Case Report: A case of IgD lambda/lambda Multiple Myeloma in patient with acute renal failure and without monoclonal spike in serum electrophoresis

Background: IgD Multiple Myeloma is a rare form of plasma cell dyscrasia and accounts for approximately 1-2% of all cases of Multiple Myeloma. It mainly affects young, male subjects; it is characterized by an aggressive course, a high production of Bence Jones protein, acute renal failure and an often unfortunate outcome compared to the other isotypes of MM. A distinctive feature is the lack of a monoclonal peak on serum protein electrophoresis (SPE). Case report: a 57-year-old man with pain in his left lower limb and weight loss goes to the Emergency Department (Emergency Department). Laboratory tests performed showed normocytic normochromic anemia (Hemoglobin 9.4 g/dL), acute renal failure (s-creatinine 2.85 mg/dL, e-GFR 23 mL/min/1.73 m². serum protein electrophoresis (SPE) detected only mild polyclonal in the gamma zone with no evidence of any monoclonal peak. Results: serum immunofixation (s-IFE) showed a monoclonal IgD l band and a monoclonal l band. The Free Light Chains (s-FLC) measurement showed a ratio of 0.04. The bone marrow biopsy confirmed an infiltration of> 20% of clonal plasma cells; renal biopsy diagnosed “cast nephropathy”. Conclusion: IgD l/l Multiple Myeloma is a rare form of this disease with a poor prognosis; an early and correct laboratory diagnosis is crucial for appropriate treatment and effective monitoring in order to improve patient outcom

Overview of DISCOVER22 experiment in the framework of INFN-LNGS Cosmic Silence activity: challenges and improvements in underground radiobiology

One of the most intriguing and still pending questions in radiobiology is to understand whether and how natural environmental background radiation has shaped Life over millions of years of evolution on Earth. Deep Underground Laboratories (DULs) represent the ideal below-background exposure facilities where to address such a question. Among the few worldwide DULs, INFN-Laboratorio Nazionale del Gran Sasso (LNGS) is one of the largest in terms of size and infrastructure. Designed and built to host neutrino and dark matter experiments, since the 1990 s the LNGS has been one of the first DULs to systematically host radiobiology experiments. Here we present the DISCOVER22 (DNA Damage and Immune System Cooperation in VEry low Radiation environment 2022) experiment recently started at LNGS. DISCOVER22 aims at investigating how the low radiation background modulates the Immune System (IS) response in in vitro and in vivo models. Underground radiobiology experiments are particularly complex and tricky to design and perform. In these studies, the accurate characterization of exposure scenarios is mandatory, but a challenging aspect is to understand how the very few ionizing tracks in the ultra-Low Radiation Environment (LRE) interact with the living matter in space and time in order to trigger different biological responses. In this Perspective, we describe these challenges and how we address them through a microdosimetric and a radiobiological approaches. We aim at linking physical microdosimetric measurements and the corresponding biological radiation responses by using radiation biophysical models that could shed light on many as yet unresolved questions

A fractal analysis of the spatial distribution of tumoral mast cells in lymph nodes and bone marrow

The spatial distribution of mast cells inside the tumor stroma has been little investigated. In this study, we have evaluated tumor mast cells distribution through the analysis of the morphological features of the spatial patterns generated by these cells, including size, shape, and architecture of the cell pattern. We have compared diffuse large B cells lymphoma (DLBCL) and systemic mastocytosis in two different anatomical localizations (lymph nodes for DLBCL and, respectively, bone marrow for mastocytosis). Results have indicated that, despite the high difference in size exhibited by the mast cells patterns in the two conditions, the spatial relationship between the mast cells forming the aggregates resulted similar, characterized by a significant tendency of the mast cells to self-organize in clusters

Analysis of short term and stable DNA damage in patients with differentiated thyroid cancer treated with 131I in hypothyroidism or with rhTSH for remnant ablation

It is well known that ionizing radiations can induce genetic damage and that oxidative stress is a major factor inducing it. Our aim was to investigate whether thyroid remnant ablation with low activities of 131I (1850 MBq), is associated with DNA damage by evaluating Comet assay, micronuclei and chromosome aberrations with multicolor fluorescent in situ hybridization (M-FISH). Methods: we studied 62 patients prepared with rhTSH or by thyroid hormone withdrawal (THW). In both groups we analyzed stable and unstable genetic alterations before 131I therapy and 1 week and 3 months after 131I administration. We also correlated the genetic damage with several variables, including the degree of radiation-induced oxidative stress, genetic polymorphisms of enzymes involved in DNA-repair and anti-oxidative stress. Results: we found comparable amount of DNA breaks evaluated by Comet assay and micronuclei test in both groups of patients at different time points, but a significant increase of stable chromosome aberrations evaluated by M-FISH (breaks and translocations) in patients prepared with THW. Overall, high chromosome damage was associated with higher retained body radioactivity and unfavorable gene polymorphism. A high level of free oxygen radicals and a low level of anti-oxidants was found in all patients at any time point. In particular, patients prepared with THW, at 3 months, had significantly higher levels of free oxygen radicals than those prepared with rhTSH. Conclusions: an increase of stable chromosome aberrations respect to baseline is detectable after administration of low doses of 131I in patients prepared with THW but not in patients prepared with rhTSH. The clinical significance of these chromosomal alterations remains to be determined

Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma

Exons 19â\u80\u9321 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy

Resident Self-Tissue of Proinflammatory Cytokines Rather Than Their Systemic Levels Correlates with Development of Myelofibrosis in <i>Gata1</i>^low Mice

Serum levels of inflammatory cytokines are currently investigated as prognosis markers in myelofibrosis, the most severe Philadelphia-negative myeloproliferative neoplasm. We tested this hypothesis in the Gata1low model of myelofibrosis. Gata1low mice, and age-matched wild-type littermates, were analyzed before and after disease onset. We assessed cytokine serum levels by Luminex-bead-assay and ELISA, frequency and cytokine content of stromal cells by flow cytometry, and immunohistochemistry and bone marrow (BM) localization of GFP-tagged hematopoietic stem cells (HSC) by confocal microscopy. Differences in serum levels of 32 inflammatory-cytokines between prefibrotic and fibrotic Gata1low mice and their wild-type littermates were modest. However, BM from fibrotic Gata1low mice contained higher levels of lipocalin-2, CXCL1, and TGF-β1 than wild-type BM. Although frequencies of endothelial cells, mesenchymal cells, osteoblasts, and megakaryocytes were higher than normal in Gata1low BM, the cells which expressed these cytokines the most were malignant megakaryocytes. This increased bioavailability of proinflammatory cytokines was associated with altered HSC localization: Gata1low HSC were localized in the femur diaphysis in areas surrounded by microvessels, neo-bones, and megakaryocytes, while wild-type HSC were localized in the femur epiphysis around adipocytes. In conclusion, bioavailability of inflammatory cytokines in BM, rather than blood levels, possibly by reshaping the HSC niche, correlates with myelofibrosis in Gata1low mice

Agomelatine: A Potential Multitarget Compound for Neurodevelopmental Disorders

Agomelatine (AGM) is one of the latest atypical antidepressants, prescribed exclusively for the treatment of depression in adults. AGM belongs to the pharmaceutical class of melatonin agonist and selective serotonin antagonist ("MASS"), as it acts both as a selective agonist of melatonin receptors MT1 and MT2, and as a selective antagonist of 5-HT2C/5-HT2B receptors. AGM is involved in the resynchronization of interrupted circadian rhythms, with beneficial effects on sleep patterns, while antagonism on serotonin receptors increases the availability of norepinephrine and dopamine in the prefrontal cortex, with an antidepressant and nootropic effect. The use of AGM in the pediatric population is limited by the scarcity of data. In addition, few studies and case reports have been published on the use of AGM in patients with attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Considering this evidence, the purpose of this review is to report the potential role of AGM in neurological developmental disorders. AGM would increase the expression of the cytoskeleton-associated protein (ARC) in the prefrontal cortex, with optimization of learning, long-term memory consolidation, and improved survival of neurons. Another important feature of AGM is the ability to modulate glutamatergic neurotransmission in regions associated with mood and cognition. With its synergistic activity a melatoninergic agonist and an antagonist of 5-HT2C, AGM acts as an antidepressant, psychostimulant, and promoter of neuronal plasticity, regulating cognitive symptoms, resynchronizing circadian rhythms in patients with autism, ADHD, anxiety, and depression. Given its good tolerability and good compliance, it could potentially be administered to adolescents and children

Superiority of Droplet Digital PCR Over Real-Time Quantitative PCR for JAK2 V617F Allele Mutational Burden Assessment in Myeloproliferative Neoplasms: A Retrospective Study

JAK2 V617F mutational status is an essential diagnostic index in myeloproliferative neoplasms (MPNs). Although widely used for detection of JAK2 V617F mutation in peripheral blood (PB), sensitive real-time quantitative PCR (qPCR) presents some methodological limitations. Recently, emerging alternative technologies, like digital droplet PCR (ddPCR), have been reported to overcome some of qPCR&rsquo;s technical drawbacks. The purpose of this study was to compare the diagnostic utility of ddPCR to qPCR for JAK2 V617F detection and quantification in samples from MPNs patients. Sensitivity and specificity of qPCR and ddPCR in the detection of the mutation were assessed by using a calibrator panel of mutated DNA on 195 JAK2 positive MPN samples. Based on our results, ddPCR proved to be a suitable, precise, and sensitive method for detection and quantification of the JAK2 V617F mutation

Formaldehyde and Acetaldehyde Exposure in &ldquo;Non-Traditional&rdquo; Occupational Sectors: Bakeries and Pastry Producers

Introduction. Formaldehyde, a colorless and highly irritating substance, causes cancer of the nasopharynx and leukemia. Furthermore, it is one of the environmental mutagens to which humans are most abundantly exposed. Acetaldehyde was recently classified as carcinogen class 1B and mutagen class 2 in Annex VI EC regulation. Occupational exposure to the two aldehydes occurs in a wide variety of occupations and industries. The aim of this study is to deepen exposure to the two aldehydes in the non-traditional productive sectors of bakeries and pastry producers. Methods. The evaluation of exposure to formaldehyde and acetaldehyde was conducted in Italy in 2019, in specific tasks and positions of 11 bakeries and pastry producers (115 measures, of which 57.4% were in fixed positions and the rest were personal air sampling). The measurements were performed using Radiello&copy; radial diffusion samplers. A logarithmic transformation of the data was performed, and the correlation between the two substances was calculated. Moreover, linear models considering the log-formaldehyde as the outcome and adjusting for log-acetaldehyde values were used. Results. The study identified high levels of acetaldehyde and formaldehyde exposure in the monitored workplaces. Higher mean values were observed in the leavening phase (8.39 &micro;g/m3 and 3.39 &micro;g/m3 for log-transformed data acetaldehyde and formaldehyde, respectively). The adjusted univariate analyses show statistically significant factors for formaldehyde as the presence of yeast, the presence of type 1 flour, the use of barley, the use of fats, the type of production, the use of spelt, and the presence of type 0 flour. Conclusions. The measurements confirmed the release of formaldehyde and acetaldehyde in bakeries and pastry industries, especially in some phases of the work process, such as leavening