The presence and titer of neutralizing antibodies (NABs) was evaluated by an antiviral biological assay in 387 samples of 111 multiple sclerosis (MS) patients treated with one of the three commercial ...preparations of interferon beta (IFNβ). Fifty NAB positive samples were found in 19 patients: 11 treated with IFNβ-1b (Betaferon®) and eight with IFNβ-1a (five with Avonex® and three with Rebif®). All the 38 NABs+ samples of patients treated with IFNβ-1b cross-reacted with IFNβ-1a of both commercial types. The median level of neutralizing units (NUs) of the sera was higher when tested against IFNβ-1a than against IFNβ-1b (p=0.000 vs. Avonexr® and p=0.003 vs. Rebif®).
In line with these data, the NABs+ sera of patients treated with IFNβ-1a cross-reacted with IFNβ-1b and the level of NUs were lower when tested against IFNβ-1b than against IFNβ-1a (p=0.003). The different amount of NUs against IFNβ types 1a and 1b could be due to the presence of aggregates in the IFNβ-1b preparation. The different levels of cross-reactivity of NABs could reduce the bioavailability and therapeutic efficacy of IFNβ in NABs+ patients switching from IFNβ-1b to IFNβ-1a.
Quantification of tumor necrosis factor-alpha (TNF-alpha) mRNA in peripheral blood mononuclear cells (PBMC) could provide information about disease activity in multiple sclerosis (MS); however, ...specific competitive methods must be utilized. A competitor cDNA, having the same sequence of the target TNF-alpha cDNA, a part from an internal 49-bp deletion, was generated and used to set-up a quantitative polymerase chain reaction (PCR) to quantify mRNA of TNF-alpha. Competitor and target were co-amplified using the same primers. The rates of generation of competitor and target TNF-alpha conformed closely to the prediction of the mathematical model, and a high level of accuracy and reproducibility was achieved. The method was applied to quantify TNF-alpha mRNA in PBMC of normal subjects and multiple sclerosis (MS) patients both during clinical relapses and remissions. A statistically significant higher level of TNF-alpha mRNA was detected during relapses than during remissions. High levels of TNF-alpha mRNA were found in 44% of relapses and 12% of samples during remissions, suggesting that TNF-alpha mRNA synthesis is abnormal in MS.
Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.
We tested ...candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens.
Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5'VNTR2R/3R and 3'UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10(-6)). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens.
A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value-better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro‐adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 ...mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low‐density lipoprotein (oxLDL)‐dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient‐derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock‐out mice through high‐fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies.
Synopsis
ACM mutations are necessary but not sufficient for disease penetrance. The contribution of oxidised lipids as novel pharmacologically targetable cofactors was demonstrated by a multi‐layer approach (patients – in vitro – in vivo), leading to an advancement in the knowledge of ACM pathogenesis.
ACM patients show high oxLDL plasma levels, which stratify ACM phenotype severity.
oxLDL worsen adipogenic differentiation of ACM cells by altering the CD36/13HODE/PPARγ axis.
By increasing oxLDL in an ACM mouse model with low penetrance, ACM‐specific tissue remodelling, functional and electrical impairments are unveiled.
NAC and Atorvastatin can prevent ACM phenotypes in vitro/in vivo.
ACM mutations are necessary but not sufficient for disease penetrance. The contribution of oxidised lipids as novel pharmacologically targetable cofactors was demonstrated by a multi‐layer approach (patients – in vitro – in vivo), leading to an advancement in the knowledge of ACM pathogenesis.
IntroductionRadiation-induced cognitive decline (RICD) occurs in 50%–90% of adult patients 6 months post-treatment. In patients with low-grade and benign tumours with long expected survival, this is ...of paramount importance. Despite advances in radiation therapy (RT) treatment delivery, better understanding of structures important for RICD is necessary to improve cognitive outcomes. We hypothesise that RT may affect network topology and microstructural integrity on MRI prior to any gross anatomical or apparent cognitive changes. In this longitudinal cohort study, we aim to determine the effects of RT on brain structural and functional integrity and cognition.Methods and analysisThis study will enroll patients with benign and low-grade brain tumours receiving partial brain radiotherapy. Patients will receive either hypofractionated (>2 Gy/fraction) or conventionally fractionated (1.8–2 Gy/fraction) RT. All participants will be followed for 12 months, with MRIs conducted pre-RT and 6-month and 12 month post-RT, along with a battery of neurocognitive tests and questionnaires. The study was initiated in late 2018 and will continue enrolling through 2024 with final follow-ups completing in 2025. The neurocognitive battery assesses visual and verbal memory, attention, executive function, processing speed and emotional cognition. MRI protocols incorporate diffusion tensor imaging and resting state fMRI to assess structural connectivity and functional connectivity, respectively. We will estimate the association between radiation dose, imaging metrics and cognitive outcomes.Ethics and disseminationThis study has been approved by the Research Subjects Review Board at the University of Rochester (STUDY00001512: Cognitive changes in patients receiving partial brain radiation). All results will be published in peer-reviewed journals and at scientific conferences.Trial registration numberClinicalTrials.gov NCT04390906.
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially ...lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic
DPYD
deletion of exons 21–23 was observed. In five patients a deep intronic mutation c.1129–5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129–5967 to c.1129–5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129–5923C>G mutation proved to be in
cis
with three intronic polymorphisms (c.483 + 18G>A, c.959–51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129–5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129–5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting
DPYD
and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing.
Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to ...assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity.
Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC).
Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 95%CI 6.7-13.5) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 95%CI 1.2-2.7), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants.
FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.
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Background: We established a novel curriculum in Cancer Survivorship Education (CSE), as a collaborative effort between our accredited training programs in Hematology/Oncology and ...Radiation Oncology. The conceptual framework for all our coursework in cancer survivorship was grounded in the recommendations from the Institute of Medicine report from 2006. As a means of refining our CSE curriculum, we introduced Evidence Table (ET) development. ETs are formatted summaries of methods, data, and outcomes from related studies used to answer specific questions. ETs facilitate the development of recommendations and standards of care. ET development was proposed to enhance the CSE experience allowing trainees to: 1) understand data supporting survivorship recommendations, 2) practice grading the evidence, 3) become more critical in appraisal of published studies, and 4) discover areas where further research is needed to substantiate cancer survivorship care plans. Methods: A total of 19 trainees participated in academic year 2013-2014 and 18 trainees in 2014-2015. Trainees were required to define key questions pertaining to survivorship, probe the literature for available data addressing these questions, and develop ETs in which the evidence was then graded. To ascertain the value of this experience from the trainees’ perspectives, anonymous and voluntary pre- and post-Workshop surveys were administered. The course was modified after the first academic year based on results of a trainee feed-back. Results: Following course modification in 2014-2015, 92% of trainees responded that they used some of the learned course information in their clinics. This represents significant improvement from 45% the previous year (p = 0.02). Significant improvement was observed (from 18% to 67%) in the perception that the course influenced trainees' approach to the medical literature. Ninety-two percent responded that they learned more about survivorship as a result of the CSE Workshop. All trainees reported that, to some extent, CSE has helped to make them better oncologists. Conclusions: ET development is a feasible, meaningful, and novel approach to fostering independent learning in cancer survivorship.
Spiders are a highly diversified group of arthropods and play an important role in terrestrial ecosystems as ubiquitous predators, which makes them a suitable group to test a variety of ...eco-evolutionary hypotheses. For this purpose, knowledge of a diverse range of species traits is required. Until now, data on spider traits have been scattered across thousands of publications produced for over two centuries and written in diverse languages. To facilitate access to such data, we developed an online database for archiving and accessing spider traits at a global scale. The database has been designed to accommodate a great variety of traits (e.g. ecological, behavioural and morphological) measured at individual, species or higher taxonomic levels. Records are accompanied by extensive metadata (e.g. location and method). The database is curated by an expert team, regularly updated and open to any user. A future goal of the growing database is to include all published and unpublished data on spider traits provided by experts worldwide and to facilitate broad cross-taxon assays in functional ecology and comparative biology. Database URL:https://spidertraits.sci.muni.cz/.
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