Parametric thermal analysis for the optimization of Double Walled Tubes layout in the Water Cooled Lithium Lead inboard blanket of DEMO fusion reactor

Within the roadmap that will lead to the nuclear fusion exploitation for electric energy generation, the construction of a DEMOnstration (DEMO) reactor is, probably, the most important milestone to be reached since it will demonstrate the technological feasibility and economic competitiveness of an industrial-scale nuclear fusion reactor. In order to reach this goal, several European universities and research centres have joined their efforts in the EUROfusion action, funded by HORIZON 2020 UE programme. Within the framework of EUROfusion research activities, ENEA and University of Palermo are involved in the design of the Water-Cooled Lithium Lead Breeding Blanket (WCLL BB), that is one of the two BB concepts under consideration to be adopted in the DEMO reactor. It is mainly characterized by a liquid lithium-lead eutectic alloy acting as breeder (lithium) and neutron multiplier (lead), as well as by subcooled pressurized water as coolant. Two separate circuits, both characterized by a pressure of 15.5 MPa and inlet/outlet temperatures of 295 °C/328 °C, are deputed to cool down the First Wall (FW) and the Breeder Zone (BZ). The former consists in a system of radial-toroidal-radial C-shaped squared channels where countercurrent water flow occurs while the latter relies in the use of bundles of poloidal-radial Double Walled Tubes (DWTs) housed within the breeder. A parametric thermal study has been carried out in order to assess the best DWTs' layout assuring that the structural material maximum temperature does not overcome the allowable limit of 550 °C and that the overall coolant thermal rise fulfils the design target value of 33 °C. The study has been performed following a theoretical-numerical approach based on the Finite Element Method (FEM) and adopting the quoted Abaqus FEM code. Main assumptions and models together with results obtained are herewith reported and critically discussed

Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity

Treating Protein Misfolding Diseases: Therapeutic Successes Against Systemic Amyloidoses

https://www.ncbi.nlm.nih.gov/pubmed/3275403

Identification of genes for normalization of RT-qPCR gene expression data: A review of published literature

Reverse-transcriptase quantitative Polymerase Chain Reaction (RT-qPCR) is a well-established technique to quantify gene expression levels and critically depends on reference genes for data normalization. We performed a review of biomedical literature to analyse the usage of RT-qPCR in relation to other techniques for transcriptional analyses and to describe practices for the identification of suitable reference genes for RT-qPCR. In the 81 analysed studies, 3 genes (GAPD, ACTB, B2M) were included in ≥70% of cases, but ranked among the most stable genes in ≤1/3 of cases. The most frequently used normalizing algorithm was geNorm (83%), followed by NormFinder (73%) and BestKeeper (32%). We also analysed transparency and good laboratory practices based on adherence to the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines, using selected validated evaluation criteria. Overall, key MIQE criteria were satisfied in ≥50% of analyzed studies, but only four criteria (details of employed kit/enzyme for reverse transcription, priming method, primers/probes and DNA polymerase) were satisfied in ≥90% of cases. Data on assay repeatability were reported only in 15% of studies. The presence of pseudogenes as a potential confounder of assay specificity was evaluated only in 13% of studies. Finally, as few as 6% of studies accounted for the presence of known mutations of singly nucleotide polymorphisms when designing assay primers/probes. Better adherence to the MIQE guidelines should be encouraged. Publicly available transcriptomic and genomic data sets could be employed to refine the identification of suitable normalizing genes and to assist assay design

Analysis of cyclin D1 mRNA expression levels in plasma cell dyscrasias: A systematic review of published literature

Overexpression of cyclin D1 (CCND1) occurs often in tumoral plasma cells, mainly - but not exclusively - as a result of the presence of the t(11;14) translocation. Of note, CCND1 mRNA overexpression or the presence of the t(11;14) translocation was shown to impact on the response to anti-plasma cell drugs and influence prognosis, both in patients with multiple myeloma and with immunoglobulin light chain (AL) amyloidosis. In this study, we performed a systematic revision of published literature on molecular assays to measure CCND1 transcript levels in plasma cell dyscrasias, in order to describe currently available assays, their technical characteristics and main applications. Relevant scientific articles were search on PubMed as of October 2020 using combinations of appropriate key words. Of 165 unique studies retrieved, 11 articles fulfilled the inclusion criteria and were further analyzed. Overall, 8 different molecular assays were described and characterized. Most of the studies focused on multiple myeloma, with some studies including also MGUS, plasma cell leukemia and/or AL amyloidosis. Assay design, technical validation and field of application of each assay were systematically reviewed. As more knowledge is gained about the impact of CCND1 expression levels on the biology of tumoral plasma cells and their response to anti-plasma cell drugs, including novel agents specifically targeting t(11;14)-positive clones, molecular assays to quantify CCND1 expression levels in tumoral plasma cells may become a useful complementation to molecular cytogenetics, towards a precision medicine approach to diagnose and treat plasma cell disorders which is based on laboratory medicine

Bone marrow microenvironment in light-chain amyloidosis: In vitro expansion and characterization of mesenchymal stromal cells

Immunoglobulin light-chain amyloidosis (AL) is caused by misfolded light chains produced by a small B cell clone. Mesenchymal stromal cells (MSCs) have been reported to affect plasma cell behavior. We aimed to characterize bone marrow (BM)-MSCs from AL patients, considering functional aspects, such as proliferation, differentiation, and immunomodulatory capacities. MSCs were in vitro expanded from the BM of 57 AL patients and 14 healthy donors (HDs). MSC surface markers were analyzed by flow cytometry, osteogenic and adipogenic differentiation capacities were in vitro evaluated, and co-culture experiments were performed in order to investigate MSC immunomodulatory properties towards the ALMC-2 cell line and HD peripheral blood mononuclear cells (PBMCs). AL-MSCs were comparable to HD-MSCs for morphology, immune-phenotype, and differentiation capacities. AL-MSCs showed a reduced proliferation rate, entering senescence at earlier passages than HD-MSCs. The AL-MSC modulatory effect on the plasma-cell line or circulating plasma cells was comparable to that of HD-MSCs. To our knowledge, this is the first study providing a comprehensive characterization of AL-MSCs. It remains to be defined if the observed abnormalities are the consequence of or are involved in the disease pathogenesis. BM microenvironment components in AL may represent the targets for the prevention/treatment of the disease in personalized therapies

Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity