bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiac and Liver Magnetic Resonance Characterization of Thalassemia Intermedia Patients: A Comparative Multicenter Study Versus Thalassemia Major Patients
Authors: Pepe Alessia , Favilli Brunella , Ramazzotti Anna , Positano Vincenzo , Borgna-Pignatti Caterina , Capra Marcello , Lai Maria-Eliana , Spasiano Anna , Pitrolo Lorella , Filosa Aldo , Cianciulli Paolo , Mascolino Antonietta , Giuffrida Gaetano , Forni Gianluca , Maggio Aurelio , Lombardi Massimo 
Published: April 2020

Abstract
Little is known about cardiac involvement in Thalassemia Intermedia (TI) using magnetic resonance imaging (MRI). Thus, we investigated myocardial and liver iron overload, myocardial fibrosis, biventricular function parameters and their inter-relationship in 60 TI using MRI. Then, we compared the data of 35 selected TI with age &lt; 39 years with that of 60 Thalassemia Major (TM) patients matched for age. Myocardial Iron Overload (MIO) was assessed using a multislice multiecho T2* approach. Biventricular function parameters were measured quantitatively by cine images. Myocardial fibrosis was evaluated by late gadolinium-enhanced. MIO was present in the 22% of TI patients, more frequently (92%) with an heterogeneous distribution. TI patients with myocardial fibrosis (32%) showed significantly reduced left ventricular ejection fraction (LVEF) (P=0.01). No significant correlation was found between myocardial fibrosis and MIO. Figure shows a TI patient with no myocardial iron overload (all 16 segments and the mid-ventricular septum with T2* values &gt; 20 ms) (A) and late enhancement (white arrows) in the antero-septal junction, in the infero-septal junction and in the mid-ventricular septum (B). In TI patients MIO was significantly lower respect to TM patients; conversely volumes, cardiac indexes, LVEF, bi-atrial areas, and liver iron overload were significantly higher. Myocardial fibrosis was comparable between the 2 groups. TI patients showed lower myocardial iron burden and more pronounced high cardiac output findings with myocardial fibrosis significantly associated to impaired heart function. These data seem to suggest using MRI also for TI patients and could place the basis to reconsider the current cardiological and haematological management in this population.
Figure Figure
Hematopoietic Stem Cells Mediate the Repair of Damaged Endothelium
Authors: Pfaffle Dana L. , Jiang Shuguang , Goldman Devorah C. , Fleming William H. 
Published: April 2020

Abstract
Recent studies indicate that vascular endothelium is an important component of the hematopoietic niche. As endothelial cells (ECs) are sensitive to radiation-induced damage, we evaluated the potential role of hematopoietic stem cells to enhance EC proliferation and repair. To test this hypothesis, lethally irradiated mice were transplanted with either 200–500 c-kit+, Sca+, lineage- (KSL) cells or an equivalent dose of unfractionated bone marrow (BM) cells (1×106 cells). Control groups included irradiated, non-transplanted, and non-irradiated, non-transplanted mice. Immediately after irradiation, all recipients were maintained on 0.8mg/ml Bromodeoxyuridine (BrdU) -containing water. Eleven days following irradiation, liver tissue was harvested and the fraction of proliferating BrdU+ ECs in the portal vein was assessed by immunostaining using both light and fluorescence microscopy. In irradiated, non-transplanted mice, 0.95% ± 0.17 SEM of portal vein ECs demonstrated the incorporation of BrdU. Transplantation of KSL cells increased the frequency of proliferating endothelial cells 2.5-fold to 2.5% ± 0.20 (p&lt;0.0006). The transplantation of an equivalent number of unfractionated BM cells further increased the frequency of proliferating ECs by more than 3.5-fold (3.75% ± 0.21; p&lt;0.0005). In non-transplanted, non-irradiated mice, BrdU+ ECs were detected at an intermediate level (2.30% ± 0.24) that is significantly higher than irradiated nontransplant recipients (p&lt;0.006). To gain a better understanding of how hematopoietic stem cells (HSCs) influence the label retention capacity of ECs, we performed a BrdU pulse-chase experiment. Lethally irradiated mice were transplanted with 200 KSL cells, allowed 4 weeks for recovery, and then maintained on BrdU drinking water for 4 weeks. Consistent with our findings from the short term experiment described above, significantly more BrdU+ ECs were detected in the portal veins of KSL transplanted mice (15.36% ± 2.07) compared to those in non-transplanted, non-irradiated mice (8.68% ± 0.54; p&lt;0.04) at the start of the chase period. During the first 24 weeks of the washout phase, BrdU+ ECs declined at a greater rate in the KSL recipients than in controls, indicating increased EC turnover. Interestingly, however, in both experimental groups, BrdU retention plateaued at 24 weeks and remained constant through 36 weeks. Taken together, our results indicate that radiation damage suppresses the incorporation of BrdU into ECs compared to steady state conditions and that this suppression can be reversed by the transplantation of either hematopoietic stem cells or unfractionated bone marrow. The extent to which BM derived ECs contribute to the proliferating EC pool will be addressed in future studies.
Detection of Functional Hematopoietic Stem Cell Niche Using Real-Time Imaging
Authors: Yin Tong , Xie Yucai , Wiegraebe Winfried , He Xi , Li Linheng 
Published: April 2020

Abstract
Hematopoietic stem cell (HSC) niches play an essential role in regulating adult stem cell self-renewal and differentiation. HSC niches have only recently been identified based on genetic models that showed a parallel increase in the numbers of both HSCs and osteoblasts, or by static immunolabeling of putative HSCs and the adjacent locations. However, osteoblasts and vasculature were viewed as separate niches with distinctive roles, their interrelationships and interactions with HSCs in vivo remain largely undefined. To study the dynamic interaction between the HSC and its niche, we developed a method of ex vivo imaging stem cells (EVISC) using two-photon microscopy. This method combined the technology of real-time imaging and the functional feature that Flk2−LSK HSCs can be prospectively isolated with high purity and can home to their niche upon transplantation into irradiated recipient mice. Using EVISC in combination with immunoassaying, we found that transplanted HSCs tended to home to the endosteal region predominantly in the trabecular bone area (TBA) compared to compact bone area (CBA) under irradiated conditions, but were randomly distributed and unstable under non-irradiated conditions. Mechanistically, we found that the ratio of expression level of SDF-1 between TBA and CBA was significantly increased in response to irradiation. By monitoring individual HSC behavior using EVISC ranging from minutes to 16-hours, we found that a small portion of the homed HSCs underwent active division in the irradiated mice, coinciding with their initial expansion as measured by flow assay and immunoassay. Our findings suggest that the endosteal region in the trabecular bone area formed a special zone, which normally maintains HSCs but promotes their expansion in response to irradiation. This zone includes both osteoblastic and vascular components and signals, which both underwent dynamic changes from homeostatic to stressed conditions.
RCHOP and RDHAP Followed by Autologous Stem Cell Transplantation (ASCT) in Mantle Cell Lymphoma (MCL) : Final Results of a Phase II Study from the GELA
Authors: Delarue Richard , Haioun Corinne , Ribrag Vincent , Brice Pauline , Delmer Alain , Tilly Herve , Salles Gilles , Van Hoof Achiel , Casasnovas Olivier , Brousse Nicole , Lefrere Francois , Hermine Olivier 
Published: April 2020

Abstract
Introduction: Treatment of mantle cell lymphoma (MCL) in younger patients (pts) is still a challenge, with questions about best induction regimen before autologous stem cell transplantation (ASCT) and impact of Rituximab. We report here the final results with extended follow-up of a prospective phase II trial.
Methods: Patients under 66 years with histologically proven, stage III-IV, MCL were included. Treatment consisted of three courses of CHOP with Rituximab at the third one and three courses of RDHAP. Peripheral blood stem cells harvest was performed and responding pts were eligible for an ASCT after high dose radio-chemotherapy with TAM6 (TBI 10 Gy, Aracytine 6 g/m², Melphalan 140 mg/m²) or BEAM if TBI could not be performed.
Results: From May 2000 to September 2003, 60 pts were included. Median age was 57 years. Characteristics of patients were as follow : bone marrow involvement 85%, leukemic disease 48%, gastrointestinal involvment 52%, PS&gt;1 6%, LDH &gt; 1N 38%. Overall response rate was high with 93% after (R)CHOP and 95% after RDHAP. Interestingly, CR was uncommon after (R)CHOP (12%), whereas high proportion of patients (61%) were in CR after RDHAP, suggesting higher efficacy of high dose AraC. Forty-nine pts were autografted (41 with TAM6) : all patients but two (96%) were in CR. With a median follow-up of 67 months, median EFS was 83 months and median OS was not reached. Five years OS was 75%. Neither toxic death nor unexpected toxicities were observed. The comparison with our previous French oligocentric study using the same regimen but without Rituximab (Lefrere, Hematologica 2007) suggests a better outcome when Rituximab is added (median EFS : 51 months).
Conclusion: This study confirms that regimens containing Aracytine and Rituximab are safe and prolong survival and may even induce cure in MCL patients. Thus, they should be used in induction treatment before ASCT. This regimen is currently compared with the classical RCHOP induction in a multicentric European protocol within the EMCL network.
Molecular Remission after Combined Immunochemotherapy Is of Prognostic Relevance in Patients with MCL: Results of the Randomized Intergroup Trials of the European MCL Network
Authors: Pott Christiane , Hoster Eva , Böttcher Sebastian , Siebert Reiner , Klapper Wolfram , Delfau Marie Helene , Unterhalt Michael , Hiddemann Wolfgang , Kneba Michael , Dreyling Martin 
Published: April 2020

Abstract
Two randomized intergroup trials of the European MCL Network investigating the impact of different combined immunochemotherapy protocols for patients with stage II-IV mantle cell lymphoma (MCL) followed by autologous stem cell transplantation for patients &lt;65 yrs and a rituximab or interferon maintenance treatment for patients &gt; 65 yrs are currently performed.
Patients and methods: 182 German patients with evidence for peripheral blood (PB) involvement as demonstrated by consensus IGH-PCR at diagnosis were analyzed for quantitative PB involvement and molecular response (MR) by Real Time Quantitative (RQ) IGH-PCR. The results were evaluated according to ESG criteria (van der Velden, Leukemia 2007) and were compared to clinical parameters at diagnosis and outcome.
Results: Patients had a median age of 61 years, an elevated LDH in 37%, B-symptoms in 42% and extranodal involvement in 36%. According to the MIPI prognostic index 20% had an adverse, 37% an intermediate and 43% a good prognosis. Median level of circulating MCL cells in PB at initial diagnosis were 6×10−2 (range 2×10-4 to 8×10-1) and correlated significantly with clinical parameters as advanced stage (p=0.0016), elevated LDH (p= 0.0026), bone marrow infiltration (p= 0.0001) and MIPI prognostic index (p&lt;0.0001). MR after induction was achieved in 55% (67/121) of all evaluable patients and correlated with stage (p=0.058), the presence of B-symptoms (p=0.016) and BM infiltration at diagnosis (p=0.011). Interestingly, the rate of MR was higher in patients receiving the protocol for elderly than for young patients (69% vs. 45% p=0.0006). This effect was especially prominent in the BM with an MRD clearance of 65% in elderly compared to only 35% in younger patients (p&lt;0.0001). BM was more sensitive for MRD detection compared to PB after rituximab containing treatment. Of 62 paired samples only 2 BM samples were BM MRD- with concomitant MRD+ in the PB, whereas 13 MRD- PB samples demonstrated MRD+ in the corresponding BM (p=0.045). Patients achieving a MR in the BM after induction demonstrated a significantly improved remission duration compared to MRD+ patients (100% vs. 66% at 24 months, p=0.0285, median observation time 15 months).
Conclusion: Quantitative detection of circulating MCL cells improves clinical risk assessment and staging accuracy. Furthermore RQ-PCR allows to evaluate the impact of different treatment modalities on tumor clearance in PB and BM. This is the first randomized trial demonstrating that achievement of MR by combined immunochemotherapy might be an early indicator for treatment outcome in MCL.
Onco-Mir-155 Targets SHIP to Regulate TNF-Dependent B-Cell Lymphoma Growth
Authors: Pedersen Irene Munk , Otero Dennis C , Kao Elaine , Sedy Ana , Hother Christoffer , Ralfkiaer Elisabeth , Rickert Robert C , Gronbaek Kirsten , David Michael 
Published: April 2020

Abstract
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of non-Hodgkin lymphomas, with an overall 3-year relapse-free survival of 53%. DLBCL consists of a germinal center B-cell (GCB-like) subgroup and an activated B-cell (ABC-like) subgroup exist, associated with good and poor prognosis, respectively. In addition to differential expression of coding genes, ABC-type lymphoma cells express high levels of the non-coding microRNA, miR-155, an onco-miR whose ectopic expression in the mouse has been shown to give rise to B-cell malignancies. DLBCL feature a dysregulated PI3 kinase pathway, which can promote proliferation and survival. PI3K is regulated by phosphatases PTEN (phosphatase and tensin homolog deleted on chromosome ten) and SHIP (SH2 domain-containing inositol 5-phosphatase). PTEN is a known tumor suppressor and is mutated in human cancer with a frequency approaching that of p53. cDNA array analyses of DLBCL patient specimens indicate that low mRNA expression level of SHIP can be used as a negative prognostic marker for survival. We have now identified SHIP as the first bona-fide target of miR-155. RT-PCR analysis of micro-dissected lymphoma samples confirmed high levels of miR-155 and low levels of SHIP in poor-prognosis ABC-cells as compared to GCB-cells. We further demonstrate that elevated levels of miR-155, and consequent abrogation of SHIP expression, is not due to point mutations or promoter hypermethylation of SHIP in primary DLBCL cells, but rather the result of a TNFa-mediated autocrine loop, a pro-inflammatory cytokine whose serum levels are elevated in DLBCL patients. Consequently, anti-TNFa regimens (Etenercept (Enbrel®), Infliximab (Remicade®)) are sufficient to reduce miR-155 levels, restore expression of SHIP, decrease p-Akt levels, and slow tumor cell growth of ABC-sub-type DLBCL cell lines. Furthermore, we observe a highly significant decrease in tumor growth when DLBCL-xenograft mice are treated with Etenercept, suggesting a novel approach for restoring tumor suppressor activity and inducing growth inhibition of these aggressive tumors. Our findings offer the first direct evidence that specific miRs can function as a the link between inflammation and cancer. Finally, our hypothesis, that TNFa promotes survival of DLBCL via miR-155, SHIP and pAkt, opens up a novel and immediately accessible (co)treatment for poor prognosis DLBCL.
MTG16, a Target of the T(16;21) in Acute Myeloid Leukemia, Is Required for Hematopoietic Stem and Progenitor Cell Functions
Authors: Steapleton Melissa Ann , Moreno Isabel , Chyla Brenda , Hiebert Scott 
Published: April 2020

Abstract
The t(8;21) and t(16;21) disrupt two closely related Myeloid Translocation Gene family members respectively, MTG8 and MTG16. Whereas the expression of MTG8 is highly regulated, MTG16 is more widely expressed and is the family member most highly expressed in hematopoietic stem cells. Therefore, to address the contribution of MTG16 to HSC functions and hematopoiesis, we created mice lacking this gene. We show that this transcriptional co-repressor is required for hematopoietic stem and progenitor cell functions such as cell fate decisions and early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells towards the granulocytic/macrophage lineage, while reducing the numbers of megakaryocyte-erythroid progenitor cells, which was shown using both flow cytometry and methylcellulose colony formation assays. In addition, inactivation of Mtg16 impaired the rapid expansion of long and short-term stem cells, multi-potent progenitor cells and megakaryocyte-erythroid progenitor cells that are required under hematopoietic stress/emergency. Due to this, the Mtg16-null mice could not respond to phenylhydrazine or 5-fluorouracil treatment and were completely defective in the colony forming unit-spleen (CFU-S) assays. Additionally, Mtg16-null bone marrow failed to repopulate the hematopoietic system when it was transplanted into an irradiated recipient mouse and also failed to compete with wild-type bone marrow in a competitive bone marrow transplant. This impairment appeared to be due to a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16(−/−) defect. Thus, like other key transcriptional co-repressors (e.g., the retinoblastoma protein, pRB, and the nuclear hormone co-repressor, N-CoR) Mtg16 is a key regulator of stem cell functions and lineage commitment in hematopoiesis.
Regulation of Stem Cell Aging by Retinoblastoma Like-1 (p107)
Authors: Oakley Erin J. , Geiger Hartmut , Van Zant Gary 
Published: April 2020

Abstract
It is well documented that both quantitative and qualitative changes in the murine hematopoietic stem cell (HSC) population occur with age. We have previously mapped a quantitative trait locus (QTL) to murine chromosome 2 that is associated with the variation in frequency of HSCs between aged C57BL/6 (B6) and DBA/2 (D2) mice. In B6 mice the HSC population steadily increases with age, whereas in D2 mice, this population declines. A QTL regulating the natural variation in lifespan between the two strains was mapped to the same location on mouse Chr 2, thus leading to the hypothesis that stem cell function affects longevity. B6 alleles of this locus, associated with expansion of the stem cell pool, are also associated with a ~50% increase in lifespan. In the present study, we characterize a congenic mouse model which was generated by introgressing D2 alleles in the QTL onto a B6 background. Using a surrogate assay to mimic aging, we analyzed the cell cycle, apoptotic and self-renewal capabilities of congenic and B6 HSCs and show that D2 alleles in the QTL affect the apoptotic and self-renewal capabilities of HSCs. Next, we used oligonucleotide arrays to compare the differential expression of B6 and congenic cells using a population enriched for primitive stem and progenitor cells. Three variables were examined using Affymetrix M430 arrays:
the effect of strain—congenic versus background; the effect of age—2 months versus 22 months; and the effects of 2 Gy of irradiation because previous studies indicated that congenic animals were highly sensitive to the effects of mild radiation compared to B6 background animals.
Extensive analysis of the expression arrays pointed to a strong candidate, the gene encoding Retinoblastoma like protein 1, otherwise known as p107. The B6 allele is associated with increased p107 expression in old HSCs therefore p107 in this context is a positive regulator of stem cell number in aged mice. Real-time PCR was used to validate the differential expression of p107 in lineage negative and lineage negative Sca-1+, c-kit+ (LSK) cells. Detailed sequence analysis of the gene revealed the presence of 4 non-synonymous, coding region single nucleotide polymorphisms (SNPs) between B6 and D2 mice, which may contribute to the differential expression of the gene and function of the protein. Perhaps most importantly, we show that overexpression of p107 in congenic HSCs increases day 21, day 28, and day 35 CAFC numbers in vivo by 2- to 4-fold, therefore confirming its role as a positive regulator of primitive progenitor populations including HSCs. These studies uncover a novel role for p107 and provide additional clues in the complex regulation of stem cell aging.
Second Primary Malignancy in Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Ghimire Krishna B , Shah Binay K. 
Published: April 2020

Introduction:
Patients with non-Hodgkin lymphoma are at significantly increased risk of second primary malignancies (SPM). There are few studies on SPM in diffuse large B-cell lymphoma. We aim to evaluate the risk of SPM after diagnosis of primary DLBCL using Surveillance, Epidemiology and End Results (SEER) database.
Methods:
We used SEER 13 database to select adult patients with primary DLBCL diagnosed between 1992- 2009. We used SEER*Stat’s Multiple Primary - Standardized Incidence Ratios (MP-SIR) to calculate SPM in DLBCL. We analyzed SPM by age (≥20, 20-59 and ≥60 years), sex and latency. Second primary malignancy was defined as a metachronous malignancy developing six months or more after an index DLBCL.
Results:
A total of 28,368 adult DLBCL patients were selected for analysis. Among them, 54.4% were male, 44.1% were &lt;60 years of age. The total number (n) of all site SPMs in DLBCL patients was 2,597, an Observed/ Expected (O/E) ratio of 1.22, P&lt; 0.05, excess risk of 30.93. The risk of following SPMs was significantly higher in the patients with DLBCL: head & neck, anus & colorectal, lung, skin (melanoma), kidney, thyroid, Kaposi sarcoma and hematological malignancies.
In young DLBCL patients (20-59 years) group, 12,509 patients developed 830 all site SPMs with O/E: 1.56, P value &lt; 0.05, excess risk 37.01. SPMs which were significantly increased as compared to general population were: head & neck, anus & colorectal, lung, kidney, thyroid, Kaposi sarcoma and hematological malignancies. Similarly, 15,859 older (≥60 years) DLBCL patients developed 1,767 all site SPMs with O/E: 1.11, P&lt; 0.05, excess risk 24.07. SPMs which were significantly increased in this age group as compared to general population were: head & neck, skin, colon, kidney, thyroid and hematologic malignancies.
There was significantly higher risk of tumors of anus & colorectal, liver, kidney, thyroid, Kaposi sarcoma and hematologic malignancies within 5 years of latency. Malignancies of head & neck, anus &, colorectal, skin, breast, urinary bladder and hematologic malignancies were significantly higher after 5 years of latency.
Conclusion:
Patients with DLBCL were at significantly increased risk of developing SPMs as compared to general population. Survivors of DLBCL need to be closely followed with special attention to SPM.

Disclosures
No relevant conflicts of interest to declare.