Circulating miRNA panel for prediction of acute graft-versus-host disease in lymphoma patients undergoing matched unrelated hematopoietic stem cell transplantation

Acute graft-versus-host disease (aGVHD) results in significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Noninvasive diagnostic and prognostic tests for aGVHD are currently lacking, but would be beneficial in predicting aGVHD and improving the safety of allo-HSCT. Circulating microRNAs exhibit marked stability and may serve as biomarkers in several clinical settings. Here, we evaluated the use of circulating microRNAs as predictive biomarkers of aGVHD in lymphoma patients after allo-HSCT from matched unrelated donors (MUDs). After receiving informed consent, we prospectively collected plasma samples from 24 lymphoma patients before and after unmanipulated MUD allo-HSCT; microRNAs were then isolated. Fourteen patients developed aGVHD symptoms at a median of 48 days (range: 32–90) post-transplantation. Two patients developed intestinal GVHD, eight cutaneous GVHD, and four multiorgan GVHD. The microRNA expression profile was examined using quantitative real-time polymerase chain reaction (qRT-PCR). MicroRNAs 194 and 518f were significantly upregulated in aGVHD samples compared with samples taken from non-aGVHD patients. Remarkably, these upregulated microRNAs could be detected before the onset of aGVHD. Pathway prediction analysis indicated that these microRNAs may regulate critical pathways involved in aGVHD pathogenesis. Considering the noninvasive characteristics of plasma sampling and the feasibility of detecting miRNAs after allo-HSCT using real-time polymerase chain reaction, our results indicate that circulating microRNAs have the potential to enable an earlier aGVHD diagnosis and might assist in individualizing therapeutic strategies after MUD allo-HSCT. Nevertheless, standardization of blood sampling and analysis protocols is mandatory for the introduction of miRNA profiling into routine clinical use

Gut microbiota markers in obese adolescent and adult patients: Age-dependent differential patterns

Obesity levels, especially in children, have dramatically increased over the last few decades. Recently, several studies highlighted the involvement of gut microbiota in the pathophysiology of obesity. We investigated the composition of gut microbiota in obese adolescents and adults compared to age-matched normal weight (NW) volunteers in order to assemble age- and obesity-related microbiota profiles. The composition of gut microbiota was analyzed by 16S rRNA-based metagenomics. Ecological representations of microbial communities were computed, and univariate, multivariate, and correlation analyses performed on bacterial profiles. The prediction of metagenome functional content from 16S rRNA gene surveys was carried out. Ecological analyses revealed a dissimilarity among the subgroups, and resultant microbiota profiles differed between obese adolescents and adults. Using statistical analyses, we assigned, as microbial markers, Faecalibacterium prausnitzii and Actinomyces to the microbiota of obese adolescents, and Parabacteroides, Rikenellaceae, Bacteroides caccae, Barnesiellaceae, and Oscillospira to the microbiota of NW adolescents. The predicted metabolic profiles resulted different in adolescent groups. Particularly, biosynthesis of primary bile acid and steroid acids, metabolism of fructose, mannose, galactose, butanoate, and pentose phosphate and glycolysis/gluconeogenesis were for the majority associated to obese, while biosynthesis and metabolism of glycan, biosynthesis of secondary bile acid, metabolism of steroid hormone and lipoic acid were associated to NW adolescents. Our study revealed unique features of gut microbiota in terms of ecological patterns, microbial composition and metabolism in obese patients. The assignment of novel obesity bacterial markers may open avenues for the development of patient-tailored treatments dependent on age-related microbiota profiles

Serum Thymus and Activation-Regulated Chemokine Level Monitoring May Predict Disease Relapse Detected by PET Scan after Reduced-Intensity Allogeneic Stem Cell Transplantation in Patients with Hodgkin Lymphoma

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New Diagnostic and Prognostic Models for the Development of Alcoholic Cirrhosis Based on Genetic Predisposition and Alcohol History

Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925–0.977) and 0.887 (95% CI 0.925–0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769–0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk

Bortezomib Plus Dexamethasone Followed by Escalating Donor Lymphocyte Infusions for Patients with Multiple Myeloma Relapsing or Progressing after Allogeneic Stem Cell Transplantation

Abstract Multiple myeloma relapsing after allogeneic stem cell transplantation (alloSCT) has a poor outcome. To assess the safety and efficacy of bortezomib and dexamethasone (VD) combination followed by donor lymphocyte infusions (DLIs) in myeloma patients relapsing or progressing after alloSCT, a prospective phase II study was designed. The treatment plan consisted of three VD courses followed by escalated doses of DLIs in case of response or at least stable disease. Nineteen patients were enrolled with a median age of 57 years (range, 33 to 67); 14 patients were allografted from human leukocyte antigen–identical siblings and 5 from alternative donors. Sixteen of 19 patients received the planned treatment, but 3 patients did not: 2 patients because of disease progression and 1 refused. After the VD phase the response rate was 62%, with 1 complete remission, 6 very good partial remissions, 5 partial remissions, 2 patients with stable disease, and 5 with progressive disease. After the DLI phase, the response rate was 68%, but a significant upgrade of response was observed: 3 stringent complete remissions, 2 complete remissions, 5 very good partial remissions, 1 partial remission, 4 with stable disease, and 1 with progressive disease. With a median follow-up of 40 months (range, 29 to 68), the 3-year progression-free survival and overall survival rates were 31% and 73%, respectively. Neither unexpected organ toxicities, in particular severe neuropathy, nor severe acute graft-versus-host disease flares were observed. VD-DLIs is a safe treatment for multiple myeloma patients relapsing or progressing after alloSCT and may be effective

The role of positron emission tomography with 18F-fluorodeoxyglucose integrated with computed tomography in the evaluation of patients with multiple myeloma undergoing allogeneic stem cell transplantation

Positron emission tomography (PET) integrated with computed tomography (PET/CT) has been reported to be useful for screening myelomatous lesions at diagnosis in patients with multiple myeloma (MM) and for monitoring response to autologous stem cell transplantation (auto-SCT). The aim of the study was to evaluate the prognostic significance of PET/CT in MM patients who received allogeneic stem cell transplantation (allo-SCT). Patients who underwent upfront auto-SCT followed by allo-SCT, either as consolidation or salvage treatment, were studied with PET/CT before and/or within 6 months after allo-SCT. The number, the maximum standard uptake value (SUV), and the location (medullary or extramedullary) of focal lesions (FLs) were recorded and investigated as predictors of progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analyses. Fifty-four patients had a PET/CT scan before allo-SCT. Of these, 22 patients (41%) had a negative PET/CT scan, 11 patients (20%) showed 1 to 3 FLs, and 21 patients (39%) had either a diffuse bone marrow involvement or more than 3 FLs. SUV was >4.2 in 21 patients (39%) and extramedullary disease (EMD) was present in 6 patients (11%). Multivariate analysis of prognostic factors before allo-SCT showed that persistence of EMD at transplantation was an independent predictor of poor PFS, whereas OS was negatively influenced by unrelated donor and SUV > 4.2. Fifty-nine patients had a PET/CT scan within 6 months after allo-SCT. Multivariate analysis of post-treatment variables showed that persistence of EMD and failure to obtain complete response or very good partial response after allo-SCT were strongly associated with shorter PFS and OS. Of the 46 patients with evaluable PET/CT scans both before and 6 months after allo-SCT, the 23 patients who maintained or reached a PET complete remission showed a significantly prolonged PFS and OS compared with the 23 patients with persistence of any PET positivity (2-year PFS: 51% versus 25%, P = .03; 2-year OS: 81% versus 47%, P = .001). This study indicates that PET/CT imaging before and after allo-SCT is significantly associated with the outcome, suggesting the utility of this technique for MM staging before allo-SCT and for response monitoring after the transplantation

Crystallization and preliminary X-ray diffraction studies of a D

A 10-mer duplex formed between a PNA containing a `chiral box' of three adjacent d-Lys-based monomers and its complementary DNA strand has been crystallized for the first time. Crystals have been obtained using PEG 8000 as precipitant and cacodylate at pH 6.3 as buffer. The crystals belong to the space group P31 or to its enantiomorph P32, with unit-cell parameters a = b = 35.00, c = 35.91 Å. A complete data set has been collected at the synchrotron source Elettra in Trieste to 1.85 Å resolution, using a single frozen crystal

MYELOID MICROVESICLES ARE A MARKER AND THERAPEUTIC TARGET FOR NEUROINFLAMMATION

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