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Saulnier N.,Catholic University of Rome | Puglisi M.A.,Catholic University of Rome | Lattanzi W.,Institute of Anatomy and Cell Biology | Castellini L.,Catholic University of Rome | And 6 more authors.
Cytotherapy | Year: 2011

Background aims: Bone marrow- and adipose tissue-derived mesenchymal stromal cells (MSC) represent promising sources for regenerative medicine. However, the precise molecular mechanisms underlying MSC stemness maintenance versus differentiation are not fully understood. The aim of this study was to compare the genome-wide expression profiles of bone marrow-and adipose tissue-derived MSC, in order to identify a common molecular stemness core. Methods. Molecular profiling was carried out using Affymetrix microarray and relevant genes were further validated by Q-PCR. Results. We identified an overlapping dataset of 190 transcripts commonly regulated in both cell populations, which included several genes involved in stemness regulation (i.e. self-renewal potential and the ability to generate differentiated cells), various signaling pathways and transcription factors. In particular, we identified a central role of the Kruppel-like factor 4 (KLF4) DNA-binding protein in regulating MSC transcriptional activity. Conclusions. Our results provide new insights toward understanding the molecular basis of MSC stemness maintenance and underline the ability of KLF4 to maintain cells in an undifferentiated state. © 2011 Informa Healthcare.


Osowski S.,Warsaw University of Technology | Osowski S.,Military University of Technology | Markiewicz T.,Warsaw University of Technology | Marianska B.,Institute of Haematology | Moszczynski L.,Warsaw University of Technology
European Signal Processing Conference | Year: 2015

The paper presents the preprocessing methods of the leukemic blast cells image in order to generate the features well characterizing different types of cells. The solved problems include: the segmentation of the bone marrow aspirate by applying the watershed transformation, selection of individual cells, feature generation on the basis of texture, statistical and geometrical analysis of the cells. These features are used as the input signals applied to the support vector machine used as the classifier. The numerical results of recognition of 12 different cell types are presented and discussed. © 2004 EUSIPCO.


Coiffier B.,Hematology | Osmanov E.A.,Cancer Research Center | Hong X.,Fudan University | Scheliga A.,Instituto Nacional Of Cancer | And 15 more authors.
The Lancet Oncology | Year: 2011

Background: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. Methods: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m2, administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. Findings: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Interpretation: Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Funding: Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc. © 2011 Elsevier Ltd.


PubMed | Haematology Unit, Shaare Zedek Medical Center, Hadassah Medical Center, Soroka University Medical Center and 7 more.
Type: Journal Article | Journal: British journal of haematology | Year: 2016

Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 472%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35g/l to negatively impact the likelihood of achieving response. The median duration of response was 84months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort was 49months (95% confidence interval [CI] 38-64) and 122months (95% CI 9-not reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity.


Colovic N.,Institute of Haematology | Colovic N.,University of Belgrade | Perunicic M.,Institute of Haematology | Jurisic V.,University of Kragujevac | Colovic M.,Institute of Haematology
Medical Oncology | Year: 2010

Skin involvement in hairy cell leukemia (HCL) at presentation is a relatively rare manifestation of the disease. A 60-year-old male patient in whom cutaneous lesions were the initial manifestation of hairy cell leukemia together with leukocytosis, monocytopenia, massive splenomegaly, and leukemic maculopapulous infiltration of the almost whole skin is described. The present case is the forth mentioned in the literature with specify of leukocytosis in peripheral blood, consisting mostly of hairy cells. The patient was treated with two courses of 2-chlorodeoxiadenosine (2-CdA, Cladribine) and splenectomy and after this cutaneous lesion disappeared and general condition is improved. © 2009 Humana Press Inc.


Samusik N.,Max Planck Institute of Molecular Cell Biology and Genetics | Krukovskaya L.,Biomedical Center | Meln I.,Institute of Haematology | Shilov E.,Biomedical Center | Kozlov A.P.,Saint Petersburg State University
PLoS ONE | Year: 2013

PBOV1 is a known human protein-coding gene with an uncharacterized function. We have previously found that PBOV1 lacks orthologs in non-primate genomes and is expressed in a wide range of tumor types. Here we report that PBOV1 protein-coding sequence is human-specific and has originated de novo in the primate evolution through a series of frame-shift and stop codon mutations. We profiled PBOV1 expression in multiple cancer and normal tissue samples and found that it was expressed in 19 out of 34 tumors of various origins but completely lacked expression in any of the normal adult or fetal human tissues. We found that, unlike the cancer/testis antigens that are typically controlled by CpG island-containing promoters, PBOV1 was expressed from a GC-poor TATA-containing promoter which was not influenced by CpG demethylation and was inactive in testis. Our analysis of public microarray data suggests that PBOV1 activation in tumors could be dependent on the Hedgehog signaling pathway. Despite the recent de novo origin and the lack of identifiable functional signatures, a missense SNP in the PBOV1 coding sequence has been previously associated with an increased risk of breast cancer. Using publicly available microarray datasets, we found that high levels of PBOV1 expression in breast cancer and glioma samples were significantly associated with a positive outcome of the cancer disease. We also found that PBOV1 was highly expressed in primary but not in recurrent high-grade gliomas, suggesting the presence of a negative selection against PBOV1-expressing cancer cells. Our findings could contribute to the understanding of the mechanisms behind de novo gene origin and the possible role of tumors in this process. © 2013 Samusik et al.


Klyuchnikov E.,University of Hamburg | Holler E.,University of Regensburg | Bornhauser M.,University Hospital Dresden | Kobbe G.,Heinrich Heine University Düsseldorf | And 7 more authors.
British Journal of Haematology | Year: 2012

Thirty myelofibrosis patients (21 males, nine females) with relapse (n = 27) or graft-rejection (n = 3) after dose-reduced allografting underwent a salvage strategy including donor lymphocyte infusions (DLIs) and/or second allogeneic haematopoietic stem cell transplantation (HSCT). Twenty-six patients received a median number of three (range, 1-5) DLIs in a dose-escalated mode starting with a median dose of 1·2 × 106 (range, 0·003-8 × 106) up to median dose of 40 × 106 T-cells/kg (range, 10-130 × 106). 10/26 patients (39%) achieved complete response (CR) to DLIs. Acute (grade II-IV) and chronic graft-versus-host (GvHD) disease occurred in 12% and 36% cases. Thirteen non-responders to DLI and four patients who did not receive DLI due to graft-rejection or acute transformation of the blast phase underwent a second allogeneic HSCT from alternative (n = 15) or the same (n = 2) donor. One patient (6%) experienced primary graft-failure and died. Acute (II-IV) and chronic GvHD were observed in 47% and 46% of patients. Overall responses after second HSCT were seen in 12/15 patients (80%: CR: n = 9, partial response: n = 3). The 1-year cumulative incidence of non-relapse mortality for recipients of a second allograft was 6%, and the cumulative incidence of relapse was 24%. After a median follow-up of 27 months, the 2-year overall survival and progression-free survival for all 30 patients was 70% and 67%, respectively. In conclusion, our two-step strategy, including DLI and second HSCT for non-responding or ineligible patients, is an effective and well-tolerated salvage approach for patients relapsing after reduced-intensity allograft after myelofibrosis. © 2012 Blackwell Publishing Ltd.


Laterza L.,Fondazione Policlinico A. Gemelli | Rizzatti G.,Fondazione Policlinico A. Gemelli | Gaetani E.,Fondazione Policlinico A. Gemelli | Chiusolo P.,Institute of Haematology | Gasbarrini A.,Fondazione Policlinico A. Gemelli
Mediterranean Journal of Hematology and Infectious Diseases | Year: 2016

Gut microbiota has gained increasing interest in the pathogenesis of immune-related diseases. In this context, graft-versus-host disease is a condition characterized by an immune response which frequently complicates and limits the outcomes of hematopoietic stem cell transplantations. Past studies, carried mostly in animals, already supported a relationship between gut microbiota and graft-versus-host disease. However, the possible mechanisms underlying this connection remain elusory. Moreover, strategies to prevent graft-versus-host disease are of great interest as well as the potential role of gut microbiota modulation. We reviewed the role of gut microbiota in the development of immune system and its involvement in the graft-versus-host disease, focusing on data available on humans.


Serban M.,Louis Turcanu | Skotnicki A.B.,Jagiellonian University | Colovic M.,Institute of Haematology | Jinca C.,Louis Turcanu | And 3 more authors.
Haemophilia | Year: 2012

Plasma-derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine ® is a high purity double-virus inactivated human plasma-derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open-label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long-term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on-demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half-life. Mean terminal elimination half-life was 27.6h and 25.0h, mean incremental recovery (IUdL -1/IUkg -1) was 1.55 and 1.60, at baseline and 3months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long-term prophylaxis, TOD and when applied after minor and major surgeries. © 2011 Blackwell Publishing Ltd.


PubMed | Fondazione Policlinico A. Gemelli and Institute of Haematology
Type: Journal Article | Journal: Mediterranean journal of hematology and infectious diseases | Year: 2016

Gut microbiota has gained increasing interest in the pathogenesis of immune-related diseases. In this context, graft-versus-host disease is a condition characterized by an immune response which frequently complicates and limits the outcomes of hematopoietic stem cell transplantations. Past studies, carried mostly in animals, already supported a relationship between gut microbiota and graft-versus-host disease. However, the possible mechanisms underlying this connection remain elusory. Moreover, strategies to prevent graft-versus-host disease are of great interest as well as the potential role of gut microbiota modulation. We reviewed the role of gut microbiota in the development of immune system and its involvement in the graft-versus-host disease, focusing on data available on humans.

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