bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Imaging to Monitor Trafficking and Engraftment of Human CD34+ Hematopoietic Stem and Progenitor Cells in Rhesus Monkeys
Authors: Tarantal Alice F. , Lee C. Chang I. , Batchelder Cynthia A. , Sutcliffe Julie L. , Cherry Simon R. 
Published: October 2019

Abstract
Significant advancements have been made in the use of noninvasive imaging techniques which includes dramatic improvements in resolution and sensitivity, and imaging systems designed specifically for animals. The non-invasive nature of these techniques allows longitudinal assessments over time, and the evaluation of protocols that could be applied in a human clinical setting. Imaging is also of great utility in situations when it is unclear where to focus the analyses, such as the challenges presented by systemic administration of transplanted cells, which can traffic to different anatomical sites. Our prior studies have shown that we can monitor gene expression in fetal and infant monkeys using reporter genes, microPET, and optical imaging. We have also shown that human mobilized peripheral blood stem cells (hPBSC) from adult male donors and male cord blood CD34+ hematopoietic stem cells (HSC) can readily engraft in fetal rhesus monkeys and persist over time. Other recent findings suggest that growth factor expansion of cord blood CD34+ HSC in vitro prior to transplant substantially increases the level of engraftment, with evidence of human hematopoietic cells in the rhesus host at levels significantly greater than the approximate 2% we previously reported. Our studies have also focused on new ways to use optical imaging to monitor transplanted hPBSC, cord blood HSC, and CD34+ precursors differentiated from human embryonic stem cells (hESC) that express firefly luciferase and a drug resistance gene, and the development of PET techniques for short-term tracking of transplanted cells. Transduced cells (1×104–20×106 cells/fetus) were transplanted intraperitoneally into fetal monkeys in the late first trimester under ultrasound guidance (N=27), then animals were monitored sonographically during gestation, and delivered by cesarean-section at term. At 1 week postnatal age and monthly thereafter animals were imaged for firefly luciferase expression (bioluminescence) following the intravenous injection of 100 mg/kg D-luciferin, and after the collection of blood and bone marrow for analysis. While evidence of the human Y chromosome (hSRY, hTSPY) was found in peripheral blood mononuclear cells and CD34+ immunoselected cells from marrow by qRT-PCR, the range of copies detected over time did not reflect the imaging findings. Foci of engrafted human cells were found to persist for ≥1 year, to date, in the rhesus host and in anatomical areas not previously identified (e.g., ribs, sternum, liver). In addition, 64Cu-PTSM radiolabeled hPBSC from the same donors were injected postnatally and cell trafficking monitored without evidence of toxicity or adverse effects. These in vivo imaging studies have provided unique insights into the fate of CD34+ cells post-transplantation, and indicate the importance of these techniques for cell transplant protocols.
A Report from the International Collaborative Gaucher Group (ICGG) Gaucher Registry
Authors: Weinreb Neal J. , Dahl Stephan vom 
Published: October 2019

Abstract
Objective: To report the latest data on patients with Gaucher disease (GD) enrolled in the ICGG Gaucher Registry.
Methods: Data from all patients enrolled in the ICGG Gaucher Registry from 1991 through 2007 were analyzed.
Results: As of December 31, 2007, 4,936 GD patients were enrolled in the ICGG Gaucher Registry by 772 physicians in 60 countries. The countries with the largest numbers of patients were the United States (36%), Israel (14%) and Brazil (10%). The majority of patients were diagnosed with GD between 4 and 30 years (mean age, 19 years). The most common genotypes were N370S/N370S (31%), N370S/L444P (16%), N370S/Rare Allele (13%), and N370S/unknown (11%). The most frequent genotype for patients with neuronopathic GD was L444P/L444P (68%). At diagnosis, anemia was reported in 37% of patients and moderate to severe thrombocytopenia in 60%. Splenomegaly was reported in 86% of patients (>5 multiples of normal [MN]) and hepatomegaly in 65% (liver volume >1.25 MN). Bone pain was present in 34% of patients and radiologic bone disease was reported in 83%. Long-term treatment with imiglucerase resulted in improved haematological parameters, decreased visceral involvement, decreased bone pain and abolition of bone crises.
Conclusions: For GD and other rare “ultra-orphan” diseases, a large longitudinal international disease registry provides the best means to investigate the natural history of the disease and the long-term effects of therapy. The strength of the ICGG Gaucher Registry data is the inclusion of a large, worldwide patient population with long periods of follow-up data, allowing for studies not otherwise possible.
The Influence of Spatially Distinct Bone Marrow Niches on HSCs
Authors: Liu Sali , Tozer Tigue , Rosa Dilani , Cunningham Cynthia , Tseng Alan , Rashidi Narges , Adams Gregor B. 
Published: October 2019

Abstract
During development, hematopoietic stem cells (HSCs) translocate from the fetal liver to the bone marrow (BM), which remains the site of hematopoiesis throughout adulthood. In the BM the HSCs are located at the endosteal surface, where cells of the osteoblastic lineage comprise a key component of the stem cell niche. While hematopoiesis occurs in many bones, the process of bone formation can actually be split into those bones that develop through endochondral ossification (long bones) and those that form through membranous ossification (flat bones). We examined the role played by the microenvironment in these two distinct bones and whether these microenvironments have differing effects on the HSCs. In vitro analysis of the BM stromal cells isolated from long bones and flat bones has demonstrated that calvaria derived stromal layers can support cobblestone area-forming cells 10-fold greater than stromal layers derived from femurs and tibia. Real-time PCR analysis of gene expression has demonstrated that flat bone stromal cells have 5-fold greater expression of N-cadherin than long bone, while other cadherins such as VE-cadherin show no difference. Correlating with this, we found that calvarial derived HSCs demonstrated increased expression of N-cadherin and also increased expression of other genes associated with cadherin signaling, such as cyclinD1. However, no difference in the cell cycle status of the HSCs derived from long bone and flat bone was noted. Functional assays are being performed in order to assess the function of these distinct BM marrow niches in vivo. It is anticipated that we will be able to begin to define the molecular cues the govern HSC physiology in different locations within the mammalian skeleton and thus provide an understanding not only into the continual migration of HSCs between different HSC niches but also the regression of hematopoiesis that occurs from the appendicular skeleton to the axial skeleton during the adult human lifespan.
Identification and Isolation of the Hematopoietic Stem Cell Niche Initiating Cell Population
Authors: Chan Charles , Chen Ching-Cheng , Kraft Daniel L. , Luppen Cynthia , Kim Jae-Beom , DeBoer Anthony , Wei Kevin Wei , Weissman Irving L. 
Published: October 2019

Abstract
Introduction: Identification and understanding of the cells and processes that can generate, sustain and influence the HSC niche and hematopoiesis are critical for the development of a more comprehensive knowledge of normal hematopoiesis, stem cell homing, trafficking, differentiation and hematopoietic pathology. Growth and renewal in many tissues are initiated by stem cells, supported by the microenvironment (niche) in which they reside. While recent work has begun to describe functional interactions between stem cells and their niches, little is known about the formation of stem cell niches.
Methods & Results: We established a functional, in vivo assay (via implantation of cells under the renal capsule) to isolate the determinants of hematopoietic stem cell (HSC) niche formation and activity. Using this novel assay, we show that a population of progenitor cells (CD45−Tie2-aV+CD105+Thy1.1−; CD105+Thy1−) sorted from 15.5 dpc fetal limbs and transplanted under the adult mouse renal capsule recruit host-derived vasculatures in a VEGF dependent manner, produce donor-derived ectopic bones through endochondral ossification, and generate a marrow cavity populated by host-derived long term reconstituting HSC (LT-HSC). In contrast, CD45−Tie2-aV+CD105+Thy1a+ (CD105+Thy1+) progenitors form bone that does not contain a marrow cavity. While analyzing these and other sorted populations, we did not observe any instances where niche was present without bone, suggesting that skeletal progenitors are necessary for initiating an HSC niche but osteoblasts alone cannot initiate and support niche activity. Suppression of factors important for HSC maintenance, such as steel factor (SLF), in progenitor populations prior to transplant did not alter their ability to initiate and support an HSC niche. On the other hand, suppression of factors involved in endochondral ossification, such as osterix and VEGF, inhibited niche generation. Furthermore, CD105+Thy1− progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification form only bone without marrow in our assay.
Conclusions: In addition to identifying the limb-derived skeletal progenitor capable of endochondral ossification involved and the basic mechanisms of HSC niche initiation, our study provides a functional framework by which future studies on HSC-niche interactions at the cellular level can be carried out.
High-Dose Methotrexate and Early Intensification of Therapy Do Not Improve 3 Year EFS in Children and Adolescents with Disseminated Lymphoblastic Lymphoma. Results of the Randomized Arms of COG A5971
Authors: Abromowitch Minnie , Termuhlen Amanda , Chang Myron , Perkins Sherrie L. , Gross Thomas , Weinstein Howard J. , Finlay Jonathan 
Published: October 2019

Abstract
The treatment of pediatric lymphoblastic lymphoma (LL) has developed in parallel with treatment strategies for childhood acute lymphoblastic leukemia using a BFM backbone. The excellent results of the NHL/BFM 90 trial prompted us to design this randomized factorial study to determine whether a regimen without high dose methotrexate (HDMTX) the CCG BFM will result in the same outcome as NHL/BFM-90 and whether intensification with anthracycline and cyclophosphamide would further improve disease free survival.
From June 2000 to October 2005, 257 patients with Murphy’s Stage III and IV (excluding CNS disease) LL were randomized to one of the four regimens. All regimens used the BFM/NHL95 backbone. The CCG BFM regimen had intrathecal (IT) methotrexate throughout interim maintenance and maintenance without IV methotrexate. The NHL BFM utilized I.V. Methotrexate 5 Gms/m2 and intrathecal MTX every 2 weeks for four doses during interim maintenance without further intrathecal MTX during maintenance. One of each backbone regimens was further intensified with anthracycline and cyclophosphamide early in induction and delayed intensification.
The median age was 10.3 years, 195 (76%) were males; 43 (17%) had >5% bone marrow involvement. Twelve patients with CNS disease were not randomized and received intensification and HD HDMTX with delayed CNS radiation (data not reported here).
Major toxicities have been related to bone marrow suppression with 4 toxic deaths, 3 due to sepsis and 1 from cerebral hemorrhage. The frequency of grade III/IV neutropenia (alone, with fever or with infection), anemia, and thrombocytopenia were higher in the intensified arms during induction. Three of the four toxic deaths occurred on the intensified arms. The three years EFS of the HDMTX vs. none is 84.5% ± .3.5% vs. 82.7± 3.8 (ρ= 0.93) and the intensification vs. none is 83.4% ±3.7 vs 83.0% ± 3.6 (ρ= 0.66). Therefore, there was no significant difference between treatment arms.
These results suggest that neither HDMTX nor early intensification improves EFS in LL. Future direction should focus on identifying biological factors early in therapy so alternative therapies may be investigated.
5-Azacytidine, Valproic Acid and ALL-Trans Retinoic Acid in INT-2/High Risk Myelodysplastic Syndromes: Results of the GIMEMA MDS0205 Multicenter Trial
Authors: Voso Maria Teresa , Santini Valeria , Finelli Carlo , Borin Lorenza , Angelucci Emanuele , Fioritoni Giuseppe , Neri Benedetta , Cortellezi Agostino , Villani Oreste , Buccisano Francesco , Martinelli Giovanni , Petti Maria Concetta , Zini Gina , Piciocchi Alfonso , Fazi Paola , Alimena Giuliana , Gobbi Marco , Liso Vincenzo , Leone Giuseppe 
Published: October 2019

Abstract
Epigenetic changes have been shown to play a role and to cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). The potential reversibility of DNA and chromatin modifications makes chromatin remodeling enzymes attractive targets for therapeutic intervention in this disease. We conducted a phase II study on the combination of the DNMT inhibitor 5-azacitidine (5-AZA), the histone deacetylase inhibitor valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with intermediate-2/high-risk myelodysplastic syndromes. Bone marrow morphology was centrally reviewed before enrolment. VPA was given at 600–1500 mg daily to reach a final plasma concentration above 50 microg/ml, then 5-AZA was added at a standard dose of 75 mg/sqm daily, subcutaneously, 7 days for 8 cycles. In case of minor response, stable disease or failure after 4 cycles, ATRA was added at 30 mg/sqm orally daily, on days 8–27 for 4 cycles. Treatment was continued in responding patients until response persisted. The protocol included 62 patients (43 males, 19 females, median age 67 years, range 53–83 yrs). Diagnosis was RAEB for 37 patients (60.7%), RAEB-t for 21 (32.8%), and CMML for 4 patients (6.5%). The IPSS was int-2 (1.5) for 46 patients and High (≥2) for 16 patients. A valproic acid concentration between 45 and 55 microg/ml was reached in a median of 7 days (range 4–28 days). Three patients died before start of treatment, while 58.7% of patients (95% C.I.: 51.3–67.1) were alive at 12 months. Out of 27 patients who completed 8 treatment cycles, 8 patients (29.6%) obtained complete and partial remission, 3 patients (11.1%) major hematological improvement while 10 patients (37.4%) showed a stable disease. Transformation into AML or progression occurred in 20 patients. RBC transfusion needs decreased significantly from a median of 3 units (range 0–16) before start of treatment to 0 (range 0–7) after 8 cycles. Neurological toxicity occurred in 6 patients. Our data show that the 5-AZA/VPA/ATRA combination is safe and feasible in poor prognosis MDS patients.
Role of MicroRNAs in Resistance to Dexamethasone in Multiple Myeloma Cell Lines
Authors: Bashir Qaiser , Bemis Lynne , Robinson William , Liu Bolin , Wang Shuiliang , Amato Carol , Riley Elizabeth , Lee Choon Kee 
Published: October 2019

Abstract
Multiple Myeloma is a B-cells malignant disease of unknown etiology. It accounts for 1% of all cancers and 14% of hematologic malignancies. Despite the advances in treatment it remains an incurable disease. One of the commonly used drugs in the treatment of multiple myeloma is Dexamethasone. Most patients respond to this drug, but eventually most then become refractory to the treatment with steroids. MicroRNAs (miRNA) are a newly identified class of small RNAs that play important regulatory roles at the post transcriptional level. They usually act by binding to the 3′untranslated region (3′UTR) of messenger RNA (mRNA) and either block their translation or lead to degradation. MM1 cell line is a well known myeloma cell line. By continued exposure to Dexamethasone two variants of MM1 cell line i.e.; MM1.S and MM1.R were developed. MM1.S remains sensitive while MM1.R is resistant to the action of Dexamethasone. It has been reported that MM1.R cell line expresses very minimal levels of glucocorticoid receptor (GR) mRNA and protein, hence rendering it resistant to the action of steroids. We hypothesized that altered regulation of microRNAs between the two cell lines leads to the down regulation of glucocorticoid receptor hence contributing to resistance to the action of steroids. QRT-PCR and Western blot were conducted to demonstrate decreased expression of GR mRNA and protein in MM1.R cell line. We identified certain microRNAs based on bioinformatics with putative docking sites in 3′UTR of GR mRNA. DNA sequencing was used to rule out any mutation in binding sites of these microRNAs. No such mutation was found in MM1.S or MM1.R cell line. qRT-PCR was than used to analyze the differential expression of predicted microRNAs. Several microRNAs were found to be differentially expressed between the two cell lines, including microRNA-183 (p < 0.05). We then transfected inhibitors and mimics of pertinent microRNAs and were able to up or down regulate the GR mRNA. We were also able to show some evidence of apoptosis in MM1.R cell line with Dexamethasone exposure. These studies suggest that microRNAs regulate expression of GR and play an important role in conferring resistance to the action of steroids. These findings shed further light on the underlying mechanisms of steroid resistance and may have important therapeutic implications in the treatment of multiple myeloma.
Marginal Zone Lymphoma: Factors That Affect the Final Outcome, a Study of 275 Patients
Authors: Mazloom Ali , Reed Valerie K , Cabanillas Fernando , Fayad Luis , Pro Barbara , Iyengar Puneeth , McLaughlin Peter , Urbauer Diana L , Dabaja Bouthaina S. 
Published: October 2019

Abstract
Purpose: Retrospective review and analysis of 275 patients with marginal zone lymphoma (MZL) to determine the prognostic factors that affect outcome in an effort to find a specific prognostic score.
Materials and Methods: Two hundred and seventy five patients with pathologically confirmed MZL were studied. Their median age was 60 years (range 18–89). Male sex was found in 123 patients (45%). Ann Arbor stage I was present in 104 patients (38%), stage II in 27 (10%), stage III in 16 (6%), stage IV in 124 (45%), and unknown in 4 (1%). Most patients were asymptomatic at presentation (90%), with 96% presenting with Zubrod score of 0 or 1. Patients were divided into three groups according to sites of involvement: extranodal (211), nodal (27), and splenic (37). Treatment strategy consisted of: observation in 75 (27%), chemotherapy in 103 (37%), combined chemotherapy and radiation in 24 (9%), and definitive radiation in 71 (26%).
Results: Both univariate and multivariate analysis showed that splenic presentation had a better outcome with a hazard ratio (HR) of 0.14 and p value=0.006, while extranodal presentation with bone marrow involvement had an inferior outcome with HR of 2.27 and p value =0.045. Two factors were found to be associated with decreased overall survival (OS) in the multivariate analysis: Older age (p=0.007) and beta 2 microglobulin >1.8 mg/L (p <0.0001). On the other hand splenic presentation and being asymptomatic at presentation were associated with an improved OS with a p value of 0.002 and 0.017, respectively. Stage at presentation had no impact on the overall survival or disease free survival, and although all patients with splenic MZL were stage IV, these patients had the best outcome. Nodal presentation had a similar survival to extranodal presentation.
Conclusion: Splenic presentation even at advanced stage is associated with a better outcome. Bone marrow involvement in patients with extranodal presentation had a lower OS. Older age, high beta 2 microglobulin, and symptoms at presentation adversely affected the overall survival of patients with MZL.
Collaboration of the Meningioma 1 (MN1) Oncogene with MLL-Fusions in Pediatric Leukemia
Authors: Liu Ting , Jankovic Dragana , Brault Laurent , Ehret Sabine , Rossi Vincenzo , Biondi Andrea , Schwaller Juerg 
Published: October 2019

Abstract
Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic marker in adult acute myeloid leukemia (AML). In pediatric leukemia, we found overexpression of MN1 in 53 of 88 cases: whereas no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL), significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia. Interestingly, 17 of 19 cases harboring fusion genes involving the mixed-lineage leukemia (MLL-X) gene showed elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM-13). In a mouse model of MLL-ENL-induced leukemia we found MN1 to be overexpressed as a consequence of provirus integration. Strikingly co-expression of MN1 with MLL-ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. Immunophenotyping and secondary transplant experiments suggested that MN1 overexpression seems to expand the L-GMP cell population targeted by the MLL-ENL fusion. Gene expression profiling allowed defining a number of potential MN1 hematopoietic targets. Upregulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse acute myeloid leukemia, as well as in pediatric leukemias with elevated MN1 levels. Our work shows that MN1 is overexpressed in a significant fraction of pediatric acute leukemia, is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-ENL most probably through modification of a distinct gene expression program that leads to expansion of a leukemic progenitor population targeted by MLL-fusion genes.