bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thalidomide in Combination with Rituximab Is Active in Waldenström’s Macroglobulinemia and May Overcome Poor Response Determinants Associated with Rituximab Monotherapy.
Authors: Treon Steven P. , Hunter Zachary , Patterson Christopher J. , Branagan Andrew R. 
Published: October 2019

Abstract
INTRODUCTION: Rituximab is active in Waldenstrom’s macroglobulinemia (WM), producing major (CR + PR) response rates of 40–50% using an extended dose schedule. Lower response rates though are observed among patients with the FcgRIIIA-158 F/F polymorphism (JCO 23:474) and higher serum IgM levels (&gt;6,000 mg/dL) (Ann Oncol 16:132). Thalidomide enhances rituximab mediated ADCC killing of lymphoplasmacytic cells and produces response rates of 25% in WM. As such, we conducted this phase II study using combination thalidomide and rituximab in patients naïve to either agent.
METHODS: Intended therapy was as follows: Weeks 1–52 Thalidomide (200 mg po qHS for 2 weeks, then 400 mg po qHS);Weeks 2–5, 13–16 Rituximab (375 mg/m2/week). Twenty-five patients were enrolled, 20 of who were previously untreated, with a baseline median age of 62 (range 44–86 yrs), BM involvement of 40 (range 5–90%), serum IgM of 3670 (range 924–8610 mg/dL), B2M of 2.6 (range 1.4–7.8 mg/L), Hct of 33.0 (range 24.5–37.7%).
RESULTS: Grade 3/4 toxicities to thalidomide included paresthesia (n=10); somnolence (n=8); rash (n=7); neuropathic pain (n=6); confusion (n=4); tremors (n=2); and bradycardia (n=2). Dose reduction occurred in all patients and led to premature discontinuation in 11 patients. All evaluable patients received the intended rituximab therapy. Paradoxical IgM spikes following rituximab occurred during both courses of therapy and were observed in 12 patients. Two patients succumbed, unrelated to therapy, and were unevaluable. Responses were as follows: CR (n=1); PR (n=15); MR (n=2); SD (n=1) for an overall and a major response rate of 78% and 70%, respectively, among evaluable patients. Four patients had no response to therapy. With a median follow-up of 19 months, 6 patients have progressed. The median duration of response was 19.6+ months (range 7 to 26+ months) Overall response was associated with median cumulative dosed thalidomide: CR/PR/MR (29,275 mg) vs. SD/NR (7,400 mg); p=0.004. Importantly, overall responses were unaffected by FcgRIIIA-158 polymorphism status (75% vs. 71% for VV/FV vs. FF); serum IgM (83% vs. 80% for &lt;6,000 vs. &gt;6,000 mg/dL); and B2M levels (86% vs. 78% for &lt;3 vs. ≥ 3 g/dL); p=NS. Lastly, following completion of therapy, 15/18 responding patients reported improvements in quality of life.
CONCLUSION: These studies demonstrate that thalidomide in combination with rituximab is highly active in WM, though additional studies are warranted to determine the ideal dose and schedule for thalidomide in view of toxicities. Moreover, thalidomide in combination with rituximab may overcome unfavorable prognostic determinants previously reported with rituximab monotherapy in WM.
Novel Fusion of the MALT1/MLT and MAP4 Genes Detected in a Diffuse Large B-Cell Lymphoma.
Authors: Murga Penas Eva M. , Hinz Kristina , Behrmann Petra , Hansmann Martin L. , Becher Claudia , Siebert Reiner , Dierlamm Judith ,   on Behalf of the Network Project “Molecular Mechanisms of Malignant Lymphomas”
Published: October 2019

Abstract
The MALT1/MLT gene codes for a human paracaspase and plays a crucial role in NF-κB activation in response to TCR induction. Rearrangements of MALT1/MLT by the translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) act by activating the NF-κB pathway and are the most frequent structural chromosomal abnormalities in extranodal marginal zone B-cell lymphomas of the MALT-type. They occur in 20 to 50% of low grade MALT lymphomas, but with only rare exception are absent in diffuse large B-cell lymphomas (DLBCL).
By screening 118 diffuse large B-cell lymphomas and 28 Burkitt’s lymphomas by interphase FISH with probes flanking MALT1/MLT (Abbott Vysis), we found two cases with a break within MALT1/MLT. Further experiments with plasmid subclones from the BAMH1 fragments of PAC 152M5, which spans the entire coding region of MALT1/MLT, confirmed the break within MALT1/MLT in one case. This patient presented with a relapse of a DLBCL, centroblastic subtype, without any concomitant low-grade component or lymphoepithelial lesions. During relapse only nodal manifestations were seen (stage IIIA), however, at the time of primary diagnosis a lymphoma infiltration of one adrenal gland was present. FISH experiments with MALT1/MLT, API2 and IGH specific probes did not identify a t(11;18) or a t(14;18). 3′ RACE-PCR revealed a novel in frame fusion of exon 9 of the MALT1/MLT gene and exon 9 of the microtubule-associated protein 4 (MAP4) gene. RT-PCR with specific primers for MALT1/MLT and MAP4 confirmed the presence of the fusion transcript MALT1/MLT-MAP4. In addition, interphase FISH showed that the translocation was accompanied by a deletion of MALT1/MLT sequences distal to the breakpoint including the caspase-like domain, which is essential for activation of the NF-κB pathway in MALT lymphomas. Corresponding to this result, 5′ RACE-PCR with specific primers for MALT1/MLT and RT-PCR with nested primers for MAP4 and MALT1/MLT did not detect the reciprocal 5′MAP4-3′MALT1/MLT transcript. The MAP4 gene on chromosome 3p21 is the major microtubule-associated protein in non-neuronal tissues and promotes microtubule polymerization. Disruption of the microtubule-dynamics is induced by microtubule-interfering drugs, such as taxanes and Vinca alkaloids.
We conclude that the 5′MALT1/MLT-3′MAP4 fusion is the pathogenetically relevant transcript in this non-reciprocal der(18)t(3;18)(p21;q21) translocation. The absence of the caspase like domain distinguishes this novel gene fusion, MALT1/MLT-MAP4, from the API2-MALT1/MLT in the t(11;18) and the IGH-MALT1/MLT in the t(14;18), in which the caspase like domain is invariably present and points to MAP4 as a new target gene with possible therapeutic implications in DLBCL.
RNAi Silencing of TEL-AML1 Reveals a Heat Shock Protein Dependent Mechanism in the Development of Leukemia.
Authors: Diakos Christofer , Gerner Christopher , Inthal Andrea , Gadner Helmut , Panzer-Grümayer Renate 
Published: October 2019

Abstract
The t(12;21) chromosomal translocation generating the TEL-AML1 fusion product is the most frequent genetic aberration of childhood acute lymphoblastic leukemia. This translocation has been shown to occur in utero and thus represents an early or even initiating event in leukemia development. However, additional molecular changes are necessary for the clinical manifestation of the disease. Despite increasing knowledge on TEL and AML1, the role of the TEL-AML1 fusion gene and its contribution to the malignant transformation is largely unknown. In particular, the mechanisms by which TEL-AML1 influences the biology of the affected cell, and thus survival and expansion, are yet to be defined. The aim of this study was to investigate the functional contribution of TEL-AML1 to the leukemic cell phenotype. We particularly sought to search for TEL-AML1 dependent genes as well as for pathways that function in a fusion gene dependent manner. The t(12;21) positive B cell precursor leukemia cell line REH was used as model system and RNA interference technology, a new and highly specific approach, was employed to block the expression of the TEL-AML1 fusion gene. The successful silencing of TEL-AML1 was demonstrated by Western blot analysis. In order to gain a broad overview of the impact of TEL-AML1 silencing upon the leukemic cell, RNA was isolated and subjected to Affymetrix gene chip analysis. In addition, we studied the proteome by high-resolution 2D electrophoresis. Expression profiling resulted in a specific pattern of differentially regulated genes after TEL-AML1 suppression with a particular emphasis on genes involved in the control of apoptosis. Genes with anti-apoptotic properties were down regulated after TEL-AML1 silencing while those that contribute to apoptosis were largely unaffected. Among the affected anti-apoptotic genes were the heat shock proteins, the most prominent representatives of which were HSP90 and HSP70. Their changes were observed at the mRNA but also at the protein level. This is of special interest, since both heat shock proteins interfere with the intrinsic as well as the extrinsic pathway of apoptosis and hence provide a powerful anti-apoptotic signal. These first data support a model in which TEL-AML1, as an early event, is functionally linked to an anti-apoptotic network and especially to the members of the heat shock protein family. Engagement of these mechanisms might rescue a cell from apoptosis and in consequence give rise to the development of a pre-leukemic clone, a reservoir for the acquisition of further mutations that might eventually give rise to leukemia. Thus, decreasing the apoptosis defence by silencing TEL-AML1 or by inhibiting the heat shock proteins might sensitize TEL-AML1 positive cells to apoptosis. This would not only be an option for future therapy of leukemias but also for the eradication of the pre-leukemic clone as a proposed source of relapse.
Immune-Mediated Protection Against BCR/ABL-Induced Leukemia: A Common Pathway Shared between IRF8/ICSBP and IFN alpha and beta.
Authors: Nardi Valentina , Mohammed Azam , Daley George Q. 
Published: October 2019

Abstract
Most Chronic Myeloid Leukemia (CML) patients are treated with the targeted agent imatinib (Gleevec), but cytogenetic remission is rarely achieved and the only cure remains bone marrow transplantation. The mainstay of therapy prior to imatinib was interferon (IFN) alpha, which induces cytogenic remission in a minority of patients. Because clinical response to IFN alpha correlates with immune system reactivity against leukemic clones, immunotherapy may be an important adjunct to imatinib. ICSBP (Interferon Consensus Sequence Binding Protein) is a tumor suppressor of CML. Ectopic expression of ICSBP in Bcr-Abl transformed cells prevents the formation of a lethal leukemia, and we have shown that this anti-leukemic effect is mediated by a long-lasting and potent CD8+ response against unknown epitopes on the leukemic cells. We have begun to characterize the immune response against CML induced by ICSBP and to understand its relationship to the anti-leukemic effects of IFN alpha. IFN alpha and IFN beta can substitute for ICSBP expression in inducing potent anti-leukemic immunity against BCR-ABL transformed cells. We could find little evidence for the direct regulation of the IFN genes by ICSBP; thus we have favored the alternative hypothesis that ICSBP and IFNs alpha and beta activate a common pathway that ultimately triggers an immune-mediated anti-leukemic response. To test this hypothesis, we compared the transcriptional profiles of BaF3 cells to those overexpressing Bcr-Abl, ICSBP, or both (unpublished data). Our data confirm the reported effects of ICSBP on genes that regulate proliferation and apoptosis in cells overexpressing Bcr-Abl (e.g. cyclin D2). In addition, our analysis revealed an interesting new mechanism through which ICSBP may stimulate an anti-leukemic immune response and Bcr-Abl expressing cells may escape immune detection. IFN alpha and beta appear to share the mechanism induced by ICSBP. Our data confirm the differential expression of several known (e.g. Proteinase 3) as well as new potential protein epitopes of the anti-leukemic immune response induced by ICSBP and the IFNs. Our in vivo experiments should shed further light on the role of the immune regulatory genes we have identified in the immune response to CML.
c-MYC Is a Major Downstream Target of NOTCH in T-Cell Acute Lymphoblastic Leukemia.
Authors: Lau Arthur , Aster Jon C. , Weng Andrew P. 
Published: October 2019

Abstract
We recently reported that activating mutations in the NOTCH1 receptor occur in a high percentage of primary human T-cell acute lymphoblastic leukemias (T-ALL). Withdrawal of NOTCH signals by treatment with γ-secretase inhibitors (GSI) or by transduction with a dominant-negative Mastermind-like-1 polypeptide (a specific NOTCH pathway inhibitor) induces growth arrest of many T-ALL cell lines, suggesting that NOTCH supplies signals that are needed for maintenance of growth of T-ALL cells. In order to identify downstream targets of NOTCH that mediate these effects, we performed gene expression profiling on NOTCH signaling-dependent T-ALL cell lines before and after NOTCH inhibition. Among a number of identified candidate genes was c-MYC, which was of particular interest given its importance in promoting cellular growth and its known dysregulation in a number of hematolymphoid neoplasms. c-MYC was down-regulated following NOTCH inhibition, and rapidly up-regulated following release of NOTCH inhibition, even in the presence of protein synthesis inhibitors, suggesting that it is a direct NOTCH transcriptional target. Further, a subset of murine and human T-ALL cell lines were rescued from GSI-mediated growth arrest by c-MYC-expressing retroviruses. The failure of c-MYC to rescue some NOTCH-dependent cell lines likely stems from differences in cellular context, such as collaborating oncogenic lesions and/or the stage of T cell development the cell lines recapitulate. Nevertheless, these data implicate c-MYC as a major downstream target of NOTCH in T-ALL.
Adenovirus Capsid Hexon Is the Main Target Protein of Adenovirus-Specific CD4+ T-Cells: Fundamentals for Targeting Adenovirus by Adoptive Immunotherapy.
Authors: Arbach Olga , Frentsch Marco , Voigt Sebastian , Chmielewicz Barbara , Kaiser Marco , Ellerbrok Heins , Lauster Roland , Radbruch Andreas , Scheffold Alexander , Ebell Wolfram , Thiel Andreas 
Published: October 2019

Abstract
Introduction: Increasing evidence has emerged that adenoviruses (AdV) can cause severe complications in immunocompromised hosts especially following hematopoietic stem cell transplantation (HSCT). So far protective immune responses in adenovirus infection have not been assessed in detail, but control of infection seems to be dependent on CD4+ T-cells. However, the main antigenic adenovirus targets for specific CD4+ T-cells are unknown.
Methods: We here use a novel technique to directly assess the entire repertoire of CD4+ T-cells specific for a defined antigen according to antigen-induced CD154 expression after short-term ex vivo stimulation. AdV-lysate-specific and AdV-hexon-specific CD4+ T-cells were isolated, expanded in vitro and further assessed for their fine specificities using recombinant AdV-proteins and AdV-lysates from various AdV-serogroups. Additionally, we evaluated the cytokine profile of AdV-lysate- and AdV-hexon-specific CD4+ T-cells.
Results: AdV-lysate-specific CD4+ T-cells reacted efficiently with AdV-hexon and penton proteins. Furthermore, CD4+ T-cells specific for hexon protein derived from AdV-serogroup B crossreact with recombinant hexon protein derived from various other AdV-serotypes and are characterized by a Th1-like cytokine profile.
Conclusion: Our results imply that adenovirus hexon protein is a suitable candidate antigen for the ex vivo generation of adenovirus-specific, serogroup cross-reactive proinflammatory CD4+ T-cells for adoptive T-cell therapies.
Study on Methylation of p15INK4B Gene and Its Mechanisms in Patients with Myelodysplastic Syndrome and Leukemia.
Authors: Tong Hongyan , Ling Maofang , Jin Jie 
Published: October 2019

Abstract
The expression and methylation of p15INK4B gene and the expression of DNA methyltransferase genes (DNMTs) in the mononuclear cells (MNCs) from bone marrow of 54 cases with hematopoietic malignances were detected by using RT-PCR, Western blot, and methylation-specific PCR. Of the 54 patients, 10 cases were low-risk MDS, 10 cases were high-risk MDS, 10 cases were acute myeloid leukemia (AML), 10 cases were acute lymphocytic leukemia (ALL), 10 cases were chronic myeloid leukemia in chronic phase (CML-CP), and 4 cases were CML in blast phase (CML-BP). 10 normal persons were studied as nective controls. The results showed that the incidence of p15INK4B methylation in cells of high-risk MDS was higher than that in low-risk MDS (6/10 VS 1/10, P=0.003), and the p15INK4B methylation was found to be associated with the down-regulation of the expressions of p15INK4B gene on both mRNA (r=−0.734, p<0.001) and protein (r=−0.664, p=0.001)levels, which indicated that the silencing of p15INK4B gene was in conjunction with hypermethylation in MDS. The expressions of p15INK4B on mRNA level and protein levels were almost detected in the MNCs from bone marrow of normal persons without the p15INK4B methylation. We also found the expression of DNMT3A and DNMT3B in high-risk MDS (densitometry readings respectively: 0.624±0.146, 0.577±0.344) were higher than in low-risk MDS (densitometry readings respectively: 0.487±0.300, 0.338±0.290) (P<0.05). The expression of DNMT1 was higher in the groups of low-risk MDS, high-risk MDS, AL and CML-CP( densitometry readings respectively: 0.487±0.218, 0.697±0.243, 0.706±0.463 and 0.867±0.375) than in normal control (densitometry reading: 0.181±0.312)(P<0.05, figure listed bellow), which indicated that up-regulated DNMTS might contribute to the hypermethylation of p15INK4B, and the higher expressions of de novo methyltransferases DNMT3A and DNMT3B may be related to the disease progression of MDS. The methylation of p15INK4B was also detected in 9/20 of AL cases accompanied by over-expressions of DNMT1, DNMT3A, and DNMT3B (densitometry readings respectively: 0.706±0.463, 1.066±0.547, and 0.530±0.428). The methylation of p15INK4B was detected in 1 of 10 cases of CML-CP patients, but all be detected in 4 case of CML-BP patients. These results indicated that the hypermethylation of p15INK4B gene may be one of the most common genetic event in pathogenesis of high-risk MDS, acute leukemia, and blast phase of CML. Furthermore, DNMT3A and DNMT3B were substantially over-expressed in the bone marrow cells of these patients. which might play an important role in the transformation from MDS to acute leukemia.
Figure Figure
Creation of a Ribosomal Protein Sa/LAMR1 Heterozygous Mouse.
Authors: Ellis Steven R. , Logsdon Paula M. , Han Junying 
Published: October 2019

Abstract
Diamond Blackfan anemia (DBA) is a severe hypoplastic anemia that generally presents early in infancy. Approximately 25% of DBA cases have been linked to mutations in the gene encoding ribosomal protein S19. The remaining cases are of unknown etiology. Our studies in yeast have identified a specific role for Rps19 in the maturation of 40S ribosomal subunits. While only one other small subunit ribosomal protein, Rps18, has a function virtually identical to Rps19 in subunit maturation, several others have functions closely related to Rps19. If the involvement of Rps19 in DBA is linked to its role in the synthesis of 40S ribosomal subunits, we would expect that one or more of these other ribosomal proteins may be responsible for DBA in patients with normal RPS19. To address a potential role for ribosomal proteins other than Rps19 in DBA we have created a transgenic mouse heterozygous at the LAMR1 locus. LAMR1 encodes ribosomal protein Sa, the mammalian homolog of the yeast ribosomal protein S0. Rps0, like Rps19, is required for the maturation of the 3′ end of 18S rRNA. We are currently in the fourth generation of out-crossing the original 129SvEv/C57BL6J chimeras to a C57BL6 background. The frequency of heterozygous pups is about that expected by Mendelian segregation suggesting that haploinsufficiency for ribosomal protein Sa does not lead to significant embryonic lethality. The heterozygous mice do, however, exhibit a higher frequency of craniofacial abnormalities and premature deaths relative to their wild-type littermates. The overall fitness of the heterozygous mice appears to be decreasing with each generation of outcrossing to the C57/BL6 background. Efforts are underway to understand the nature of the premature deaths and to obtain detailed hematological profiles on the LAMR1 heterozygous mice.
The Molecular Signature of Iron Metabolism in Polycythaemia Mice.
Authors: Schumacher Armin , Mok Henry , Mlodnicka Agnieszka E. , Hentze Matthias W. , Muckenthaler Martina 
Published: October 2019

Abstract
Recent positional cloning of the radiation-induced polycythaemia (Pcm) mutation revealed a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), the sole cellular iron exporter identified to date. The microdeletion causes aberrant transcription initiation and results in the absence of the iron-responsive element in the 5′ untranslated region of the vast majority of Fpn1 transcripts, thereby disrupting translational regulation of Fpn1 expression. Pcm mutant mice exhibit the gamut of iron balance disorders, ranging from iron deficiency at birth to tissue iron overload by young adulthood. Consistent with the perinatal iron deficiency, Pcm pups display a microcytic, hypochromic anemia. Strikingly, the majority of young adult Pcm heterozygous animals display a transient erythropoietin (Epo)-dependent polycythemia with peak hematocrits of up to 80%, eponymous of the mutant strain. Here we report a molecular definition of the regulatory mechanisms governing the dynamic changes in iron balance in Pcm heterozygous mice between 3 and 12 weeks of age. Therein, hepatic and/or duodenal response patterns of iron transporters, such as Trfr, cybrd1 and Slc11a2, defined the transition from early postnatal iron deficiency to iron overload by 12 weeks of age. A significant delay in developmental upregulation of hepcidin (Hamp), the pivotal hormonal regulator of iron homeostasis, correlated with high levels of Fpn1 expression in hepatic Kupffer cells during postnatal development. Conversely, upon upregulation of Hamp expression at 12 weeks of age, Fpn1 expression decreased, indicative of a Hamp-mediated homeostatic loop. Aged cohorts of Pcm mice exhibited low levels of Fpn1 expression in the context of an iron-deficiency erythropoiesis and profound iron sequestration in reticuloendothelial macrophages, duodenum and other tissues. Similar to the anemia of chronic disease, these findings are consistent with decreased iron bioavailability due to sustained downregulation of Fpn1 levels by Hamp. Therefore, iron-deficiency erythropoiesis marks both the beginning and the endpoint of the hematopoietic defects in Pcm mice. However, whereas the embryonic/perinatal anemia results from primary organismal iron deficiency, adult Pcm mice develop anemia due to decreased iron bioavailability despite organismal iron overload. The polycythemia develops at the transition phase between the two disease states, governed by unimpeded Epo signaling. We conclude that regulatory alleles, such as Pcm, with highly dynamic changes in iron balance are ideally suited to interrogate the genetic circuitry regulating iron metabolism.