Zinc is an essential trace element for living organisms and their biological processes. Zinc plays a key role in more than 300 enzymes and it is involved in cell communication, proliferation, ...differentiation and survival. Zinc plays also a role in regulating the immune system with implications in pathologies where zinc deficiency and inflammation are observed. In order to examine the experimental evidence reported in the literature regarding zinc levels in the body of patients with autoimmune disorders compared to control individuals, a systematic review and meta-analysis were performed. From 26,095 articles identified by literature search, only 179 of them were considered potentially relevant for our study and then examined. Of the 179 articles, only 62 satisfied the inclusion criteria. Particularly for Fixed Model, Zn concentration in both serum (mean effect = -1.19; confidence interval: -1.26 to -1.11) and plasma (mean effect = -3.97; confidence interval: -4.08 to -3.87) samples of autoimmune disease patients was significantly lower than in controls. The data presented in our work, although very heterogeneous in the manner of collecting and investigating samples, have proved to be extremely consistent in witnessing a deficiency of zinc in serum and plasma of patients compared to controls.
A panel of chronic lymphocytic leukemia (CLL) experts from Tuscany propose a real-life diagnostic and therapeutic approach CLL that considers the role of genomic and somatic prognostic factors in ...risk stratification and treatment decisions. Safety and efficacy of new agents has been demonstrated now not only in clinical trials but also in many real-world series. The BTK inhibitors, ibrutinib and acalabrutinib, and BH3 mimetic venetoclax are now indicated as first-line therapy and chemoimmunotherapy can be spared to the majority of CLL patients, thus preventing unnecessary hematological and non-hematological toxicity and second primary tumors. For treatment, FISH for 17 p and P53 mutational status are essential. IGHV mutation can be done at diagnosis or before treatment. Echography is the gold standard radiological investigation in CLL, at both diagnosis and response evaluation. Chemotherapy is virtually abandoned. Age, genetic risk, and patient comorbidities have to be carefully evaluated for treatment decision. With the availability of different drugs, there is a need for a uniform and shared approach in daily therapeutic choice. The proposed approach is based on current evidence and guidelines as well as results from clinical trials and daily clinical experience.
Iron overload may represent an additional clinical problem in patients with Myelodysplastic Syndromes (MDS), with recent data suggesting prognostic implications. Beyond red blood cells transfusions, ...dysregulation of hepcidin, the key iron hormone, may play a role, but studies until now have been hampered by technical problems. Using a recently validated assay, we measured serum hepcidin in 113 patients with different MDS subtypes. Mean hepcidin levels were consistently heterogeneous across different MDS subtypes, with the lowest levels in refractory anemia with ringed sideroblasts (RARS, 1.43 nM) and the highest in refractory anemia with excess blasts (RAEB, 11.3 nM) or in chronic myelomonocytic leukemia (CMML, 10.04 nM) (P = 0.003 by ANOVA). MDS subtypes remained significant predictors of hepcidin in multivariate analyses adjusted for ferritin and transfusion history. Consistently with current knowledge on hepcidin action/regulation, RARS patients had the highest levels of toxic non-transferrin-bound-iron, while RAEB and CMML patients had substantial elevation of C-Reactive Protein as compared to other MDS subtypes, and showed lost of homeostatic regulation by iron. Growth differentiation factor 15 did not appear as a primary hepcidin regulator in this series. If confirmed, these results may help to calibrate future treatments with chelating agents and/or hepcidin modulators in MDS patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
One of the main issues in the treatment of patients with chronic lymphocytic leukemia (CLL) deals with the choice between continuous or fixed-duration therapy. Continuous ibrutinib (IB), the ...first-in-class BTK inhibitor, and obinutuzumab-chlorambucil (G-CHL) are commonly used therapies for elderly and/or comorbid patients. No head-to-head comparison has been carried out. Within the Italian campus CLL network, we performed a retrospective study on CLL patients without TP53 disruption treated with IB or G-CHL as first-line therapy. Patients in the G-CHL arm had a higher CIRS score and the worst renal function. The overall response rates between the G-CHL and IB arms were similar, but more complete remissions (CRs) were achieved with G-CHL (
= 0.0029). After a median follow-up of 30 months, the progression-free survival (PFS,
= 0.0061) and time to next treatment (TTNT,
= 0.0043), but not overall survival (OS,
= 0.6642), were better with IB than with G-CHL. Similar results were found after propensity score matching and multivariate analysis. While PFS and TTNT were longer with IB than with G-CHL in IGHV unmutated patients (
= 0.0190 and 0.0137), they were superimposable for IGHV mutated patients (
= 0.1900 and 0.1380). In the G-CHL arm, the depth of response (79%
. 68%
. 38% for CR, PR and SD/PD;
< 0.0001) and measurable residual disease (MRD) influenced PFS (78%
. 53% for undetectable MRD
. detectable MRD,
= 0.0203). Hematological toxicities were common in the G-CHL arm, while IB was associated with higher costs. Although continuous IB provides better disease control in CLL, IGHV mutated patients and those achieving an undetectable MRD show a marked clinical and economic benefit from a fixed-duration obinutuzumab-based treatment.
Type 1 diabetes incidence presents a decreasing gradient in Europe from the Nordic countries to the Mediterranean ones. Exception to this gradient is represented by Sardinia, the second largest ...Mediterranean island whose population shows the highest incidence in Europe, after Finland. The genetic features of this population have created a fertile ground for the epidemic of the disease, however, as well as being strikingly high, the incidence rate has suddenly presented a continuous increase from the '50s, not explainable by accumulation of new genetic variants. Several environmental factors have been taken into account, possibly interacting with the genetic/epigenetic scenario, but there are no strong evidences to date.
The present study investigated the hypothesis that geochemical elements could create permissive environmental conditions for autoimmune diabetes. An ecological analysis was performed to test possible correlations between the values of eight elements in stream sediments and type 1 diabetes incidence rate in Sardinia.
Analyses revealed negative associations between elements, such as Co, Cr, Cu, Mn, Ni, Zn, and type 1 diabetes incidence.
The results suggest a possible protective role of some elements against the onset of the disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Unimodal TRBC1 pattern correlates with T cell clonality.•A TRBC1-including multiparametric panel improves clonality assessment sensitivity.•Monitoring TRBC1 helps in identifying small T-cell clones ...of uncertain significance.•TRBC1 represents an opportunity to overcome time-consuming diagnostic strategies.
The identification of mature T cell neoplasms by flow cytometry is often challenging, due to overlapping features with reactive T cells and limitations of currently available T cell clonality assays. The description of an antibody specific for one of two mutually exclusive T cell receptor (TCR) β-chain constant regions (TRBC1) provides an opportunity to facilitate the detection of clonal TCRαβ+ T cells based on TRBC-restriction. Here we prospectively analyzed 14 healthy controls and 63 patients with the flow cytometry protocol currently used for suspected T cell neoplasm implemented with immunostaining targeting TRBC1. Specimens were firstly classified in 3 groups based on clinical records data, laboratory findings and immunophenotypic features. T cell clonality was assessed by TCR Vβ repertoire analysis and the new rapid TRBC1 assay. Results showed that TRBC1 unimodal expression was unequivocally associated with samples presenting with immunophenotypic aberrancies. Moreover, we demonstrated that the use of TRBC1 is useful in solving uncertain cases and confirmed the high sensitivity of the method in identifying small T cell clones of uncertain significance (T-CUS). Finally, we found a high degree of concordance (97%) comparing the currently available clonality assessment methods with the proposed new method. In conclusion, our results provided real-life evidence of the utility of TRBC1 introduction in the flow cytometric clonality evaluation for the routine diagnostic work-up of T cell neoplasms.
Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to ...identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing. Overall response rate (ORR) was 52%, including complete response (CR) in 28 patients (17%). In multivariate analysis, ASXL1 mutations predicted a lower ORR (Odds Ratio OR = 0.85, p = 0.037), whereas TET2mut/ASXL1wt genotype predicted a higher CR rate (OR = 1.18, p = 0.011) independently of clinical parameters. With a median follow-up of 36.7 months, overall survival (OS) was 23.0 months. In multivariate analysis, RUNX1mut (Hazard Ratio HR = 2.00, p = .011), CBLmut (HR = 1.90, p = 0.03) genotypes and higher WBC (log10(WBC) HR = 2.30, p = .005) independently predicted worse OS while the TET2mut/ASXL1wt predicted better OS (HR = 0.60, p = 0.05). CMML-specific scores CPSS and GFM had limited predictive power. Our results stress the need for robust biomarkers of HMA activity in CMML and for novel treatment strategies in patients with myeloproliferative features and RUNX1 mutations.
•TET2mut/ASXL1wt genotype predicts higher complete response rate and prolonged survival in CMML with hypomethylating agents.•Conversely, RUNX1mut and CBLmut genotypes are associated with poorer outcome, independently of higher leukocyte count.•CPSS and GFM prognostic scores showed modest performance when calculated at initiation of hypomethylating agents.
Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML. Response and survival in MDS and AML patients treated with HMAs is difficult to predict. We explore the predictive role of recurrent somatic mutations in a large retrospective cohort of 174 HMA-treated CMMLs. Consistent with MDS studies, we report a higher response rate in TET2mut/ASXL1wt patients. We also identify a CMML-specific molecular pattern (RUNX1mut or CBLmut) associated with shorter survival. Our results can inform treatment decision in CMML, for instance by using HMAs prior to transplant in TET2mut/ASXL1wt patients.
South-Western Sardinia (SWS) is a high risk area for Multiple Sclerosis (MS) with high prevalence and spatial clustering; its population is genetically representative of Sardinians and presents a ...peculiar environment. We evaluated the MS environmental risk of specific heavy metals (HM) and geographical factors such as solar UV exposure and urbanization by undertaking a population-based cross-sectional study in SWS.
Geochemical data on HM, UV exposure, urbanization and epidemiological MS data were available for all SWS municipalities. Principal Component Analysis (PCA) was applied to the geochemical data to reduce multicollinearity and confounding criticalities. Generalized Linear Mixed Models (GLMM) were applied to evaluate the causal effects of the potential risk factors, and a model selection was performed using Akaike Information Criterion.
The PCA revealed that copper (Cu) does not cluster, while two component scores were extracted: 'basic rocks', including cobalt, chromium and nickel, and 'ore deposits', including lead and zinc. The selected multivariable GLMM highlighted Cu and sex as MS risk factors, adjusting for age and 'ore deposits'. When the Cu concentration increases by 50 ppm, the MS odds are 2.827 (95% CI: 1.645; 5.07) times higher; females have a MS odds 2.04 times (95% CI: 1.59; 2.60) higher than males.
The high frequency of MS in industrialized countries, where pollution by HM and CO poisoning is widespread, suggests a relationship between environmental exposure to metals and MS. Hence, we suggested a role of Cu homeostasis in MS. This is a preliminary study aimed at generating hypotheses that will need to be confirmed further.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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