bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunosuppression for Myelodysplastic Syndrome: Association between a Score Based on Presenting Features and Long-Term Survival.
Authors: Sloand Elaine M. , Saunthrararajah Yogan , Battiwalla Minoo , Nakamura Ryo , Boss Carol , Aliyu Zakari Y. , Young Neal S. , Barrett John 
Published: April 2020

Abstract
Immunosuppressive therapy (IST) can improve cytopenias in selected patients with myelodysplastic syndrome (MDS). Between 1998 and 2004, 133 patients with MDS (FAB classification RA, RA, or RARS ) were enrolled in NHLBI IST protocols: 74 received ATG (Pharmacia, 40mg/kg x 4 days); 43 received a combination of ATG and CsA Fourteen received cyclosporine (CsA) to maintain levels above 100 ng/ml for up to 6 months. Average follow-up was 41 months (range 1 week to 10 years). Previously, we reported that responses to ATG alone were most likely in HLA DR15 individuals of younger age and with a shorter duration of red cell transfusion-dependence. We applied a score based on these factors to assign patients into high probability (HP) and low probability (LP) of response to immunosuppression. Here, we use the score to analyze effectiveness of different IST and compare survival, response, and leukemic progression in HP and LP patients. Patients with HP were more likely to respond to any IST schedule than were patients with LP (85% vs 8%; p&lt;0.0001) and they had longer survival when compared to LP patients (90% vs 38% alive at 3 years; P&lt;0.0001). There were no differences in response or survival between HP patients treated with ATG or with ATG/CsA; CsA-alone treated patients were too few for survival evaluation. Other factors positively affecting survival were response to therapy (p=.0004) and female sex (p=0.03). Neither bone marrow cellularity nor cytogenetics independently affected response or survival; patients with monosomy 7 and 5q- were in the LP group while patients with trisomy 8 predominated in the HP group. In general, patients with trisomy 8 and 5q- survived comparably to patients with normal cytogenetics, but patients with monosomy 7 had statistically shorter survival (p=0.007) than patients with normal cytogenetics or trisomy 8. The scoring system further segregated 95 patients within IPSS int-1 into a HP group with 92% 3 year survival vs 39% for LP patients (p&lt;.0001). Mortality in the HP group was a consequence of cytopenias, while most deaths in the LP were from leukemia: only 2/50 (4%) of patients in the HP group developed leukemia compared with 30% of LP patients followed for a mean of 57 months (hazard ratio = 11; 95% CI 2.566 to 12.18; p&lt; P&lt;0.0001). These findings suggest that immunological characteristics may be independent factors determining the outcome of IST in patients with MDS.
Figure Figure
Non-Myeloablative Allografting from HLA-Identical Sibling Donors for Treatment of CML.
Authors: Kerbauy Fabio R. , Lange Thoralf , Gooley Ted , Shizuru Judith , Radich Jerald , Maloney David G. , Agura Edward , Bruno Benedetto , Epner Elliot , Chauncey Thomas , Blume Karl , Storb Rainer , Niederwieser Dietger , Sandmaier Brenda M. 
Published: April 2020

Abstract
We retrospectively analyzed data from 24 patients with chronic myeloid leukemia (CML) treated with HLA-matched related donor hematopoietic cell transplantation (HCT) after non-myeloablative conditioning with 2 Gy total body irradiation (TBI), given either alone (n=8) or in combination with 3 days of fludarabine, 30mg/m2/day (n=16). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. CML patients in first chronic phase (CP1) (n=14), second chronic phase (n=4) or accelerated phase (n=6) who were not candidates for conventional HCT, were enrolled in a median of 28.5 (range, 11–271) months after diagnosis. The median age at HCT was 58 (range, 27–71) years. Unmodified G-CSF mobilized peripheral blood stem cell grafts containing medians of 7.9 (range, 2–18.1) x106 CD34+ cells/kg and 3.4 (range 1.7–2.4) x 108 CD3+ cells/kg, respectively, were infused. The median number of days in which ANC was less than 0.5 x 109/L was 5 (range, 0–8) days and 12 patients maintained ANCs greater than 0.5 x 109/L after HCT. Only 2 patients developed platelet counts less than 20 x 109/L. All patients had initial donor engraftment (&gt;5% donor T-cell chimerism) at day 28 after transplant, and 17 (71%) achieved sustained full donor chimerism (&gt;95% donor T-cell chimerism). There were 4 rejections followed by autologous hematopoietic reconstitution among 8 patients not given fludarabine, and donor lymphocyte infusions (DLI) were ineffective to reverse rejections. Fifteen (60%) patients achieved CR and 13 (54%) had complete molecular remissions, (defined as RT-PCR negativity for bcr-abl). Thirteen of 24 patients (54%) were alive and in CR at a median of 36 (range, 4–49) months after HCT. There were 5 (21%) deaths from non-relapse causes, one of them (4%) during the first 100 days. The incidences of grade II, III and IV acute GVHD were 38%, 4%, and 8%, respectively. The 2-year incidence of chronic extensive GVHD was 32%. The 2-year estimated overall survivals for patients in CP1 (n=14) and beyond CP1 (n=10) were 70% and 56%, respectively. Ten patients in CP1 received conditioning with fludarabine in addition to 2 Gy TBI; all ten achieved CR and 9 complete molecular remissions. Seven of 10 patients are alive in molecular remissions with a median follow-up of 36 (range, 6–49) months. In summary, non-myeloablative HCT were well tolerated in a group of patients who were older and/or medically infirm and therefore ineligible for myeloablative HCT. This approach should be considered for patients who fail to respond to initial conventional therapy and are not eligible for myeloablative conditioning regimens. The effectiveness of non-myeloablative compared to conventional myeloablative HCT will need to be definitively assessed in Phase III clinical trials.
Genetic and Functional Characterization of Isolated Stromal Cell Lines from the Aorta-Gonado-Mesonephros (AGM)-Region.
Authors: Weisel Katja C. , Gao Ying , Shieh Jae-Hung , Kanz Lothar , Moore Malcolm A.S. 
Published: April 2020

Abstract
The aorta-gonads-mesonephros (AGM) region autonomously generates adult repopulating hematopoietic stem cells (HSC) in the mouse embryo and provides its own HSC-supportive microenvironment. Stromal cells from adult bone marrow, yolk sac, fetal liver and AGM have been used in coculture systems for analysing growth, maintenance and differentiation of hematopoietic stem cells. We generated &gt;100 cloned stromal cell lines from the AGM of 10.5 dpc mouse embryos. In previous studies, we tested these for support of murine adult and human cord blood (CB) CD34+ cells. We could demonstrate that 25 clones were superior to the MS5 bone marrow stromal cell line in supporting progenitor cell expansion of adult mouse bone marrow both, in 2ndry CFC and CAFC production. In addition we demonstrated that 5 AGM lines promoted in absence of exogenous growth factors the expansion of human CB cells with progenitor (CFC production for at least 5 weeks) and stem cell (repopulation of cocultured cells in NOD/SCID assay) function. Now, we could show that one of the isolated stromal cell lines (AGM-S62) is capable in differentiating undifferentiated murine embryonic stem (mES) cells into cells of the hematopoietic lineage. A sequential coculture of mES-cells with AGM-S62 showed production of CD41+ hematopoietic progenitor cells at day 10 as well as 2ndry CFC and CAFC production of day 10 suspension cells. Hematopoietic cell differentiation was comparable to standard OP9 differentiation assay. With these data, we can describe for the first time, that a stromal cell line other than OP9 can induce hematopoietic differentiation of undifferentiated mES cells. Hematopoietic support occurs independently of M-CSF deficiency, which is the characteristic of OP9 cells, because it is strongly expressed by AGM-S62. To evaluate genes responsible for hematopoietic cell support, we compared a supporting and a non-supporting AGM stromal cell line by microarray analysis. The cell line with hematopoietic support clearly showed a high expression of mesenchymal markers (laminins, thrombospondin-1) as well as characteristic genes for the early vascular smooth muscle phenotype (Eda). Both phenotypes are described for stromal cells with hematopoietic support generated from bone marrow and fetal liver. In addition, the analysed supporting AGM stromal cell line interestingly expressed genes important in early B-cell differentiation (osteoprotegerin, early B-cell factor 1, B-cell stimulating factor 3), which goes in line with data demonstrating early B-cell development in the AGM-region before etablishing of fetal liver hematopoiesis. Further studies will show the significance of single factors found to be expressed in microarray analyses. This unique source of &gt; 100 various cell lines will be of value in elucidating the molecular mechanisms regulating embryonic and adult hematopoiesis in mouse and man.
Intrahepatic Portal Application of Autologous CD133+ Bone Marrow Stem Cells to the Liver - Early Experience with a Novel Concept To Support Hepatic Regeneration.
Authors: Esch Jan Schulte am , Knoefel Wolfram T. , Klein Michael , Ghodsizad Alireza , Fuerst Guenter , Poll Ludger W. , Saleh Andreas , Piechaczek Christoph , Feifel Nico , Stockschlaeder Marcus , Stoldt Volker , Stoecklein Nikolas , Tustas Roy Y. , Eisenberger Claus F. , Peiper Matthias , Haeussinger Dieter , Hosch Stefan B. 
Published: April 2020

Abstract
The liver has a large capacity for regeneration after surgical resection. However, below a critical level of future liver remnant volume, liver resection is accompanied by significant increase of postoperative liver failure and mortality. There is accumulating evidence for the contribution of hematopoetic stem cells to participate in liver regeneration. Here we report on three patients that were subjected to intra portal application of CD133+ bone marrow stem cells to support a standard concept of preoperative proliferation of the prospective liver mass. In all three cases, scheduled for right hepatic trisegmentectomy, isolated portal venous embolisation (PVE) of liver segments I and IV–VIII routinely utilized to expand left lateral hepatic segments II/III (prospective remaining liver mass) was questionably sufficient. Autologous bone marrow cells were enriched for stem cell marker CD133 utilizing an immunomagnetic device. For characterisation, each preparation of Cells was subjected to FACS-analyses for markers CD34, CD45 and CD133. Absolute numbers of 2.4 to 12.3 mio CD133+ cells were porto-venously applied to the left-lateral liver segments following PVE of contra lateral liver segments. The treatment with CD133+ was well tolerated without obvious side effects. CT-scan volumetry revealed 2.5 fold increased mean proliferation rates of left-lateral segments when compared to a group of three consecutive patients, treated with the same therapeutic concept - except the application of stem cells. Two to three weeks after intervention, future remnant liver volume was sufficient to perform expanded liver resection, which was applied safely to all patients. This first experience with a novel concept of portovenous application of CD133+ bone marrow cells subsequent to porto-venous embolisation encourages to carry out future controlled trials to evaluate the effectiveness of this approach to boost liver regeneration processes.
Myeloma Cells Suppress Osteoblast Differentiation by Secreting a Soluble Wnt Inhibitor, sFRP-2.
Authors: Oshima Takashi , Abe Masahiro , Asano Jin , Hara Tomoko , Kitazoe Kenichi , Sekimoto Etsuko , Tanaka Yoichi , Shibata Hironobu , Hashimoto Toshihiro , Ozaki Shuji , Kido Shinsuke , Inoue Daisuke , Matsumoto Toshio 
Published: April 2020

Abstract
Multiple myeloma (MM), a malignancy of plasma cells, develops in the bone marrow, and generates devastating bone destruction. Along with enhanced bone resorption, clinical evidence has also suggested suppression of bone formation as a contributing factor to the bone loss in MM. In contrast to recent understanding on mechanisms of osteolysis enahnced in MM, little is known about factors responsible for impaired bone formation. A canonical Wingless-type (Wnt) signaling pathway has recently been shown to play a critical role in osteoblast differentiation. Therefore, in the present study, we aimed to clarify mechanisms of suppression of osteoblast differentiation by MM cells with a particular focus on a canonical Wnt signaling pathway. Because several secreted Frizzled related protein (sFRP) and DKK family members are known as soluble Wnt antagonists, we first examined the expression of sFRP-1, 2 and 3 and DKK-1 in MM cell lines including U266, RPMI8226 and ARH77. All cell lines expressed sFRP-2 and sFRP-3 mRNA observed by RT-PCR. However, sFRP-1 was not expressed in any cell line, and Dkk-1 was expressed only in U266 cells at mRNA levels. We next conducted Western blot analyses for these factors and detected only sFRP-2 in immunoprecipitants of conditioned media as well as cell lysates of all these cell lines. However, no other factors were found at protein levels. Furthermore, sFRP-2 mRNA and protein expression was detected in most MM cells from patients with advanced or terminal stages of MM with bone destruction including plasma cell leukemia (3/4 and 8/10, respectively). In order to examine a biological role for sFRP-2, we added recombinant sFRP-2 to MC3T3-E1 cell culture together with BMP-2. Exogenous sFRP-2 partially suppressed alkaline phosphatase activity but almost completely mineralized nodule formation enhanced by BMP-2. Furthermore, sFRP-2 immunodepletion significantly restored mineralized nodule formation in MC3T3-E1 cells suppressed by RPMI8226 and ARH77 CM. These results suggest that sFRP-2 alone is able to suppress osteoblast differentiation induced by BMP-2 and that MM cell-derived sFRP-2 is among predominant factors responsible for defective bone formation in MM. Because MM cell-derived factors such as DKK-1, IGF-BP4 and IL-3 other than sFRP-2 have been implicated as an inhibitor of osteoblast differentiation, sFRP-2 may act alone or in combination with such other factors to potently suppress bone formation in MM. Taken together, MM cells may cause an imbalance of bone turnover with enhanced osteoclastic bone resorption and concomitantly suppressed bone formation, which leads to devastating destruction and a rapid loss of bone.
TNFRSF6 (Fas Antigen) Mutations in Patients with Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease).
Authors: George Tracy I. , Ma Lisa , Nagy Peter L. , Natkunam Yasodha , Warnke Roger A. , Dorfman Ronald F. , Arber Daniel A. 
Published: April 2020

Abstract
Sinus histiocytosis with massive lymphadenopathy (SHML or Rosai-Dorfman disease) is a rare histiocytic proliferation of unknown etiology. There is a known association between SHML and immune disorders. Recently, histologic changes of SHML have been found in lymph nodes of patients with autoimmune lymphoproliferative syndrome (ALPS), a disorder most commonly associated with mutations in the TNFRSF6 gene that encodes the Fas antigen. We retrospectively analyzed tissue from 22 patients with SHML for TNFRSF6 gene mutations using isolated genomic DNA from paraffin-embedded tissue followed by screening of PCR products for the promoter regions and all exons (1–9) of the gene for possible mutation by high performance liquid chromatography. Mutations were confirmed by direct sequencing. We identified six patients (27%) with SHML and mutations of the TNFRSF6 gene as listed below, including three cases (14%) with potentially significant mutations (*) involving promotor and splice donor regions, and frameshift mutations. The samples with mutations had a 4:2 male:female ratio with a mean/median age of 39/43 years (range 7–68 years) compared to a 9:7 male:female ratio, mean/median age of 42/43 years (range 12–76 years) for the non-mutated samples. No differences in site of disease were identified in the mutated versus non-mutated groups. None of the samples had morphologic features to suggest ALPS. These results suggest that at least a subset of cases of SHML are associated with disruption of the Fas apoptotic pathway. Additional study of other components of the apoptotic pathway may be warranted in this disease.
Cases with TNFRSF6 mutations.
Case No. Nucleotide Change Localization Codon Amino acid change **Numbering for the promoter sequence, according to www.mutationdiscovery.com. All other numbering according to GeneBank accession number M67454. 1 c217+34A&gt;G Intron 7 c217+40A&gt;G Intron 7 2 T779C Exon 7 195 Val --&gt; Ala 3 c217+1G&gt;A Intron 7 Splice defect* T763C Exon 7 190 Val --&gt; Ala c217+182A&gt;G Intron 7 c217+183A&gt;G Intron 7 C1425T Exon 9II 3′UTR * 4 597del T Exon 4 135 Frameshift* 5 T/C 4656** Promoter * c189+4A&gt;T Intron 6 5′ consensus splice donor site* C729T Exon 6 179 Leu --&gt; Phe 6 c218-84A&gt;G Intron 7
A Phase I, Multi-Dose, Dose Escalation Study of SGN-40 (anti-huCD40 mAb) in Patients with Refractory or Recurrent Multiple Myeloma.
Authors: Hussein Mohamad A. , Niesvizky Ruben , Munshi Nikhil , Berenson James C. , Anderson Kenneth C. , Ryan Kate , Baumgartner Karen , Miller Dennis M. , McDonald Michael 
Published: April 2020

Abstract
CD40 is a type I transmembrane protein that upon binding to CD40 ligand regulates important biologic effects in the immune system. CD40 is also highly expressed on hematologic tumors, which has raised interest in the potential for its use as a tumor target for antibody-based cancer therapy. SGN-40 is a humanized monoclonal antibody that selectively binds to human CD40 and induces apoptosis and growth inhibition of a wide variety of B-cell derived cancer cell lines in vitro. Our preclinical work has confirmed the in vitro cytotoxicity of SGN-40 against human multiple myeloma (MM) cells via several mechanisms. These include induction of cytotoxic ligands of TNF superfamily; suppression of IL-6-induced proliferative and anti-apoptotic effects, as well as antibody-dependent cell-mediated cytotoxicity (Tai, et al, Cancer Research64, 2846–2852, April 15, 2004). Since ≥ 90% of MM cells express CD40, targeting CD40 using SGN-40 presents a potential novel treatment strategy. Based on these preclinical data, a phase I study is being conducted to define the toxicity profile, characterize the pharmacokinetics (PK), and evaluate antitumor effects of SGN-40 in patients with refractory or recurrent MM. Four weekly doses ranging from 0.5 to 16 mg/kg are planned to be administered to groups of at least three patients per cohort. Patients will be followed for up to 6 weeks post their last dose. Currently, a total of seven patients have been treated with SGN-40 at dose levels of 0.5 and 1.0 mg/kg. No grade 3 or 4 non-hematologic dose limiting toxicities have been observed. One patient experienced a transient Grade 3 decrease in hemoglobin. Decrease in CD19 positive B-cells were noted for patients treated at both dose levels. Changes in serum and urine M protein levels were measured to estimate potential anti-tumor effects of SGN-40. Of the seven patients evaluated, one patient at 0.5 mg/kg dose had stable disease, based on serum M protein, over the 10 week study period. Clinical evaluation with dose escalation of this agent continues and updated safety, PK and antitumor data will be presented.
BMS-354825 Potently Inhibits the Kinase Activity of KIT Activation Loop Mutations Associated with Systemic Mastocytosis and Induces Apoptosis of Mastocytosis Cell Lines.
Authors: Schittenhelm Marcus , Shiraga Sharon , Lee Francis Y. , Heinrich Michael C. 
Published: April 2020

Abstract
Activating mutations of the activation loop (AL) of KIT are reported in several human neoplasms including a subset of patients with AML or systemic mast cell disorders. The small molecule tyrosine kinase inhibitor, imatinib, is a potent inhibitor of wild type KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GI stromal tumors. However, KIT AL mutations such as D816V that are typically found in AML and systemic mast cell disease are insensitive to imatinib (IC50 &gt; 5–10 micromolar). In addition, acquired AL mutations are associated with imatinib resistance in GI stromal tumors. Experimental models of these diseases suggests that targeted inhibition of AL-mutant KIT in such cells would result in decreased proliferation and induction of apoptosis. BMS-354825 is a synthetic small-molecule ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomoloar range. In addition, BMS-354825 also inhibits many of the acquired BCR-ABL mutations associated with imatinib-resistant CML. Notably, BMS-354825 binds to the ATP-binding site in ABL regardless of the conformation of the AL and is therefore able to potently inhibit the kinase activity of AL-mutants of BCR-ABL. BMS-354825 is currently being tested in phase I studies for safety and efficacy in the treatment of imatinib-resistant CML as well as for various solid tumors. We investigated the inhibitory potential of BMS-354825 against KIT AL-mutants expressed by different mastocytosis/mast cell leukemia cell lines. We first examined the activity of BMS-354825 against the kinase activity of wild-type KIT kinase expressed by M07e cells. BMS-354825 potently inhibited the kinase activity of SLF-dependent M07E cells with an IC50 of 1–10 nM for autophosphorylation and cellular proliferation. In contrast, the IC50 for inhibition of GM-CSF-dependent proliferation was ~5 micromolar. BMS-354825 also potently inhibited the proliferation of the human mast cell leukemia cell line HMC-1 that expresses a juxtamembrane KIT V560G mutant kinase (IC50 1–10 nM). Notably, BMS-354825 inhibited autophosphorylation of KIT D816V with an IC50 of ~100 nM. Similar potency for inhibition of proliferation and induction of apoptosis (IC50 150–400 nM) was seen using three different cell lines expressing human D816V or the homologous murine D814Y KIT kinase. We conclude that BMS-354825 potently inhibits the kinase activity of wild-type KIT and imatinib-resistant KIT AL-mutant kinases associated with AML and systemic mast cell disorders. If BMS-354825 proves to be safe and tolerable in ongoing phase I trials, it should be further tested in clinical studies targeting patients with human malignancies associated with imatinib-resistant KIT AL-mutations.