bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin targets intestinal immune system signaling pathways in a high-fat diet-induced mouse model of obesity and insulin resistance
Authors: Brīvība Monta , Silamiķele Laila , Kalniņa Ineta , Silamiķelis Ivars , Birzniece Līga , Ansone Laura , Jagare Lauma , Elbere Ilze , Kloviņš Jānis 
Published: September 2023

IntroductionResearch findings of the past decade have highlighted the gut as the main site of action of the oral antihyperglycemic agent metformin despite its pharmacological role in the liver. Extensive evidence supports metformin’s modulatory effect on the composition and function of gut microbiota, nevertheless, the underlying mechanisms of the host responses remain elusive. Our study aimed to evaluate metformin-induced alterations in the intestinal transcriptome profiles at different metabolic states. MethodsThe high-fat diet-induced mouse model of obesity and insulin resistance of both sexes was developed in a randomized block experiment and bulk RNA-Seq of the ileum tissue was the method of choice for comparative transcriptional profiling after metformin intervention for ten weeks. ResultsWe found a prominent transcriptional effect of the diet itself with comparatively fewer genes responding to metformin intervention. The overrepresentation of immune-related genes was observed, including pronounced metformin-induced upregulation of immunoglobulin heavy-chain variable region coding Ighv1-7 gene in both high-fat diet and control diet-fed animals. Moreover, we provide evidence of the downregulation NF-kappa B signaling pathway in the small intestine of both obese and insulin-resistant animals as well as control animals after metformin treatment. Finally, our data pinpoint the gut microbiota as a crucial component in the metformin-mediated downregulation of NF-kappa B signaling evidenced by a positive correlation between the Rel and Rela gene expression levels and abundances of Parabacteroides distasonis, Bacteroides spp., and Lactobacillus spp. in the gut microbiota of the same animals. DiscussionOur study supports the immunomodulatory effect of metformin in the ileum of obese and insulin-resistant C57BL/6N mice contributed by intestinal immunoglobulin responses, with a prominent emphasis on the downregulation of NF-kappa B signaling pathway, associated with alterations in the composition of the gut microbiome.
Comparing two strategies of counter-defense against plant toxins: a modeling study on plant–herbivore interactions
Authors: Chakraborty Suman , Gershenzon Jonathan , Schuster Stefan 
Published: September 2023

IntroductionVarious herbivorous insects prefer toxic plants as their hosts, although this may appear paradoxical. They have evolved specific adaptations (called counter-defenses) against the toxins. For example, the two-component chemical defense system of plants of the Brassicaceae family against herbivores consists of glucosinolates (GLSs) and the activating enzyme myrosinase. GLS hydrolysis by myrosinase leads to isothiocyanates (ITCs), which are toxic and deterrent to many insect herbivores. Two different types of counter-defenses can be distinguished: a preemptive counter-defense that prevents the GLSs from being hydrolyzed to ITCs due to metabolic redirection and direct counter-defense, where the ITCs are formed but then metabolized to non-toxic conjugates. In general, preemptive counter-defense is only a possibility if the plant stores a precursor of the toxin, which is activated upon attack. Preemptive counter-defense is believed to be more efficient due to the lower exposure to ITCs, but this has not been satisfactorily demonstrated experimentally.MethodsHere, we derive on theoretical grounds the conditions under which preemptive counter-defense reduces exposure to ITCs compared to direct counter-defense by studying the dynamics of GLS defense and counter-defense with two separate ordinary differential equation models. We model how herbivory transfers the GLSs to the insect gut with the leaf material. Thereafter, we describe the insects’ exposure to toxins by deriving the dynamics of ITCs in the gut during feeding with the two types of counter-defenses.Results and discussionBy calculating the area under the curve (AUC) of the ITC concentrations, we show, based on empirical data, that herbivores with a preemptive detoxification system are usually less exposed to ITCs. In addition, our models explain how the decline in the level of ITCs is achieved by both counter-defenses, which helps to understand the overall mechanisms and benefits of these techniques. Our results may also apply to plant defenses by inactive toxin precursors other than GLSs as well as to insects that sequester such precursors for their own defense.
Identification of key claudin genes associated with survival prognosis and diagnosis in colon cancer through integrated bioinformatic analysis
Authors: Alghamdi Rana A. , Al-Zahrani Maryam H. 
Published: September 2023

The claudin multigene family is associated with various aberrant physiological and cellular signaling pathways. However, the association of claudins with survival prognosis, signaling pathways, and diagnostic efficacy in colon cancer remains poorly understood.Methods: Through the effective utilization of various bioinformatics methods, including differential gene expression analysis, gene set enrichment analysis protein-protein interaction (PPI) network analysis, survival analysis, single sample gene set enrichment analysis (ssGSEA), mutational variance analysis, and identifying receiver operating characteristic curve of claudins in The Cancer Genome Atlas colon adenocarcinoma (COAD).Results: We found that: CLDN2, CLDN1, CLDN14, CLDN16, CLDN18, CLDN9, CLDN12, and CLDN6 are elevated in COAD. In contrast, the CLDN8, CLDN23, CLDN5, CLDN11, CLDN7, and CLDN15 are downregulated in COAD. By analyzing the public datasets GSE15781 and GSE50760 from NCBI-GEO (https://www.ncbi.nlm.nih.gov/geo/), we have confirmed that CLDN1, CLDN2, and CLDN14 are significantly upregulated and CLDN8 and CLDN23 are significantly downregulated in normal colon, colon adenocarcinoma tumor, and liver metastasis of colon adenocarcinoma tissues from human samples. Various claudins are mutated and found to be associated with diagnostic efficacy in COAD.Conclusion: The claudin gene family is associated with prognosis, immune regulation, signaling pathway regulations, and diagnosis of COAD. These findings may provide new molecular insight into claudins in the treatment of colon cancer.
ARPC1B is a novel prognostic biomarker for kidney renal clear cell carcinoma and correlates with immune infiltration
Authors: Tang Yong-Fei , Qiao Bin , Huang Ya-Bing , Wang Ming 
Published: September 2023

Background: Actin-related protein 2/3 complex subunit 1B (ARPC1B) is reported to be involved in tumorigenesis and progression. However, its role in kidney renal clear cell carcinoma (KIRC), correlation with tumor-infiltrating immune cells, and prognostic significance remain unclear.Methods: Data sets from the TCGA, GTEx, GEPIA, GEO, UALCAN, and CPTAC databases were extracted and analyzed to investigate the expression difference, prognosis, and clinicopathological features of ARPC1B. Single-sample Gene Set Enrichment Analysis (ssGSEA), CIBERSORT, and TISCH2 analysis were used to examine the relationship between ARPC1B expression and tumor immune infiltration in KIRC. The potential function of ARPC1B in KIRC was explored by GO functional annotation and KEGG pathway analysis. The TIDE algorithm was used to predict and analyze the relationship between ARPC1B expression and response to immune checkpoint blockade (ICB). The expression of ARPC1B was further validated by using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC).Results: The study showed that ARPC1B expression was an independent prognostic factor of KIRC, with high ARPC1B expression being associated with poor overall survival (OS). Enrichment of GO annotation and pathway analysis showed multiple immune-related functional pathways affected by ARPC1B such as regulation of immune effector process, inflammatory response regulation, antigen processing and presentation, asthma, autoimmune thyroid disease, graft versus host disease, intestinal immune network for IgA production, and type I diabetic mellitus. Moreover, ARPC1B expression positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in KIRC. Importantly, high ARPC1B expression predicted a low response to ICB in KIRC.Conclusion: This study indicates that ARPC1B expression is an independent prognostic biomarker for OS in KIRC patients. High ARPC1B expression is closely associated with MDSCs and Tregs infiltration. These findings suggest that ARPC1B may serve as a biomarker for prognosis and immune infiltration in KIRC, potentially aiding in the development of novel treatment strategies to improve the survival outcomes for KIRC patients.
Ellagic acid effects on disease severity, levels of cytokines and T-bet, RORγt, and GATA3 genes expression in multiple sclerosis patients: a multicentral-triple blind randomized clinical trial
Authors: Jafari Karegar Sahar , Aryaeian Naheed , Hajiluian Ghazaleh , Suzuki Katsuhiko , Shidfar Farzad , Salehi Masoud , Ashtiani Bahram Haghi , Farhangnia Pooya , Delbandi Ali-Akbar 
Published: September 2023

BackgroundMultiple sclerosis (MS) is a chronic autoimmune disease. Ellagic acid is a natural polyphenol and affects the fate of neurons through its anti-inflammatory and antioxidant properties. The present study aimed to investigate ellagic acid effects on disease severity, the expression of involved genes in the pathogenesis of MS, and the levels of related cytokines.MethodsThe present study was a triple-blind clinical trial. Eligible patients were randomly assigned to two groups: Ellagic acid (25 subjects) for 12 weeks, receiving 180 mg of Ellagic acid (Axenic, Australia) and the control group (25 subjects) receiving a placebo, before the main meals. Before and after the study, the data including general information, foods intake, physical activity, anthropometric data, expanded disability status scale (EDSS), general health questionnaire (GHQ) and pain rating index (PRI), fatigue severity scale (FSS) were assessed, as well as serum levels of interferon-gamma (IFNγ), interleukin-17 (IL-17), interleukin-4 (IL-4) and transforming growth factor-beta (TGF-β), nitric-oxide (NO) using enzyme-linked immunoassay (ELISA) method and expression of T-box transcription factor (Tbet), GATA Binding Protein 3 (GATA3), retinoic acid-related orphan receptor-γt (RORγt) and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes were determined using Real-Time Quantitative Reverse Transcription PCR (RT-qPCR) method.FindingsEllagic acid supplementation led to a reduction in IFNγ, IL-17, NO and increased IL-4 in the ellagic acid group, however in the placebo group no such changes were observed (−24.52 ± 3.79 vs. -0.05 ± 0.02, p &lt; 0.01; −5.37 ± 0.92 vs. 2.03 ± 1.03, p &lt; 0.01; −18.03 ± 1.02 vs. -0.06 ± 0.05, p &lt; 0.01, 14.69 ± 0.47 vs. -0.09 ± 0.14, p &lt; 0.01, respectively). Ellagic acid supplementation had no effect on TGF-β in any of the study groups (p &gt; 0.05). Also, the Tbet and RORγt genes expression decreased, and the GATA3 gene expression in the group receiving ellagic acid compared to control group significantly increased (0.52 ± 0.29 vs. 1.51 ± 0.18, p &lt; 0.01, 0.49 ± 0.18 vs. 1.38 ± 0.14, p &lt; 0.01, 1.71 ± 0.39 vs. 0.27 ± 0.10, p &lt; 0.01). Also, ellagic acid supplementation led to significant decrease in EDSS, FSS and GHQ scores (p &lt; 0.05), and no significant changes observed in PRI score (p &gt; 0.05).ConclusionEllagic acid supplementation can improve the health status of MS patients by reduction of the inflammatory cytokines and Tbet and RORγt gene expression, and increment of anti-inflammatory cytokines and GATA3 gene expression.Clinical trial registration: (https://en.irct.ir/trial/53020), IRCT20120415009472N22.
Complete patient exposure during paediatric brain cancer treatment for photon and proton therapy techniques including imaging procedures
Authors: De Saint-Hubert Marijke , Boissonnat Guillaume , Schneider Uwe , Bäumer Christian , Verbeek Nico , Esser Johannes , Wulff Jörg , Stuckmann Florian , Suesselbeck Finja , Nabha Racell , Dabin Jérémie , Vasi Fabiano , Radonic Stephan , Rodriguez Miguel , Simon Anne Catherine , Journy Neige , Timmermann Beate , Thierry-Chef Isabelle , Brualla Lorenzo 
Published: September 2023

BackgroundIn radiotherapy, especially when treating children, minimising exposure of healthy tissue can prevent the development of adverse outcomes, including second cancers. In this study we propose a validated Monte Carlo framework to evaluate the complete patient exposure during paediatric brain cancer treatment.Materials and methodsOrgan doses were calculated for treatment of a diffuse midline glioma (50.4 Gy with 1.8 Gy per fraction) on a 5-year-old anthropomorphic phantom with 3D-conformal radiotherapy, intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity modulated pencil beam scanning (PBS) proton therapy. Doses from computed tomography (CT) for planning and on-board imaging for positioning (kV-cone beam CT and X-ray imaging) accounted for the estimate of the exposure of the patient including imaging therapeutic dose. For dose calculations we used validated Monte Carlo-based tools (PRIMO, TOPAS, PENELOPE), while lifetime attributable risk (LAR) was estimated from dose-response relationships for cancer induction, proposed by Schneider et al.ResultsOut-of-field organ dose equivalent data of proton therapy are lower, with doses between 0.6 mSv (testes) and 120 mSv (thyroid), when compared to photon therapy revealing the highest out-of-field doses for IMRT ranging between 43 mSv (testes) and 575 mSv (thyroid). Dose delivered by CT ranged between 0.01 mSv (testes) and 72 mSv (scapula) while a single imaging positioning ranged between 2 μSv (testes) and 1.3 mSv (thyroid) for CBCT and 0.03 μSv (testes) and 48 μSv (scapula) for X-ray. Adding imaging dose from CT and daily CBCT to the therapeutic demonstrated an important contribution of imaging to the overall radiation burden in the course of treatment, which is subsequently used to predict the LAR, for selected organs.ConclusionThe complete patient exposure during paediatric brain cancer treatment was estimated by combining the results from different Monte Carlo-based dosimetry tools, showing that proton therapy allows significant reduction of the out-of-field doses and secondary cancer risk in selected organs.
Clinical and pathological factors and outcome of central nervous system metastasis in breast cancer
Authors: Dettwiler Dimitri , Chiru Elena-Diana , Daetwyler Eveline , Dougoud-Chauvin Vérène , Gross Markus W. , Kurzeder Christian , Zippelius Alfred , Schötzau Andreas , Vetter Marcus 
Published: September 2023

BackgroundIn Switzerland, approximately 6000 new breast cancer cases and 1300 deaths are reported annually. Brain metastasis from breast cancer (BMBC) has a major effect on prognosis. This study aimed to identify prognostic factors for overall survival (OS) in a cohort of Swiss patients with BMBC. This study evaluated the prognosis on older BMBC, which has not been completely addressed in the literature.MethodsWe performed a retrospective chart review analysis with the primary endpoint of OS after a diagnosis of BMBC. The study population was divided into 2 groups based on an OS cut-off value of 12 months after diagnosis. Univariate and multivariate analyses of several risk factors, including age, were performed. To evaluate differences in OS according to age, we performed a secondary analysis to examine the prognostic value of clinical symptoms, metastatic pattern, and lymph node involvement in an older (≥65 years) vs. younger (&lt;65 years) cohort.ResultsFrom 1989 to 2019, 55 patients were identified as having BMBC, among whom 47 patients were confirmed to be dead. The median patient age was 58 years (range 25–83 years). Comorbidities were present in 45 (81.8%) patients. The median survival in the OS &lt;12 and OS ≥12 months groups was 4.3 and 30.7 months, respectively (p&lt;0.001). Multivariate analysis revealed no significant differences in terms of comorbidities, medication use, M-stage, and symptomatology between the 2 groups. Additionally, there was no significant difference in OS in the 2 subgroups of patients aged &lt;65 and ≥65 years.DiscussionWe concluded that age should not be a decisive factor in therapy planning for advanced breast cancer patients with BMBC.
Mental and physiological wellbeing while rowing across the North Atlantic: a single-case study of subjective versus objective data
Authors: Zeiner Klaus , Dabiri Babak , Burns Ciara , Kummer Lena , Kaniusas Eugenijus 
Published: September 2023

Introduction: Unassisted rowing across the Atlantic Ocean is an extreme undertaking challenging the human body in every possible way. The reported rowing journey lasted for 42 days in a small vessel with 12 rowers, each rowing for 12 h a day, broken into 3 h shifts. This schedule disrupts the natural circadian cycle and autonomic balance, affecting subjective and objective wellbeing and sleep quality, that lack continuous empirical quantification.Methods: With a self-reported questionnaire and objective heart rate variability measurements every second day in a single female rower, we monitor evolutions of the subjective sleep quality and mental wellbeing as well as autonomic body control over the journey duration. We evaluate the hypothesis that extreme rowing impairs subjective and objective data in a similar way over time and that 3 h shifts diminish the circadian rhythm of the autonomic body control.Results: The sleep quality was mainly influenced by wake ups during sleep, while mental wellbeing was predominantly influenced by physical exhaustion. The perceived sleep quality and wellbeing dropped 2–3 days after the start with the rower not yet accommodated, in the middle of the journey with major wake ups, and again 5–6 days prior to the end with major exhaustion of the participant. Evolutions of the subjective perceptions diverge from that of the heart rate variability. The body’s autonomic recovery during short sleep periods progressively decreases over the journey duration while the vagal activity rises and the sympathovagal balance shifts towards vagal tone. The shifts of 3 h weaken the circadian rhythm of the heart rate variability.Discussion: Our results demonstrate how human body meets extreme mental and physical exhaustion on the high seas. The gained physiological and psychological insights also offer a basis for effective preparation of undertakings involving extreme physical exhaustion and sleep deprivation.
The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression
Authors: Garel Nicolas , Drury Jessica , Thibault Lévesque Julien , Goyette Nathalie , Lehmann Alexandre , Looper Karl , Erritzoe David , Dames Shannon , Turecki Gustavo , Rej Soham , Richard-Devantoy Stephane , Greenway Kyle T. 
Published: September 2023

BackgroundSubanesthetic ketamine has accumulated meta-analytic evidence for rapid antidepressant effects in treatment-resistant depression (TRD), resulting in both excitement and debate. Many unanswered questions surround ketamine’s mechanisms of action and its integration into real-world psychiatric care, resulting in diverse utilizations that variously resemble electroconvulsive therapy, conventional antidepressants, or serotonergic psychedelics. There is thus an unmet need for clinical approaches to ketamine that are tailored to its unique therapeutic properties.MethodsThis article presents the Montreal model, a comprehensive biopsychosocial approach to ketamine for severe TRD refined over 6 years in public healthcare settings. To contextualize its development, we review the evidence for ketamine as a biomedical and as a psychedelic treatment of depression, emphasizing each perspectives’ strengths, weaknesses, and distinct methods of utilization. We then describe the key clinical experiences and research findings that shaped the model’s various components, which are presented in detail.ResultsThe Montreal model, as implemented in a recent randomized clinical trial, aims to synergistically pair ketamine infusions with conventional and psychedelic biopsychosocial care. Ketamine is broadly conceptualized as a brief intervention that can produce windows of opportunity for enhanced psychiatric care, as well as powerful occasions for psychological growth. The model combines structured psychiatric care and concomitant psychotherapy with six ketamine infusions, administered with psychedelic-inspired nonpharmacological adjuncts including rolling preparative and integrative psychological support.DiscussionOur integrative model aims to bridge the biomedical-psychedelic divide to offer a feasible, flexible, and standardized approach to ketamine for TRD. Our learnings from developing and implementing this psychedelic-inspired model for severe, real-world patients in two academic hospitals may offer valuable insights for the ongoing roll-out of a range of psychedelic therapies. Further research is needed to assess the Montreal model’s effectiveness and hypothesized psychological mechanisms.
Interplay of Digital Proximity App Use and SARS-CoV-2 Vaccine Uptake in Switzerland: Analysis of Two Population-Based Cohort Studies
Authors: Daniore Paola , Moser André , Höglinger Marc , Probst Hensch Nicole , Imboden Medea , Vermes Thomas , Keidel Dirk , Bochud Murielle , Ortega Herrero Natalia , Baggio Stéphanie , Chocano-Bedoya Patricia , Rodondi Nicolas , Tancredi Stefano , Wagner Cornelia , Cullati Stéphane , Stringhini Silvia , Gonseth Nusslé Semira , Veys-Takeuchi Caroline , Zuppinger Claire , Harju Erika , Michel Gisela , Frank Irène , Kahlert Christian R. , Albanese Emiliano , Crivelli Luca , Levati Sara , Amati Rebecca , Kaufmann Marco , Geigges Marco , Ballouz Tala , Frei Anja , Fehr Jan , von Wyl Viktor 
Published: September 2023

Objectives: Our study aims to evaluate developments in vaccine uptake and digital proximity tracing app use in a localized context of the SARS-CoV-2 pandemic.Methods: We report findings from two population-based longitudinal cohorts in Switzerland from January to December 2021. Failure time analyses and Cox proportional hazards regression models were conducted to assess vaccine uptake and digital proximity tracing app (SwissCovid) uninstalling outcomes.Results: We observed a dichotomy of individuals who did not use the SwissCovid app and did not get vaccinated, and who used the SwissCovid app and got vaccinated during the study period. Increased vaccine uptake was observed with SwissCovid app use (aHR, 1.51; 95% CI: 1.40–1.62 [CI-DFU]; aHR, 1.79; 95% CI: 1.62–1.99 [CSM]) compared to SwissCovid app non-use. Decreased SwissCovid uninstallation risk was observed for participants who got vaccinated (aHR, 0.55; 95% CI: 0.38–0.81 [CI-DFU]; aHR, 0.45; 95% CI: 0.27–0.78 [CSM]) compared to participants who did not get vaccinated.Conclusion: In evolving epidemic contexts, these findings underscore the need for communication strategies as well as flexible digital proximity tracing app adjustments that accommodate different preventive measures and their anticipated interactions.