bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Inhibition of Receptor Pathways for Macrophage-Specific Cytokines by HIV-1 Nef Protein.
Authors: Okada Seiji , Harada Hideki , Suzu Shinya 
Published: April 2020

Abstract
HIV-1 Nef protein is a well-known major determinant of the pathogenicity of the virus and much attention has been given to Nef to explain its contribution to HIV-1 pathogenesis. One of the important features of Nef is the binding to a variety of host intracellular proteins. Hck, a member of Src family tyrosine kinases, is one of the binding partners of Nef. Meanwhile, Src kinases including Hck are key regulators for signaling pathways of several cytokine receptor systems. We therefore investigated whether Nef would affect cytokine receptor signaling pathways. Both GM-CSF and M-CSF are primary cytokines for monocytes/macrophages, and regulates their development and effector functions. We introduced a conditionally active Nef (Nef-estrogen receptor hormone binding-domain fusion protein) into the human leukemia cell line of which proliferation was dependent on those cytokines, and analyzed their ligand-dependent proliferation and receptor signaling events. Nef activation did not apparently affect the proliferation mediated by GM-CSF but markedly caused the inhibition of proliferation mediated by M-CSF, indicating that Nef selectively inhibited the M-CSF receptor pathways. In fact, Nef inhibited the tyrosine-phosphorylation/activation of M-CSF receptor and the molecular association with the activated receptor, which was the earliest signaling events induced by M-CSF. We found that Nef-activated Hck constitutively associated with M-CSF receptor complex. Since the formation of the molecular complex should occur under physiological conditions, i.e., upon M-CSF stimulation, the constitutive association occurred in Nef-active cells was an aberrant interaction. These results suggested that HIV-1 Nef interfered with M-CSF receptor signaling through Hck activation and thereby inhibited M-CSF bioactivity. The experiments in which Nef, Hck and M-CSF receptor were transiently expressed within 293 T cells in various combinations supported the notion (Suzu S et al., Blood 2005). The selective inhibition of Nef on cytokine signaling might result in the modification of macrophage functions such as cytokine/chemokine production, creating an immunologic environment favorable for HIV-1 virus production.
Hodgkin’s Disease and HIV Infection (HD-HIV) in Pre- and Post-HAART Era: The GICAT (Italian Cooperative Group on AIDS and Tumors) Experience in 139 Patients.
Authors: Tirelli Umberto , Vaccher Emanuela , Rossi Giuseppe , Schiantarelli Clara , Fasan Marco , Spina Michele 
Published: April 2020

Abstract
Background: Hodgkin’s disease (HD) in HIV infected patients shows aggressive tumour behaviour including a high frequency of unfavourable histologic subtypes, advanced stage and extranodal involvement and a poor outcome. The introduction of highly active antiretroviral therapy (HAART) has opened a new prospective in the treatment of patients with HD-HIV.
Methods: We analysed the results of four consecutive prospective phase II studies carried out within the GICAT since 1988.
Results: Table 1 summarizes the results of the prospective studies.
Conclusions: Since the widespread use of HAART, CR rate is improving and OS and DFS as well. The concomitant use of HAART and chemotherapy is feasible and advisable in our experience. In the HAART era HD seems to be a more successfully treatable malignancy, although at higher incidence and probably with the same aggressive behaviour at presentation as in the pre-HAART era.
Table 1: Results REGIMEN # of PTS HAART + CT STAGE III–IV CR RATE OS DFS EBV 17 No 88% 53% 11 mos -- EBVP 35 No 83% 74% 16 mos 53% at 3-yrs STANFORD V 59 Yes 71% 81% 68% at 2-yrs 70% at 2-yrs VEBEP 28 Yes 68% 75% 86% at 2-yrs 90% at 2-yrs
Gain of Chromosome 21 Is Associated with Early Treatment Sensitivity in Childhood Acute Lymphoblastic Leukemia.
Authors: Steinemann Doris , Cario Gunnar , Stanulla Martin , Tauscher Marcel , Hinrichsen Tanja , Michaelsen Gudrun , Viehmann Susanne , Lichter Peter , Schrappe Martin , Schlegelberger Brigitte 
Published: April 2020

Abstract
Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) at 5 and 12 weeks of treatment, has evolved as the strongest prognostic factor in pediatric ALL patients treated according to the BFM regime. In this study, ten patients with a poor treatment response (MRD load ≥ 10−3 at week 12, MRD-high risk, HR) and five treatment-sensitive (no measurable MRD at weeks 5 and 12, MRD-standard risk, SR) patients were investigated by means of high-resolution bacterial artificial chromosome (BAC) array-based comparative genomic hybridization (array-CGH). To ensure homogeneity with regard to prognostic factors, the following inclusion criteria were used: B cell precursor or common ALL, DNA index of 1.0, no BCR/ABL, no MLL/AF4, no TEL/AML1 rearrangements. A gain for all chromosome 21-related BAC clones was observed in all SR patients. None of the ten HR patients showed a gain of any region of chromosome 21. This result could be confirmed by means of fluorescence in situ hybridization using the LSI AML1/ETO DC probe set. Besides the basic level of chromosome 21 gain, higher levels of gain or amplification observed for individual regions were found in three SR patients. Recurrent genomic alterations in the group of HR patients were loss of chromosomal region 2p11.22 (9/10), a gain of 8q24.13 (7/10) and loss of 14q32 (8/10). To see whether these findings may help to further subdivide the intermediate risk group patients (any MRD positivity at week 5, MRD load &lt; 10−3 at week 12) we additionally analyzed three patients of this group: two patients in long-term complete remission and one patient who relapsed 29 months after diagnosis. Again, a gain for all chromosome 21-related clones was detected in both patients in complete remission. In contrast, the leukemic sample of the relapsed patient demonstrated no gain of chromosome 21. We conclude that array CGH analysis in childhood ALL may lead to the identification of additional prognostic markers. The relevance of the observed gain of chromosome 21 has to be validated in a larger set of patients.
A Plateau after 30 Months of Follow-Up in B -Lineage Childhood Acute Lymphoblastic Leukemia (ALL) with t(1;19)(q23;p13)/E2A-PBX1?.
Authors: Baruchel André , Chevret Sylvie , Auvrignon Anne , Ballerini Paola , Michel Gérard , Gabert Jean , Vermylen Christiane , Perel Yves , Bilhou-Nabera Chrystèle , Lejars Odile , Schmitt Claudine , Jonveaux Pierre , Soulier Jean , Vandenaker Jacqueline , Auclerc Marie-Françoise , Leblanc Thierry , Leverger Guy ,   for the FRALLE Group
Published: April 2020

Abstract
Late events are observed in B-lineage ALL with no plateau seen if a sufficient observation period is provided. The prognosis of childhood ALL associated to the t(1;19)(q23;p13)/E2A-PBX1 translocation has improved over the two last decades. The purpose of this study is to define the kinetics of relapse in a large cohort of children and to raise the possibility of a plateau in that entity. We identified 110 children treated for a B-lineage ALL harbouring a t(1;19(q23;p13) and/or E2A-PBX1 fusion transcript from 1987 to 2004 in the FRALLE protocols (FRALLE 83: n= 3, FRALLE 87–89: n=18, FRALLE 92 (phase II): n=10, FRALLE 93: n=48, FRALLE 2000 (still opened: n=31). Analysed features included: male sex (50, 45%), age (median: 6.9y; Q1–Q3: 3.5–12), CNS disease (4, 3.5%), leucocytosis (median: 21.4 G/L; Q1–Q3: 10.8–53.4), D8 poor prednisone response (PPR) (5/79, 6%), M1 D21 marrow response (103, 94%), and CR (108, 98%). For an accurate comparison, the subgroup of pts with t(1;19) included in the FRALLE 93 protocol (n=48) was compared to the 1,147 children aged more than 1 y with B- lineage ALL treated in the same protocol. Significant differences in the t(1;19) cohort were: excess of girls (65% vs. 46%; p= .01), and older age (median: 7 vs. 4.7; p= .01)). No differences in early response to treatment (D8, D21, D35) were seen. All the 110 patients received chemotherapy only, except 3 who received an autologous BMT for D8 PPR as recommended by the FRALLE 93 protocol. At a median FU of 65 months, 18 events have been recorded including 17 relapses (bone marrow: 13, CNS: 4) and 1 secondary tumor (abdominal Burkitt lymphoma) giving a 5 y and 10 y EFS of 78.7%. If “modern era” only is considered (&gt; 1992), 5 y and 10 y EFS is 85.5%. Relapses occurred at a median time of 422 days (range: 72–899) in the whole t(1;19) cohort. In those from FRALLE 93, the median time to relapse (MTTR) was 280 days, that is significantly lower than the one observed in the control group defined above (MTTR = 894 days, Wilcoxon test, p = .01).
Conclusions: We confirm that a high cure rate is now associated to that subgroup of childhood ALL. The main finding is that no event except from the secondary Burkitt lymphoma (1705 d) was registered after 30 months from diagnosis in that cohort of 110 children with t(1;19)/E2A-PBX1 translocation associated ALL. It is then conceivable to announce cure at 36 months in that subgroup with an extremely low possibility of mistake, thus much earlier and with more confidence than in the other B-lineage ALL.
CD10− Pre-B Acute Lymphoblastic Leukemia (ALL): A Distinct High-Risk Subgroup of Adult ALL.
Authors: Gleissner Beate , Goekbuget Nicola , Rieder Harald , Hoelzer Dieter , Thiel Eckhard 
Published: April 2020

Abstract
Introduction: Immunological subtyping and molecular genetic analysis enable risk-adapted treatment of acute lymphoblastic leukemia (ALL). Translocations involving the mixed lingeage leukemia (MLL) gene characterize one poor-prognosis subtype of adult B-lineage precursor ALL correlating with a CD19+/CD10−/cytoplasmic (cy) IgM− immunophenotype (pro-B ALL).
Patients and Methods: Immunophenotyping was performed on 2,408 newly diagnosed ALL specimens indentifying pro-B ALL, TdT+/CD19+/CD10−/cyIgM−/surface(S)Ig−; c-ALL, TdT+/CD19+/CD10+/cyIgM−/SIg−; and pre-B ALL, TdT+/CD19+/CD10+/cyIgM+/SIg−. Ambiguous cases of CD10-positivity (5–15% CD10-positivity) were rechecked by a second antibody. BCR-ABL RT-PCR and cytogenetics were performed. CD10-negative blasts also underwent MLL-AF4 RT-PCR. FISH using directly labelled probes for MLL was done in selected cases. Patients were treated according the German Multicenter Adult ALL trials (GMALL) with MLL-rearrangement positive patients treated in the high-risk arm.
Results: Immunophenotyping identified 70 CD10-negative pre-B ALL specimens (TdT+CD19+cyIgM+). Fifty-six of these 70 CD10-negative pre-B ALL specimens contained a sufficient amount of blasts for molecular analysis. A total of 46/56 CD10-negative pre-B ALL were assigned to MLL-rearrangement positivity, revealing either MLL-AF4 fusion by RT-PCR (n = 38) or an 11q23/MLL translocation by cytogenetics (n = 4) or FISH (n = 4).
Looking at clinical characteristics, MLL-rearrangement-positive patients were characterized by a higher median white blood cell count (P = .0002) and their blasts showed frequently neuroglial antigen 2 chondroitin sulfate proteoglycan (P = .02).
Forty CD10− pre-B ALL patients with molecular genetic and/or cytogenetic data were evaluable for the treatment response and outcome. A complete remission (CR) was achieved in 6 of 7 (86%) MLL-rearrangement-negative and in 27 of 33 (82%) MLL-rearrangement-positive patients (P = .06). CR was maintained by 2 of 6 (33.3%) MLL-rearrangement-negative and 7 of 27 (26%) MLL-rearrangement-positive patients. The probability of remission duration after 3 years was 0.37 (± 0.29 SE) in MLL-rearrangement-negative versus 0.28 (± 0.13 SE) in MLL-rearrangement-positive patients contributing essentially to the overall survival at 3 years after diagnosis of 0.15 (± 0.06 SE) in patients with CD10-negative pre-B ALL.
Conclusion: Our data identify CD10− cytoplasmic Ig-positive pre-B ALL as a rare (2.2%) but distinct immunosubtype of adult ALL that is characterized by a high MLL rearrangement rate and a worse outcome with conventional intensified treatment strategies.
Microarray Analyses in a Case-Control Cohort of T-ALL Samples Identifies Gene Signature of Potential Prognostic Significance.
Authors: Winter Stuart S. , Khawaja Hadya , Jiang Zeyu , Kooperberg Charles , Ferrando Adolfo , Look Thomas , Larson Richard S. 
Published: April 2020

Abstract
Risk stratification remains limited for patients being treated for T-ALL due to a lack of biologic predictors of outcome. As a consequence, treatment assignment on modern protocols has been largely achieved through random assignment. Recent observations have suggested that overexpression of specific gene(s) may provide a reliable means to risk stratify patients. We hypothesized that microarray analysis may identify gene sets that distinguish both therapeutic response and patient outcome in T-ALL. We analyzed the gene expression profiles of 45 primary T-ALL samples (24 CCR, 21 relapse) from a matched, case control study with sufficient cRNA for microarray analysis (COG #8704). We performed oligonucleotide microarray analysis using Affymetrix U133Av.2 genechips which have approximately 54,000 target genes and ESTs. Following heirarchical clustering in dChip and R Language analyses (Chiaretti et al. Blood, 2004), but using RMA normalization, we identified 37 genes that serve as reliable predictors of CCR or relapse. Leave-one-out least discriminant analysis cross-over validation further constrained our prognostic gene identifiers to 21 genes of robust significance. These 21 genes predict 87 % of CCR and 82% of relapse accurately (p&lt;0.0001, two-tailed Fisher’s exact test). These results were verified by qRT-PCR. Transcriptional factors previously described as having prognostic significance were not identified in our study. Twenty-six of the 45 cases received high dose L-asparaginase (16 CCR, 10 relapse) on the companion study. As a result, we examined whether a distinct signature could be also identified that distinguishes response to dose-intensified asparaginase treatment for patients with T-ALL. Using the same approach, a 27-member gene signature was identified that accurately predicted response in 24 of the 26 cases (92 %; 2 cases of relapse were misclassified). These results have identified two sets of genes that may be further pursued as prognostic indicators in T-ALL or as predictors of response to therapy.
Molecular Monitoring of Residual Disease (MRD) during Induction and Intensification Phases in Low Risk Adult B Cell ALL Treated According to the MRC UKALL12 Protocol.
Authors: Foroni Letizia , Mitchell Wayne , Rai Lena J. , Casanova Anouska , Gerrard Gareth , Patel Bella , Richards Sue , Fielding Adele , Goldstone Anthony H. 
Published: April 2020

Abstract
Introduction and aims. Molecular monitoring of minimal residual disease (MRD) using Immunoglobulin (IG) and T cell receptor (TCR) targets has provided an independent and prognostically significant parameter of outcome in adult and childhood acute lymphoblastic leukaemia (ALL). The aim of our study was to evaluate the impact of molecular tests carried out during the first 20 to 24 weeks of chemotherapy for MRD in a standard risk group of adult B cell ALL patients.
Patients and Methodology. We evaluated MRD tests in 63 patients with B cell ALL (37M/26F). Median age of our cohort was 24 yrs (range: 15.5–54.6 yrs) while median WBC was 9.9 (range: 1.1–553 × 109l). All were negative for the t(9;22) or t(4;11) translocation and received standard induction chemotherapy or auto stem cell transplant (A-SCT) only. All patients had at least one molecular marker which was tested by quantitative or semi-quantitative PCR with sensitivity ≥1E4 and all tests were carried out at time of morphological remission. End-points were relapse or continuous clinical remission (CCR) with follow up ≥12 months. Time point for molecular evaluation were post induction phase 1, TP1 (up to 1.8 mo), post induction phase 2 (1.8–3.5 mo), post intensification (3.5–5.7 mo). Median follow up was 92 months for patients in CCR (range 12–141 mo) and 15.5 months for patients who relapsed (range: 2.4–49 mo).
Results. Thirty-five patients in complete morphological remission were tested at TP1. Relapse free survival (RFS) tests showed a statistically significant correlation (p=0.02) between MRD positive tests and relapse (n=19 pts) and MRD negative tests (n=16 pts) and relapse free survival. In addition, pts with resistant disease at TP1 (n=10; not included above) and MRD positive pts were indistinguishable as far as relapse FS and both faired extremely poorly (Figure A).
Thirty patients were analysed at TP2. RFS confirmed the significant association between MRD positivity and poor outcome (n=16 pts) and MRD negativity and CCR (n=14 pts) (p=0.03) (Figure B).
MRD data were also available for 43 patients at TP3. Association of MRD positive tests (n=15 pts) and MRD negative tests (n=28 pts) with poor and good outcome, respectively (p=0.0006) (Figure C) was strongest at this time point. Outcome correlated with level of MRD at all time points, with poorer outcome in patients with MRD &gt;1E3.
Conclusions. Molecular monitoring during induction and intensification for standard risk B cell ALL patients treated with UKALL12 protocol provides a prognostically significant parameter for the management of adult ALL in otherwise morphological remission and may in the future be used for patients’ stratification.
Figure Figure
The Value of Molecular Monitoring for Residual Disease (MRD) in Early Morphological Remitters among Adults Diagnosed with B Cell ALL and Treated According to the MRC UKALL12 Protocol.
Authors: Foroni Letizia , Mitchell Wayne , Rai Lena J. , Richards Sue , Fielding Adele , Goldstone Anthony H. 
Published: April 2020

Abstract
Molecular monitoring of minimal residual disease (MRD) has become an independent and prognostically significant parameter in assessing outcome in adult and childhood acute lymphoblastic leukaemia (ALL). The aim of our study was to evaluate the impact of MRD in a standard risk group of adult B cell ALL patients who had achieved morphological remission following induction phase 1 therapy as part of the MRC UKALL12 protocol.
Patients and Methodology. MRD tests were evaluated in fourty-seven patients with adult B cell ALL. They were negative for the t(9;22) or t(4;11) translocation and had received chemotherapy based treatment or auto stem cell transplant (A-SCT) only. Median age was 23 yrs (range 15.5–54.6 yrs); median WBC was 9.6 (range 1.1–163×109/l) with a predominance of common (28 pts) and pre B ALL (12 pts).
All patients had at least one molecular marker which was tested by quantitative or semi-quantitative PCR with sensitivity ≥1E4. End points were either clinical relapse or disease free survival in complete remission with follow up ≥12 months. Time point for molecular evaluation were post induction phase 1, TP1 (median 0.9 mo; range: 0.6–1.8 mo) and post induction phase 2 (median 2.79 mo; range 1.8–3.5 mo).
Results. Thirty three pts were tested at TP1 following morphological remission. Relapse free survival (RFS) analysis showed a statistically significant association between MRD positive tests (in 16 pts) and relapse, and MRD negative tests (in 17 pts) and CCR (p=0.03) (Figure 1, left diagram).
Twenty five pts were analysed at TP2 following their early morphological remission. At this time point we observed the strongest association between MRD negative tests (in 13 pts) and CCR (in 10 pts) and MRD positive (12 pts) and relapse (in 11 pts) (p=0.01)(Figure 1, right diagram).
Conclusions. Molecular monitoring of MRD shows that even among early morphological remitters a group of MRD positive patients can be identified that have poor overall outcome and may benefit from tailored therapies. Molecular assessment of residual disease should be used to stratify treatment in future adult ALL trials.
Figure Figure
Targeting CD20 and CD22 with Rituximab in Combination with CMC-544 Results in Improved Anti-Tumor Activity Against Non-Hodgkin’s Lymphoma (NHL) Pre-Clinical Models.
Authors: Hernandez-Ilizaliturri Francisco J. , Devineni Suresh , Arora Sarika , Knight Joy , Czuczman Myron S. 
Published: April 2020

Abstract
CMC-544 is an IgG4 CD22-humanized targeted immunoconjugate of calicheamicin. Upon CD22 biding, CMC-544 internalizes inducing cell apoptosis in vitro/in vivo against NHL with minimal modulation of the immune system. In addition to direct cell-death, rituximab, anti-CD20 monoclonal antibody (mAb), can induce complement-dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC). Combination of mAbs directed against unique tumor-associated targets can potentially enhance anti-tumor activity. Objectives: To study the effects of targeting CD20 and CD22 using rituximab in combination with CMC-544. Material and Methods: For in vitro studies, a panel of NHL cell lines [Raji, SUDHL-4, SU-DHL-10, Ramos, and two rituximab resistant cell lines (RRCL), [2R and 4RH] were exposed to CMC-544 (0.4pg/ml to 0.4μg/ml) +/− Rituximab (10μg/ml) or appropriate controls for 24 or 48 hrs. DNA synthesis was quantified by [H3]Thymidine incorporation and apoptosis was detected by multiparameter flow cytometric analysis and Poly(ADP-ribose) polymerase (PARP) cleavage. For ADCC/CMC studies, 51Cr-labeled NHL cells were exposed to CMC-544 (0.4μg/ml) prior to treatment with rituximab (10mg/ml) and peripheral blood mononuclear cells (Effector: Target ratio 40:1) or human serum, respectively. 51Cr-release was measured and the percentage of lysis was calculated. Statistical analysis of results was performed using the Chi-square test. For in vivo studies, 6–8-week old SCID mice were inoculated via tail vein injection (iv) with Raji cells (1 × 106 on day 0). Animals were assigned to receive 8 doses of either saline, CMC-544 (40μg/kg/dose), rituximab (10mg/kg/dose iv), or rituximab alternating with CMC-544. Antibodies were administered iv every other day starting on day +5. Survival analysis was performed by Kaplan-Meier curves and p values calculated using log rank test. Results: Exposure of various NHL cells to CMC-544 resulted in a dose-dependent significant decrease in cell proliferation and apoptosis. Rituximab-associated CMC or ADCC was not further enhanced by CMC-544 in vitro. In vivo studies demonstrated that the mean survival for animals treated with CMC-544 increased when compared to control mice [64 days (95% C.I. 48–80; 22 days (95% C.I. 21–23), respectively, P=0.001]. To a lesser degree rituximab monotherapy resulted in significant anti-tumor effects and the median survival reached 44 days (95% C.I. 31–56). Notably, animals treated with rituximab in combination with CMC-544 had the longest median survival (not reached at +90 days, log rank P=0.007). Conclusions: Our data suggest targeting CD20 and CD22 by rituximab and CMC-544 resulted in a longer survival in lymphoma-bearing SCID mice. Clinical trials with this combination will be needed to confirm these results for the treatment of lymphoma patients