Atypical chronic myeloid leukemia (aCML) is a rare MDS/MPN disease characterized by the absence of BCR::ABL1 rearrangement and well known typical mutations associated with myeloproliferative ...disorders. Mutational landscape associated with this disease was recently described with frequent involvement of SETBP1 and ETNK1 mutations. CCND2 mutations have not been frequently detected in MPN or MDS/MPN patients. We describe two cases of aCML with two CCND2 mutations in 280 and 281 codons which rapidly develop progressive characteristics, and we reviewed the literature about this unfavorable association, suggesting a role as a new possible marker of aggressive disease.
Key points
What's already known about this topic?
Discordant NIPT results can rarely unravel maternal malignancies, especially when multiple chromosomal imbalances are reported. Both solid and ...hematological neoplasms have been described.
What does this study add?
This is the first case of a discordant NIPT result due to Chronic Lymphocytic Leukemia associated with trisomy of the chromosome 12. Putative maternal malignancy should be considered and investigated through sensitive techniques even in presence of a single chromosomal anomaly. This must be considered especially when the imbalance is known to recur in hematological neoplasms.
Background: Older patients (pts) with acute myeloid leukemia (AML) have a particularly dismal outcome, because of adverse features of AML in the elderly and frailty. The median duration of complete ...remission (CR) last less than 1 year. The optimal management of older AML pts in daily clinical practice has not been determined. Regular treatment options include best support care, low dose cytarabine (Ara-c) and intensive chemotherapy (anthracycline combined with ara-c). Recently, the DNA methyltransferase inhibitor Azacitidine (AZA) has demonstrated significant activity and favorable tolerability in AML pts also showing a survival advantage.
Materials and Methods: Between May 2013 and July 2016, at our institution, 19 pts with a diagnosis of AML (13 males and 7 females) were judged to be ineligible for intensive chemotherapy due to age or comorbidities. They received a 5-day regimen of cytoreductive chemotherapy with ara-c at a dosage of 100 mg\mq\day i.v. continuous infusion. On the sixth day, on termination of Ara-c infusion, all pts had ≤30% bone marrow blasts. Therefore, AZA was administered at a dosage of 75 mg\mq\day subcutaneously for 7 days, continuing the therapy every 28 days. The median age of pts was 75 years (range, 49 to 79 years), with 17 pts (89%) aged over 65 years. Six pts (32%) had poor molecular and cytogenetic risks markers, and six other pts (32%) had either antecedent myelodisplastic/myeloproliferative diseases or therapy related AML. The response to therapy according to the AML IWG criteria was assessed by bone marrow aspiration immediately after Ara-c infusion, after one AZA cycle and every 6 months thereafter. Baseline pts characteristics are summarized in Table 1.
Results: The median number of administered AZA cycles was 6 (range, 1-25 cycles). Fifty eight percent (11/19) of pts received ≥6 AZA clycles. The median overall survival was 6 months (range, 1-26 months). According to AML IWG criteria, 8 pts (42%) achieved CR after Ara-c and a single AZA cycle. Of these, 5 pts (62%) are currently alive in CR, with median duration of response of 7 months (range: 5-12 months), while 3 pts (38%) died after 4, 12, and 22 months after diagnosis. One pt (5%) achieved a partial response (PR) after one AZA cycle, maintaining at present the same response after 3 months of therapy. Other 8 pts (42%) obtained stable disease (SD). Of these, 3 pts (37%) are currently in SD after 2, 8 and 10 months of therapy, while 5 pts (64%) died within a median of 5 months (range: 2 - 18 months) after AML diagnosis. Finally 1 pt (5%) was refractory dying after 2 months of diagnosis, and another pt (5%) died after first AZA cycle for sepsis. Fever and infections were the most common non-hematologic toxic events after Ara-c chemotherapy and first AZA cycle (17/19 pts, 90%). While subsequent AZA cycles were well tolerated.
Conclusion: We suggest that the use of Ara-c-AZA combination is feasible in elderly AML pts. However, the relatively small number of pts studied and short follow up preclude definitive conclusion. The study is still accruing patients.
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No relevant conflicts of interest to declare.
Proteomic approaches are commonly secondary to genetic studies but are essential in the multi-disciplinary field of hematological research. As opposed to mRNA microarray data, proteomics provides a ...better understanding of which proteins are actually expressed, although the identification of specific proteins remains challenging (Unwin et al Blood Rev 2014; Boyd J Proteomics 2010). In neoplastic hematology such as CLL, protein studies have contributed to the elucidation of disease mechanisms, defined prognostic or therapeutic biomarkers (Boyd J Proteomics 2010). In this study we used proteomics and 2DE analysis to evaluate differential protein expression patterns after treatment with Len. Len can improve immune dysfunction in CLL by repairing F-actin polymerization and signaling at the immunological synapse (Ramsay et al 2008 J Clin Invest). Our previous data obtained from MALDI-TOF analysis identified Tβ4, a G-actin sequestering protein involved in the regeneration of injured tissues and cell migration, as a downregulated protein in CLL patients, also confirmed by an independent GEP analysis comparing B-cell from CLL cases (n=80) and normal controls (n=6), supported by Tβ4 mRNA down-regulation in CLL (3604±1244 vs 5715±1004, respectively; mean±SD; p=0.001). Here, we investigated whether purified B-CLL cells respond differently to the chemoattractant SDF1a and whether different protein expression patterns can be identified after exogenous Tβ4 and Len treatment using 2DE analysis.
Highly purified B-CLL lymphocytes were isolated from untreated Binet stage A CLL patients prospectively enrolled from diagnosis (O-CLL1 protocol, clinicaltrial.gov identifier NCT00917540) and healthy controls. Tb4 was identified by MALDI TOF using 100 patient samples. Next, cells were pre-treated with Len (5uM) and then treated with Tb4 (100nM) for 30min. Cells were plated in transwells using 5.0 um pores with SDF1a as chemoattractant for migration assays. Protein was extracted from CLL cell pellets by RIPA buffer and quantified. Sample preparation and 2DE was performed as described by Scielzo et al (J Clin Inves, 2005). Protein samples (100 ug) were applied to 7-cm IPG strips, pH 3-11NL (Amersham Biosciences), respectively, by in-gel rehydration. Isoelectric focusing was performed with a Protean i12 IEF system (Biorad). Strips were equilibrated and loaded onto 9-16% gradient acrylamide SDS-PAGE gels for the second dimension separation. Silver nitrate staining (Sinha P et al Proteomic, 2001) was used to visualize proteins and images were digitally acquired (ChemiDoc MP, Biorad) and spots were analyzed using PDQuest basic 2D Gel Analysis Software (Biorad).
CLL samples with the lowest Tβ4 expression (n=12) also had higher F-actin levels as evaluated by FC analysis than normal controls. B-CLL strongly responded to the migratory stimulus SDF-1a, which was further increased (by 20%) in presence of Len treatment, likely due to an alteration in actin remodeling and changes in the expression of unknown proteins. Purified CD19+CD5+ leukemic cells were lysed and proteins resolved on 2DE and visualized by silver nitrate staining. The protein profile analysis on silver-stained gels showed a number of protein spots ranging from 18 to 60kDa that were differentially expressed with respect to untreated cells. Our preliminary qualitative analysis suggests that there are groups of proteins with a lower expression in the presence of Tβ4 or Len, which are more strongly inhibited following exposure to their combination. Conversely, an opposite pattern of protein expression was observed whereby an additive effect on protein expression was observed by combined exposure to Tβ4 and Len. This approach allowed us to identify an altered protein expression pattern after treatment with Len and Tβ4, and may be useful to identify changes in expression profiles of CLL proteins, which may translate into functional differences in the malignant clone.
No relevant conflicts of interest to declare.
Innovative Biomaterials for Bone Regrowth Iaquinta, Maria Rosa; Mazzoni, Elisa; Manfrini, Marco ...
International journal of molecular sciences,
01/2019, Letnik:
20, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The regenerative medicine, a new discipline that merges biological sciences and the fundamental of engineering to develop biological substitutes, has greatly benefited from recent advances in the ...material engineering and the role of stem cells in tissue regeneration. Regenerative medicine strategies, involving the combination of biomaterials/scaffolds, cells, and bioactive agents, have been of great interest especially for the repair of damaged bone and bone regrowth. In the last few years, the life expectancy of our population has progressively increased. Aging has highlighted the need for intervention on human bone with biocompatible materials that show high performance for the regeneration of the bone, efficiently and in a short time. In this review, the different aspects of tissue engineering applied to bone engineering were taken into consideration. The first part of this review introduces the bone cellular biology/molecular genetics. Data on biomaterials, stem cells, and specific growth factors for the bone regrowth are reported in this review.
Intercellular adhesion is a key function for epithelial cells. The fundamental mechanisms relying on epithelial cell adhesion have been partially uncovered. Hsa-microRNA-1249-3p (hsa-miR-1249-3p) ...plays a role in the epithelial mesenchymal transition in carcinoma cells, but its physiological function in epithelial cells is unknown. We aimed to investigate the role and molecular mechanisms of hsa-miR-1249-3p on epithelial cell functions. Hsa-miR-1249-3p was overexpressed in human epithelial cells and uterine cervical tissues, compared to cervical carcinoma cells and precancerous tissues, respectively. Hsa-miR-1249-3p was analyzed to verify its regulatory function on Homeobox A13 (HOXA13) target gene and its downstream cell adhesion gene β-catenin. Functional experiments indicated that hsa-miR-1249-3p inhibition prompted the mRNA and protein overexpression of HOXA13 which, in turn, led to the β-catenin protein expression. Moreover, hsa-miR-1249-3p inhibition induced a strong colony forming ability in epithelial cells, suggesting the miR involvement in cell adhesion machinery. These data indicate that hsa-miR-1249-3p regulates the expression of HOXA13 and its downstream cell adhesion gene β-catenin, possible resulting in cell adhesion modification in epithelial cells. This study will allow the set-up of further investigations aimed at exploring the relationship between the hsa-miR-1249-3p/HOXA13 axis and downstream cell adhesion genes.
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