bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutation of Mouse MAYP/PSTPIP2 Causes a Macrophage Autoinflammatory Disease.
Authors: Chitu Violeta , Grosse Johannes , Marquardt Andreas , Hanke Petra , Schmittwolf Carolin , Zeitlmann Lutz , Schropp Patricia , Barth Bettina , Yu Philipp , Paffenholz Rainer , Stumm Gabriele , Nehls Michael , Stanley E. Richard 
Published: October 2019

Abstract
Macrophage actin-associated tyrosine phosphorylated protein (MAYP), a Pombe Cdc15 Homology (PCH) family protein also known as proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), is involved in the regulation of macrophage motility (Chitu et al., 2005). Mutations in a closely related gene, PSTPIP1/CD2 binding protein 1 (CD2BP1) cause a dominantly inherited autoinflammatory disorder known as PAPA syndrome. A mutant mouse obtained by chemical mutagenesis exhibited an autoinflammatory disorder characterized by macrophage infiltration and inflammation leading to osteolysis and necrosis in paws and necrosis of ears. Positional cloning of this recessive mutation, termed Lupo, identified a T to A nucleotide exchange leading to an amino acid substitution (I282N) in the sequence of MAYP. MaypLp/Lp disease was transferable by bone marrow transplantation and developed in the absence of lymphocytes. Consistent with the involvement of macrophages, lesion development could be prevented by the administration of chlodronate liposomes. MAYP is expressed in monocytes/macrophages and a Mac1+ sub-fraction of granulocytes. LPS stimulation increases its expression in macrophages. Due to instability of the mutant protein, MAYP expression is reduced 3-fold in MaypLp/Lp macrophages and upon LPS stimulation does not rise above the level of unstimulated wt cells. MaypLp/Lp mice expressed elevated circulating levels of IL-4, Rantes, TGF-beta and MCP-1 and in vitro their macrophages exhibit altered cytokine production. These studies suggest that MAYP plays an anti-inflammatory role in macrophages.
Down-Regulation of Cellular Vascular Endothelial Growth Factor (VEGF) Levels Induces Differentiation of Leukemic Cells into Leukemic-Dendritic Cells in Patients with Acute Myeloid Leukemia.
Authors: Kang Hyun-Kyu , Park Jung-Sun , Choi Bo-Hwa , Nguyen Thanh-Nhan , Zhu Xiao-Wei , Cho Duck , Nam Jong-Hee , Kim Young-Jin , Kim Hyeoung Joon , Lee Je-Jung 
Published: October 2019

Abstract
Vascular endothelial growth factor (VEGF), produced by most tumors, not only plays an important role in tumor angiogenesis but also can inhibit the maturation of dendritic cells (DCs) from hematopoietic progenitors. In this study, we investigated the relationship between the clinical characteristics of patients with acute myeloid leukemia (AML) and the generation of DCs from the leukemic cells, and found that cellular VEGF level in leukemic cells affected the generation of leukemic-DCs in vitro. Leukemic-DCs were successfully generated from 16 of 21 AML patients, and generated leukemic DCs exhibited high level of HLA-DR and CD54 expression, and intermediate level of CD80, CD86, CD83, and CD1a expression. Leukemic-DCs also were able to stimulate allogeneic T cell proliferation and cytotoxic activities against autologous leukemic cells. The failure of generation of leukemic-DCs from leukemic cells in some AML patients was related with its cellular VEGF levels. The leukemic cells that failed to generate leukemic-DCs had significantly higher cellular VEGF levels than that of generated leukimic-DCs (p = 0.005), and neutralizing of VEGF with anti-VEGF Ab inhibited the cellular VEGF level at the transcription level as determined by RT-PCR analysis, and at the protein level determined by West blotting and ELISA. Inhibition of cellular VEGF levels induced the generation of leukemic-DCs determined by increased levels of surface markers, namely, CD40, CD80, CD86, and HLA-DR. Moreover, inhibition of cellular VEGF levels also increased IL-12 production and allosimulatory capacity of leukemic-DCs, suggesting functional differentiation of leukemic-DCs. Interestingly, cellular VEGF levels also are inversely related to the achievement of complete remission for induction therapy (p = 0.02). Taken together, these results suggest that cellular VEGF levels during the differentiation of AML cells to leukemic-DCs are a predictive marker of the positive response of the AML patients to the remission-inducing therapy, and down-regulation of cellular VEGF levels can be one target of cancer immunotherapy by generating of sufficient number of DCs in AML patients.
Proteasome Inhibitors Affect the Function of Human Dendritic Cells and Induce Caspase-Mediated Apoptosis.
Authors: von Schwarzenberg Karin , Nencioni Alessio , Bringmann Anita , Kanz Lothar , Patrone Franco , Ballestrero Alberto , Brossart Peter 
Published: October 2019

Abstract
Proteasome inhibitors (PI) show antitumor activity against a broad spectrum of human malignancies both in vitro and in vivo. Yet, the consequences of exposure to these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effect of the proteasome inhibitors on human monocyte-derived dendritic cells (DCs). Exposure to PI results in a reduced activation induced DC maturation and cytokine production, inhibition of their migratory capacity and impaired ability to stimulate T-cell responses. These functional and phenotypic alterations were paralleled by a decreased phosphorylation of the MAP kinase member ERK1/2 while not affecting p38. Furthermore, incubation of DC with bortezomib inhibited the expression of nuclear localized transcription factors that were shown to be important for DC differentiation and function like IRF3, Rel-b and c-rel. Addition of PI to culture medium induced apoptosis of differentiated DCs and strongly reduced the yield of viable DCs when given to monocytes before differentiation to DCs was induced. DC apoptosis was accompanied by caspase activation as detected by caspase-3 and PARP cleavage. Cytochrome c cytosolic relocalization was detectable following exposure to bortezomib and was not prevented by caspase inhibition. This points to the mitochondrial damage as to an upstream event in DC apoptosis via proteasome inhibition. While not affecting Bcl-2 levels, bortezomib was found to promote Bax upregulation in DCs, thus providing a possible explanation for mitochondria dysfunction in response to this compound. In conclusion, this study shows that besides the inhibition of Nf-kB bortezomib is affecting several other pivotal signal transduction pathways in human cells and suggests that inhibition of DC function and induction of apoptosis in DCs may represent a mechanism by which bortezomib can affect the immune responses in patients treated with this compound.
Short-Term Effect of Oral Treatment with Miglustat in Type 1 Gaucher Disease.
Authors: Giraldo Pilar , Alonso Dora , Acedo M. , Franco Rafael , Barez Alberto , Corrales Alejandro , Serrano D. , Roldan Vanessa , Latre Paz , Alfonso Pilar , Pocovi Miguel 
Published: October 2019

Abstract
Background and objective Miglustat (Zavesca®), an inhibitor of the enzyme glucosylceramide synthase, is an orally active molecule that has been shown to be a safe and effective therapy for type I GD. Here we report on our experience of miglustat monotherapy for the treatment of type 1 Gaucher disease (GD) patients in Spain.
Design and Methods: We designed a prospective, open-label study of 21 patients with mild-to- moderate type 1 GD, to investigate the efficacy and tolerability of miglustat over a 12-month period in therapy-naïve patients and in patients who have previously received enzyme replacement therapy (ERT). Clinical assessments, including haematological parameters and organomegaly, were carried out prior to and after 6 and 12 months of miglustat therapy. In addition, the results were compared with data analysed retrospectively from 40 patients with type 1 GD who had been treated for 6 months with ERT. The data following 6 months of miglustat therapy are presented here.
Results At present, 16 patients have completed 6 months of miglustat treatment. All patients with anaemia had improved haemoglobin concentrations, and in the treatment-naive group a mean increase of 1 g/dl was observed. Platelet counts improved in patients with thrombocytopenia and were maintained in patients with counts within normal limits at baseline. Chitotriosidase activity was maintained in switched patients and decreased in naïve patients. Miglustat was well tolerated, and the efficacy after 6 months therapy was comparable to that observed in the clinical trials and in patients treated with ERT for 6 months. Interpretation and conclusions In our experience, properly selected patients with mild to moderate type I GD had a satisfactory clinical and biochemical response to 6 months of miglustat therapy. The therapy was well tolerated, and clinical benefits were comparable to those obtained with ERT.
Mild Renal Impairment as a Potential Prognostic Factor in Patients with Solid Tumors and Hematological Malignancies.
Authors: Kleber Martina , Bauchmüller Kris , Ihorst Gabriele , Koch Bernd , Engelhardt Monika 
Published: October 2019

Abstract
The outcome of cancer patients (pts) is influenced by a variety of coexisting conditions. Renal impairment has been shown to be one major risk factor in a number of diseases, such as myocardial infarction (MI), and is associated with dismal clinical outcome. However the influence of milder degrees of renal disease is less well defined, especially not yet in pts with solid tumors (ST) or hematological malignancies (HM). Between 8/2004-3/2005, we analyzed 167 ST and HM pts. Of 108 male and 59 female pts, 94 had ST and 73 HM. Their median age was 59 years (range; 18–91). Local vs. advanced (=metastatic) disease was present in 36 vs. 131 pts, respectively. Disease specific parameters, such as tumor diagnoses, sex, age, local vs. advanced disease, performance status (Karnofsky index=KI), number of concurrent diagnoses, cardiovascular risk factors such as body-mass index (BMI), presence of stroke or transient ischemic attack (TIA) and comorbidities (Satariano index=SI) were determined, also serum creatinine (creat), cystatin C (cC) and ProBNP (BNP). The glomerular filtration rate (GFR) was estimated by use of the ’Modification of Diet in Renal Disease’ (MDRD) equation (NEJM2004; 351:1285). The SI included heart diseases, diabetes, cancer, respiratory, gallbladder, and liver deteriorations. Pts were compared within GFR-, cC-, creat- and comorbidity-groups. Despite a median of 3 (range; 0–8) concurrent diagnoses, the KI in all pts was almost normal with a median of 90% (range; 30–100) and the median SI was 1 (range; 0–3). The median MDRD of all pts was 88ml/min/1.73m2 (14–240), and groups with GFR ≥75 (I), 60–74.9 (II), 45–59.9 (III) and <45 (IV) consisted of 105, 26, 23 and 13 pts, respectively. Of note was that pts showing a decreased GFR (<75ml/min/1.73m2) were older, had a significantly higher BMI (p=0.013), increased number of concurrent diagnoses (p=0.0486), and elevated creat- (p<0.0001), cC- (p<0.0001) and BNP-levels (p<0.0001; all Wilcoxon 2-sample tests). GFR - as compared to creat- or cC-levels - demonstrated this correlation best. Renal impairment (determined by elevated creat levels) was associated with increased odds ratios of 1.4 (95%CI 0.5–4.2), 1.5 (95%CI 0.7–3.2), 2.3 (95%CI 0.1–38.3) and 7.2 (95%CI 1.8–28.3) for comorbidities, such as diabetes, hypertension, apoplex and MI, respectively, which for the latter proved to be of statistical significance (p=0.0044). These observations indicate that grouping pts according to their renal function may be one way of determining specific risk groups. Comparing creat-, cC- and GFR-levels, the latter seems most valuable for determining mild or moderate renal impairment. Especially prior MI and elevated BNP levels will be studied further, since both seem closely associated with risks for renal impairment. Ongoing studies will determine, if mild renal disease is also a risk factor for adverse clinical outcome in ST and HM pts.
A Distinct Molecular Signature of Purified Cancer Stem Cells: Evidence for a Hematopoietic Stem Cell Origin of the 5q- Syndrome.
Authors: Nilsson Lars , Edén Patrik , Olsson Eleonor , Månsson Robert , Åstrand-Grundström Ingbritt , Strömbeck Bodil , Tehranchi Ramin , Theilgaard-Mönch Kim , Hast Robert , Hellström-Lindberg Eva , Samuelsson Jan , Bergh Gösta , Johansson Bertil , Sigvardsson Mikael , Borg Åke , Jacobsen Sten-Eirik W. 
Published: October 2019

Abstract
Herein we present the first global gene expression profile of purified cancer stem cells (CSCs). Constituting 0.08% of bone marrow cells, CD34+CD38−Thy-1+ cells represent the CSCs in 5q− myelodysplastic syndromes. The global gene expression pattern of purified 5q− CD34+CD38−Thy-1+ stem cells was overall very similar to the global gene expression of normal hematopoietic stem cells and not progenitor cells, supporting that 5q− stem cells originate in and outcompete normal CD34+CD38−Thy-1+ stem cells. However, a few distinct differences in gene expression distinguish 5q− from normal stem cells and might therefor be of potential pathogenetic importance. BMI1, a critical regulator of self-renewal is up-regulated in most 5q− patients stem cells, which could explain the obvious advantage of the 5q− stem cells over normal stem cells. The myeloid transcription factor CEBPα was clearly down-regulated in 5q− CD34+CD38+Thy-1− progenitors compared to normal progenitors, consistent with the typical deficient myeloid differentiation seen in 5q− syndrome. In contrast, CEBPα was rather up-regulated in 5q− stem cells from several patients. Thus, these studies demonstrate the importance of specifically identifying, characterizing and eventually targeting CSCs.
Mechanism of Altered Nucleo-Cytoplasmic Traffic of Nucleophosmin in Acute Myelogenous Leukemia Carrying Exon-12 NPM Mutations (NPMc+ AML).
Authors: Falini Brunangelo , Bolli Niccolo , Shan Jing , Martelli Maria Paola , Nicoletti Ildo , Liso Arcangelo , Pasqualucci Laura , Rosati Roberto , Roti Giovanni , Diverio Daniela , Mannucci Roberta , Cazzaniga Giovanni , Biondi Andrea , Saglio Giuseppe , Pane Fabrizio , Lo-Coco Francesco , Pelicci Pier-Giuseppe , Martelli Massimo F. , Gu Wei , Mecucci Cristina 
Published: October 2019

Abstract
We recently found that about one-third of adult AML (60% of all AML with normal karyotype) display aberrant cytoplasmic expression of nucleophosmin (NPM) which is due to mutations occurring at the exon-12 of NPM gene (Falini B, et al., Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype..N Engl J Med2005; 352: 254–266). Hereby, we clarify the molecular mechanism underlying cytoplasmic NPM accumulation that yet remained to be elucidated. AML-associated mutated NPM alleles encode abnormal NPM proteins (25 mutants so far identified) which have acquired at the C-terminus a nuclear export signal-(NES) motif and lost at least one of tryptophan residues 288 and 290 which determine nucleolar localization. Both alterations are crucial for mutant NPM export from nucleus to cytoplasm. In fact, the cytoplasmic NPM accumulation is blocked by leptomycin-B and ratjadones which are specific inhibitors of exportin-1/CRM1, and by re-insertion of tryptophan residues 288 and 290, which respectively relocate NPM mutants in the nucleoplasm and nucleoli. Thus, for cytoplasmic accumulation of NPM to occur, the NES motif and tryptophan mutations must act in concert. Possibly, when NPM mutans enter the nucleus by virtue of their nuclear localization signals (NLS), their capability to bind nucleoli must be hindered at least partially to become a CRM-1 target. Specific antibodies anti-NPM mutant proteins showed that the mutants localized exclusively in the cytoplasm and recruited in that site the wild-type NPM protein which is physiologically located in the nucleoli. These findings suggest that the NPM mutants may interfere with the functions of wild-type NPM and possibly contribute to leukemogenesis. Immunostaining of 393 AML cases using anti-NPM monoclonal antibodies predicted the presence of NPM exon-12 mutations in all 191 NPM-cytoplasmic positive cases. This finding is consistent with the fact that, despite genomic heterogeneity, all NPM mutants contain a NES motif which, in the presence of altered tryptophans, promotes their rapid export from the nucleus to the cytoplasm. The immunohistochemical test is diagnostically relevant since it can be used as simple first-step procedure in molecular-genetic characterization of AML and as a surrogate for mutational analysis in selected cases. These findings are also clinically relevant since cytoplasmic NPM/NPM mutations are predictors of good response to induction therapy and favourable prognosis in AML with a normal karyotype.
Array-CGH and Gene Expression Profiling Based Molecular Characterization of Myeloid Leukemia Cell Lines.
Authors: Rucker Frank G. , Sander Sandrine , Dohner Konstanze , Dohner Hartmut , Pollack Jonathan R. , Bullinger Lars 
Published: October 2019

Abstract
Myeloid leukemias are characterized by cytogenetic and molecular-genetic aberrations resulting in altered gene expression. Nevertheless, so far still little is known regarding the underlying mechanisms of leukemogenesis. To model and investigate the different aspects of leukemia pathogenesis a widely accepted approach is to use immortalized leukemia cell lines. While these provide powerful tools for the investigation of gene function, the dissection of signal transduction pathways and the analysis of drug effects, to our knowledge only few studies have addressed the question whether hematopoietic cell lines represent reliable model systems.
In order to improve the molecular characterization of these model systems we therefore analyzed 18 myeloid leukemia cell lines using DNA microarray technology. To determine the secondary aberrations acquired in addition to their characteristic primary cytogenetic aberrations during numerous passages in vitro, we first analyzed all cell lines by array-CGH (comparative genomic hybridization). Using a BAC/PAC platform with an average resolution of ~ 1.5 Mb across the entire genome we identified recurrent losses and gains, as well as high level amplifications like e.g. an amplification in 4q12 (Kasumi1) and in 8q24 (HL60). The parallel analysis of gene expression using a whole genome cDNA microarray platform helped to further delineate potential candidate genes in the affected regions (e.g. overexpression of KIT in the 4q12 and MYC in the 8q24 amplicon). Furthermore, unsupervised hierarchical cluster analysis revealed distinct gene signatures pointing towards dysregulated transcriptional networks. Comparison of our findings with acute myeloid leukemia patient data (Bullinger et al. 2004) showed the signatures underlying characteristic cytogenetic aberrations like e.g. t(15;17) were conserved in cell lines. Interestingly, these signatures were also quite robust as they displayed a highly significant correlation with published cell line data profiled on a different DNA microarray platform in a different laboratory.
Thus, our analyses demonstrate that cell lines exhibit conserved signatures correlating with the primary balanced cytogenetic aberrations, and that most cell lines even when grown and analyzed under different conditions provide highly robust signatures. Therefore, our refined molecular characterization of myeloid cell lines supports the utility of cell lines as powerful model systems and provides additional insights into the molecular mechanisms of leukemogenesis.
Risk Factors of Outcomes after Haploidentical Hematopoietic Stem Cell Transplants for Children with High Risk Acute Leukaemia. A Survey on Behalf of the EBMT.
Authors: Cornish Jaqueline , Klingebiel Thomas , Labopin Myriam , Darbyshire Phillip J. , Hough Rachel , Locatelli Franco , Niethammer Dietrich , Dini Giorgio , Rocha Vanderson 
Published: October 2019

Abstract
In the absence of an HLA identical donor, T-cell depleted haploidentical hematopoietic stem cell transplantation (HSCT) is an alternative option to treat children with high risk or relapsed acute leukaemia. However very few data is available in a large series of children. With the aim to study risk factors of outcomes we have analyzed 196 children (<16 years old) with ALL (n=131) or AML (n=65) transplanted with a T-cell depleted bone marrow (n=18) or peripheral blood related haploidentical HSCT from 1995 to 2004 in Europe. The median age was 8 years and median follow-up 22 months. In the AML group, 13 (20%) children were transplanted in CR1, 22 (34%) in CR2 and 30 (46%) in advanced phase and in ALL group, 28 (21%) in CR1, 74 (56%) in CR2 and 81 (62%) in more advanced phase. The majority of the patients did not receive drugs for GVHD prophylaxis and all received myeloablative conditioning (61% of TBI). Cumulative incidence with competing risk and KM estimates were used to calculate outcomes probabilities. The median days of neutrophil recovery was 14 days (4–72) and 85% of patients had signs of engraftment. Acute GVHD II–IV was observed in 17% of the patients (8% had grade III–IV). Two-years overall LFS, relapse incidence and TRM were 27±4%, 43±3%, 30±3%, respectively. Patients transplanted with AML or ALL had similar outcomes. LFS was 28±6%for AML and 27±4% for ALL. Among the risk factors analysed only the disease status at transplantation was associated with LFS and relapse incidence. Outcomes are listed below according to disease status at transplant.
Outcomes at two years CR1 (n=41) CR2 (n=74) Advanced (n=81) p value Transplant related mortality 32+/−8% 26+/−5% 33+/−5% 0.44 Relapse 32+/−8% 40+/−6% 51+/−6% 0.03 Leukaemia free survival 36+/−8% 34+/−6% 16+/−4% <0.0001
In fact, in a multivariate analysis for LFS and relapse only patients transplanted in remission had better LFS and decreased relapse incidence compared with non remission patients (p<0.001 and p=0.006, respectively). No risk factor was found to be associated with TRM. Most frequently, causes of death were relapse (60%) or infections (22%). In conclusion, haploidentical HSCT is an alternative option to treat children with high risk acute leukaemia in the absence of HLA identical donor.