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Fee Klupp,1 Christina Giese,1 Niels Halama,2 Clemens Franz,1 Felix Lasitschka,3,4 Arne Warth,3 Thomas Schmidt,1 Matthias Kloor,5 Alexis Ulrich,1 Martin Schneider1 1Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany; 2National Center for Tumor Diseases, Medical Oncology and Internal Medicine VI, Tissue Imaging and Analysis Center, Bioquant, University of Heidelberg, Heidelberg 69120, Germany; 3Institute of Pathology, University of Heidelberg, Heidelberg 69120, Germany; 4Tissue Bank of the National Center for Tumor Diseases, Heidelberg 69120, Germany; 5Department of Applied Tumor Biology, German Cancer Research Center, Heidelberg 69120, Germany Purpose: Smurf2 is a member of the homologous to E6-AP carboxyl terminus family of E3 ubiquitin ligases. Changes in their expression pattern are known to contribute to tumorigenesis. Smurf2 plays a decisive role in cell differentiation, proliferation, and migration and exhibits a dual role in cancer – functioning as both oncogene and tumor suppressor. Dysregulation of Smurf2 in different cancer types has been described, besides colorectal cancer (CRC). We therefore examined the expression and oncogenic potential of Smurf2 in human CRC patients.Materials and methods: Expression levels of Smurf2 were analyzed via qRT-PCR in CRC specimens and healthy mucosa from 98 patients who had undergone surgery due to CRC. Spatial expression of Smurf2 was additionally studied by immunohistochemistry. siRNA-mediated knockdown of Smurf2 was applied for migration and invasion assays in DLD-1 and SW-480 cells.Results: Smurf2 was significantly overexpressed in CRC tissue compared to corresponding healthy colon mucosa. Smurf2 expression levels differed significantly between microsatellite instable (MSI) and microsatellite stable (MSS) CRC. In patients suffering from MSS CRC, high tumoral expression of Smurf2 was significantly associated with impaired overall survival. Consistently, in vitro analysis revealed that knockdown of Smurf2 reduced the invasive and migratory potential of MSS CRC cells.Conclusion: Smurf2 expression is upregulated in CRC specimens and affects survival dependent on patients’ MSI status. Moreover, Smurf2 supports cancer cell migration and invasion, collectively suggesting an oncogenic function in CRC. Keywords: Smurf2, colorectal cancer, MSS status, prognosis, biomarker

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

Este artigo é um recorte de uma pesquisa desenvolvida na Universidade Federal de Santa Maria (UFSM), com sete professores bacharéis iniciantes no Centro de Ciências da saúde. O estudo teve como foco compreender a temática da aprendizagem da docência iniciante em contextos emergentes, e configurou-se como uma pesquisa qualitativa, com a abordagem narrativa sociocultural. A produção dos dados se deu por meio de entrevistas narrativas a partir de tópicos guia. Nos achados evidenciamos as necessidades emergentes do acolhimento aos docente iniciantes, nesta fase de muitas dúvidas e incertezas. Nesse sentido, e como desdobramento da pesquisa, construiu-se um protótipo de página de acolhimento aos docentes.

Early-life exposure to natural and synthetic chemicals can impact acute and chronic health conditions. Here, a suspect screening workflow anchored on high-resolution mass spectrometry was applied to elucidate xenobiotics in breast milk and matching stool samples collected from Nigerian mother-infant pairs (n = 11) at three time points. Potential correlations between xenobiotic exposure and the developing gut microbiome, as determined by 16S rRNA gene amplicon sequencing, were subsequently explored. Overall, 12,192 and 16,461 features were acquired in the breast milk and stool samples, respectively. Following quality control and suspect screening, 562 and 864 features remained, respectively, with 149 of these features present in both matrices. Taking advantage of 242 authentic reference standards measured for confirmatory purposes of food bio-actives and toxicants, 34 features in breast milk and 68 features in stool were identified and semi-quantified. Moreover, 51 and 78 features were annotated with spectral library matching, as well as 416 and 652 by in silico fragmentation tools in breast milk and stool, respectively. The analytical workflow proved its versatility to simultaneously determine a diverse panel of chemical classes including mycotoxins, endocrine-disrupting chemicals (EDCs), antibiotics, plasticizers, perfluorinated alkylated substances (PFAS), and pesticides, although it was originally optimized for polyphenols. Spearman rank correlation of the identified features revealed significant correlations between chemicals of the same classification such as polyphenols. One-way ANOVA and differential abundance analysis of the data obtained from stool samples revealed that molecules of plant-based origin elevated as complementary foods were introduced to the infants’ diets. Annotated compounds in the stool, such as tricetin, positively correlated with the genus Blautia. Moreover, vulgaxanthin negatively correlated with Escherichia-Shigella. Despite the limited sample size, this exploratory study provides high-quality exposure data of matched biospecimens obtained from mother-infant pairs in sub-Saharan Africa and shows potential correlations between the chemical exposome and the gut microbiome.

Abstract Background The Coordinated medical Care (CoCare) project aimed to improve the quality of medical care in nursing homes by optimizing collaboration between nurses and physicians. We analyze the impact of the CoCare intervention on overall survival. Methods The effect of time-varying treatment on 3-year overall survival was analyzed with treatment as time-varying covariate within the entire cohort. To reduce bias due to non-random assignment to treatment groups, regression adjustment was applied. Therefore, age, sex, and level of care were used as potential confounders. Results The study population consisted of 8,893 nursing home residents (NHRs), of which 1,330 participated in the CoCare intervention. The three-year overall survival was 49.8% in the entire cohort. NHRs receiving the intervention were associated with a higher survival probability compared to NHRs of the control group. In a univariable cox model with time-dependent treatment, the intervention was associated with a hazard ratio of 0.70 [95%CI 0.56–0.87, p = 0.002]. After adjustment for age, sex and level of care, the hazard ratio increased to 0.82 but was still significant [95%CI 0.71–0.96, p = 0.011]. Conclusion The analysis shows that optimizing collaboration between nurses and physicians leads to better survival of NHRs in Germany. This adds to the already published favorable cost-benefit ratio of the CoCare intervention and shows that a routine implementation of optimized collaboration between nurses and physicians is highly recommended.

A substantial body of research exists on the use of remote sensing in urban contexts. However, only a limited number of studies have contributed to our understanding of the socioeconomic conditions of different urban areas. This research aims to demonstrate the potential of very high-resolution images and geospatial data by examining the interrelations between socioeconomic data retrieved from household surveys in the city of Kigali and spatial data on urban morphology retrieved by satellite imagery. As the surveys yielded large amounts of data of varying levels of measurement (categorical and numeric), we present different methods of statistical correlation, data mining, and machine learning to highlight socioeconomic patterns within the spatial data. The results demonstrate a significant correlation between the share of different building types, building density, average building heights, and distances to public infrastructure with a range of surveyed data, including building properties, household members, financial resources, and overall lifestyle habits. This highlights the potential of remote sensing and geospatial data to provide valuable insights into the socioeconomic conditions of urban areas. It also underscores the importance of using advanced statistical methods, data mining, and machine learning to enhance our understanding of urban morphology and its socioeconomic implications. However, it is important to acknowledge the limitations of such approaches, including the lack of information on ownership, potential for false inference and the direction of causation, which require further investigation.

Abstract Introduction To date, there has been little research on the general health literacy of trans and gender diverse individuals, even though previous research undermines the importance of good health literacy in this sample. The aim of the article is therefore to describe the general health literacy of trans and gender diverse individuals based on a German survey. Methods In September 2022, a survey study was conducted in which health literacy was recorded using HLS-EU-16. Data will be presented descriptively; gender differences will be explored using a Χ 2 - test and a univariate analysis of variance (ANOVA). Results Out of N = 223 participants, n = 129 individuals (57.8%) identified as non-binary; n = 49 (22.0%) identified themselves as male, while n = 45 (20.2%) identified as female. Mean age was 28.03 years. Overall, 26.4% of all the participants showed an inadequate health literacy, as proposed by the HLS-EU-16. In trend, health-related task related to media use were more often perceived as easy compared to the German general population. Conclusion Individuals, who identify as trans and gender diverse may have a general health literacy below average compared to the German general population. However, tasks related to media use were perceived as easy, which might be a good starting point for health literacy related interventions. Trial registration DRKS00026249, Date of registration: 15/03/2022.

Abstract Taurine-respiring gut bacteria produce H2S with ambivalent impact on host health. We report the isolation and ecophysiological characterization of a taurine-respiring mouse gut bacterium. Taurinivorans muris strain LT0009 represents a new widespread species that differs from the human gut sulfidogen Bilophila wadsworthia in its sulfur metabolism pathways and host distribution. T. muris specializes in taurine respiration in vivo, seemingly unaffected by mouse diet and genotype, but is dependent on other bacteria for release of taurine from bile acids. Colonization of T. muris in gnotobiotic mice increased deconjugation of taurine-conjugated bile acids and transcriptional activity of a sulfur metabolism gene-encoding prophage in other commensals, and slightly decreased the abundance of Salmonella enterica, which showed reduced expression of galactonate catabolism genes. Re-analysis of metagenome data from a previous study further suggested that T. muris can contribute to protection against pathogens by the commensal mouse gut microbiota. Together, we show the realized physiological niche of a key murine gut sulfidogen and its interactions with selected gut microbiota members.

Abstract Background Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with kidney function. By combining these findings with post-GWAS information (e.g., statistical fine-mapping to identify independent association signals and to narrow down signals to causal variants; or different sources of annotation data), new hypotheses regarding physiology and disease aetiology can be obtained. These hypotheses need to be tested in laboratory experiments, for example, to identify new therapeutic targets. For this purpose, the evidence obtained from GWAS and post-GWAS analyses must be processed and presented in a way that they are easily accessible to kidney researchers without specific GWAS expertise. Main Here we present KidneyGPS, a user-friendly web-application that combines genetic variant association for estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics consortium with annotation of (i) genetic variants with functional or regulatory effects (“SNP-to-gene” mapping), (ii) genes with kidney phenotypes in mice or human (“gene-to-phenotype”), and (iii) drugability of genes (to support re-purposing). KidneyGPS adopts a comprehensive approach summarizing evidence for all 5906 genes in the 424 GWAS loci for eGFR identified previously and the 35,885 variants in the 99% credible sets of 594 independent signals. KidneyGPS enables user-friendly access to the abundance of information by search functions for genes, variants, and regions. KidneyGPS also provides a function (“GPS tab”) to generate lists of genes with specific characteristics thus enabling customizable Gene Prioritisation (GPS). These specific characteristics can be as broad as any gene in the 424 loci with a known kidney phenotype in mice or human; or they can be highly focussed on genes mapping to genetic variants or signals with particularly with high statistical support. KidneyGPS is implemented with RShiny in a modularized fashion to facilitate update of input data ( https://kidneygps.ur.de/gps/ ). Conclusion With the focus on kidney function related evidence, KidneyGPS fills a gap between large general platforms for accessing GWAS and post-GWAS results and the specific needs of the kidney research community. This makes KidneyGPS an important platform for kidney researchers to help translate in silico research results into in vitro or in vivo research.

Abstract The Microsporum canis complex consists of one zoophilic species, M. canis, and two anthropophilic species, M. audouinii and M. ferrugineum. These species are the most widespread zoonotic pathogens causing dermatophytosis in cats and humans worldwide. To clarify the evolutionary relationship between the three species and explore the potential host shift process, this study used phylogenetic analysis, population structure analysis, multispecies coalescent analyses, determination of MAT idiomorph distribution, sexual crosses, and macromorphology and physicochemical features to address the above questions. The complex of Microsporum canis, M. audouinii and M. ferrugineum comprises 12 genotypes. MAT1-1 was present only in M. canis, while the anthropophilic entities contained MAT1-2. The pseudocleistothecia were yielded by the mating behaviour of M. canis and M. audouinii. Growth rates and lipase, keratinolysis and urea hydrolytic capacities of zoophilic M. canis isolates were all higher than those of anthropophilic strains; DNase activity of M. ferrugineum exceeded that of M. canis. The optimum growth temperature was 28 °C, but 22 °C favoured the development of macroconidia. Molecular data, physicochemical properties and phenotypes suggest the adaptation of zoophilic M. canis to anthropophilic M. ferrugineum, with M. audouinii in an intermediate position.

Abstract Background Aquaporins (AQPs) have been recognized to promote tumor progression, invasion, and metastasis and are therefore recognized as promising targets for novel anti-cancer therapies. Potentially relevant AQPs in distinct cancer entities can be determined by a comprehensive expression analysis of the 13 human AQPs. Methods We analyzed the presence of all AQP transcripts in 576 different normal lung and non-small cell lung cancer (NSCLC) samples using microarray data and validated our findings by qRT-PCR and immunohistochemistry. Results Variable expression of several AQPs (AQP1, -3, -4, and -5) was found in NSCLC and normal lung tissues. Furthermore, we identified remarkable differences between NSCLC subtypes in regard to AQP1, -3 and -4 expression. Higher transcript and protein levels of AQP4 in well-differentiated lung adenocarcinomas suggested an association with a more favourable prognosis. Beyond water transport, data mining of co-expressed genes indicated an involvement of AQP4 in cell-cell signalling, cellular movement and lipid metabolism, and underlined the association of AQP4 to important physiological functions in benign lung tissue. Conclusions Our findings accentuate the need to identify functional differences and redundancies of active AQPs in normal and tumor cells in order to assess their value as promising drug targets.

Abstract Introduction Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder and information on this disease is limited, especially with regard to its management and prognosis. It has become generally accepted that DIPNECH is a precursor lesion to pulmonary carcinoid tumors. Case presentation Here we report on a 60-year-old female patient with DIPNECH and an associated pulmonary adenocarcinoma. Conclusion This case contributes to a better understanding of the disorder and its associated pathologies.

The majority of transgender and gender-nonconforming people (TGNC) report negative experiences with doctors in the healthcare system. As there is little knowledge about the communication behaviour of doctors towards TGNC, this survey aimed to assess the self-reported trans-inclusive communication of doctors and their willingness to communicate trans-inclusively, as well as their self-perceived barriers to it. A mixed-methods survey was applied for this. Firstly, we measured self-reported trans-inclusive communication behaviour based on the CommTrans questionnaire. Based on this, the overall willingness, as well as self-perceived barriers (qualitative) to communication, were assessed. In total, N = 57 doctors took part in the survey. Most participants reported not introducing themselves using pronouns (79.4%). Of these, 61.4% said that they would not be able to do this in the future either. Perceived barriers were classified into the following eight categories: necessity, sample-dependency, habit, structural barriers in practice, uncertainties in dealing with the topic, limits of patient-centredness, gender as a binary concept, and transphobia. In summary, doctors in Germany show different degrees of trans-inclusive communication. It is likely that this has a negative effect on TGNC, their health and access to the healthcare system.

We report a case of long-term complete response to selective intra-arterial radiation therapy in a 48-year-old female patient with metastatic liver disease from undifferentiated uterine sarcoma.

Normal function of the C-terminal Eps15 homology domain-containing protein 1 (EHD1) has previously been associated with endocytic vesicle trafficking, shaping of intracellular membranes, and ciliogenesis. We recently identified an autosomal recessive missense mutation c.1192C>T (p.R398W) of EHD1 in patients who had low molecular weight proteinuria (0.7–2.1 g/d) and high-frequency hearing loss. It was already known from Ehd1 knockout mice that inactivation of Ehd1 can lead to male infertility. However, the exact role of the EHD1 protein and its p.R398W mutant during spermatogenesis remained still unclear. Here, we report the testicular phenotype of a knockin mouse model carrying the p.R398W mutation in the EHD1 protein. Male homozygous knockin mice were infertile, whereas the mutation had no effect on female fertility. Testes and epididymes were significantly reduced in size and weight. The testicular epithelium appeared profoundly damaged and had a disorganized architecture. The composition of developing cell types was altered. Malformed acrosomes covered underdeveloped and misshaped sperm heads. In the sperm tail, midpieces were largely missing indicating disturbed assembly of the sperm tail. Defective structures, i.e., nuclei, acrosomes, and sperm tail midpieces, were observed in large vacuoles scattered throughout the epithelium. Interestingly, cilia formation itself did not appear to be affected, as the axoneme and other parts of the sperm tails except the midpieces appeared to be intact. In wildtype mice, EHD1 co-localized with acrosomal granules on round spermatids, suggesting a role of the EHD1 protein during acrosomal development. Wildtype EHD1 also co-localized with the VPS35 component of the retromer complex, whereas the p.R398W mutant did not. The testicular pathologies appeared very early during the first spermatogenic wave in young mice (starting at 14 dpp) and tubular destruction worsened with age. Taken together, EHD1 plays an important and probably multifaceted role in spermatogenesis in mice. Therefore, EHD1 may also be a hitherto underestimated infertility gene in humans.