bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stro-1 Positive and Stro-1 Negative Human Mesenchymal Stem Cells Express Different Levels of Immunosuppression.
Authors: Francois Sabine , Zhang Yizhuo , Bensidhoum Morad , Mazurier Christelle , Nasef Aisha , Bouchet Sandrine , Mathieu Noelle , Gorin Norbert-Claude , Lopez Manuel , Bourgeade Michel , Thierry Dominique , Chapel Alain , Fouillard Loic 
Published: April 2020

Abstract
Mesenchymal stem cells (MSC) have been shown to elicit immunosuppressive effect on allogeneic lymphocyte response. However, MSC are heterogeneous and data on the inhibitory abilities of different MSC subsets are lacking. The Stro-1 antigen potentially defines a more pure and more primitive MSC subset
We compared the suppressive property of expanded Stro-1+ and Stro-1− MSC when add to mixed lymphocyte reactions (MLR) or to mitogen response assays. Results showed that T lymphocyte proliferation was significantly more inhibited by expanded Stro-1+ (11.0%~63.7% of maximal response) than by expanded stro-1− MSC (35.5%~106% of maximal response) (p&lt;0.01). Results indicated that as few as 1,000 expanded Stro-1+ MSC could induce a similar inhibition of lymphocyte proliferation than 10 times more (10,000 cells) expanded Stro-1− MSC −. Stro-1+ MSC was the main population responsible for T cell inhibition. The expression of genes coding for inhibitors of T-cell activation and proliferation (IL-10, LIF, IDO, TGF-b1, HGF, HLA-G), for adhesion molecules (VCAM, LFA-3), and for chemotactic factors (IL-8, SDF-1) was analysed by semi-quantitative real time RT-PCR in the Stro1+ and Stro1- MSC. Results are expressed as a fold increase in the mRNA level in expanded Stro-1+ compared to Stro-1− MSC. IL-10 (0.24 fold p=0.002) and TGF-β1 (0.43 fold, p=0.03) were down regulated in expanded Stro-1+ compared to Stro-1− MSC. LIF (106 fold, p=0.025), IDO (6130 fold, p=0.04), HGF (24 fold, p=0.01), and HLA-G (260 fold, p= 0.02) were up regulated in expanded Stro-1+ compared to Stro-1− MSC. VCAM-1 and LFA-3 were up regulated in expanded Stro-1+ compared to Stro-1− MSC (28.2 fold, p=0.03 and 298.4 fold, p=0.04 for VCAM-1 and LFA-3 respectively): IL-8 was over expressed in expanded Stro-1+ (4.9 fold, p=0.0015). There was no significant difference between expanded Stro-1+ and Stro-1− MSC for SDF-1. These results suggest that LIF, IDO, HGF, HLA-G inhibitory factors and VCAM1, LFA-3 adhesion molecules are mainly responsible for the different T cell inhibition observed between Stro-1+ and Stro-1− MSC.
These findings suggest that in clinics a Stro-1+ pre-selection of MSC might produce a more effective immunosuppression especially for the prevention and the treatment of graft versus host disease.
Association of HLA-E Polymorphism with the Incidence of Severe Bacterial Infections in Sickle Cell Anemia.
Authors: Tamouza Ryad , Fortier Catherine , Diagne Ibrahima , Diallo Dapa A. , Labie Dominique , Girot Robert , Charron Dominique 
Published: April 2020

Abstract
While it is commonly admitted that the susceptibility to severe infections (septicemia, meningitis, or osteomyelitis) in Sickle Cell Anemia (SCA) patients is a major cause of mortality and morbidity, these complications remains poorly explained. However, several lines of evidence highlight the involvement of an immunogenetic modulation, including both innate and adaptive immune responses. HLA-E belongs to the HLA-class I non-classical family and is ubiquitously expressed. HLA-E molecules bind either to self-peptides from the leader sequences of various HLA-class I molecules and thus modulate NK (Natural killer) cell activation/inhibition, or to the microbial derived-peptides from human viruses or bacteria to induce T cell responses. Only two functional alleles, HLA-E*0101 and HLA-E*0103, differing by a single amino acid substitution in the α2 heavy chain domain and by their cell surface expression level, have been reported so far. In order to evaluate whether the HLA-E polymorphism could influence the incidence of severe bacterial infections in SCA, we analyzed a cohort of 99 SCA patients living in Paris, but for the majority, originating from black Africa. All patients were older than 5 years of age at inclusion. Among the cohort, 51 presented at least one severe bacterial infection and 48 did not disclose any major infectious episode in their clinical history. Statistical analysis showed that the incidence of severe bacterial infections are high when the patient’s genotype was HLA-E*0101/E*0101 (47% in the first group versus 21% in the second group; χ2 = 7.54 p = 0.006, pc = 0.01, OR: 3.28, [95%CI = 1.28–9.07]), supporting a negative effect of this genotype. The genetic association herein found between HLA-E polymorphism and severe bacterial infections is of relevance, given the emerging evidence for the involvement of HLA-E molecules in pathogen-derived peptide presentation to human CD8+ T cells and hence in host response to pathogens. Furthermore, these data are in agreement with our previous findings in bone marrow transplantation settings, were the homozygous state for HLA-E*0101 allele is also a risk factor for early severe bacterial infections. Both situations by constitutively lowering the overall threshold of resistance to infection, might unmask anti infectious genetic factors normally silent.
Elevated Plasma Arginase Levels in Hemoglobinopathies.
Authors: Larkin Sandra K. , Morris Claudia R. , Styles Lori A. , Kuypers Frans A. 
Published: April 2020

Abstract
The decreased bioavailability of arginine (Arg) and the resulting lower nitric oxide (NO) production has been shown to be an important factor in the pathology of sickle cell disease (SCD) and thalassemia. Vascular alterations leading to pulmonary hypertension are important factors of heart failure and death in these hemoglobinopathies. Red blood cell (RBC) hemolysis in these patients will release arginase into the circulation and contribute to the reduction of plasma Arg levels, change the Arg-to-ornithine ratio, and increase other downstream amino acid metabolites. Such compounds, including proline and polyamines, may contribute to vascular and airway remodeling. To study the contribution of arginase released from RBC, we measured the arginase activity and arginase protein concentration in the plasma and RBC lysates of normal controls, SCD patients, and thalassemia patients.
Arginase activity was determined by the conversion of 14C-labeled guanidine-L-arginine to 14C-labeled urea, then to 14CO2 by urease and trapped as Na214CO3 for scintillation counting. Arginase and hemoglobin concentration were measured by ELISA (BioVendor, Candler, NC and Bethyl Labs Inc., Montgomery, TX respectively). Mean cellular hemoglobin concentration was measured with a Coulter Counter (Beckman Coulter, Fullerton, CA) or Technicon H3 analyzer (Tarrytown, NY). RBC were separated by density gradient centrifugation with OptiPrep (Axis Shield, Dundee, UK). Arginase specific activity (SA) was calculated by dividing the activity by the concentration to yield mole of Arg metabolized per g of arginase per hour. We found a higher level of arginase in the plasma and RBC of SCD and thalassemia patients as compared to normal controls. These levels correlated with cell-free hemoglobin content (plasma) or reticulocyte count (RBC). The light density fraction (&lt;1.077 g/ml) of RBC, enriched in reticulocytes, showed higher arginase levels confirming increased arginase levels in young RBC. Interestingly, as the plasma arginase protein and activity increased with cell-free hemoglobin, the SA decreased. Similarly in RBC lysates, the SA decreases with hemoglobin concentration. This suggests that a factor exists within the RBC that negatively modulates arginase activity. Due to the high SA of arginase at low hemoglobin concentrations, low levels of intravascular hemolysis can generate relatively high levels of Arg breakdown.
We conclude that low levels of intravascular hemolysis of RBC with increased arginase content in SCD and thalassemia, play a role in the altered Arg metabolism and decreased NO production. While the reason for high levels of arginase in the RBC as well as complete clinical impact of elevated arginase activity in plasma remain to be determined, dysregulated Arg metabolism and a shift toward Arg catabolic products, may be associated with the development of pulmonary hypertension and mortality in SCD and thalassemia.
Gene Expression Profiling Can Identify Novel MRD Markers for AML.
Authors: Woodward Eleanor L. , Gilkes Amanda F. , Walsh Val , Austin Steve J. , Daly Sarah B. , Lin J. A. , Grimwade David , Burnett Alan K. , Mills Kenneth I. 
Published: April 2020

Abstract
In AML, the majority of patients &lt;60 years of age will enter remission but at least 50% will subsequently relapse, therefore the monitoring of minimal residual disease (MRD) during treatment has become an important issue. Current molecular markers for MRD are mainly limited to the RT-PCR detection of the fusion genes resulting from recurrent translocations which paradoxically are mostly limited to favourable risk groups who are least likely to relapse leaving the majority of the patients, including those with a normal karyotype, without a molecular marker suitable for monitoring.
Two hundred and twenty patients have been assessed by gene expression profiling using Affymetrix U133A chips and the data analysed with the aim of identifying novel MRD markers for patients who do not currently have a suitable marker. As an initial “proof of principle”, we have identified possible MRD markers for patients with either t(15;17), t(8;21) or inv(16) and correlated with changes in expression of these markers with clinical changes as measured by established molecular MRD markers (PML-RARα or WT1).
Of the expression profile from 22,283 probe sets in 29 cases of t(15;17), 20 genes were identified which had at least a two fold over expression which was unique to the t(15;17) subgroup. Of these several of the probe sets were related to the same gene, but from the reduced gene list 2 (HGF and ILGF binding protein) were selected for quantitation by quantitative PCR. Similarly the expression profile identified 20 genes which were unique to the 15 cases of t(8;21), and 20 genes which were unique to the 19 cases of inv(16). These included ETO and MYH11 representing the respective 3′ end of the respective fusion transcript. Three other genes (PRAME, POU4F1, and IL5RA) were selected for the t(8;21) cases and ST18, CLIP-170 and MNI for the inv(16) cases. When the relative quantitative expression of each of these “unique” genes was correlated with the expression of the established markers of minimal residual disease (PML-RARα or WTI) there was good correlation. These data suggest that gene expression profiling can identify ‘unique’ genes which can be used to develop specific markers for minimal residual disease monitoring for a larger proportion of cases of AML than is currently available.
High Incidence of t(7;12)(q36;p13) with Involvement of HLXB9 in Infant AML.
Authors: von Bergh Anne R.M. , van Drunen Ellen , van Wering Elisabeth R. , Meijerink Jules P. , Pieters Rob , Beverloo Berna 
Published: April 2020

Abstract
The ETV6/TEL gene (12p13) is rearranged in a spectrum of hematological malignancies resulting in the formation of a functional fusion gene or an ETV6 promoter enforced transcription of over 25 different partner genes. The t(7;12)(q36;p13) is a recurrent translocation with a heterogeneous breakpoint distribution in 7q36. We have shown a fusion transcript between HLXB9 and ETV6 in infant AML with t(7;12), however a fusion transcript is not consistently found. To study the incidence of t(7;12) and the involvement of HLXB9 in infant and childhood acute leukemia we screened 320 infants and pediatric patients younger than 36 months by FISH. We studied the presence of an HXLB9-ETV6 fusion and quantified the expression of various genes in the proximity of the 7q36 breakpoints. Cases studied by FISH included 1) 179 ALL and 54 AML patients younger than 36 months diagnosed in the Netherlands between 1991–1997 or 2003–2004, obtained from the DCOG; (ALL: 14 age 0–12 months, 55 age 12–24 months, 110 age 24–36 months; AML: 16 age 0–12 months, 22 age 12–24 months, 16 age 24–36 months); and 2) 85 infant-ALL from the Interfant-99 study and 2 additional infant-AML. In total, six AML patients were found to carry the t(7;12)(q36;p12) of which 5 were infants and 1 was 18-months old. This indicates that the t(7;12) encompasses 30% of infant AML. In ALL the t(7;12) seems to be uncommon, only one of the 264 patients harbored the t(7;12). The t(7;12) was associated with a poor clinical outcome. A fusion of ETV6 to HLXB9 was found in four AML with t(7;12). The expression of 7q36 genes (HLXB9, NOM1, Lmbr1, RNF32 and SHH) was determined by real-time PCR in several groups: t(7;12)+ cases, t(7;12)- AML, t(7;12)- ALL and healthy individuals. NOM1, Lmbr1, RNF32 and SHH were equally expressed among t(7;12)+ and other groups. However, the HLXB9 expression was highly increased in t(7;12)+ compared to every control group, including those with an HLXB9-ETV6 fusion, suggesting that ectopic expression of HLXB9 is commonly involved in the t(7;12)(q36;p13).
Detection of Proteins Related to Therapeutic Outcome, Including Drug Resistance, in Acute Myeloid Leukemia Using Mass Spectrometry and Gel Based Proteomic Profiling.
Authors: Stenke Leif , Orre Lukas , Dhar Sumeer , Larsson Rolf , Lewensohn Rolf , Lehtiö Janne 
Published: April 2020

Abstract
To further improve and individualize curative treatment approaches for patients with AML, novel proteins and protein functions need to be discovered. In particular, the mechanisms responsible for chemotherapy resistance appear essential to unravel. Clinical proteomics may help to provide such information. We have used a chip-based technique, surface enhanced laser desorption/ionization mass spectrometry (SELDI-MS), to compare protein expression profiles in AML. With this technique proteins in the molecular weight area of 2–40 kDa can be spotted. For selected samples, a two-dimensional electrophoresis (2DE) method was employed, allowing detection of proteins between 15–120kDa. In the first part of the study, mononuclear peripheral blood cells were obtained from 8 AML patients clinically sensitive to and 7 patients clinically resistant to doxorubicin-containing induction chemotherapy. The clinical outcome correlated to results from parallel in vitro drug testing using the FMCA method. In addition, two variants of the human leukemic cell line CEM, one sensitive and one resistant to teniposide (CEM/VMI), were analysed. In the second part of the study, global proteomic profiles from 24 selected AML patients with good vs. poor clinical outcome (remission duration) were investigated. A total of 812 proteins were detected in the mononuclear cells obtained from the 15 doxorubicin-treated patients. Twenty of these proteins were distinguished as different between the sensitive vs. resistant patient groups. Assessing the CEM cell lines by utilizing four different affinity surfaces on ProteinChip™ arrays, approximately 450 peptides and proteins were detected. Between 29 and up to 65 proteins were detected as differentially expressed between the sensitive and the resistant CEM variants. Using the 2DE technology, approximately 1000 spots were matched on the CEM cell lines, with 47 clear expression level differences between the sub cell lines. In clustering analysis using the protein profile data we could demonstrate clear clustering of sensitive and resistant patient and cell line cells according to sensitivity measurements (IC50). Using these methods we have selected a panel of putative resistance related proteins, which are currently being identified and validated. Data from the second phase of the study, derived from 24 selected AML cell populations, are presently being analyzed. In conclusion, significant differences in protein profile expression were observed between cells obtained from AML patients with clinically divergent treatment responses. Further studies aim at identifying key proteins and protein functions to allow for improved therapeutic efficacy.
The First Fully Experimental In Vivo Model of Human Leukemogenesis: Human Hematopoietic Stem Cells Infected with MLL-ENL Induce Pro-B Acute Lymphoblastic Leukemia in NOD/SCID Mice.
Authors: Barabe Frederic , Kennedy James A. , Dick John E. 
Published: April 2020

Abstract
Identification of genes and translocations involved in human leukemia, as well as classification and clustering by gene arrays, have greatly evolved in the past years. However, the mechanisms of human leukemogenesis remain to be elucidated and the failure to develop an in vivo model where primary human hematopoietic cells are transformed into leukemic cells represents a significant limitation.
Using a retrovirus encoding the oncogene MLL-ENL resulting from the t(11;19)(q23;p13.3) translocation found in acute myeloid leukemias (AML) as well as in acute lymphoblastic leukemias (ALL) of B or T cell origin, we infected lineage-negative cord blood cells and injected those cells into sub-lethally irradiated NOD/SCID mice. 15 to 20 weeks after injection, all the mice developed an aggressive pro-B acute lymphoblastic leukemia characterized by immature B cells (CD10+, CD19+, CD20−, IgD−, IgM−) involving more than 90% of bone marrow. Spleen and thymus were increased in size and infiltrated with &gt;90% leukemic cells. Furthermore, analysis of the lungs and liver showed significant infiltration of these organs. Transplantation of leukemic cells from primary mice to secondary recipients was able to recapitulate the disease with the same phenotype and the same organ involvement in a shorter period of time.
If MLL-ENL transduced cells are grown in suspension culture with IL-3 and SCF, there is massive proliferation of cells blocked in differentiation along the monocytic lineage. In contrast to untransduced cells, colony-forming progenitors were maintained long term in these cultures and could be serially replated, suggestive of an enhanced capacity for self-renewal. After 50 to 70 days in culture, these cells were injected in NOD/SCID mice and mice were analyzed after 12 to 15 weeks. Monoblastic cells were engrafted in the bone marrow and spleen with the same phenotype of the cultured cells (CD33+, CD11b+, CD15+, HLA DR+). These cells were able to engraft secondary and tertiary recipients formally demostrating increased self-renewal capacity of the transformed stem cell. In a limited number of primary mice, transplanted with high cell doses, AML developed at 15 weeks post-transplant.
To our knowledge, these results provide the first in vivo model where human hematopietic stem/progenitor cells are transformed into leukemia. Remarkably, depending on the cellular environment, MLL-ENL can induce ALL or AML in primary cells as a sole genetic event, although we cannot rule out the spontaneous acquistion of additional co-operating genetic or epigenetic abnormalities. This model provides a significant step forward to understand the mechanisms involved in human leukemogenesis.
Estimating Immunoregulatory Gene Networks in Human Herpesvirus Type 6 (HHV-6)-Infected T Cells.
Authors: Takaku Tomoiku , Ohyashiki Junko H. , Zhang Yu , Ohyashiki Kazuma 
Published: April 2020

Abstract
The immune response to viral infection involves complex network of dynamic gene and protein interactions. Comprehensive gene expression analysis of the host immune response against viruses has been extensively studied, however, the mechanism of virus-induced immune response is not completely understood. This might be due in part to the difficulty of finding pathologically relevant genes, despite the fact that DNA microarray technology can simultaneously monitor the expression of thousands of genes. Likewise, it is hard to estimate how each gene interferes during the viral infection. Thus, construction of gene networks from microarray gene expression data is becoming an important challenge in the post-genome era. Human herpesvirus 6 (HHV-6) is a β-herpesvirus that is closely related to human cytomegalovirus. HHV-6 shows a predominant tropism for CD4 T lymphocytes, on which it exerts marked cytopathic effects. Understanding of the clinical spectrum of HHV-6 is still evolving, however, in vitro interactions between HHV-6 and other viruses, such as the human immunodeficiency virus (HIV), and their relevance to the in vivo situation has become increasingly apparent. We present here the dynamic gene network of the host immune response during human herpesvirus type 6 (HHV-6) infection in an adult T cell leukemia (ATL) cell line. Using a pathway-focused oligonucleotide DNA microarray, we found a possible association between chemokine genes regulating Th1/Th2 balance and genes regulating T-cell proliferation during HHV-6B infection. Gene network analysis using an integrated comprehensive workbench, VoyaGene® revealed that a gene encoding a TEC-family kinase, ITK, might be a putative modulator in the host immune response against HHV-6B infection. We conclude that Th2-dominated inflammatory reaction in host cells may play an important role in HHV-6B infected T cells, thereby suggesting the possibility that ITK might be a therapeutic target in diseases related to dysregulation of Th1/Th2 balance. This study describes a novel approach to find genes related with the complex host-virus interaction using microarray data employing the Bayesian statistical framework.
Figure Figure