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Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Open-mindedness is defined as one's willingness and ability to consider opposing beliefs and perspectives and give them a serious, impartial consideration by setting aside one's commitment towards one's own beliefs and perspectives. Learning to prepare and teach open-minded lessons is a crucial skill for student teachers because it fosters an atmosphere in which pupils feel free to express their own views and to learn about the views of others. The aim of this experiment was to examine which instructional strategy best supports student teachers' learning to prepare an open-minded citizenship education lesson. Therefore, participants (n = 176) processed an instruction on how to prepare an open-minded citizenship education lesson through learning by teaching on video, preparing to teach, or re-study (control condition), and as a post-test designed a lesson plan. We examined the completeness and accuracy of the explanations of the instructional content, feelings of social presence and arousal, open-mindedness levels, the completeness and accuracy of the lesson plans, and the conceptual knowledge of the instructional content. In addition, the lesson plans were graded on overall quality. Results showed that all participants scored higher on open-mindedness as measured with the Actively Open-minded Thinking scale after the experiment than before the experiment. Participants in the control condition prepared significantly more accurate and complete open-minded lessons than participants in the other two conditions, suggesting they have gained better understanding of the instructional content. There were no significant differences between the conditions on the other outcome measures.

Abstract Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting.

Abstract Despite being the predominant seal species in the Australian-New Zealand region and serving as a key indicator of marine environmental health, little is known about infectious diseases in New Zealand fur seals (Long-nosed fur seal; Arctocephalus forsteri). Several papillomaviruses have been identified in earless seals and sea lions, with the latter linked to cutaneous plaques and invasive squamous cell carcinoma. To date, no papillomaviruses have been reported in fur seals. We used traditional veterinary diagnostic techniques and metatranscriptomic sequencing of tissue samples to investigate the virome of New Zealand fur seals. We identified a novel papillomavirus, provisionally termed A. forsteri papillomavirus 1 (AforPV1) in an animal with clinically and histologically identified oral papilloma-like lesions. RT-PCR confirmed the presence of AforPV1 only in oral papilloma samples from the affected individual. Phylogenetic analysis of the complete 7926 bp genome of AforPV1 revealed that it grouped with taupapillomaviruses found in related Carnivora species. These findings highlight the need for further research into the disease associations and impact of undiagnosed and novel viruses on New Zealand fur seals.

Background: Enabling, supporting and promoting positive health-related behaviours is critical in addressing the major public health challenges of our time, and the multifaceted nature of behaviours requires an evidence-based approach. This statement seeks to suggest how a much-needed enhanced use of behavioural and cultural science and insights for health could be advanced. Study design and methods: and methods: Public health authorities of Europe and Central Asia and international partner organizations in September 2023 met in Copenhagen, Denmark, to discuss the way forward. Drawing on 1) country reporting to WHO, 2) interview study with public health authorities and 3) the meeting deliberations, this meeting statement was developed. Results: The meeting statement presents a joint call for step-change accelerated use of evidence-based approaches for health behaviours. Actionable next steps for public health authorities and international and regional development partners in health are presented. Conclusions: The way forward involves increased resource allocation, integration of behavioural insights into health strategies, advocacy through case and cost-effectiveness examples and capacity building.

Abstract Background Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some ‘challenging‐to‐treat’ cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB. Methods We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient‐derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single‐agent and a combination of PI3K/mTOR inhibitors with PD‐1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single‐cell RNA/TCR sequencing of serially collected biopsies. Results PI3K/mTOR over‐activation (pS6high) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB‐resistant humanized uLMS PDX model, fostering adaptive anti‐tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti‐tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD‐1+ T cells displaying an exhausted phenotype. When combined with anti‐PD‐1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single‐agent anti‐PD‐1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper‐expansion of a cytotoxic CD8+ T‐cell population supported by a CD4+ Th1 niche. Conclusions Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.

El objetivo de este trabajo es comparar la calidad de vida de los trabajos precarios de cantera y ladrillo del municipio de San Luis Potosí y minería artesanal de mercurio en Camargo, Querétaro. Se realizó trabajo de campo y observación no participativa. Durante el periodo de investigación de campo en 2019-2020 se aplicó un cuestionario a un total de 118 trabajadores. Los datos fueron organizados y tratados con el programa Excel (versión Microsoft Office 365) y analizados dentro del marco de los enfoques de la antropología ambiental y de la vida cotidiana. En ambos contextos, se encontró que los trabajadores presentan un nivel alto de marginación, enfermedades crónicas, inactividad física, consumo de alcohol y tabaco, además de que no cuentan con equipo de protección, de acuerdo con la ocupación, tienen diferentes riesgos laborales. Además, no cuentan con contrato laboral. Aunado a ello, la familia participa en las labores. Los escenarios de precariedad laboral identificados presentaron algunas comorbilidades crónico-degenerativas diagnosticadas, nulo equipo de protección para realizar sus actividades, riesgos laborales y poco acceso a servicios de salud. Por lo tanto, requieren de esfuerzos y abordajes multidisciplinarios que permitan evaluar, atender y visibilizar sus condiciones con la finalidad de prevenir, intervenir y transformar la precariedad laboral en trabajo decente.

Abstract The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell–cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3 + CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC.

Abstract Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A + NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A + NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.

Abstract Background Mammographic population screening in The Netherlands has increased the number of breast cancer patients with small and non-palpable breast tumors. Nevertheless, mammography is not ultimately sensitive and specific for distinct subtypes. Molecular imaging with targeted tracers might increase specificity and sensitivity of detection. Because development of new tracers is labor-intensive and costly, we searched for the smallest panel of tumor membrane markers that would allow detection of the wide spectrum of invasive breast cancers. Methods Tissue microarrays containing 483 invasive breast cancers were stained by immunohistochemistry for a selected set of membrane proteins known to be expressed in breast cancer. Results The combination of highly tumor-specific markers glucose transporter 1 (GLUT1), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF1-R), human epidermal growth factor receptor 2 (HER2), hepatocyte growth factor receptor (MET), and carbonic anhydrase 9 (CAIX) 'detected' 45.5% of tumors, especially basal/triple negative and HER2-driven ductal cancers. Addition of markers with a 2-fold tumor-to-normal ratio increased the detection rate to 98%. Including only markers with >3 fold tumor-to-normal ratio (CD44v6) resulted in an 80% detection rate. The detection rate of the panel containing both tumor-specific and less tumor-specific markers was not dependent on age, tumor grade, tumor size, or lymph node status. Conclusions In search of the minimal panel of targeted probes needed for the highest possible detection rate, we showed that 80% of all breast cancers express at least one of a panel of membrane markers (CD44v6, GLUT1, EGFR, HER2, and IGF1-R) that may therefore be suitable for molecular imaging strategies. This study thereby serves as a starting point for further development of a set of antibody-based optical tracers with a high breast cancer detection rate.

Las crisis humanitarias pueden presentarse en sitios afectados por amenazas químicas, físicas, biológicas y sociales, sobre todo cuando estas amenazas interaccionan entre sí y causan una sindemia. A fin de evitar las crisis, en estos sitios se hace necesario introducir medidas de mitigación que hemos enmarcado bajo el término de “escenarios humanitarios”. Debido a su naturaleza, la implementación de dichas acciones de intervención requiere de la conformación de grupos operativos multidisciplinarios y de una estrategia de trabajo que permita integrarlos con la comunidad afectada. En el caso de la población infantil, el grupo operativo recibió el nombre de unidad de riesgos infantiles en sitios contaminados (RISC), es decir, en localidades impactadas por amenazas químicas, físicas o biológicas. La estrategia consta de las siguientes seis fases: i) planificación para el estudio y la visita al sitio; ii) participación de la comunidad para identificar amenazas, vulnerabilidades y rutas de exposición (el camino que deben seguir los contaminantes desde su fuente hasta la población receptora), así como para el trabajo conjunto en las siguientes fases; iii) priorización de riesgos identificados mediante el monitoreo ambiental y uso de biomarcadores de exposición y efectos; iv) prevención de riesgos a través de la creación de diversas capacidades y alternativas para la prevención ante amenazas sindémicas (CAPAS); v) promoción para implementar las CAPAS mediante la comunicación de riesgos y la capacitación local; y vi) protección con medidas que incluyen propuestas de telesalud, progreso social e innovación para mejorar la cobertura sanitaria. La estrategia ha sido aplicada en diferentes contextos, en algunos de los cuales, ha sido enriquecida con el análisis del respeto de los derechos humanos.

Feline calicivirus (FCV) causes upper respiratory tract disease (URTD) and sporadic outbreaks of virulent systemic disease (FCV-VSD). The basis for the increased pathogenicity of FCV-VSD viruses is incompletely understood, and antivirals for FCV-VSD have yet to be developed. We investigated the clinicoepidemiology and viral features of three FCV-VSD outbreaks in Australia and evaluated the in vitro efficacy of nitazoxanide (NTZ), 2'-C-methylcytidine (2CMC) and NITD-008 against FCV-VSD viruses. Overall mortality among 23 cases of FCV-VSD was 39%. Metagenomic sequencing identified five genetically distinct FCV lineages within the three outbreaks, all seemingly evolving in situ in Australia. Notably, no mutations that clearly distinguished FCV-URTD from FCV-VSD phenotypes were identified. One FCV-URTD strain likely originated from a recombination event. Analysis of seven amino-acid residues from the hypervariable E region of the capsid in the cultured viruses did not support the contention that properties of these residues can reliably differentiate between the two pathotypes. On plaque reduction assays, dose-response inhibition of FCV-VSD was obtained with all antivirals at low micromolar concentrations; NTZ EC50, 0.4-0.6 µM, TI = 21; 2CMC EC50, 2.7-5.3 µM, TI > 18; NITD-008, 0.5 to 0.9 µM, TI > 111. Investigation of these antivirals for the treatment of FCV-VSD is warranted.

The aim of this experiment was to examine the effect of different instructional strategies on student teachers' confirmation bias. Confirmation bias refers to the selectivity in finding and using evidence that fits one's own beliefs or hypotheses while neglecting evidence that is opposite to one's own beliefs or hypotheses (Nickerson, 1998). Dutch student teachers (n = 141) took a confirmation bias pre-test and were then randomly assigned to three conditions; teaching on video (TOV), preparing to teach (PTT) and re-study (CC). All participants received text-based instruction on confirmation bias and how it can be mitigated. They also practised with confirmation bias tasks and they received feedback on their answers. Subsequently, participants in the TOV and PTT conditions prepared a lesson about the instructional content and in the TOV condition they taught this lesson on video. After the learning phase, TOV and PTT participants completed a social presence questionnaire. All participants completed an arousal questionnaire and a confirmation bias post-test and a transfer test. The results showed that confirmation bias was reduced to a similar extent in all conditions. Results also showed that the quality of the prepared lesson was highest for TOV participants suggesting they had gained better understanding of the confirmation bias than PTT participants. Furthermore, in contrast to our expectations, PTT participants reported highest social presence scores. TOV participants experienced higher arousal levels compared to CC participants. Transfer scores did not differ between conditions. We discuss theoretical explanations of the findings from the present study.

Background: Running-related injuries (RRI) are common in novice runners. Reducing early training running volume with strengthening activities may improve RRI without impeding running performance. Objectives: 1. Gather feasibility data for a randomized, controlled trial comparing a strengthening-based program to a conventional running program; 2. Assess RRI; and 3. Assess running performance. Methods: Seventy-four university students (38 females, 21 ± 2.3 years, 68.2 ± 10.8 kg, BMI: 22.6 ± 2.97), all novice runners, were randomized in two groups, i.e., a strengthening and running group (INT) and a running group (CON). The completed sessions, RRI, dropout, and maximal aerobic speed were recorded through an online application. Results: The INT group had 52.6% attrition, while the CON group had 41.7%. The INT group had 56.6% adherence, while the CON group had 45.7%. The Chi-square test showed no significant difference in RRI incidence across groups (CHI2 = 2.958, p value = 0.08). A two-way ANOVA showed no significant difference in maximal aerobic speed across groups (p = 0.822) or before and after training (p = 0.304). Conclusions: This pilot study confirmed the feasibility of this randomized, controlled trial with a needed sample size of 194. However, novice runners had greater attrition rates when starting. Based on those limited data, strengthening activities that replaced running volume did not improve RRI or maximal aerobic speed.

Cat ownership is common in Chile, but data on the regional prevalence of infectious agents are limited. A sero-molecular survey of 120 client- or shelter-owned domestic cats in greater Santiago was performed. Whole blood DNA was tested for the novel hepatitis-B-like virus, domestic cat hepadnavirus (DCH) by conventional PCR (cPCR) and quantitative PCR (qPCR), and for feline leukaemia virus (FeLV) by qPCR. Point-of-care serology for FeLV p27 antigen and antibodies recognising feline immunodeficiency virus (FIV) p15 and p24 was performed. DCH DNA was detected in the serum of 2/120 cats (1.67%). Sequencing and phylogenetic analysis showed that the DCH detected in Chile occupies a position outside the main clustering of DCH in the near-complete genome tree. Progressive (antigen-positive, provirus-positive) and regressive (antigen-negative, provirus-positive) FeLV infections were identified in 6/120 (5%) and 9/120 (7.5%) of cats. A total of 2/120 (1.7%) cats had dual FeLV/FIV infection, and another 2 cats had FIV infection alone. This study shows that the global footprint of DCH includes South America with a low molecular frequency in Chile, similar to that reported in the USA. Progressive FeLV infection is relatively common in urban Chile, and male cats are at greater risk than females. Testing and control measures for pathogenic retroviruses are indicated. The potential impact of FeLV, FIV and DCH on Chile’s wildcat species is worthy of further investigation.

Background and Purpose: Evidence regarding radiation-induced lymphopenia and its negative impact on oncological outcome is incrementing. Therefore, the aim of this study is to evaluate the feasibility of lymphocyte-rich organs at risk (LOAR) sparing in pelvic irradiation for localized prostate cancer and to estimate its impact on the effective dose to circulating immune cells (EDIC). Materials and Methods: Twenty patients with pelvic nodal and prostate or prostate bed irradiation were included. The following bone marrow (BM) structures were delineated as LOARs using semi-automatic segmentation: lumbosacral spine (Ls-BM), ilium (Il-BM), lower pelvis (Lp-BM), and the combined whole-pelvis (Wp-BM). Twenty new lymphocyte sparing treatment plans (LS plans) were calculated, optimizing doses to LOARs while maintaining strict coverage of the targets and respecting standard OARs dose constraints. Finally, we elaborated an EDIC calculation model for pelvic irradiation. Results: LS plans showed a statistically significant dose decrease for LOAR compared to standard of care plans without compromising target coverage nor classic OAR dose constraints: in prostate plans, the V40Gy for Ls-BM, Il-BM, and Lp-BM was decreased by 23 %, 36 %, 52 % respectively. For prostate bed plans, the V40Gy for Ls-BM, Il-BM, and Lp-BM was decreased by 25 %, 59 %, 56 %, respectively. For Wp-BM, the V10Gy, V20Gy, and Dmean have been decreased by 3 %, 14 %, 15 %, and by 5 %, 15 %, 17 %, respectively for prostate and prostate bed plans. A statistically significant decrease in EDIC was seen for LS plans in both groups. Conclusions: We successfully demonstrated the feasability of lympocyte-sparing treatment planning in pelvic irradiation, also proposing a model for EDIC calculation.

Benign and malignant orbital tumours develop from the orbit or invade it from the surrounding tissues. Ocular melanoma is a rare but potentially devastating malignancy arising from the melanocytes of the uveal tract, conjunctiva, or orbit. The poor overall survival depends mainly on its high metastatic rate. Signs and symptoms are variables mainly depending on the size of the tumour. Its treatment consists generally of surgery, radiotherapy or both. We report a case of a patient suffering from unilateral blindness for the last 10 years with a recent swelling of the orbit. The pathological analysis described a uveal melanoma. The patient benefitted from a total orbital exenteration with reconstruction using a temporal flap. Thereafter, the patient received adjuvant radiotherapy and immunotherapy. The patient was in complete remission. No recurrence was highlighted after 2 years of follow-up.

Abstract In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.

The European Synchrotron Radiation Facility (ESRF)'s large-volume press (LVP) instrument, at beamline ID06-LVP, is in constant evolution and made a significant step-change at the Extremely Brilliant Source upgrade; with improved beam characteristics (stability and focussing) and detection capabilities, with the installation of a custom-built Dectris 900 kW CdTe device. Over the same time-frame, higher pressure regimes have been reached through use of improved 6/6 compression, with the incorporation of a Drickamer device, and through the use of harder carbide grades in 6/8. The combined use of in-situ X-ray diffraction, imaging and pulse-echo ultrasonic high-pressure experiments has been enhanced. Temperature generation and measurement methods have been upgraded. User interaction is improved with live data inspection and treatment possible. Data calibration and integration have been thoroughly revised. Here, we describe the current status and highlight recent upgrades at ID06-LVP, with examples drawn from user measurements and in-house testing. [ABSTRACT FROM AUTHOR]

Highlights Tissue microarrays and germline DNA from women recruited to the phase 3 trial, ICON7, underwent quantitative immunofluorescence for c-MET/VEGFR-2 co-expression and genetic sequencing for single nucleotide polymorphisms (SNPs) VEGF-pathway genes. High c-MET/VEGFR-2 co-localisation on tumour tissue independently predicted worse survival in bevacizumab-treated epithelial ovarian cancer. The VEGFR-2 rs2305945 SNPs also independently predict worse survival in bevacizumab-treated epithelial ovarian cancer.