bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact on Transplant Outcome of Karyotyping Analysis in Apheresis Products for Autologous PBSC Transplantation in De Novo Acute Leukemias (AL).
Authors: Delannoy Bertrand , Nicolini Franck E. , Le Quoc-Hung , Clapisson Gilles , Philip Irene , Raus Nicole , Tigaud Isabelle , Charrin Christiane , Thomas Xavier , Chelghoum Youcef , Tavernier Emmanuelle , Lheritier Veronique , Michallet Mauricette 
Published: October 2019

Abstract
Autologous stem cell transplantation as consolidation therapy for de novo AL is able to improve long-term survival especially after second complete remission (CR). In this study, we retrospectively analyzed the karyotyping results performed in 79 out of 101 harvested autologous PBSC from 38 de novo AML patients and 8 de novo ALL in CR. We secondly, analyzed their impact on overall survival (OS) and event-free survival (EFS) post-transplant. All patients had abnormal medullar karyotype at diagnosis. We determined two groups of patients: (1) group 1 with chromosomal abnormalities in harvested PBSC included 10 AML [4 males and 6 females, median age: 53 years (45–66.5)] with at diagnosis 3 favorable, 4 intermediate and 3 unfavorable-risk karyotype ; 2 M0, 3 M2, 1 M3, 2 M4, 2 M5 according to Fab classification ; and 9 autotransplanted patients in CR1 and 1 in CR2 and (2) group 2 without any chromosomal abnormalities in harvested PBSC including 27 AML+ 9 ALL [22 males and 14 females, median age : 44 years (19–70)] ; 1 M0, 1 M1, 4 M2, 5 M3, 11 M4, 5 M5 with at diagnosis 18 favorable prognosis, 1 intermediate and 8 unfavorable-risk karyotype ; among ALL patients, 7 B ALL and 2 T ALL and at transplant, 29 autotransplant in CR1, 6 in CR2 and 1 in CR3]. Cytapheresis products collected contained a median number of 7.7x 108/Kg (5.2–17.3) and 6.79x108/Kg (1.26–16.4) mononuclear cells and 19x106/Kg (3–43) and 20.5x106/Kg (1–4O) CD34+ cells in group 1 and in group 2 respectively. All PBSC harvested were reinfused. Conditionning regimen was quite similar in the two groups and most of the patients of group 1 (60%) and group 2 (70%) received cyclophosphamide and TBI. The hematopoietic reconstitution was similar in the 2 groups [neutrophiles > 0.5 G/l: 26 days in group1 versus 19 days in group 2 (p=0,86)]. At 3 years after transplant, there was a trend for a better OS (54.7% CI 95% 40–74.8) (p=0.06) and EFS (52.5% 95%CI 39.6–74) (p=0.05) in patients who received PBSC without any chromosomal abnormalities compared to patients receiving PBSC with abnormal karyotype (OS : 30% 95% CI 11.6–77.3 ; EFS : 30% 95% CI 11.6–77.3). In conclusion, results observed from autologous harvested PBSC karyotyping are promising but a larger number of patients and a longer follow-up could enable to reach a more important significance.
Autologous Hematopoietic Stem Cell Transplantation in Patients with Severe and Refractory Crohn’s Disease.
Authors: Oyama Yu , Craig Robert M. , Traynor Ann E. , Burt Richard K. , Statkute Laisvyde 
Published: October 2019

Abstract
Background & Aims
Crohn’s disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. In theory, immune ablation followed by autologous hematopoietic stem cell transplantation (HSCT) can induce remission by reconstituting a new immune system.
Methods
We conducted a phase I HSCT study in 12 patients with severe CD. Candidates were less than 60 years old with a Crohn’s Disease Activity Index (CDAI) of 250–400 despite conventional therapy including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34+ enriched. The immune ablative conditioning regimen consisted of 200mg/kg cyclophosphamide, and 90mg/kg equine antithymocyte globulin.
Results
The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range 8–11) and 9 (range 9–18), respectively. The infused CD34+ and CD3+ cell counts were 5.64 x 106/kg (range 1.73–9.93) and 0.59 x 104/kg (range 0.3–3.09), respectively. Initial median CDAI was 291 (range 250–358). Symptoms and CDAI improved dramatically (figure 1), and radiographic and colonoscopy findings improved gradually over months to years following HSCT. Ten out of twelve patients entered sustained remission defined by a CDAI ≤ 100. After median follow-up of 17.5 months (range 6–37), only one patient has developed recurrence of active CD which occurred 15 months post-HSCT.
Conclusion
Autologous HSCT may be peformed safely and has a marked salutary effect on CD activity. Randomized studies will be needed to confirm the efficacy of this therapy.
Figure Figure
Leukemic B Cells from Patients with Chronic Lymphocytic Leukemia Show Anomalous Lyn Tyrosine Kinase which Contributes to Defective Apoptosis.
Authors: Trentin Livio , Brunati Anna Maria , Contri Antonella , Cabrelle Anna , Miorin Marta , Cesaro Luca , Pinna Lorenzo , Semenzato Gianpietro , Donella-Deana Arianna 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of mature B lymphocytes in the G0/G1 phase of the cell cycle, expressing B-cell related (i.e. CD19, surface immunoglobulins) and unrelated molecules (CD5 and CD23). The signal transduction pathways underlying the abnormalities of these leukemic cells are poorly understood and no data are available on deregulated cell signalling in B-CLL. Since Lyn activation plays a pivotal role in the signaling cascade triggered by BCR engagement, we investigated whether this kinase may be involved in CLL pathogenesis. In this study, we investigated freshly isolated and purified malignant B cells obtained from 40 CLL patients and we observed that the Src-kinase Lyn, the switch molecule coupling B-cell-receptor to downstream signaling, displays anomalous properties. Western blot and confocal analyses demonstrated that Lyn is overexpressed at the protein level in leukemic cells as compared to normal B-lymphocytes with a substantial aliquot of the kinase anomalously present in the cytosol of leukemic cells. While in normal B lymphocytes Lyn activation is triggered by B-cell-receptor engagement with anti-IgM antibodies, in freshly isolated leukemic cells this kinase is constitutively active and accounts for high basal protein tyrosine-phosphorylation and low responsiveness to IgM-ligation. To address the question of whether the upregulation of Lyn protein and activity plays a role in the defective apoptosis of leukemic cells, we investigated the relationship between Lyn and the cell survival of malignant lymphocytes in the presence of either dexamethazone and cyclosporin A, which are known to induce apoptosis of human lymphocytes, or PP2 and SU6656, which are selective inhibitors of Lyn. When leukemic cells were cultured in the presence of cyclosporin A or dexamethazone, a marked increase in apoptosis was observed as compared to cells cultured in medium alone, and this effect correlated with a great decrease in both basal activity and protein level of Lyn. The exposure of the leukemic cells to PP2 and SU6656 caused both the inhibition of the overexpressed Lyn activity and marked cell apoptosis. These findings suggest a direct correlation between high basal Lyn activity and defects in the induction of apoptosis in leukemic cells. They also support a critical role for Lyn in B-CLL pathogenesis and identify this tyrosine kinase as a potential therapeutic target for drugs capable of inducing apoptosis in B-CLL leukemic cells.
Down Syndrome (DS) Patients with Intermediate Risk (IR) Acute Lymphoblastic Leukemia (ALL): Events and Outcome on Children’s Cancer Group (CCG) 1891 Study.
Authors: Franklin Janet , Larsen Staci , Dorey Fred , Butturini Anna , Fu Cecelia , Lange Beverly , Sather Harland , Gaynon Paul 
Published: October 2019

Abstract
We performed a retrospective review of the events and outcome for DS patients enrolled on CCG study 1891, a randomized clinical trial open 1990–1993 for children less than 10 years old with IR newly diagnosed ALL. Of the 1204 eligible patients enrolled, 33 (2.7%) patients had DS. DS patients were randomized in an identical manner to other enrolled patients to one of three treatment regimens: single delayed intensification (single DI), double DI, or single DI with intensified pulses of vincristine/prednisone during maintenance. This trial demonstrated an improved EFS at 6 years of 79% for the overall study group that was randomized to the double DI arm. A separate subset analysis of survivorship in the DS patients was performed using the STATA program and then compared to the Non-Downs Syndrome (NDS) study patients. 14/33 (42%) DS patients had a M1 marrow on Induction Day 7 while 19/33 (58%) DS patients had an Induction Day 7 bone marrow of M2 or M3 status. Of these 19 DS patients with slow early response, 9/19 (47%) went on to have serious events ( 3 induction failures, 3 relapses, 2 septic deaths, 1 CNS hemorrhage) compared to 2/14 (14%) rapid responders with DS that had events ( 1 relapse, 1 septic death). DS patients that had an M2 or M3 marrow response on Induction Day 7 had more adverse events than their NDS patient cohort with the same M2 or M3 bone marrow response. (p=0.02) DS patients who achieved M1 marrow status on Day 7 demonstrated a similar number of events as NDS patients with the same bone marrow response. (p=0.83) Detailed chart review demonstrated that congenital anomalies (cardiac, gatrointestinal) did not account for the greater risk of adverse events in these DS patients: 10/33 DS patients had congenital anomalies but none of these patients relapsed and only 1 died. Of all 8 patient deaths in the DS subset ( rapid and slow responders), 3 were sepsis related deaths in remission while 4 were due to relapse and 1 due to hemorrhage. Remission induction for the DS patients was 91% ( 30/33 with M1 marrow at Day 29 of Induction) compared to 98% for the overall study cohort. There was a 9% (3/33) induction failure rate; two of these three patients went into remission with an off study re-induction and have had long term disease free survival. Efficacy of the three treatment regimens in the DS patients, as measured by EFS and survival, mirrored that of the general study population. Although the DS patient numbers are small, it appears that an intensified therapy regimen provides benefit to DS patients similar to their NDS cohort. With the intensified therapy, DS patients may derive a similar improved benefit from very aggressive supportive care as a potential means of decreasing fatal sepsis and bleeding events.
Substantially High Frequency of Chromosome 7q Interstitial Deletion in B-Cell Lymphoproliferative Disorders.
Authors: Lu Gary , Zhang John , Latorre Katherine , Hibbard Michele , Chen Sing-Tsung 
Published: October 2019

Abstract
It has been well known that cytogenetics study plays an important role in cancer patient care, in particular in the diagnosis, treatment and prognosis of hematological malignancies. The MCIM test system, a combination of studies of cell morphology (M), cytogenetics (C), immunophenotype (I) and molecular genetics (M), has become a useful test system in hematologic disease diagnosis. It provides physicians more comprehensive and accurate diagnostic laboratory information. Deletions in the long arm of chromosome 7 are among the most common abnormalities observed in hematologic disorders. These changes were usually viewed as markers for myeloid malignancies, in particular myelodysplastic syndrome and acute myeloid leukemia. Recently, interstitial 7q deletions, a subset of the 7q deletions, have been found to be associated with B-cell lymphoproliferative disorders (LPDs). The correlation of narrow 7q deletions with specific subsets of B-cell LPDs has been extensively studied. However, the frequency of interstitial 7q deletions associated with B-cell LPDs has not been well investigated. We recently studied 7q deletions collected from our clinical cases done by the MCIM system at US Labs over the past two years. Deletions of chromosome 7q were observed in 85 of 19,483 cases. Interstitial 7q deletions were detected in 46 of the 85 cases with 7q deletions. In combination with the findings of flow cytometry, interstitial 7q deletions were found to be associated with B-cell LPDs in 10 out of the 46 cases, accounting for 21.7% of all the observed interstitial 7q deletions and 11.8% of all the 7q deletions. The B-cell LPDs associated with 7q interstitial deletion are diverse, including hairy cell leukemia, atypical chronic lymphocytic leukemia, splenic marginal zone lymphoma, and large B-cell lymphoma. Interestingly, the deleted region in the 10 cases with B-cell LPDs in this study was solely confined to 7q22-32. This is so far, to our knowledge, the largest series reported in the literature. Our investigation showed that the frequency of 7q interstitial deletions associated with B-cell LPDs is substantially high. We conclude that (1) association of B-cell LPDs must be taken into account when an interstitial 7q deletion is observed, in particular when the deleted region is confined to 7q22-32; (2) together with the flow cytometry analysis in the MCIM system within a clinical laboratory diagnostic facility, cytogenetics study can provide clinicians more accurate diagnostic information, thus strengthening patient care by improving the management of hematological malignancies. (The authors are grateful to Deanna Collins for her cooperation to collect the data in this study.)
VTD (Velcade, Thalidomide, Dexamethasone) as Primary Therapy for Newly-Diagnosed Multiple Myeloma.
Authors: Wang Luhua M. , Weber Donna M. , Delasalle Kay B. , Alexanian Raymond 
Published: October 2019

Abstract
The combination of thalidomide and dexamethasone (TD) has induced disease remission in 69% of 132 newly diagnosed patients with multiple myeloma (MM) treated at our center, with preventable and/or manageable side effects, and represents our primary treatment of choice. By adding bortezomib (Velcade), the 3-drug combination (VTD) has induced remission in 55% of patients with myeloma resistant to standard therapies, twice the frequency observed with bortezomib alone (Zangari, Barlogie et al, 2003). From 6/03 to 6/04, we combined bortezomib with thalidomide (100–200 mg each evening) and dexamethasone (20 mg/m2 on days 1–4, 9–12, 17–20) with therapeutic anticoagulation for 25 previously untreated patients with MM. Bortezomib was given at a dose of 1.0 (n=2), 1.3 (n=11), 1.5 (n=7), 1.7 (n=4) or 1.9 (n=1) mg/m2 IV on days 1, 4, 8 and 11, every 4 weeks to patients for 2–3 cycles of VTD. Median age was 63 (39–81), median B2M 5.1 mg/L (1.7–19), Hgb <10.5 g/dl in 60%, corrected serum calcium >11.5 mg/dl in 17%, and high tumor mass in 32% of patients. Grade 3 or 4 toxicities included non-neutropenic infection (2), orthostatic hypotension (1), DVT (1), neutropenia (1), thrombocytopenia (1); grade 3 or 4 neuropathy was not seen. Median nadir of ANC was 2360/ul and of platelets 135,000/ul with no correlation between bortezomib dose and myelosuppression. An initial dose of bortezomib of 1.5 mg/m2 IV x 4 was safe unless age > 70 and/or drugs for hypertension were taken concurrently. Responses were confirmed (>75% reduction serum myeloma protein and/or >95% reduction Bence Jones protein) in 19 patients (76%) and when defined by less stringent Blade criteria in 21 patients (84%); median time to remission was 0.6 mo (range 0.3–1.8) by either criteria in comparison with 1.1 mo (range 0.3–8.1) after TD (p<.01). Disease resistance was recognized by one month in 5 of 6 patients rated as unresponsive. Autologous blood stem cells were collected easily with G-CSF alone in 12 patients who were intensified a median 3.6 months after initial therapy; all 4 patients with primary resistant disease who received such therapy achieved partial remission. The frequency of CR to VTD could not be assessed because of early intensification. All patients are alive after median follow-up of 6 months (range 2–14). VTD induced a slightly higher frequency of PR, and significantly more rapid onset of remission, than those observed in similar patients treated previously with TD. No more than 2 courses of therapy were necessary before intensification or maintenance, so that the potential side effects and cost of more therapy were avoided. Results appeared superior to those observed with any prior program for previously untreated patients with MM at our center.
Effects of B7.2−/− Mature Dendritic Cells on Tolerance Induction to Alloantigens in Fetal Mice Following In Utero Transplantation with Lineage Depleted Bone Marrow.
Authors: Bhattacharyya Swati , Cowan Morton J. 
Published: October 2019

Abstract
In utero hematopoietic stem cell transplantation (IUT) has the potential to cure a variety of marrow stem cell defects without using marrow ablative therapy. However IUT for diseases other than SCID has been unsuccessful. To better understand the barriers to successful IUT we wanted to define the role of the B7.1/B7.2 co-stimulatory molecules in inducing tolerance to allogeneic donor bone marrow cells in the fetal murine recipient. We studied the relative role of B7.1 and B7.2 expression on dendritic cells (DC) on engraftment and in generating donor specific tolerance in fetal mice. Mature DC (mDC) from B7.1−/− or B7.2−/− donors and wild type (wt) lineage depleted (lin−) C57Bl/6 (B6) bone marrow (BM) were injected into gestational day (GD) 14 Balb/c fetuses. Recipients of lin− wt BM and B7.1−/− mDC had a significantly lower survival (47.4%, p<0.01) associated with mild-moderate GvHD compared to the recipients of B7.2−/− mDC and lin− BM (82.3%) where none developed GvHD. Engraftment results in blood at 6 weeks post IUT showed, B7.1−/− recipients had multilineage engraftment (4.7±0.8% T cells and 5.7± 1.1% granulocytes) in their blood, but by 12 weeks, only donor CD3+ (predominantly CD8+) cells (2.1±1.3%) were present. The percent H2Kb+ (donor) T cells (predominantly CD4+) in the blood of recipients of lin− wt BM and B7.2−/− was 11.8±8.5% at 6 weeks p<0.001 and 6.5±2.5% at 12 weeks, p=0.006. The circulating donor CD4+ cells were Th2 (CD4+CD25−IL4+IL10+) and Treg (CD4+CD25+IL4−IL10−). Both fractions inhibited the T cell proliferative response in the MLR. Long term engraftment in thymic tissues was found in the tolerant recipients of lin− wt BM and B7.2−/− mDC (13.4±8.3% donor CD3+ T cells). We also found prolonged (rejection by day 36) acceptance of donor skin grafts in 7 of 12 recipients of B7.2−/− mDC and 2 of 5 recipients of B7.2−/− mDC and lin−BM. All third party C3H grafts were rejected by day 14 and 80% of the Balb/c (self) skin grafts were permanently accepted. We hypothesized that tolerized animals would behave similarly to recipients of megadoses of syngeneic BM with an increase in multilineage engraftment. We injected a total of 200x106 male wt B6 lin− BM cells over 5 days into adult IUT recipients of B7.1−/− or B7.2−/− mDC ± lin− wt BM and wt age-matched allogeneic and syngeneic (female) controls. Mice that had received B7.2−/− mDC + lin− BM in utero showed multi-lineage engraftment in the blood. In contrast, the in utero recipients of B7.1−/− mDC + lin− BM showed no significant engraftment (p<0.05). In conclusion, donor DC costimulatory molecules significantly affect survival, engraftment and GvHD; and these responses to B7.2−/− mDC and lin− BM appear to be mediated by both Th2 and Treg donor cells.
HDAC3, a Class I Histone Deacetylase, Interacts with the P38 Pathway and Suppresses MAPK11-Mediated ATF-2 Activation and TNF Gene Expression.
Authors: Mahlknecht Ulrich , Will Jutta , Varin Audrey , Herbein Georges 
Published: October 2019

Abstract
During inflammatory events, the induction of immediate-early genes, such as tumor necrosis factor α (TNF), is regulated by signaling cascades including the JAK/STAT, NF-kB, and the p38 mitogen-activated protein kinase (MAPK) pathways, which result in phosphorylation-dependent activation of transcription factors. We observed the direct interaction of HDAC3, a class I histone deacetylase, with MAPK11 (p38 beta isoform) by west-western-based screening analysis, pull-down assay and two-hybrid system analysis. Results further indicated that HDAC3 decreases the MAPK11 phosphorylation state and inhibits the activity of the MAPK11-dependent transcription factor ATF-2. LPS-mediated activation of ATF-2 was inhibited by HDAC3 in a time- and dose-dependent manner. Inhibition of HDAC3 expression by RNA interference resulted in increased ATF-2 activation in response to LPS stimulation. In agreement with decreased ATF-2 transcriptional activity by HDAC3, HDAC3 repressed TNF gene expression and TNF protein production observed in response to LPS stimulation. Therefore, our results indicate that HDAC3 interacts directly and selectively with MAPK11, represses ATF-2 transcriptional activity and acts as a regulator of TNF gene expression in LPS stimulated cells, especially in mononuclear phagocytes.
Activation of the P38 MAPK Pathway Mediates Resistance to Ara-C y Bcr/Abl Positive Cells.
Authors: Sanchez Victor J. , Aceves Clara I. , Gomez Juan C. , Manso Felix , Romero Juan R. , Melo Junia V. , Sanchez-Prieto Ricardo 
Published: October 2019

Abstract
The chimeric protein Bcr/Abl has been connected to several signalling pathways such as AKT, JNK or ERK1/2. Here, we present evidence showing that Bcr/Abl is able to modulate the p38 MAPK pathway. Transient transfection experiments indicated that over-expression of Bcr/Abl in 293T is able to activate p38 MAPK or induce p73 stabilization, suggesting that c-Abl and Bcr/Abl share some biological substrates. Interestingly, the control exerted by Bcr/Abl on the p38 MAPK pathway was not only mediated by the tyrosine kinase activity of Bcr/Abl. In fact, Bcr alone is able to induce P38 MAPK activation specifically through MKK3. Supporting these observations Chronic Myeloid Leukaemia-derived K562 cells or BaF 3 cells stably transfected with Bcr/Abl showed higher levels of phosphorylated p38 MAPK compared to Bcr/Abl-negative cells. Interestingly, Bcr/Abl-negative cells activated p38 MAPK in response to Ara-C, while Bcr/Abl-positive cells were unable to activate p38 MAPK. Furthermore, inhibition of p38 MAPK activation by SKF860002 induces a resistant phenotype in Bcr/Abl negative cells. Our results demonstrate that the interference of Bcr/Abl in the p38 MAPK pathway is a key mechanism for explaining resistance to Ara-C in Bcr/abl positive cells.