56 research outputs found

    Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses:A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring

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    Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients

    X chromosome inactivation skewing is common in advanced carotid atherosclerotic lesions in females and predicts secondary peripheral artery events

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    BACKGROUND AND AIM: Sex differences in atherosclerosis have been described with female plaques being mostly perceived as stable and fibrous. Sex-specific mechanisms such as mosaic loss of the Y chromosome in men have been linked to cardiovascular health. In women, X-linked mechanisms such as X chromosome inactivation (XCI) skewing is common in several tissues. Yet, information on the role of XCI in female atherosclerotic plaques is lacking. Here, we investigated the presence of XCI skewing in advanced atherosclerotic lesions and its association with cardiovascular risk factors, histological plaque data, and clinical data. METHODS: XCI skewing was quantified in 154 atherosclerotic plaque and 55 blood DNA samples of women included in the Athero-Express study. The skewing status was determined performing the HUMARA assay. Then, we studied the relationship of XCI skewing in female plaque and cardiovascular risk factors using regression models. In addition, we studied if plaque XCI predicted plaque composition, and adverse events during 3-years follow-up using Cox proportional hazard models. RESULTS: XCI skewing was detected in 76 of 154 (49.4%) plaques and in 27 of 55 (67%) blood samples. None of the clinical risk factors were associated with plaque skewing. Plaque skewing was more often detected in plaques with a plaque hemorrhage (OR [95% CI]: 1.44 [1.06-1.98], P = 0.02). Moreover, skewed plaques were not associated with a higher incidence of composite and major events but were specifically associated with peripheral artery events during a 3-year follow-up period in a multivariate model (HR [95%CI]: 1.46 [1.09-1.97]; P = 0.007). CONCLUSIONS: XCI skewing is common in carotid plaques of females and is predictive for the occurrence of peripheral artery events within 3 years after carotid endarterectomy

    A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial)

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    Background. Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects. Methods. A randomized multicenter pragmatic clinical trial comparin

    Measuring and modifying plasma density profiles to confine high power lasers

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    A Computational Model for Tail Undulation and Fluid Transport in the Giant Larvacean

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    Flexible propulsors are ubiquitous in aquatic and flying organisms and are of great interest for bioinspired engineering. However, many animal models, especially those found in the deep sea, remain inaccessible to direct observation in the laboratory. We address this challenge by conducting an integrative study of the giant larvacean, an invertebrate swimmer and “fluid pump” of the mesopelagic zone. We demonstrate a workflow involving deep sea robots, advanced imaging tools, and numerical modeling to assess the kinematics and resulting fluid transport of the larvacean’s beating tail. A computational model of the tail was developed to simulate the local fluid environment and the tail kinematics using embedded passive (elastic) and active (muscular) material properties. The model examines how varying the extent of muscular activation affects the resulting kinematics and fluid transport rates. We find that muscle activation in two-thirds of the tail’s length, which corresponds to the observed kinematics in giant larvaceans, generates a greater average downstream flow speed than other designs with the same power input. Our results suggest that the active and passive material properties of the larvacean tail are tuned to produce efficient fluid transport for swimming and feeding, as well as provide new insight into the role of flexibility in biological propulsors

    Nectophore coordination and kinematics by physonect siphonophores

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    Siphonophores are ubiquitous and often highly abundant members of pelagic ecosystems throughout the open ocean. They are unique among animal taxa in that many species use multiple jets for propulsion. Little is known about the kinematics of the individual jets produced by nectophores (the swimming bells of siphonophores) or whether the jets are coordinated during normal swimming behavior. Using remotely operated vehicles and SCUBA, we video recorded the swimming behavior of several physonect species in their natural environment. The pulsed kinematics of the individual nectophores that comprise the siphonophore nectosome were quantified and, based on these kinematics, we examined the coordination of adjacent nectophores. We found that, for the five species considered, nectophores located along the same side of the nectosomal axis (i.e. axially aligned) were coordinated and their timing was offset such that they pulsed metachronally. However, this level of coordination did not extend across the nectosome and no coordination was evident between nectophores on opposite sides of the nectosomal axis. For most species, the metachronal contraction waves of nectophores were initiated by the apical nectophores and traveled dorsally. However, the metachronal wave of Apolemia rubriversa traveled in the opposite direction. Although nectophore groups on opposite sides of the nectosome were not coordinated, they pulsed with similar frequencies. This enabled siphonophores to maintain relatively linear trajectories during swimming. The timing and characteristics of the metachronal coordination of pulsed jets affects how the jet wakes interact and may provide important insight into how interacting jets may be optimized for efficient propulsion
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