bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non Hodgkin Lymphomas Showing Microsatellite Instability (MSI-H NHL) Are Characterized by Both Specific Biological and Clinical Features.
Authors: Borie Claire , Raphael Martine , Buhard Olivier , Duval Alex 
Published: April 2020

Abstract
Cancers showing microsatellite instability (MSI-H) constitute a frequent subset of human tumors characterized by mismatch repair (MMR) deficiency. This phenotype is well known to occur in the Human Non Polyposis Colorectal Cancer (HNPCC) syndrome, as well as in about 10–15% of sporadic colorectal, gastric and endometrial cancers. Of interest, we recently demonstrated that it was also strikingly associated with a subset of Non Hodgkin Lymphomas (NHL) developed in either HIV positive (HIV-RL, e.g. HIV-related Lymphomas) or iatrogenically immunosuppressed (PTLD, e.g. Post-Transplantation Lymphoprolipherative Disorders) patients. We here further characterize this new subset of immunodeficiency-related lymphomas (ID-RL) at both the biological and clinical levels. By using specific markers of the MSI-H phenotype, we extended our molecular screening to a series of 161 NHL developed in either immunocompetent (n = 136) or immunodeficient (n =25, including 4 HIV-RL and 21 PTLD) hosts. Clinically, MSI-H NHL were found to be:
mostly PTLD (12/114, e.g 10%), and more rarely HIV-RL (4/131, e.g. 3%) (p = 0;05; fisher’s exact test): mostly T-cell NHL (4/17, e.g. 24% of T-cell ID-RL, as compared to 10/224, e.g 4% of B-cell ID-RL); late occurring PTLD after organ transplantation associated or not with EBV (52% EBV negative and 48% EBV positive).
Biologically, MSI-H NHL presented with:
primary MMR defects involving MLH1, MSH2 or MSH6; secondary mutational events at target genes for instability, as already reported (RAD-50, BAX, CASP-5 and others…); frequent V599E activating mutation within the BRAF gene (3/9, e.g. 30%); stable cytogenetic profiles characterized by only few chromosomal rearrangements if any.
Taken together, these data show that oncogenic mechanisms involved in MSI-H NHL differ from those already known to be associated with other ID-RL, e.g. Chromosomal Instability or EBV-related pathways, and that they should now be considered as a distinct tumor entity.
Down-Regulation of Bax and Bak in Immuno-Chemotherapy Resistant Non-Hodgkin’s Lymphoma Cells.
Authors: Olejniczak Scott H. , Clements James L. , Bangia Naveen , Hernandez-Ilizaliturri Francisco J. , Czuczman Myron S. 
Published: April 2020

Abstract
The balance between pro-apoptotic (Bax, Bak) and anti-apoptotic (Bcl-2, Bcl-xL, Mcl-1) Bcl-2 family proteins is essential for the maintenance of B-cell homeostasis. Disruption of this critical balance occurs in the majority of B-cell neoplasms. Clinically, high Bcl-2/Bak and Bcl-2/Bax ratios have been associated with decreased median survival (7.3 years and 3.8 years, respectively) in follicular lymphoma patients1. Recent work in mouse embryonic fibroblasts deficient for the multi-domain pro-apoptotic Bcl-2 family proteins Bax and Bak has shown that they are essential for induction of cell death following apoptotic stimuli that act through the mitochondrial (intrinsic) pathway2. The vast majority of clinically available anti-neoplastic agents, including rituximab, are known to induce cell death via this pathway and therefore likely rely on Bax and/or Bak to exert their anti-tumor effects. Alteration in expression of Bax and/or Bak could therefore underlie acquired resistance to rituximab and chemotherapy in NHL patients. To study the phenomenon of rituximab resistance we developed several rituximab-resistant cell lines (RRCL) that we subsequently showed were also resistant to chemotherapy. RRCL were generated by exposing Raji, SU-DHL-4 and RL cells to escalating doses of rituximab +/− human serum and subsequently cloning by limited dilution. In our present work we studied the efficacy of clinically-applicable chemotherapeutic agents against RRCL. Additionally we studied the intrinsic apoptotic pathway in an attempt to explain shared mechanisms of resistance to chemotherapy and rituximab. We found that RRCL have dramatically reduced levels of both Bax and Bak proteins by Western blot while levels of Bcl-2, Bcl-xL and Mcl-1 protein were comparable to parental cells. Transfection of RRCL with Bax or Bak sensitized them to apoptotic cell death. Currently, we are attempting to validate previous studies that have shown that down-regulation of Bax and/or Bak correlates with a poor prognosis in NHL. Additionally, we are exploring the mechanism(s) by which Bax and Bak are down-regulated in RRCL and primary patient samples.
FOXP3 Expression in Diverse T-Cell Lymphomas.
Authors: Beltrán-Gárate Brady E. , Quiñones Pilar , Morales Domingo , Huamani-Zavala Julia , Mejía Osbert , Vidurrizaga Miriam , Malaga Jose , Castillo-Aguirre Jorge , Riva Luis , de Mendoza Fernando Hurtado , Carrasco-Yalan Antonio A. 
Published: April 2020

Abstract
BACKGROUND: Foxp3 is a key regulatory gene required for the development and function of:
regulatory CD4+CD25high T cells (Treg) specialized in maintaining the balance between immunity and tolerance and activated conventional CD4+CD25low T cells without suppressive activity.
Until now it is not yet possible to study human FOXP3+ Treg irrespective of their CD25 expression. Previous studies had reported FOXP3+ T cells in Adult T-cell Leukemia/Lymphoma cells (ATLL) related to HTLV-1 and in other lymphomas types the FOXP3 expression was only detected in the reactive T-cell background.
AIM: To determine the specifity and prognostic value of the FOXP3 expression in T-cell lymphomas.
METHODS: A retrospective study was performed on 46 samples collected from diverse T-cell lymphomas in our institution. A highly sensitive immunohistochemical method was used to demonstrate FOXP3 protein expression with a mouse monoclonal antibody (clone 236A/E7ABCAM) in most formalin-fixed paraffin-embedded tissue sections from lymph nodes, skin, bone marrow and extranodal sites samples as cavum and stomach. We did not co-stained with CD25 and considered a FOXP3+ tissue when positivity was &gt; 80% of toumor cells. Correlation with survival was done.
RESULTS: Among the 46 evaluable T-cell lymphomas collected, 33 were ATLL, 7 mycosis fungoids (MF) and 6 unspecified peripheral T-cell lymphomas (U-PTCL). Among the 33 ATLL: lymphomatous=17, acute=11, smoldering=1, chronic=1, cutaneous=1 and undefined=2. FOXP3 expression in tumour cells was detected in 24% (8/33) of ATLL cases, was negative in MF tumour cells and detected in 33% (2/6) of U-PTCL. Interestingly FOXP3 expression between 30–40% was expressed in 3 MF cases associated to Treg cells. Among the ATLL cases FOXP3 positivity were obtained in 35% (6/17) of lymphomatous type; 18% (2/11) of acute ones and none in others ATLL types studied. We failed to demonstrated any correlation between FOXP3 status and survival.
CONCLUSIONS: FOXP3 is expressed in ATLL and T-cells peripheral lymphoma. Treg presence in the tumour environment plays an important immune system response role and its identification should be fundamental.
Hemin Confers Resistance to Imatinib (Glivec)-Induced Cell Death but Enhances Nilotinib (AMN107) Cytotoxicity in Human K-562 CML Leukemia Cells.
Authors: Bonovolias Ioannis D. , Manley Paul W. , Tsiftsoglou Asterios S. 
Published: April 2020

Abstract
Imatinib (Glivec) and Nilotinib (AMN107) are selective inhibitors of the Bcr-Abl, Kit and PDGFR tyrosine kinases, developed by Novartis Pharma AG to treat CML and other malignancies by promoting apoptosis (Manley P.W., et al. Biochim Biophys Acta 1754(1–2):3–13, 2005). Heme (iron protoporphyrin-IX) and its oxidized form Hemin, are key regulators of key cellular functions in mammalian cells and Hemin protects normal and leukemia cells from cytotoxic agents (Tsiftsoglou A.S. et al., Pharmacology & Therapeutics 111(2):327–345, 2006). We have recently observed that Hemin, like Erythropoietin (EPO), protects human Ph+ K-562 CML leukemia cells from Imatinib-induced cell death. We extended this observation and investigated whether Hemin also counteracts Nilotinib-induced cytotoxicity in cells. K-562 CML leukemia cells were treated (from 0h to 96h) separately with each of the inhibitors added at different concentrations (0.01 μM to 1 μM) in the presence and absence of Hemin (90 μM) and assessed for their ability to proliferate, differentiate into erythroid lineage or undergo cell death. K-562 cells pre-treated with Hemin prior to be being exposed to Imatinib and/or Nilotinib were used to demonstrate whether induction of differentiation by Hemin alters their developmental stage and susceptibility to either inhibitor. Our results thus indicate that:
Hemin confers resistance to Imatinib in a substantial proportion of cells (20–30%). Priming cells with Hemin gradually decreased susceptibility to Imatinib-induced cell death. Considering that the intracellular Heme in CML cells may overcome the Imatinib effect, this resistance could affect the clinical outcome of CML patients treated with Imatinib. Conversely, Hemin enhanced cell death induced by Nilotinib in the concentration range 0.01 μM to 1 μM.
These findings indicate that Imatinib and Nilotinib induce cell death in K-562 CML leukemia cells, via pathways affected differently by Hemin. Experiments are now in progress to delineate the mechanisms via which Hemin exerts such disparate action (antagonistic and synergistic) on these inhibitors in human leukemias.
Imatinib High Dose (800 mg): Results of a Phase II Trial of the GIMEMA (Gruppo Italiano Malattie Ematologiche Dell’Adulto) CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.
Authors: Rosti Gianantonio , Castagnetti Fausto , Amabile Marilina , Testoni Nicoletta , Poerio Angela , Marzocchi Giulia , Breccia Massimo , Palandri Francesca , Intermesoli Tamara , Stagno Fabio , Specchia Giorgina , Abruzzese Elisabetta , Giannoulia Panagiota , Saglio Giuseppe , Pane Fabrizio , Rancati Francesca , Nagler Arnon , Haznedaroglu Ibrahim , PorkKa Kimmo , Hjorth-Hansen Henrik , Nielsen Johan L. , Simonsson Bengt , Martinelli Giovanni , Baccarani Michele 
Published: April 2020

Abstract
Imatinib has become the treatment of choice for CML. The standard dose (SD) for CP CML is 400 mg daily: results are less favourable in pts at high or intermediate Sokal risk vs low Sokal risk ones. In intermediate Sokal risk, the IRIS trial (Hughes et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response (MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses (HD - 800 mg daily) of ima may be more effective. The GIMEMA CML Working party is conducting a phase II, multi-istitutional prospective study (serial n. CML/021) to investigate the effects of imatinib HD in intermediate Sokal risk. Between Jan, 2004 and May, 2005, 25 centers enrolled 82 pts (80 eval); median age 56 yrs (26–79). Pts evaluable at 3,6 and 12 mos are 80, 77 and 65, respectively. The median observation time is 12 mos. At 3 and 6 mos, 83% and 97% of the pts reached a stable CHR. At 6 mos, 86% obtained a CCgR and 53% of CCgR pts a MMolR (Bcr-Abl/Abl × 100 ratio &lt; 0.1%). At 12 mos, the CCgR rate was 90% and the MMolR rate was 57%. One patient progressed to accelerated/blastic phase. The compliance to HD treatment was good: at 3, 6 and 12 mos 55%, 52% and 52% of the pts received a median daily dose of imatinib &gt; 600 mg. Non hematopoietic AEs accounted for the great majority of dose reductions. The results of this trial further indicate that imatinib HD induces higher and more rapid responses in intermediate Sokal risk CML pts in early chronic phase, being superior to the results obtained with SD (IRIS) and in the range of the MD Anderson results (Kantarjian et al Blood 2004 103:2873). A second project is reserved to high Sokal risk CML pts in early CP: a multinational group, within EuropeanLeukemianet CML WP, is conducting a phase III trial (1:1) of imatinib 400 mg vs 800 mg. By July 31, 2005, 141 patients have been enrolled: GIMEMA (88 pts), Nordic CML Study Group (Sweden, Denmark, Norway and Finland) (25 pts), Turkey (25 pts) and Israel (3 pt).
Synergistic Activity of Nilotinib and Established Chemotherapeutic Agents in Imatinib-Sensitive and -Resistant BCR-ABL-Positive Leukemia Cells.
Authors: Radujkovic Aleksandar , Topaly Julian , Ho Anthony D. , Zeller W.J. , Fruehauf Stefan 
Published: April 2020

Abstract
Resistance towards the tyrosine kinase inhibitor (TK) imatinib frequently emerges in advanced stages of chronic myelogenous leukemia (CML) and complicates disease treatment. Nilotinib (AMN107) represents a novel BCR-ABL TK inhibitor with reported antiproliferative activity against imatinib-resistant cells in vitro. Since combination chemotherapy is a strategy to increase the antileukemic efficacy, we were interested whether combinations of nilotinib and other established chemotherapeutic agents such as mafosfamide, busulfan, treosulfan, daunorubicin or mitoxantrone display synergistic activity in different imatinib-sensitive and -resistant BCR-ABL-positive CML cells. Tetrazolium-based MTT assays (48 h incubation) revealed as expected that substantially higher concentrations of single agent nilotinib are required for growth inhibition of the imatinib-resistant K562-R (IC50=19.76±4.94 μM) and LAMA84-R (IC50=0.14±0.03 μM) cell lines as compared to the imatinib-sensitive counterparts (IC50=0.10±0.03 μM for K562 and IC50=0.03±0.01 μM for LAMA84, respectively). Combination treatment of both imatinib-sensitive LAMA84 and -resistant LAMA84-R cells resulted in variable antiproliferative effects. Combination index (CI) values calculated according to the median-effect method of Chou and Talalay denoted mostly additive (CI=1) and antagonistic (CI&gt;1) effects. In both lines a clear synergistic activity with CI&lt;1 could be observed only for the combination nilotinib plus mitoxantrone. By comparison in the imatinib-sensitive K562 and -resistant K562-R lines all applied combinations showed improved antileukemic efficacy with CI values predominantly lower than 1 indicating synergism between nilotinib and most of the substances investigated (see Table I, n=3, results are given as mean CI values at different growth inhibition levels (fraction affected, Fa)).

In BaF3 cells expressing imatinib-resistant mutants of BCR-ABL (E255K and T315I) IC50-values of single agent nilotinib were 0.37±0.04 μM and 23.58±1.92 μM, respectively. Importantly, combination treatment of imatinib-resistant BaF3 cells with both nilotinib plus daunorubicin and nilotinib plus mitoxantrone led to enhanced antiproliferative effects with synergism (CI&lt;1) at high growth inhibition levels even in the T315I resistant mutant cell line (see Table II, n=3).

The results demonstrate the ability of established chemotherapeutic agents to enhance the antileukemic efficacy of nilotinib and indicate the potential of the applied combinations for further study in the clinical setting.
AMD3100 Inhibits Chemotaxis towards SDF-1 and CXCR4-Mediated Stroma-Contact in a Dose-Dependent Manner, Resulting in Increased Susceptibility to Imatinib.
Authors: Dillmann Falk M. , Veldwijk Marlon R. , Calandra Gary , Zeller Werner J. , Ho Anthony D. , Fruehauf Stefan 
Published: April 2020

Abstract
Besides new efforts in the treatment with tyrosine-kinase-inhibitors like imatinib were made, Chronic myelogenous leukemia (CML) still remains chronic with a progression of the disease by time. New ways of treatment have to be found to eradicate the malignant clone in the bone marrow.
In our study we are evaluating whether an inhibition of the SDF-1-CXCR4-axis by the selective CXCR4 receptor antagonist AMD3100 results in increased cell kill of the BCR-ABL+ cell line BV-173 when combined with treatment with imatinib. AMD3100 significantly blocks binding of the FACS-anti-CXCR4-Mab to its corresponding receptor. Furthermore, AMD3100 significantly inhibits SDF-1 mediated chemotaxis towards 500ng/ml SDF-1 to 0.71±0.15 of spontaneous transmigration at the highest concentration (100μM) of AMD3100 whilst SDF-1 500ng/ml leads to 1.4±0.06 fold spontaneous transmigration (n=3). Even lower concentrations (10μM and 1μM) still significantly reduce transmigration to a level lower than spontaneous transmigration. Also migration into the SDF-1 producing stromal-cell line FBMD-1 was dose-dependently significantly reduced to 56.7% ± 8.6% migration of untreated controls at 100μM AMD3100 (n=4). Lower concentrations also significantly reduced migratory activity of BV-173. In a stroma-dependent co-culture AMD3100 dose-dependently increased susceptibility of BV-173 towards simultaneous treatment with Imatinib at a dose of 1.6μM. We saw 23% ± 8% PI+ cells in the control without AMD3100 vs. 40% ± 12% PI+ cells al 100μM AMD3100 (n=3; p=0.06). Incubation with 10μM and 1μM AMD3100 only resulted in a slight increase of PI+ cells to 28% ± 13% at 1μM and 29% ± 3 at 10μM respectively.
The same assays on the AML-cell line HL-60 and on the BCR-ABL+ cell line SD-1 led to a significant reduction in SDF-1 dependent chemotaxis and stromal-dependent migration especially at the 100μM concentration but on a level with higher transmigration rates. Interestingly, for these cell lines we found lower CXCR4 surface expression (MFI: 478 ± 71 for the BV-173 vs. 29 ± 8 for the HL-60 and 17 ± 1.5 for the SD-1) going hand in hand with lower effects on migration rates following incubation with AMD3100 than we could show for the CML cell line BV-173.
We conclude that co-treatment with AMD3100 and Imatinib leads to a sensitization of BCR-ABL+ leukaemia cells which is dependent on the baseline CXCR4 expression. This is a promising strategy to reduce residual BCR-ABL+ leukaemia cell load in CML patients.
Philadelphia Chromosome (Ph’) Secondary Clones in Chronic Myeloid Leukemia (CML) Are Not Indicative of Resistance to IFNa- or Imatinib-Based Treatment Regimens.
Authors: Falchi Lorenzo , Prontera Paolo , Luzi Debora , Festuccia Viola , Emili Rita , Gottardi Enrico , Donti Emilio , Liberati Anna Marina 
Published: April 2020

Abstract
The rate of complete karyotypic remission (CKR) and complete molecular remission (undetectable BCR/ABL specific transcript by real-time quantitative-PCR (Gabert J et al. Leukemia: 2003; 17: 2318–57) and NESTED/real-time-PCR (Guo JQ et al.; Leukemia: 2002; 15:2447–53)) to various therapies was analysed in 35, of the 114 CML patients observed in our institution, who showed cytogenetic clonal evolution. Overall, 52 karyotypic abnormalities additional to Ph’ were documented at the time of diagnosis (early clonal evolution) or late in the course of the disease (late clonal evolution). Seven of 12 patients with early clonal evolution achieved one (5 pts) or more (2 pts) CKRs, for a total number of 9, in response to IFNα (2 CKRs), IFNα plus ARA-C (1 CKR), imatinib (5 CKRs) or imatinib-IFNα combination (1 CKRs). Six of the 23 patients with late clonal evolution achieved one or more CKRs during the course of their disease after treatment with IFNα (2), IFNa plus ARA-C (1) or imatinib (5). In addition, 7 of the 13 CK responders reached a complete molecular remission in response to IFNa (1), IFNa plus ARA-C (1) imatinib (1), or imatinib plus IFNa (4). The 5 complete molecular remissions documented in patients with early clonal evolution, were observed following treatment with IFNα plus ARA-C (1), imatinib (1), or imatinib plus IFNα (3). Two patients with late clonal evolution obtained complete molecular remission in response to IFNα and imatinib plus IFN therapy, respectively. Cytogenetic and molecular response rates were higher in patients with early (58%, 57%) than in patients with late secondary clones (26%, 33%), while there were no significant differences in time to achieve cytogenetic (2–20 months vs 1–25 months) or molecular (3–26 months vs 13–52 months) remission and the duration of response (11 months, range 4–42 vs 10 months, range 7–46 and 2–19 vs 3–13+ months, respectively) between the two groups. Finally, no relationship was evident between the type of additional karyotypic anomalies and sensitivity to treatment. In fact, clones bearing complex translocations (2), isoPh’ (2), trisomy 8 (2), translocations other than Ph’ (2), partial chromosome monosomy (11-q, 1) or loss of chromosome Y alone (1) or associated with other anomalies (−6 and −14 or −21 or isoPh’) (3) all responded to therapy. In conclusion, although the small sample size, these findings suggest that the presence of karyotypic abnormalities additional to Ph’ in CML is not associated to disease resistance to therapy.
Loss of JAK2 in CML Cell Lines.
Authors: Vaughan Beverly , Howard Julie , Brazma Diana , Nacheva Elisabeth 
Published: April 2020

Abstract
Chronic Myeloproiferative Disorders (CMPDs) are a spectrum of haematological malignancies of which the molecular pathogenesis remains unknown. Chronic Myeloid Leukaemia (CML) being the only disorder with a recognisable pathogenomic abnormality, the Ph chromosome. Recent published data has supported the role of tyrosine kinases in the disease pathogenesis, in particular the role of a cytoplasmic tyrosine kinase JAK2. It has been shown that &gt;80% of Polycythaemia Vera (PV) patients and 30% of Essential Thrombocythaemia (ET) patients demonstrate a clonal and recurrent mutation V617F in the JH2 pseudo-kinase domain of JAK2 located on 9p24.1. Our array CGH investigations of cell lines, established from lymphoid and myeloid blast phase samples revealed a complex pattern of imbalances affecting the short arm of chromosome 9: on the background of 2–3-fold amplification, a loss of the 9p24.1 region, which harbours the JAK 2 sequences was repeatedly observed. FISH using BAC DNA probes from the 9p24.2 and 9p23 region was carried out to map the JAK2 gene and the flanking sequences. Results so far indicate the presence of both imbalances (amplifications & deletions) and rearrangements involving the JAK2 region in 5 cell lines. An on going FISH study of CMPD patients (CML, PV, ET and MF) with normal and abnormal karyotypes has revealed 9p24 imbalances in 18% (5 out of 28). The observation of JAK2 aberrations in a range of haematological malignancies demonstrates the potential importance of tyrosine kinases in the leukemogenesis. The pathegenomic significance of aberrations found in the region surrounding JAK2 has yet to be defined and our study demonstrates the importance of molecular cytogenetics as a tool in understanding the significance of JAK2 in CMPDs.