bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Characterization of Wnt/β-Catenin Pathway Inhibition in Multiple Myeloma Cell Lines Using a Novel Class of Small Molecules.
Authors: Strovel Jeffrey W. , Lawrence Tammy , Natarajan Pachai , Glanowski Stephen , Lonskaya Irina , Weaver Zoe , Padia Janka , Watthey Jeffrey W. , Cholody Wieslaw M. , Hamilton J. Michael , Bol David K. , Horrigan Stephen K. 
Published: April 2020

Abstract
Multiple Myeloma (MM) is a fatal form of hematologic cancer characterized by the clonal expansion of plasma cells in the bone marrow. Recent finding by several research laboratories have shown that Wnt/β-Catenin signaling pathway is activated in MM leading to the translocation of β-Catenin to the nucleus where it binds to T cell factor (TCF) and drives transcription of genes involved in the progression of cancer (Derksen et. Al., PNAS 2004). The mechanism by which Wnt/β-Catenin signaling is activated in MM is not well understood, however, β-Catenin is expressed in the majority of MM cell lines and inhibition of the pathway with a dominant negative form of TCF4 or the small molecule PKF115-584 have shown anti-proliferative effects in in vitro and in vivo cell line and xenograft models making inhibition of Wnt/β-Catenin signaling a promising modality for the treatment of MM (Sukhdeo et al., PNAS 2007). To this end, Avalon Pharmaceuticals has developed a series of small molecule compounds, lead candidate series-363 (LC-363), with potent inhibitory effects on Wnt/β-Catenin signaling and anti-proliferative effects in colon cancer cell lines and in vivo models (EORTC, 2007). LC-363 compounds down regulate expression of the noted β-Catenin/TCF transcriptional targets c-jun, fra-1, and PPARδ as well as increase expression of the Dickkopf family of secreted proteins 1 and 3 which inhibit Wnt signaling. In this study, we report on the in vitro characteristics of LC-363 in MM cell line models. We show that LC-363 compounds have broad and potent growth inhibitory and cytotoxic effects on MM cell lines. Additionally, these effects are mediated through a G1 phase cell cycle block, apoptosis, and decrease in cytoplasmic levels of β-Catenin. Importantly, we show the relationship between expression level of β-Catenin protein and sensitivity to LC-363 compounds in terms of growth inhibition and apoptosis. Lastly, we describe the gene expression signatures induced by LC-363 in MM cell models across multiple time and dose studies to detail their dynamic effects on expression of genes within the Wnt/β-Catenin signaling pathway. In conclusion, we believe that inhibition of Wnt/β-Catenin signaling is a viable therapeutic alternative for treatment of MM patients with activated Wnt/β-Catenin signaling and to that end; LC-363 compounds are promising candidates currently in pre-clinical development for treatment of cancers with activated Wnt/β-Catenin signaling including MM.
Prospective Identification of Resistance Mutants to the JAK2 Inhibitor TG101348.
Authors: Hood John D. , Alomia Marcela , Cao Jon , Chow Chun , Ehab Hanna , Dan Lohse , Ching Mak Chi , Andy McPherson , Glenn Noronha , Betty Tam , Hong Zhu , Soll Richard 
Published: April 2020

Abstract
Introduction: Clinical resistance to kinase inhibitors is an emerging theme in targeted, oncology therapies. For example, Gleevec resistance results due to a host of mutations in bcr-abl, the kinase associated with chronic myelogenous leukemia (CML), and have necessitated the development of 2nd generation inhibitors dasatinib and notilinib. More recently, mutations in JAK2 kinase have recently been identified as the key molecular drivers for the majority of patients with the chronic MPDs polycythemia vera, essential thrombocythemia and myelofibrosis with myeloid metaplasia. TG101348 is a selective inhibitor of JAK2 kinase and represents a novel therapy for these MPDs.
Methods: In order to better understand what mutations may occur in clinic as a result of TG101348 treatment, we used N-ethyl-N-nitrosourea (ENU)-exposed human erythroleukemia (HEL) cells to evaluate resistance mutations to TG101348. In brief, ENU pretreated HEL cells were exposed to 3 uM TG101348, a dose that is 10X the cellular IC50, for 28 days followed by genotyping to determine the incidence and location of kinase domain mutants that arose in resistant cells.
Results: Eleven different mutations were identified, with the most prevalent mutations in associated with the ATP binding pocket. In cells bearing these mutations TG101348 did not inhibit STAT5 phosphorylation, cellular proliferation or induced apoptosis at concentrations up to 3 uM, whereas in wildtype HEL cells it did. Consistent with the mutations arising specific for TG101348, JAK2 inhibitors which are derived from chemically distinct series were equally potent on wildtype or TG101348 resistant HEL cells.
Conclusions: A series of JAK2 point mutations were identified which generate resistance to the JAK2 inhibitor TG101348 in JAK2V617F-bearing cells. None of these mutations corresponded to any mutations that have been previously reported for MPD patients and therefore the clinical relevance of these mutations is not yet known. While these ENU induced mutations do not yet have clinical correlates, monitoring for their presence in any patients who do not respond to TG101348 in clinical trials may shed light on mechanisms of resistance as they occur.
Active Immunotherapy with Mitumprotimut-T (FavId®, Id-KLH) Following Rituximab Induction in Patients (pts) with Follicular B-Cell Lymphoma (FL): Progression Free Survival (PFS) at 4-Year Follow Up.
Authors: Koc Omer , Redfern Charles , Wiernik Peter , Rosenfelt Fred , Winter Jane , Guthrie Troy , Kaplan Lawrence , Holman Peter , Densmore John , Hainsworth John , Lin Thomas S. , Castillo Rene , Janakiraman Nalini , Bender John 
Published: April 2020

Abstract
Background: We report here PFS with a 4-year follow-up of previously reported results from a Ph 2 trial in which both treatment-naïve (TN) and relapsed/refractory (R/R) pts with FL with stable disease (SD) or a clinical response (PR or CR/CRu) following 4 weekly doses of rituximab received mitumprotimut-T active immunotherapy (Koc et al, Blood, 2006; 108: #691).
Treatment: Pts received rituximab (375 mg/m2 i.v. weekly × 4) and those with stable or responding disease assessed at Week 11 received mitumprotimut-T (1 mg sq monthly × 6) starting on Week 12 along with Leukine® (sargramostim, GM-CSF, 250 mcg, sq) on days 1-4. Pts continued to receive booster injections on a reduced schedule (every 2 months (mos) × 6, then quarterly) until disease progression. Radiological scans were performed every 3 mos for the first 2 years on study, then every 6 mos thereafter and reviewed centrally. Objective response and disease progression were assessed using modified IWG criteria.
Results: 89 pts had ≥SD following rituximab and received mitumprotimut-T + Leukine, 54 R/R and 35 TN. There were 2 CRs and 40 PRs following rituximab for a pre mitumprotimut-T objective response rate (ORR) of 47%. The overall response for the combined treatment was 63% (18 CR, 38 PR). During the mitumprotimut-T treatment phase, 16 pts (9 TN, 7 RR) converted to CR/CRu. The following table presents PFS for all pts and patient subsets.
Conclusion: These data show that 43% of all rituximab responders and 51% of TN rituximab responders remain in remission with 42 mos follow up. These results appear favorable when compared to published results of single-agent rituximab studies in pts with TN FL, where the reported 3-yr PFS are ∼20%, and suggest a clinical benefit to adding mitumprotimut-T to rituximab therapy. This hypothesis is being tested in an ongoing Ph 3 study of rituximab single agent vs. rituximab followed by mitumprotimut-T + GM-CSF. A total of 349 pts have been randomized and 78% are TN. An interim blinded analysis of response in the first 226 randomized pts showed an ORR of 70% with 47% of pts in CR/CRu (Freedman et al, Blood2006; 108:#2756).
Subjects Progression-Free at: Group n 12 mos 24 mos 36 mos 42 mos All Efficacy-Evaluable Subjects 89 61% 38% 31% 29% Relapsed/Refractory Subjects 54 57% 31% 22% 19% Treatment-Naive Subjects 35 67% 48% 44% 44% All rituximab Responders 43 70% 50% 43% 43% Relapsed/Refractory Responders 19 63% 41% 33% 33% Treatment-Naive Responders 24 75% 57% 51% 51%
B Cell Lymphomas Escape Bone Morphogenetic Protein (BMP) Induced Growth Inhibition: Downregulation of BMP Receptors and Upregulation of Inhibitory Smads.
Authors: Huse Kanutte , Bakkebo Maren , Oksvold Morten , Smeland Erlend B. , Myklebust June H. 
Published: April 2020

Abstract
Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily and mediate their effects mainly through the Smad signaling pathway. TGF-β is one of the most potent negative regulators in hematopoietic cells, and many cancers develop reduced sensitivity towards TGF-β induced growth inhibition by several mechanisms, including functional loss of TGF-β receptors and Smad proteins. We have previously shown that BMP-6 inhibits the growth of normal peripheral blood B cells. As high BMP-6 mRNA expression is associated with poor outcome in diffuse large B cell lymphoma (DLBCL; Rosenwald et al, N Engl J Med 2002), we hypothesized that reduced sensitivity towards BMP-induced growth inhibition might contribute to lymphomagenesis. In the current study, 10 B lymphoma cell lines (representing Burkitt, DLBCL and FL) and tumor material from lymphoma patients were investigated to unravel the role of BMPs in lymphomas. We found that 5 – 7 out of 10 lymphoma cell lines were resistant towards BMP-2, -4, -6 and -7 induced growth inhibition. In comparison, only 3 of the cell lines were resistant towards TGF-β. Analysis of BMP receptor expression by FACS analysis showed that all lymphoma cell lines and the malignant B cells from primary lymphoma biopsies expressed the BMPR type I Alk-2, whereas the expression of Alk-3 and Alk-6 was variable. Interestingly, the expression of BMPRII was low or undetectable in BMP-6 resistant cell lines, whereas it was highly expressed in 3 out of 4 sensitive cell lines. Also, malignant B cells from lymphoma biopsies showed reduced levels of BMPRII, suggesting that downregulation of BMPRII is a mechanism for evading BMP induced growth inhibition. Interestingly, upregulation of Smad6 or Smad7 was seen in 3 of the BMP-6 resistant cell lines and might represent another way of escaping the inhibitory effects of BMP. The lymphoma cell lines were investigated for endogenous production of BMPs by real-time RT-PCR, and 2 out of 10 cell lines had detectable BMP-6 mRNA, whereas 7 cell lines expressed BMP-7 mRNA. Analysis of purified malignant B cells or normal tumor infiltrating T cells from patient biopsies, confirmed the expression of BMP-6 and BMP-7 in the malignant B cells. Altogether, the data suggest that escape from BMP induced growth inhibition might contribute to increased tumor growth in B cell lymphomas.
Chemokine Receptor Expression Profile in the Model of Parotid MALT Lymphomagenesis: De Novo Expression of CXCR6.
Authors: Deutsch Alexander J.A. , Aigelsreiter Ariane , Steinbauer Elisabeth , Linkesch Werner , Beham-Schmid Christine , Schaider Helmut , Neumeister Peter 
Published: April 2020

Abstract
Chemokine receptors mediate migration and activation of lymphocytes through binding of their ligands. Several recent studies have revealed important contributions of chemokine receptors and their ligands to the development and progression/dissemination of hematopoietic neoplasms. Strong expression of CXCR5 and its ligand BCA-1 was detected in transformed B cells in H. pylori positive gastric MALT lymphoma. Because the knowledge of chemokine receptor expression in parotid MALT lymphoma is limited, we performed a comprehensive study on tissue samples of parotid glands (P), parotid glands affected by Sjoegren Syndrome (SS), parotid MALT lymphoma (MALT) and extranodal diffuse large B cell lymphoma (eDLBCL). By investigating the expression of all 19 known chemokine receptor at mRNA levels by real time PCR using a semi quantitative approach and of 3 chemokine receptors (CCR1, CCR5 and CXCR6) at protein levels we propose a model of MALT lymphoma that the development from a non neoplastic event to Sjoegren Syndrome or malignant transformation is accompanied by significant deregulations in the chemokine receptor expression profile: in the development of SS CCR5 was 783 times up regulated and CCR6, CCR8 and CCR10 mRNAs were de novo expressed; in the progression process of SS to parotid MALT CCR7, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1 and XCR1 were de novo expressed and CCR10 lost its expression; during the transformation of MALT to eDLBCL, CCR1, CCR8 and CXCR3 were 13 times down regulated and CX3CR1 and XCR1 lost their expression. Expression of CCR1, CCR5 and CXCR6 were confirmed by immunohistochemistry. The present results support a model of a stepwise progression of parotid MALT lymphoma from a non neoplastic event to Sjoegren Syndrome and finally overt MALT lymphoma guided by differentially expressed chemokine receptors and their ligands.
Ocular Adnexal Marginal Zone B Cell Lymphoma Has Characteristic Deletion at Chromosome Band 6q23.3-24.1 Whose Target Is TNFAIP3.
Authors: Honma Keiichiro , Tsuzuki Shinobu , Nakagawa Masao , Karnan Sivasundaram , Kim Won-Seog , Kim Yoon-Duk , Ko Young-Hyeh , Seto Masao 
Published: April 2020

Abstract
Marginal zone B cell lymphoma (MZBCL) occupies a distinct disease entity in WHO classification, and it has been suggested that recurrent chromosomal aberrations, such as t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32) are associated with its lymphomagenesis. However, the frequency of chromosomal alteration in marginal zone B cell lymphomas varies according to the anatomical region, and genetic abnormalities other than recurrent translocations involved in the pathogenesis of MZBCL have not yet been fully identified. In this study, we aimed to investigate genomic aberrations in ocular MZBCL and to compare them with those of tumors from other anatomical sites by using genome-wide array comparative genomic hybridization (CGH). The study population comprised 24 cases of primary ocular MZBCL, 11 of pulmonary MZBCL, and seven of nodal MZBCL. FISH analysis for MALT1 gene alteration was performed for ocular and nodal MZBCL and RT-PCR for the detection of API2-MALT1 transcript was performed for pulmonary MZBCL. The recurrent genomic alterations of ocular MZBCL were losses of chromosomes 6q23.3(9/24, 38%), and gains of 3(9/24, 38%), 15(4/24, 16%), 18q(4/24, 16%). T(11;18)(q21;q21) was not detected. The genomic alteration of pulmonary MZBCL included recurrent loss of 13q34 (2/11, 19%). Fusion transcript of t(11;18)(q21;q21) was detected in five out of eight cases (63%). Nodal MZBCL showed neither recurrent genome alteration nor any change in MALT1 gene copy number. In conclusion of genome-wide array CGH analysis, the array CGH profile of ocular MZBCL is distinct from those of pulmonary and nodal MZBCL. The novel finding was recurrent deletion in the 2.9 Mb region at chromosome band 6q23.3–q24.1 including homozygous loss in ocular adnexal marginal zone B cell lymphoma. These findings suggest that deletion of chromosome band 6q23.3–24.1 may constitute a crucial genetic alteration in the lymphomagenesis of ocular MZBCL. For a further examination, we used contig bacterial artificial chromosome (BAC) array CGH, containing the 24 BAC clone to cover the 2.9 Mb region, to analyze nine cases with chromosome band 6q23.3–q24.1 loss. We narrowed the minimal common region down to a length of 586 kb with two genes and four expressed sequence tags (ESTs). All of these genes and ESTs were subjected to RT-PCR and real-time quantitative RT-PCR, and correlation between genomic loss and expression level was found only in TNFAIP3. We thus concluded that the TNFAIP3 gene is the candidate gene for this deleted region. TNFAIP3 is an inhibitor of NF-kB signaling so that loss of this gene may result constitutive activation of NF-kB which was also implicated in MALT lymphomas with t(11;18)(q21;q21) or t(14;18)(q32;q21). Thus, TNFAIP3 may act as a tumor suppressor gene in ocular adnexal marginal zone B cell lymphoma.
Decreased Hepcidin Level in Iron Deficiency Anemia after Successful Helicobacter pylori Eradication Therapy: A Preliminary Data.
Authors: Cho Yo-Han , Lee Sun-Young , Song Eun Young , Yun Yeo Min , Yoon So Young , Lee Mark H. 
Published: April 2020

Abstract
Background/Aim: Hepcidin, a hepatic antimicrobial protein, is usually over-expressed in iron deficiency anemia. However, whether gastric Helicobacter pylori (H. pylori) infection effects a change in hepcidin level in iron deficiency anemia is still uncertain. We evaluated whether H. pylori eradication decreased hepcidin level and increased hemoglobin and ferritin levels in iron deficiency anemia.
Method: From October 2006 to April 2007, nine females (mean age of 32.2 year-old) who were diagnosed as iron deficiency anemia without definite blood loss, were included in the study. All the subjects underwent upper gastrointestinal endoscopy and colonoscopy to diagnose gastric H. pylori infection and to exclude any source of gastrointestinal bleeding. Blood samplings for hemoglobin, hematocrit, iron (Fe), total iron binding capacity (TIBC), ferritin and hepcidin tests were taken just before H. pylori eradication and four weeks after H. pylori eradication and oral iron supplement therapy, respectively. Serum prohepcidin level was measured by Hepcidin Prohormone ELISA (Solid Phase Enzyme-Linked Immunosorbent Assay) kits. Statistical analysis was done by Wilcoxon signed rank test.
Result: H. pylori eradication was successful in all the subjects who revealed negative in urea breath test. Hemoglobin, hematocrit, Fe, TIBC and ferritin levels improved in all the subjects after H. pylori eradication (Table 1). Mean serum hepcidin level was 224.8 ± 23.2 ng/ml initially, but decreased to 179.7 ± 40.8 ng/ml after H. pylori eradication therapy (p = 0.015).
Conclusion: Our result provides evidence that hepcidin level decreases after successful H. pylori eradication with the improvement of iron deficiency anemia. A fall in serum hepcidin level resulting from successful H. pylori eradication reflects that hepcidin is an important mediator of iron absorption in iron deficiency anemia associated with gastric H. pylori infection.
Table 1. Results of blood tests before and after Helicobacter pylori eradication Before H. pylori eradication After H. pylori eradication p-value* *Wicoxon signed ranks test Fe, iron; TIBC, total iron binding capacity Hemoglobin (g/dl, mean ± SD) 7.67 ± 2.01 10.76 ± 2.43 0.008 Hematocrit (%, mean ± SD) 26.36 ± 5.76 34.26 ± 5.76 0.008 Fe (ug/dl, mean ± SD) 11.78 ± 4.21 45.00 ± 54.39 0.038 TIBC (ug/dl, mean ± SD) 480.78 ± 51.39 427.00 ± 66.30 0.008 Ferritin (ng/ml, mean ± SD) 2.67 ± 0.99 7.39 ± 6.38 0.021 Hepcidin (ng/ml, mean ± SD) 224.80 ± 23.23 179.70 ± 40.84 0.015
Erythropoietin Therapy Does Not Benefit Transfusion-Dependent Primary Myelofibrosis Patients and Treatment Response Is Infrequent with a Baseline Hemoglobin Level ≥ 10 g/dL.
Authors: Huang Jocelin , Lasho Terra L. , Li Chin Yang , Pardanani Animesh D. , Mesa Ruben A. , Tefferi Ayalew 
Published: April 2020

Abstract
BACKGROUND: The potential risks of tumor growth promotion and thromboembolism associated with erythropoietin (Epo) therapy warrant cautious use of erythropoiesis stimulating agents (ESA). Recent data suggest a surprising and significant association between ESA use and increased incidence of leukemic transformation in primary myelofibrosis (PMF) (data from an analysis separately submitted for American Society of Hematology meeting, 2007). It is prudent, therefore, to avoid unnecessary ESA exposure in PMF, especially in patients with low likelihood of treatment response.
METHODS: Diagnosis of PMF was based on World Health Organization criteria. Study inclusion required availability of treatment history with ESA and adequate follow-up. We excluded patients who were receiving hemoglobin-improving agents concomitantly with an ESA, such as prednisone, androgens, danazol, or thalidomide. Transfusion dependency was defined by a history of minimum 2 units of red blood cell transfusions in a 1-month period for a hemoglobin &lt; 8.5 g/dL, not associated with bleeding. An adequate treatment response was defined as a minimum 2.0 g/dL increase in hemoglobin level or becoming transfusion-independent over a minimum 1-month period.
RESULTS: A master database of PMF patients seen at the Mayo Clinic from 1976 through 2006 was queried to identify 43 patients (median age 67 years; 35% females) treated with ESAs and in whom adequate follow-up was available to determine response. Prior to ESA treatment, median hemoglobin was 9.2 g/dL (range 7.0–11.9), and 16 (37%) were red blood cell transfusion-dependent. In 25 patients, pre-treatment serum Epo level was available (median 34 mU/mL; range 2–323). Among the 43 study patients, 16 (37%) were previously treated with other PMF-specific therapies, and 18 (42%) were receiving cytoreductive treatment concurrent with an ESA. Overall, 23% of patients (10 of 43) responded to treatment with ESA. The response rate was 0% (0 of 16) in the transfusion-dependent group compared to 37% (10 of 27) in the transfusion-independent group (p=0.007). Among the transfusion-independent patients, the proportion of ESA responders was significantly higher in the presence of a baseline hemoglobin level &lt; 10 g/dL prior to treatment (p=0.009). ESA response was not correlated with baseline serum Epo level in the context of either all 43 study patients (p=0.68) or the 27 transfusion-independent patients (p=0.39). ESA response was not affected by PMF-specific treatment history (p=0.46), use of concurrent cytoreductive therapy (p=0.28), cytogenetic findings (p=0.62), JAK2V617F presence (p=0.69) or its allele burden at time of initial PMF diagnosis (p=0.16).
CONCLUSIONS: Clear benefit of ESAs in PMF is limited to red blood cell transfusion-independent patients and those with baseline hemoglobin levels less than 10 g/dL.