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The adoption of whole genome sequencing (WGS) in clinical oncology is challenged by low data quality and increased artifacts in standard-of-care formalin-fixed paraffin-embedded (FFPE) samples. Analysis of 56 fresh frozen (FF) and FFPE matched pairs demonstrates that FFPE processing results in a median 20-fold enrichment in artifactual calls across mutation classes and impairs detection of clinically relevant biomarkers such as homologous recombination deficiency (HRD). We demonstrate that implementation of consensus calling reduces artifactual structural variant (SV) calls by 98% but is not sufficient in mitigating artifactual calls for single nucleotide variants (SNVs) and indels as compared to FF data. We develop FFPErase, a machine learning framework that filters SNV/indel artifacts and delivers clinical grade variant reporting allowing accurate quantification of clinically relevant biomarkers. Comparison of FFPErase WGS calls to clinical reporting by FDA-approved panel tests demonstrates 99% sensitivity and enables reporting of 24% more clinically relevant findings. Artifact mutations from FFPE are a major barrier blocking WGS adoption in clinical oncology. FFPErase, a machine learning framework, eliminates these with high accuracy in multiinstitutional datasets, delivering clinical-grade variant reports.

Optimal selection of patients with locally advanced rectal cancer for watch and wait (WW) and optimal management during follow-up remain challenging. We employed a primary-tumor-informed whole genome sequencing (WGS) assay to detect circulating tumor DNA (ctDNA) and estimate tumor fraction (TF) before, during and after neoadjuvant therapy. ctDNA was detected in 95% of baseline samples, and TF was a significant baseline predictor of sustained clinical complete response (scCR). High TF during or after neoadjuvant therapy was associated with lower likelihood of scCR and higher risk of relapse. Very low TF during surveillance was detected in a large proportion of patients who did not experience a recurrence, suggesting the existence of persisting low amounts of ctDNA. WGS-based ctDNA assessment thus provides high sensitivity, which is crucial for treatment de-escalation, but additional research is needed to also ensure good specificity (the trial is registered in ClinicalTrials.gov with the identifier NCT02008656).

Malignant T-cell transformation after chimeric antigen receptor (CAR) T-cell therapy has been described, but the contribution of CAR integration to oncogenesis is not clear. Here we report a case of a T-cell lymphoma harboring a lentiviral integration in a known tumor suppressor, TP53 , which developed in a patient with multiple myeloma after B-cell maturation antigen (BCMA) CAR T-cell therapy. A woman with multiply relapsed multiple myeloma had complete remission with cilta-cel, but a low-grade T-cell lymphoma soon developed in the GI tract that contained an insertion of the CAR construct disrupting expression of p53.

Background: Exercise is one of the most recommended management strategies by treatment guidelines for fibromyalgia (FM); however, the mechanism through which exercise improves pain in FM is still unknown. Objective: We aimed to summarize the hypothesized theoretical mechanisms for the pain-relieving effects of exercise in people with FM. Eligibility Criteria: Randomized controlled trials (RCTs) in English reporting mechanisms for pain-relieving effects of exercise in the ‘Introduction’ and ‘Discussion’ sections and significant within- group or between-group effects of exercise interventions were included. Sources of Evidence: We searched the databases Ovid MEDLINE(R), EMBASE, CINAHL, COCHRANE, Sports Discuss, and AMED with the keywords: exercise and fibromyalgia until December 2021. Charting Methods: Two authors independently performed title/abstract, full-text review, and data abstraction using a data abstraction form. The hypothesized mechanisms from individual studies were grouped into three categories. Results: The literature search resulted in 2147 studies, out of which 220 studies were considered for full-text review. A total of 50 RCTs proposing 29 unique mechanisms for the pain-relieving effects of exercise were included. These mechanisms were divided into three categories: physical, neuro-physiological, and psychological. The neuro-physiological category was further subdivided into exercise-induced hypoalgesia (EIH), pain sensitization, the autonomic system, the immune system, the endocrine system, and miscellaneous categories. The most frequently hypothesized mechanisms were EIH (n = 15), autonomic modulation (n = 7), improved sleep (n = 6), muscle oxygenation (n = 6), self-efficacy (n = 5), mental health (n = 4), and benefits of the aquatic environment (n = 12). While all exercise interventions involved FM patients, most of the supporting evidence for these mechanisms was cited from previous studies conducted on healthy samples. No studies performed analyses to demonstrate causal associations between the mechanisms and outcomes. Conclusion: Multiple mechanisms were hypothesized for the positive influence of exercise in people with FM. Future studies using causal analyses, such as mediation analysis, are recommended to validate these mechanisms.

The microalga Aphanizomenon flos-aquae (AFA) has garnered attention for its potential therapeutic benefits in various health conditions, primarily through its use in nutraceutical formulations. While biological effects of AFA have been extensively studied in preclinical models, including murine systems, its nutrigenomic and epigenetic impacts remain underexplored. This study investigates the potential epigenetic mechanisms of AFA, focusing on its ability to modulate DNA methylation, a key regulatory process in gene expression. Specifically, we examined the influence of AFA on the methylation status of genes encoding pro-inflammatory interleukins, as these cytokines play a crucial role in immune response modulation and inflammation. Given the known impact of AFA on inflammatory markers, we aimed to determine whether the effects of AFA involve direct or indirect modulation of DNA methylation patterns in genes associated with inflammation. Our findings, presented here for the first time, reveal the capacity of AFA to influence DNA methylation, with implications for its role in cellular regulatory processes. These results warrant further investigation into precise mechanisms of action of AFA and its potential in clinical applications targeting inflammation-related pathways.

Quantitative estimates of vector populations and their infectivity in the wild and in cultivated compartments of agroecosystems have been carried out to elucidate the role of the wild compartment in the epidemiology of Flavescence dorée (FD). Seven sites were selected for the investigations in the Piedmont Region of Italy. They were characterized by a high variety of agricultural and ecological landscape features, and included a vineyard surrounded by wild vegetation. In order to describe abundance and prevalence of FD-infected vectors in the cultivated and wild compartments of the vineyard agroecosystem, adults of Scaphoideus titanus were collected by yellow sticky traps inside and outside the vineyard over the period July 10th–September 9th, 2015. They were counted and singly analyzed for the presence of FD phytoplasmas by PCR. Multifactorial correlations among vector population level, prevalence of infected insects inside and outside the vineyards, disease prevalence in cultivated and wild Vitis plants, and location of wild Vitis plants with respect to the vineyard were analyzed. Abundance of S. titanus adults significantly decreased from the end of July onwards, particularly inside the vineyard (average range 22.7 ± 2.5 insects/trap). Percentage of FD-positive S. titanus was significantly higher outside the vineyard (up to 48% on average) compared to inside the vineyard (up to 34% on average), and increased during the season in both compartments.

The microalga Aphanizomenon flos-aquae (AFA) has garnered attention for its potential therapeutic benefits in various health conditions, primarily through its use in nutraceutical formulations. While biological effects of AFA have been extensively studied in preclinical models, including murine systems, its nutrigenomic and epigenetic impacts remain underexplored. This study investigates the potential epigenetic mechanisms of AFA, focusing on its ability to modulate DNA methylation, a key regulatory process in gene expression. Specifically, we examined the influence of AFA on the methylation status of genes encoding pro-inflammatory interleukins, as these cytokines play a crucial role in immune response modulation and inflammation. Given the known impact of AFA on inflammatory markers, we aimed to determine whether the effects of AFA involve direct or indirect modulation of DNA methylation patterns in genes associated with inflammation. Our findings, presented here for the first time, reveal the capacity of AFA to influence DNA methylation, with implications for its role in cellular regulatory processes. These results warrant further investigation into precise mechanisms of action of AFA and its potential in clinical applications targeting inflammation-related pathways.

Recent single-cell multi-omic and spatial analyses of synovial biopsies have transformed our understanding of myeloid cell-driven mechanisms underlying human joint pathology and tissue homeostasis in Rheumatoid arthritis (RA). However, the developmental trajectories of synovial tissue macrophage (STM) subsets in humans remain poorly understood, due in part to the lack of models that faithfully replicate synovial tissue niches. This hinders the exploration of the therapeutic potential of targeting specific synovial myeloid cell clusters. Using multi-omics analyses of synovial tissue from an allogeneic bone marrow transplant recipient, we show that joint-specific tissue-resident STM subsets, including both health- and disease-associated clusters, can derive from peripheral blood monocytes. Analysis of embryonic synovial joints revealed that macrophage localization and maturation in the joints are preceded by local stromal niche specialisation, indicating that synovial fibroblasts (FLS) provide tissue-specific instructive cues to STM precursors. To elucidate human STM developmental trajectories, we established a SNP-based fate-tracking human synovial organoid system by embedding distinct blood-derived myeloid precursors, together with FLS clusters from RA synovial biopsies and endothelial cells, into 3D structures. These organoids reproduced key synovial tissue features, including lining and sublining architecture and stromal-myeloid cell cluster composition. Importantly, they supported differentiation of all resident STM subsets: homeostatic lining TREM2 macrophages, their pathogenic TREM2 SPP1 counterparts that characterize the RA hyperplastic lining, and both homeostatic and RA-associated perivascular LYVE1 STM clusters, all traced to monocytic precursors. In summary, we show that development of STM subsets is driven by fibroblast-conditioned spatial niches. We have established a novel, tractable ex vivo platform to dissect the niche-specific cues driving homeostatic versus pathogenic phenotypic clusters.

We report correlations in underground seismic measurements with horizontal separations of several hundreds of meters to a few kilometers in the frequency range 0.01Hz to 40Hz. These seismic correlations could threaten science goals of planned interferometric gravitational-wave detectors such as the Einstein Telescope as well as atom interferometers such as MIGA and ELGAR. We use seismic measurements from four different sites, i.e. the former Homestake mine (USA) as well as two candidate sites for the Einstein Telescope, Sos Enattos (IT) and Euregio Maas-Rhein (NL-BE-DE) and the site housing the MIGA detector, LSBB (FR). At all sites, we observe significant coherence for at least 50% of the time in the majority of the frequency region of interest. Based on the observed correlations in the seismic fields, we predict levels of correlated Newtonian noise from body waves. We project the effect of correlated Newtonian noise from body waves on the capabilities of the triangular design of the Einstein Telescope's to observe an isotropic gravitational-wave background (GWB) and find that, even in case of the most quiet site, its sensitivity will be affected up to \\(\\sim\\)20Hz. The resolvable amplitude of a GWB signal with a negatively sloped power-law behaviour would be reduced by several orders of magnitude. However, the resolvability of a power-law signal with a slope of e.g. \\(\\alpha=0\\) (\\(\\alpha=2/3\\)) would be more moderately affected by a factor \\(\\sim\\) 6-9 (\\(\\sim\\)3-4) in case of a low noise environment. Furthermore, we bolster confidence in our results by showing that transient noise features have a limited impact on the presented results.