cancerous tissues, consequently generating systemic anticancer immunoreactivity. CarboCell can be injected through standard thin-needle technologies and has inherent imaging contrast which secure accurate intratumoral positioning. In particular, here we report the therapeutic performance for a dual-drug CarboCell providing sustained release of a Toll-like receptor 7/8 agonist and a transforming growth factor-β inhibitor in preclinical tumor models in female mice.

Abstract Objective Investigate the feasibility of detecting early treatment-induced tumor tissue changes in patients with advanced lung adenocarcinoma using diffusion-weighted MRI-derived radiomics features. Methods This prospective observational study included 144 patients receiving either tyrosine kinase inhibitors (TKI, n = 64) or platinum-based chemotherapy (PBC, n = 80) for the treatment of pulmonary adenocarcinoma. Patients underwent diffusion-weighted MRI the day prior to therapy (baseline, all patients), as well as either + 1 (PBC) or + 7 and + 14 (TKI) days after treatment initiation. One hundred ninety-seven radiomics features were extracted from manually delineated tumor volumes. Feature changes over time were analyzed for correlation with treatment response (TR) according to CT-derived RECIST after 2 months and progression-free survival (PFS). Results Out of 14 selected delta-radiomics features, 6 showed significant correlations with PFS or TR. Most significant correlations were found after 14 days. Features quantifying ROI heterogeneity, such as short-run emphasis (p = 0.04(pfs)/0.005(tr)), gradient short-run emphasis (p = 0.06(pfs)/0.01(tr)), and zone percentage (p = 0.02(pfs)/0.01(tr)) increased in patients with overall better TR whereas patients with worse overall response showed an increase in features quantifying ROI homogeneity, such as normalized inverse difference (p = 0.01(pfs)/0.04(tr)). Clustering of these features allows stratification of patients into groups of longer and shorter survival. Conclusion Two weeks after initiation of treatment, diffusion MRI of lung adenocarcinoma reveals quantifiable tissue-level insights that correlate well with future treatment (non-)response. Diffusion MRI-derived radiomics thus shows promise as an early, radiation-free decision-support to predict efficacy and potentially alter the treatment course early. Critical relevance statement Delta-Radiomics texture features derived from diffusion-weighted MRI of lung adenocarcinoma, acquired as early as 2 weeks after initiation of treatment, are significantly correlated with RECIST TR and PFS as obtained through later morphological imaging. Key Points Morphological imaging takes time to detect TR in lung cancer, diffusion-weighted MRI might identify response earlier. Several radiomics features are significantly correlated with TR and PFS. Radiomics of diffusion-weighted MRI may facilitate patient stratification and management. Graphical Abstract

Abstract Given the profound societal impact of conspiracy theories, probing the psychological factors associated with their spread is paramount. Most research lacks large-scale behavioral outcomes, leaving factors related to actual online support for conspiracy theories uncertain. We bridge this gap by combining the psychological self-reports of 2506 Twitter (currently X) users with machine-learning classification of whether the textual data from their 7.7 million social media engagements throughout the pandemic supported six common COVID-19 conspiracy theories. We assess demographic factors, political alignment, factors derived from theory of reasoned action, and individual psychological differences. Here, we show that being older, self-identifying as very left or right on the political spectrum, and believing in false information constitute the most consistent risk factors; denialist tendencies, confidence in one’s ability to spot misinformation, and political conservativism are positively associated with support for one conspiracy theory. Combining artificial intelligence analyses of big behavioral data with self-report surveys can effectively identify and validate risk factors for phenomena evident in large-scale online behaviors.

Abstract In the age of misinformation, conspiracy theories can have far-reaching consequences for individuals and society. Social and emotional experiences throughout the life course, such as loneliness, may be associated with a tendency to hold conspiracist worldviews. Here, we present results from a population-based sample of Norwegians followed for almost three decades, from adolescence into midlife (N = 2215). We examine participants’ life trajectories of loneliness using latent growth curve modeling. We show that people reporting high levels of loneliness in adolescence, and those who experience increasing loneliness over the life course, are more likely to endorse conspiracy worldviews in midlife.

Abstract Background Social anxiety disorder (SAD) most commonly develops in adolescence—a period of life that includes a transition to upper secondary school. The aim of this study is to investigate the extent to which social anxiety in adolescence is associated with the completion of upper secondary school and progression to higher education. Methods This longitudinal study includes 8,192 adolescents aged 13–19 years who participated in the Norwegian Young-HUNT 3 population-based study. Social anxiety is measured employing (1) diagnostic interview screening questions (interview) and (2) a self-reported symptom index (questionnaire). Notably, we define the cohorts based on these two methods. Using national educational data (2008–2019), we follow educational attainment among the cohorts until they turn 25 years of age. Results We found that adolescents who screened positive (SP) for SAD had a predicted probability of upper secondary school completion at 21 years of age that was 14% points lower than those who screened negative (SN). Further, differences remained when looking at completion rates at age 25 years. Moreover, predicted probabilities for completion were inversely associated with increasing levels of self-reported social anxiety symptoms. Similarly, the proportion of the completers of an academic program in the SP group that were enrolled in higher education by 25 years of age, were lower than for the SN group (87 vs. 92%). Conclusion Social anxiety in adolescence, both self-reported symptoms and diagnostic screening, has long-term negative impact on upper secondary school completion and to some extent enrollment to higher education.

Abstract Background It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma. Methods RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70+ tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs. Results In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70+ tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70+ tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner. Conclusions We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70+ cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.

This paper presents and critically discusses the 'logos approach to quantum mechanics' from the point of view of the current debates concerning the relation between metaphysics and science. Due to its alleged direct connection with quantum formalism, the logos approach presents itself as a better alternative for understanding quantum mechanics than other available views. However, we present metaphysical and methodological difficulties that seem to clearly point to a different conclusion: the logos approach is on an epistemic equal footing among alternative realist approaches to quantum mechanics., Author(s): Raoni Wohnrath Arroyo [sup.1] [sup.2] [sup.3], Jonas R. Becker Arenhart [sup.2] [sup.4] [sup.5] Author Affiliations: (1) grid.411087.b, 0000 0001 0723 2494, Centre for Logic, Epistemology and the History of [...]

Introduction: Studying the behavior on nonlinear HRV indexes in situations mediated by exercise may reveal other ways to analyze HRV recovery after stress situations. To investigate the acute effects of beet extract on autonomic recovery following an acute resistance exercise session. Methods: This is a randomized, crossover, double-blind and placebo-controlled trial. We assessed 12 healthy male adults who participated in two protocols in randomized days: Beetroot extract (600mg in capsule) and Placebo (600mg in capsule). Both protocols were applied 120 minutes prior to an exercise resistance session (75% 1RM). Nonlinear dynamics of HRV (Symbolic analysis, SampEn, DFA and HR fragmentation) were studied before, during exercise and during recovery from strength exercise. Results: Beetroot extract protocol intensified the recovery of the symbolic analysis of HRV via index 0V% (zero opposite variations) and 2UV% (two unlike variations); accelerating the recovery of fractal analysis (DFA); nevertheless, it was unable to trigger changes during recovery in SampEn and HR fragmentation. Conclusion: Ingestion of beetroot extract prior to resistance exercise improves nonlinear HRV dynamical autonomic recovery following physical effort.

Abstract Recent research suggests that music can affect evaluations of other groups and cultures. However, little is known about the objective and subjective musical parameters that influence these evaluations. We aimed to fill this gap through two studies. Study 1 collected responses from 52 American participants who listened to 30 folk-song melodies from different parts of the world. Linear mixed-effects models tested the influence of objective and subjective musical parameters of these melodies on evaluations of the cultures from which they originated. Musical parameters consistently predicted cultural evaluations. The most prominent musical parameter was musical velocity, a measure of number of pitch onsets, predicting more cultural warmth, competence and evolvedness and less cultural threat. Next, with a sample of 212 American participants, Study 2 used a within-subjects experiment to alter the tempo and dissonance for a subset of six melody excerpts from Study 1, testing for causal effects. Linear mixed-effects models revealed that both dissonance and slow tempo predicted more negative cultural evaluations. Together, both studies demonstrate how musical parameters can influence cultural perceptions. Avenues for future research are discussed.