bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Formation and Survival of Regulatory T Cells in CLL.
Authors: Jak Margot , Mous Rogier , Remmerswaal Ester BM , Spijker René , Jaspers Annelieke , Yagüe Adriana , Eldering Eric , van Lier René A.W. , van Oers Marinus H. J. 
Published: April 2020

Abstract
Background. In healthy individuals it has been shown that regulatory T cells (Treg) differentiate from rapidly proliferating memory T cells. Rapid proliferation in combination with high susceptibility to apoptosis, make the Treg population highly dynamic. Tregs are thought to play an important role in immune evasion by malignancies. High Treg numbers in patients with malignancies are often associated with poor prognosis. An important question to be answered is whether tumor cells can promote the expansion and activation of Tregs. Recently it has been described that chronic lymphocytic leukemia (CLL) patients have increased numbers of Treg, with highest Treg frequencies in progressive patients1. The mechanism of this expansion however remains unknown. In the present study, we analysed the mechanism behind Treg expansion in CLL.
Results. Neither analysis of the T cell receptor (TCR) repertoire nor CD45 isoform expression of Treg from CLL patients provided evidence for chronic (tumor) antigenic stimulation as a possible cause for Treg expansion in CLL. Furthermore, we found no correlation with CMV serology, which has been demonstrated to influence the CD8+ T cell repertoire in CLL. However, in line with recent studies demonstrating that CD70+ NHL cells are strong inducers of Treg, we found evidence for increased formation of Treg in CLL via CD70 costimulation. We observed that CD40 ligand activated CLL cells (which might be considered a model for lymph node CLL cells2) strongly induced CD70-dependent formation of Treg. RT-MLPA expression analysis of 34 apoptosis-regulating genes showed that in comparison to other CD4+ T cells, Treg of both healthy individuals and CLL patients had a high expression of pro-apoptotic Noxa and a low expression of anti-apoptotic Bcl-2. Strikingly, Bcl-2 levels of Treg in CLL patients were significantly higher than in healthy individuals. Finally, the different apoptotic profile resulted in differences at the functional level, since Treg from CLL patients were more resistant to drug-induced apoptosis than Treg from healthy individuals.
Conclusion. Treg in CLL may accumulate both by increased formation, facilitated by CD27-CD70 interaction in the lymph node proliferation centres, and decreased sensitivity to apoptosis due to a shifted Noxa-Bcl-2 balance. Since high Treg numbers might negatively affect the course of disease, targeting these mechanisms may provide additional therapeutic approaches in CLL.
Mtss1 Suppresses BCR-ABL Induced Cell Migration and Is Downregulated in CML Stem Cells.
Authors: Schemionek Mirle , Agrawal Shuchi , Stehling Martin , Tenen Daniel G. , Hamilton Ashley , Holyoake Tessa , Steidl Ulrich , Berdel Wolfgang E. , Schwab Albrecht , Müller-Tidow Carsten , Koschmieder Steffen 
Published: April 2020

Abstract
Migration and adhesion properties of hematopoietic stem cells (HSC) are disrupted in chronic myeloid leukemia (CML). Egression of these cells from the bone marrow is associated with cytoskeletal changes including actin remodeling. In a microarray screen of differentially regulated genes in HSC from BCR-ABL positive transgenic mice, we found downregulation of multiple genes involved in actin-associated changes of cell structure, adhesion, and migration (i.e. intersectin-1, cortactin, Mtss1, synaptopodin, and Gem GTPase). Mtss1 was further studied since it has been described to be a binding partner of Rac, which is essential for BCR-ABL mediated transformation, and a potential tumor suppressor. Using quanitative RT-PCR, Mtss1 downregulation (6-fold) was confirmed in HSC and unfractionated bone marrow and spleen cells from SCLtTA/BCR-ABL transgenic mice after 3 weeks of BCR-ABL induction as well as in human BCR-ABL positive cell lines. Treatment of BCR-ABL positive (32D/BCR-ABL, K562, KYO-1) but not BCR-ABL negative (32D, U937) cell lines with 5μ M Imatinib led to upregulation of Mtss1 mRNA (5- to 10-fold) and protein, suggesting that downregulation of Mtss1 is dependent on BCR-ABL kinase activity. Retroviral transduction of Mtss1 into 32D/BCR-ABL cells almost completely inhibited BCR-ABL induced cell motility of individual cells seeded on murine bone marrow stromal cells in time-lapse video experiments over the course of two hours. Interestingly, we found that retroviral transduction of Mtss1 into 32D/BCR-ABL cells completely suppressed migration of these cells to extra-hematopoietic sites in vivo upon intravenous transplantation into syngeneic C3H mice. Moreover, when Mtss1-transduced cells were injected subcutaneously, the size of the tumors was significantly decreased as compared to empty vector-transduced 32D/BCR-ABL cells (p&lt;0.05), confirming that Mtss1 may be a tumor suppressor.
These results demonstrate that Mtss1 antagonizes BCR-ABL induced cell migration and is downregulated by BCR-ABL in CML stem cells, suggesting that downregulation of Mtss1 and other cytoskeletal adaptor proteins may be required for egression of CML stem cells from the bone marrow niche. Since the same Mtss1 protein domain is responsible for both Rac and actin binding, Mtss1 may interfere with Rac function and thereby inhibit the effects of Rac on migration and cytoskeletal dynamics of HSC.
HLA-Identical Allogeneic Stem Cell Transplantation (alloSCT) for Patients with Primary Cutaneous T-Cell Lymphoma (CTCL): A Retrospective Analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (EBMT-LWP).
Authors: Duarte Rafael , Canals Carme , Onida Francesco , Olavarria Eduardo , Arcese William , Ferrant Augustin , Narni Franco , Bacigalupo Andrea , Bunjes Donald , Rowe Jacob , Lambertenghi Giorgio , Schmitz Norbert , Sureda Anna 
Published: April 2020

Abstract
Patients with aggressive forms of Mycosis Fungoides (MF), Sézary syndrome (SS) and other less common subtypes of primary CTCL have a dismal prognosis with conventional therapy. A potential role for alloSCT in these patients has been suggested by a number of case-reports and small series. We conducted a retrospective registry analysis of 64 recipients who received an alloSCT from HLA-identical donors (52 related, 12 unrelated) for advanced CTCL reported to EBMT between 1997 and 2006: 23 MF, 21 SS, 16 primary cutaneous anaplastic large cell lymphoma and 4 subcutaneous panniculitis-like T-cell lymphoma; 38 patients were male, 26 were female; median age was 46 years (5–65); median follow up of survivors was 28 months. AlloSCT was performed at a median of 22 (3–313) months from initial diagnosis, following a median of 3 (1–8) prior lines of therapy, the stem cell source was PB in 54 cases and BM in 10 cases, reduced-intensity conditioning (RIC) was used in 41 (64%) cases. Twenty-three percent of patients were in complete response (CR) and 26% in partial response (PR) at the time of alloSCT. All other patients were primary refractory (RE, 25%) or progressed after a previous response (PG, 26%). Non-relapse mortality was 24% at 3 years, and appeared higher in patients receiving myeloablative conditioning (MAC) than in those receiving RIC alloSCT (35% vs 16%; p=0.06). Acute graft versus host disease (GVHD) occurred in 37% of patients at risk, and chronic GVHD in 69% of patients alive at day +100. The cumulative incidence of disease relapse (36% at 3 years) was significantly higher in patients with advanced disease status at alloSCT (RE/PG 46% vs CR/PR 21%; p=0.01), but similar in patients with related and unrelated donors (p=0.39) and receiving MAC or RIC (p=0.6). Progression free survival (PFS) at 3 years was 41%, with a significant advantage for patients in CR/PR at alloSCT (58% vs 26%; p&lt;0.01), but not for type of conditioning (MAC 45% vs RIC 44%; p=0.4) or donor type (related 46% vs unrelated 33%; p=0.2). Out of 22 patients who relapsed, 10 remain alive and 4 of these were in CR at last follow up, possibly indicating that a proportion of patients achieved a better control of CTCL following relapse after alloSCT. Overall survival for the whole series was 55% at 3 years, with a trend towards an improved OS for patients with disease in CR/PR at transplant (65% vs 46%; p=0.1). Overall, outcome after allogeneic transplantation appears superior to that expected for such patients under conventional therapy. Our analysis reinforces the important role of alloSCT in advanced stage CTCL in a relatively large registry-based series.
Graft Versus Host Disease (GVHD) Prophylaxis with Everolimus and Tacrolimus Is Associated with a High Incidence of Sinusoidal Obstruction Syndrome and Microangiopathy – Results of the EVTAC Trial
Authors: Platzbecker Uwe , Bonin Malte , Goekkurt Eray , Radke Joergen , Kiani Alexander , Stoehlmacher Jan , Schetelig Johannes , Ehninger Gerhard , Bornhauser Martin 
Published: April 2020

Abstract
Beyond disease biology, the success of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies is mainly determined by the occurrence and extent of graft versus host disease (GVHD). Therefore, prevention of GVHD is the major goal and challenge in clinical HSCT. A calcineurin-inhibitor combined with methotrexate is the standard graft versus host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus is a derivative of sirolimus, which also seems to mediate anti-leukemia effects. Given the potential synergism and favourable toxicity profile of everolimus and tacrolimus (EVTAC) after allogeneic HSCT we sought to investigate the efficacy of this combination in patients with either myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). We report a combination of everolimus (days 0–56) and Tacrolimus (from day −1 on) in 24 patients (pts, median age 62 years) with either MDS (n=17) or AML (n=7) undergoing intensive busulfan-based conditioning followed by HSCT from related (n=4) or unrelated matched (n=12) or 1-allele mismatched (n=8) donors. All pts engrafted and only one experienced grade IV mucositis. However, although everolimus was scheduled to be administered up to day 56, patients received the drug a median of 44 days (range 10–56) only. The reason for premature discontinuation (50%) were either occurrence of early-onset (day 6) GVHD associated hyperbilirubinemia CTC grade 4 (n=1), transplantation-associated microangiopathy (TMA, n=3), sinusoidal obstructive syndrome (SOS) of the liver (n=6) or a drop of platelets after engraftment by at least 50% (n=2). Nine pts (37%) developed grade II–IV acute GVHD, however, chronic extensive GVHD was observed in 11 of 17 (64%) evaluable pts. TMA occurred in 7 pts (29%) with two cases of acute renal failure. In five out of seven patients with TMA either tacrolimus (n=4) or everolimus (n=1) blood through levels were slightly above the upper target level at the time of TMA appearance. The study was terminated prematurely because additional 6 pts (25%) developed SOS, which was fatal in two cases. With a median follow-up of 26 months, the 2-year overall survival rate is 47%. In conclusion, although this new combination appears to be effective as prophylactic regimen for acute GVHD, the incidence of TMA and SOS seems to be higher compared to other regimens. As a result this combination cannot be recommended as prophylactic regimen after busulfan-based intensive conditioning. However, studies in the context of TBI-based or reduced-intensity conditioning regimens might come to a different conclusion.
The Zebrafish Ortholog of Hemojuvelin Participates in Notochord and Somite Development, but Fails to Regulate Embryonic Hepcidin Expression
Authors: Gibert Yann , Lattanzi Victoria J. , Holzheimer Jason , Burnett Sarah F. , Fraenkel Paula G. 
Published: April 2020

Abstract
Hemojuvelin (hjv), a member of the repulsive-guidance molecule (RGM) family upregulates the iron regulatory hormone hepcidin in a BMP-dependent manner in mammalian cells. A mutation interfering with hjv’s ability to bind neogenin has been identified in patients with juvenile hemochromatosis, while furin cleavage of hjv has also been implicated in its function. Previously, we demonstrated that hepcidin expression in zebrafish embryos increases in response to iron loading or activation of the BMP pathway. We hypothesized that hjv would regulate hepcidin expression in zebrafish embryos and used whole mount in situ hybridization and morpholino knockdowns to study the expression and function of hjv. We found that hjv is strongly and sequentially expressed in the notochord and somites and that knockdown of hjv resulted in severe defects in these structures. Hjv was not expressed in the liver and knockdown of hjv failed to affect the timing, intensity, or location of hepcidin expression. Furthermore, knockdown of hjv failed to prevent the upregulation of hepcidin expression caused by overexpression of BMP2b. Zebrafish hjv exhibits conservation at the site required for binding neogenin, however zebrafish hjv and all nonmammalian RGM’s lack the furin cleavage motif. We found that morpholino knockdown of the zebrafish orthologs of neogenin or furin failed to affect hepcidin expression. Taken together, these data indicate that
regulation of hepcidin expression in the zebrafish embryo is BMP-responsive, but independent of hjv, furin, or neogenin zebrafish hjv participates in notochord and somite development, which we propose as the ancestral function of hjv.
Distinct Expression Patterns in Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) Characterized by Uniparental Disomy.
Authors: Bullinger Lars , Kronke Jan , Botzenhardt Ursula , Heinrich Sabrina , Urlbauer Katja , Miller Simone , Schon Christian , Schlenk Richard F. , Holzmann Karlheinz , Dohner Konstanze , Dohner Hartmut 
Published: April 2020

Abstract
Genome-wide single nucleotide polymorphism (SNP) analyses have revealed uniparental disomy (UPD) to be a common event in cytogenetically normal acute myeloid leukemia (CN-AML) occurring in approximately 20% of cases. Acquired UPD results in copy number neutral loss of heterozygosity (LOH). Comparing matched tumor and germline DNA samples recurrent acquired UPDs affecting chromosomes 11p and 13q were identified. As DNA microarray-based gene expression profiling (GEP) has recently been shown to powerfully capture the molecular heterogeneity of leukemia, we sought to identify gene expression patterns associated with recurrent UPD in CN-AML.
We profiled a set of clinically annotated CN-AML specimens (n=66) entered on a multicenter trial for patients &lt;60 years (AMLSG 07-04) which had been characterized by either 50k or 500k Affymetrix SNP microarrays. All cases were analyzed using Affymetrix microarrays (Human Genome U133 Plus 2.0 Arrays). In this data set we investigated 12 UPDs (affecting chromosomes 1p, 2p, 6p, 11p, 13q and 19q) and applied supervised analyses to define gene-expression patterns associated with UPDs on chromosome 11p and 13q.
For the case with an acquired UPD on 19q a gene dosage effect could be demonstrated. Genes located in the 36 Mb large UPD region showed a significantly lower average expression (p&lt;0.001; t-test). Similarly, we observed a gene dosage effect in one of the UPDs observed on chromosome 1 (p=0.0097; t-test), whereas for the other UPDs no significant association between LOH and gene expression levels could be identified. Despite small sample numbers supervised analyses revealed a biologically meaningful gene expression signatures associated with acquired UPD 11p and 13q. In accordance with the association of UPD 13q with FLT3-ITD, the UPD13q gene expression signature was enriched for genes associated with FLT3-ITD. The UPD11p expression pattern was characterized by genes found to be down-regulated in CEBPAmut CN-AML cases, such as down-regulation of homeobox genes HOXA9, HOXA10, HOXB2, and MEIS1. Notably, the UPD11p signature was also characterized by the expression of e.g. UGT2B28, P2RX5, PGDS, CAPN1, NDFIP1, and TRIB2, an expression profile that has been shown to be associated with CEBPAmut CN-AML as well as AML cases with epigenetic CEBPA silencing.
Thus, our findings represent a starting point to further dissect CN-AML characterized by recurrent UPD, and ongoing analyses will provide additional insights into leukemia biology.
Recombinant Interleukin-11 (rhIL-11) in Women with Refractory Menorrhagia and Von Willebrand Disease.
Authors: Jankowitz Rachel C. , Ragni Margaret V. , Chapman Holly L. , Merricks Elizabeth P. , Kloos Mark T. , Dillow Aaron M. , Franck Helen , Nichols Timothy C. 
Published: April 2020

Abstract
Von Willebrand disease (VWD) is the single most common congenital bleeding disorder, and among women, menorrhagia is the most common bleeding symptom. Although DDAVP is the treatment of choice for those with type 1 VWD, its use may be limited by tachyphylaxis, allergic reactions, or unresponsiveness. We previously showed that recombinant human IL-11 (rhIL-11, Neumega), a gp-130 signaling cytokine with hematopoietic and anti-inflammatory activity, increases VWF levels 2–3 fold when given subcutaneously daily in individuals with mild VWD, and is well tolerated. We, therefore, initiated a Phase II clinical trial to determine the efficacy and safety of rhIL-11 in women with VWD and refractory menorrhagia, despite estrogen, DDAVP, and/or other treatment. We report the results of the first four subjects, age 28–40, with VWF:RCo 0.22–0.37 U/ml at diagnosis, normal VWF multimers, and bleeding severity scores (BSS) 4–6. rhIL-11 was given in a daily subcutaneous dose of 25 mcg/kg for 4 days, followed by monthly home self-injection for up to 7 days during each of six consecutive menstrual cycles, beginning on the first day of each cycle. Menstrual bleeding severity was measured by
a validated bleeding pictorial assessment chart (BPAC) (Janssen, Obstet Gynecol, 1995) and cycle severity rating (CSR), as compared with two pre-treatment baseline menstrual cycles. BPAC scores were compared with standardized cutoff score for menorrhagia of 185.
Cycle severity ratings (CSR) were rated on a nominal scale, with 0=mild bleeding; 1=moderate bleeding, less than usual cycle; 2= moderately severe bleeding, not as severe as worst cycle; and 3=severe bleeding, as severe as worst cycle. The drug was well tolerated with less than grade 1 toxicity, including mild conjunctival erythema and mild fluid retention (fingers) in one each. Following treatment with rhIL-11, there was a significant reduction in BPAC and cycle severity rating during the seven days the drug was given, as compared with the first seven days in cycles prior to rhIL-11 (see Table). Cycle length also shortened, but this did not reach significance. These was an associated increase in VWF:RCo, VWF:Ag, and FVIII:C on day 4 of rhIL-11 dosing, as compared with pre-rhIL-11 levels day 1. These data suggest that rhIL-11 improves hemostasis and reduces bleeding severity when used during the first seven days of menses in women with VWD. Further studies are needed to confirm these findings.
Mensural Cycle Bleeding Severity in Women with VWD With and Without rhIL-11
No. Cycles Bleeding Pictorial Chart (BPAC) No. &gt;185 Cycle Severity Rating (CSR) Cycle Length (Day) VWF:Rco U/ml VWF:Ag U/ml FVIII:C U/ml Significance, *p&lt;0.05; †p&lt;0.01; ‡p=0.014 CYCLES WITHOUT rhIL-11 7 6/7 (85.7%) 2.0±5 12±5 0.92±0.13 1.16 ± 0.06 0.60±0.09 CYCLES WITH rhIL-11 15 4/15 (23.5) ‡ 1.1±0.2† 7±1 1.71±0.17† 1.70±0.17† 1.02 ± 0.12*
Biomarkers of Cartilage and Bone Damage as a Measure of Joint Damage in Haemophilia.
Authors: Jansen Nathalie W.D. , Roosendaal Goris , Lundin Bjorn , Heijnen Lily , Theobald Matthias , Bijlsma Johannes W.J. , Lafeber Floris P.J.G. 
Published: April 2020

Abstract
Purpose Biomarkers of bone and cartilage turnover have frequently been evaluated for joint diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). Results have thus fare not been very conclusive. Some biomarkers such as urinary CTXII and serum COMP appear to correlate with severity of joint degeneration, whereas other are less distinctive. Hemophilic arthropathy (HA) is a very progressive joint degeneration as a result of frequent joint bleeds. From clinical practice it is concluded that the rate of degeneration exceeds that of OA and RA joints. This degeneration has characteristics of both inflammation mediated (as seen in RA) and degenerative (as seen in OA) joint disease. Furthermore, the joint damage is largely restricted to 3 major joints (ankle, knees, and elbows). Therefore, it might be that this rapidly progressive, localized joint degeneration can be used for the evaluation and validation of biomarkers of cartilage and bone turnover. In the present study we therefore investigated whether commercially available biomarkers of cartilage and bone in blood and/or urine are associated with severity of joint damage in patients with haemophilic arthropathy.
Methods Blood and urine were collected from 36 patients suffering from haemophilia. Urine samples were assessed for the amount of CTX-I and CTX-II. Serum samples were assessed for the amount of CTX-I, CTX-II, COMP, C1,2C, C2C, and CS846. Radiographs of ankles, knees and elbows were scored according to Pettersson, a radiographic joint score specific for haemophilic arthropathy based on cartilage and bone changes.
Results U-CTX-II (R=0.39; p=0.01), C1,2C (R=0.31; p=0.04) and CS846 (R=0.31; p=0.03) showed (marginal) correlations with the Pettersson score. Slightly better correlations were obtained when only narrowing of joint space width (JSW) as one of the items in the Pettersson score was used. The other biomarkers showed no correlation with the Pettersson score. Also the bone biomarkers did not correlate with specific bone changes. Interestingly, combined indexes of different markers, based on linear stepwise regression analysis, increased the correlation significantly up to R=0.65; p≤0.001) for the combination of U-CTX-II, COMP and CS846.
Conclusions The present results show that even despite this rapidly progressive degeneration of 6 large joints, from the individual biomarkers determined only U-CTX-II, C1,2C and CS846 show correlation with the severity of arthropathy. Importantly, a relation improved when the markers were related to the process they are supposed to describe (cartilage degeneration markers with JSW narrowing). Most important, combination of markers, significantly improve the relation with the radiographically determined joint degeneration. In general however, it may be concluded that these markers alone seem not of sufficient value for evaluation of joint damage yet.