Autologous Hematopoietic Stem Cell Transplantation (AHSCT): Standard of Care for Relapsing–Remitting Multiple Sclerosis Patients

Abstract Autologous hematopoietic stem cell transplantation (AHSCT) has been used in the treatment of highly active multiple sclerosis (MS) for over two decades. It has been demonstrated to be highly efficacious in relapsing–remitting (RR) MS patients failing to respond to disease-modifying drugs (DMDs). AHSCT guarantees higher rates of no evidence of disease activity (NEDA) than those achieved with any other DMDs, but it is also associated with greater short-term risks which have limited its use. In the 2019 updated EBMT and ASBMT guidelines, which review the clinical evidence of AHSCT in MS, AHSCT indication for highly active RRMS has changed from “clinical option” to “standard of care”. On this basis, AHSCT must be proposed on equal footing with second-line DMDs to patients with highly active RRMS, instead of being considered as a last resort after failure of all available treatments. The decision-making process requires a close collaboration between transplant hematologists and neurologists and a full discussion of risk–benefit of AHSCT and alternative treatments. In this context, we propose a standardized protocol for decision-making and informed consent process

Assessment of selenium levels and risk factors for stroke and other cardiovascular disease: a cross sectional study in a seleniferous area of Punjab, India

Background and aims: Rural areas of Punjab in India have been found to have soil rich in selenium (Se); about 2160 hectare area is seleniferous and is populated by about 10,000 inhabitants. Selenium concentrations in these villages were reported to be as high as 65 times over non-seleniferous areas. The aim of this cross-sectional study was to evaluate selenium levels in blood, hair and nails in a group of subjects living in this area, and to evaluate the correlation between selenium exposure levels and a relevant cardiovascular risk factor and blood pressure. Methods: In a random sample of rural residents in three districts of a seleniferous area of Punjab, we determined selenium concentration in hair, nail clippings and serum samples. Analyses were carried out using atomic absorption spectrophotometry at National Dairy Research Institute (NDRI), Karnal, India. Data analysis was performed using the STATA 15.0 software (STATA Corp. TX). Results: A total of 680 human subjects were recruited in this study, with a male/female ratio of 0.65 and a median age of 43 (IQR 32-52). Medium selenium levels in blood, hair and nail were 86.7 µg/l (IQR 55.9-200.3), 20.7 µg/g (IQR 12.6-40.3) and 56.9 µg/g (IQR 42.8-83.9), respectively, with lower levels in women in all three kind of samples. Concerning systolic blood pressure, Pearson’s correlation coefficients were 0.102 (95 % CI -0.025 to 0.226, p=0.116); 0.076 (95% CI -0.010 to 0.160, p=0.085); 0.072 (95% CI -0.015 to 0.157, p=0.104) with blood, hair and nail, respectively. For diastolic blood pressure, Pearson’s correlation coefficients are 0.106 (95% CI -0.022 to 0.230, p=0.104), 0.036 (95% CI -0.050 to 0.122, p=0.409), 0.049 (95% CI -0.038 to 0.135, p=0.272), respectively. Conclusions: Our findings indicate a positive correlation between selenium content in blood, hair and nails and increasing systolic and diastolic pressure levels, in line with previous epidemiologic findings, indicating a possible health concern for this highly exposed population. The possible relation between selenium over-exposure and onset of hypertension and other cardiovascular diseases deserves further investigation

Arsenic trioxide and ascorbic acid interfere with the BCL2 family genes in patients with myelodysplastic syndromes: an ex-vivo study.

BACKGROUND: Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); its mechanisms of action have already been evaluated in vitro, but the in vivo activity is still not fully understood. Since ATO induces apoptosis in in vitro models, we compared the expression of 93 apoptotic genes in patients’ bone marrow before and after ATO treatment. For this analysis, we selected 12 patients affected by MDS who received ATO in combination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530, EudracT Number 2005-001321-28. METHODS: Real-time PCR quantitative assays for genes involved in apoptosis were performed using TaqMan® Assays in 384-Well Microfluidic Cards “TaqMan® Human Apoptosis Array”. Quantitative RT-PCR for expression of EVI1 and WT1 genes was also performed. Gene expression values (Ct) were normalized to the median expression of 3 housekeeping genes present in the card (18S, ACTB and GAPDH). RESULTS: ATO treatment induced up-regulation of some pro-apoptotic genes, such as HRK, BAK1, CASPASE-5, BAD, TNFRSF1A, and BCL2L14 and down-regulation of ICEBERG. In the majority of cases with stable disease, apoptotic gene expression profile did not change, whereas in cases with advanced MDS more frequently pro-apoptotic genes were up-regulated. Two patients achieved a major response: in the patient with refractory anemia the treatment down-regulated 69% of the pro-apoptotic genes, whereas 91% of the pro-apoptotic genes were up-regulated in the patient affected by refractory anemia with excess of blasts-1. Responsive patients showed a higher induction of BAD than those with stable disease. Finally, WT1 gene expression was down-regulated by the treatment in responsive cases. CONCLUSIONS: These results represent the basis for a possible association of ATO with other biological compounds able to modify the apoptotic pathways, such as inhibitors of the BCL2 family

Detection of SF3B1 p.Lys700Glu Mutation by PNA-PCR Clamping in Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Mutations in SF3B1 are found in 20% of myelodysplastic syndromes and 5–10% of myeloproliferative neoplasms, where they are considered important for diagnosis and therapy decisions. Sanger sequencing and NGS are the currently available methods to identify SF3B1 mutations, but both are time-consuming and expensive techniques that are not practicable in most small-/medium-sized laboratories. To identify the most frequent SF3B1 mutation, p.Lys700Glu, we developed a novel fast and cheap assay based on PNA-PCR clamping. After setting the optimal PCR conditions, the limit of detection of PNA-PCR clamping was evaluated, and the method allowed up to 0.1% of mutated SF3B1 to be identified. Successively, PNA-PCR clamping and Sanger sequencing were used to blind test 90 DNA from patients affected by myelodysplastic syndromes and myeloproliferative neoplasms for the SF3B1 p.Lys700Glu mutation. PNA-PCR clamping and Sanger sequencing congruently identified 75 negative and 13 positive patients. Two patients identified as positive by PNA-PCR clamping were missed by Sanger analysis. The discordant samples were analyzed by NGS, which confirmed the PNA-PCR clamping result, indicating that these samples contained the SF3B1 p.Lys700Glu mutation. This approach could easily increase the characterization of myelodysplastic syndromes and myeloproliferative neoplasms in small-/medium-sized laboratories, and guide patients towards more appropriate therapy

NF-κB dysregulation in microRNA-146a–deficient mice drives the development of myeloid malignancies

MicroRNA miR-146a has been implicated as a negative feedback regulator of NF-κB activation. Knockout of the miR-146a gene in C57BL/6 mice leads to histologically and immunophenotypically defined myeloid sarcomas and some lymphomas. The sarcomas are transplantable to immunologically compromised hosts, showing that they are true malignancies. The animals also exhibit chronic myeloproliferation in their bone marrow. Spleen and marrow cells show increased transcription of NF-κB–regulated genes and tumors have higher nuclear p65. Genetic ablation of NF-κB p50 suppresses the myeloproliferation, showing that dysregulation of NF-κB is responsible for the myeloproliferative disease

Proposing new procedures for the management and prevention of foodborne diseases: An Italian experience

Background and aim: Foodborne diseases are a public health issue with more than 4,000 outbreaks in 2021 in European Union countries and United Kingdom and their management is important for prevention and controls of outbreaks. Recently, new technological tools and strategies, including whole genome sequencing (WGS), have become available to allow the highest level of discrimination in the investigation of foodborne outbreak. In this study, we presented the updated procedure for assessment of foodborne disease in a community of a Northern-Italy region, Emilia-Romagna. Methods: In the Reggio Emilia National Health Service Local Unit (AUSL-RE), foodborne disease monitoring and control are managed by the following health services: public health and hygiene (SIP); hygiene of foodstuffs and nutrition (SIAN) and veterinary public health (SSPV) composing the developed MTA group (‘Gruppo Malattie Trasmesse da Alimenti’). Among the new tools being implemented, there is a shared computerized folder and new related managements procedures available to MTA members only, allocating information regarding any material useful to the MTA group. Results: The main new features of the new procedure are: information sharing in all phases of the management of the infectious episode, integration of the three services through the creation of the MTA group and updated criteria for procedure activation, and finally a dedicated training programme. Conclusions: Timely investigation, management and control of MTA outbreaks is essential for both health and economic reasons. The new features and procedures implemented in this Italian community may allow to identify rapidly the causes of a case or outbreak and better counteract their spread. (www.actabiomedica.it)