bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autologous Stem Cell Transplantation after Myeloablative Therapy in First Remission May Be Beneficial in Patients with Advanced Stage Follicular Lymphoma after Front-Line Therapy with R-CHOP. An Analysis of Two Consecutive Studies of the German Low Grade Lymphoma Study Group (GLSG)
Authors: Hiddemann Wolfgang , Buske Christian , Kneba Michael , Dreyling Martin , Schmitz Norbert , Lengfelder Eva , Schmits Rudolf , Reiser Marcel , Metzner Bernd , Unterhalt Michael 
Published: October 2019

Abstract
The addition of Rituximab (R) to front-line combination chemotherapy has substantially improved the long term perspectives of patients with advanced stage follicular lymphoma (FL) resulting in median progression free survival (PFS) times of more than 36 months. In this situation the potential role of myeloablative herapy with subsequent autologous stem cell transplantation (ASCT) in 1st remission needs to be critically reassessed. For this purpose two consecutive studies of the GLSG were analyzed both randomizing in 1st remission for Interferon alpha (IFN) maintenance therapy versus ASCT. In the GLSG trial ‘96 initial therapy comprised a randomized comparison of CHOP versus Mitoxantrone, Chlorambucil and Prednisone (MCP) (total patient number 312) while in GLSG study ‘00 CHOP was randomly compared to R-CHOP (total patient number 268). Hence, both studies had an identical treatment arm of CHOP followed by either IFN maintenance or ASCT. In both studies, the identical treatments revealed superimposable results with a 5 years PFS of 27% after CHOP and IFN maintenance and 66% after CHOP followed by ASCT. Taking these data as internal control R-CHOP followed by IFN maintenance achieved a 5 year PFS of 67% which is hence comparable to CHOP followed by ASCT. R-CHOP followed by ASCT, however, revealed a 5 year PFS of 79% with only one relapse after 24 months.
Figure Figure
Although the difference between R-CHOP followed by IFN maintenance or ASCT is currently not yet significant it strongly suggests a beneficial effect of ASCT in the era of R-CHOP front-line therapy particularly for intermediate of high risk patients with advanced stage FL.
Generation of vFLIP Transgenic Mice: A Model to Study KSHV-Associated Lymphomagenesis
Authors: Ballon Gianna , Chadburn Amy , Perez Rocio , Liu Yi-Fang , Sasaki Yoshiteru , Cesarman Ethel 
Published: October 2019

Abstract
Primary effusion lymphoma (PEL) is a distinct subtype of aggressive non-Hodgkin’s lymphoma (NHL), specifically associated with infection by Kaposi’s sarcoma-associated herpesvirus (KSHV) and occurring more frequently in HIV-infected individuals. Several in vitro observations suggest that vFLIP, a viral protein expressed during latency, is an important viral oncogene. It is essential for the survival of KSHV-infected PEL cells, mainly by constitutively activating the NF-kB pathway. In order to assess the role of vFLIP in the pathogenesis of PEL, we knocked a cDNA encoding vFLIP, preceded by a loxP-flanked neoR-Stop cassette and followed by Frt-flanked IRES-eGFP sequences, into the ubiquitously expressed ROSA26 locus. A specifically restricted expression of the transgene in CD19+ B-cells has been achieved by crossing the ROSA26. vFLIP knock-in mice with mice expressing cre recombinase under the control of the CD19 promoter. These mice have also been crossed with transgenic mice expressing KSHV LANA, which is considered to also be a viral oncogene, to assess a potential synergistic effect of these two KSHV latent proteins in the lymphomagenic process of PEL. vFLIP expression in the CD19+ B-cells results in splenomegaly, with an increase in both T and B-cells, and with a relative increase of the T versus B-cell ratio. Although primary follicles were enlarged, the expression of vFLIP in the CD19+ B-cells results in lack of germinal center formation in the spleen, lymph nodes and intestine, and in partially impaired class-switching recombination. vFLIP transgenic mice had an increased number of plasmablast-like cells expressing lambda light chain, reminiscent of a phenomenon seen in KSHV-associated multicentric Castleman’s disease (MCD). These results indicate that by constitutively activating the NF-κB pathway in pre-germinal center B-cells expressing CD19, the normal B-cell differentiation is impaired, and provide clues about possible aberrant differentiation in PEL and MCD.
Rituximab (R) + Hypercvad Alternating with R-Methotrexate/Cytarabine after 9 Years: Continued High Rate of Failure-Free Survival in Untreated Mantle Cell Lymphoma (MCL)
Authors: Romaguera Jorge , Fayad Luis , Rodriguez Alma , Hagemeister Fb , Pro Barbara , McLaughlin Peter , Younes Anas , Samaniego Felipe , Shah Jatin , Weaver Pamela , Hartig Kim , Cabanillas Fernando , Kwak Larry , Kantarjian Hagop , Wang Michael 
Published: October 2019

Abstract
MCL has a poor outcome with current non-intense therapies. We present an update of our results utilizing an intense chemotherapy regimen comprising fractionated cyclophosphamide, doxorubicin, vincristine and dexamethasone to which rituximab has been added (R-HyperCVAD, one cycle), alternating with rituximab and high dose methotrexate/cytarabine (R-MA, one cycle) for a total of 6–8 cycles (J Clin Oncol 2006 Feb 1;24(4):724). Treatment was started at most within 2 months from the initial evaluation. Overall survival (OS) was defined as the time from start of treatment until recurrence or death from any cause. Failure-free survival (FFS) was defined as the time from start of treatment until recurrence or death from toxicity or death from treatment-related malignancy. Of 97 consecutive evaluable patients, 87% achieved a complete response (CR) or unconfirmed CR after 6 cycles and did not receive additional therapy. With a median follow up on 84 months (7 years), the overall survival and failure-free survival at 7 years was 60% and 43%, respectively. Among patients 65 years of age or younger, the 7-year OS and FFS was 68% and 52%, respectively. Important prognostic variables included age (65 yrs or less vs > 65 yrs; initial serum B2 microglobulin 3 or less mg/dL vs > 3); and initial serum lactate dehydrogenase (normal vs > normal). Further subset analysis will be presented at the meeting.
Figure Figure
Rituximab Maintenance Treatment of Relapsed/Resistant Follicular Non- Hodgkin’s Lymphoma: Long-Term Outcome of the EORTC 20981 Phase III Randomized Intergroup Study
Authors: Van Oers Marinus H.J. , Van Glabbeke Martine , Baila Liliana , Giurgia Livia , Klasa Richard , Marcus Robert E , Wolf Max , Kimby Eva , Hagenbeek Anton 
Published: October 2019

Abstract
Background. In 2005 we analyzed the results of a prospective randomized phase III intergroup trial evaluating the role of rituximab (R) both in remission induction and maintenance treatment of 465 relapsed/resistant follicular lymphoma (FL) patients. Major conclusions were that addition of R to CHOP induction yielded an increased ORR and CR rate, and that R maintenance strongly improved median progression free survival (PFS), both after induction with CHOP and R-CHOP, and overall survival (OS (van Oers et al Blood2006;108:3295). At that time the median follow for the maintenance phase was 33 months. Now we report the long-term outcome of maintenance treatment, with a median follow up of 6 years from start of maintenance.
Study design. Patients with stages III or IV FL at initial diagnosis and relapsed after or resistant to a maximum of two non-anthracycline containing systemic chemotherapy regimens, were randomized to remission induction with either 6 cycles of standard CHOP (once every 3 weeks) or CHOP + R (375 mg/m2 at day 1 of each cycle of CHOP). Those with a complete or partial remission after 6 cycles of therapy underwent a second randomization to no further treatment (observation) or maintenance treatment with R (375 mg/m2 once every 3 months) until relapse or for a maximum period of two years.
Results. 465 patients were randomized to induction with either CHOP (231) or R-CHOP (234). As reported, CHOP and R-CHOP induction yielded similar partial response rates (57% vs.56%), but significantly different CR rates (16% and 29%; p=0.0001). 334 patients were randomized to either R maintenance treatment (167) or observation (167). R maintenance resulted in a highly significant improvement of PFS: median 3.7 years versus 1.3 years in the observation arm (p<0.0001; hazard ratio 0.55). The advantage of R maintenance was observed both after CHOP induction (p< 0001: HR 0.37) and R-CHOP induction (p= 0.003; HR 0.69). The 5 years OS was 74% in the R maintenance arm and 64 % in the observation arm (p=0.07). That the highly improved PFS after R maintenance did not translate into a significant OS advantage might partially be explained by the fact that 41% of progressing patients received R as salvage therapy. This varied according to treatment arm: from 59% after CHOP followed by observation to 26% after R-CHOP followed by R maintenance. R maintenance was associated with a significant increase in grade 3/4 infections: 9.7% vs.2.4% (p= 0.01). 7 of the 167 patients had to discontinue R maintenance because of toxicity, mostly recurrent infection.
Conclusion. With long term follow-up we confirm the superior PFS with R maintenance. The improvement of OS did not reach statistical significance, possibly due to the abundant use of R in post-protocol salvage treatment.
Bortezomib Induces Thrombocytopenia by Inhibiting Proplatelet Formation but Not Proliferation and Endomitosis in Human Primary Megakaryocytes
Authors: Nogami Wataru , Yamane Akiko , Nakamura Takanori , Matsuki Eri , Ikeda Yasuo , Miyakawa Yoshitaka 
Published: October 2019

Abstract
The proteasome inhibitor bortezomib has therapeutic activity in patients with multiple myeloma. The most common adverse event from its application is thrombocytopenia, which has kinetics that differ from those induced by other cytotoxic agents. After treatment with bortezomib, platelet counts usually decrease within a couple of days but rapidly recover toward baseline during the rest periods between each cycle. The lowest count of platelets in each cycle does not worsen during the 8 courses of bortezomib treatment. Furthermore, bortezomib does not induce any cytotoxic injury in megakaryocyte in the murine model. Therefore, we postulated that bortezomib-induced thrombocytopenia is caused by inhibition of the platelet releasing process without megakaryocyte toxicity. In vitro assays using human bone marrow-derived CD34-positive hematopoietic stem cells revealed that bortezomib did not inhibit colony formation and endomitosis of human primary megakaryocytes in the presence of recombinant human thrombopoietin (rhTPO). As proplatelet formation (PPF) is often used as the indicator of the platelet releasing process in vitro, we evaluated the inhibitory effects of bortezomib for PPF. Seven days after culture of human CD34-postive cells with 10 ng/ml rhTPO, mature megakaryocytes were enriched by discontinuous bovine serum albumin gradients (purity>90%). The enriched mature megakaryocytes were treated with various concentrations of bortezomib for a further 4 days and the percentage of megakaryocytes bearing PPF was calculated under a microscope. Bortezomib dose-dependently inhibited PPF from mature megakaryocytes. Other proteasome inhibitors such as lactacystin and MG132 also demonstrated inhibitory effects on PPF without inhibiting colony formation of megakaryocytes. Since the inhibition of transcriptional factor NF-kB activity is one of the major pathways of proteasome inhibitors, we evaluated the effects of NF-kB inhibitors such as (−)-DHMEQ and Bay11-7082. Both of these inhibitors also demonstrated inhibitory effects on PPF but did not inhibit the colony formation of megakaryocytes. To exclude the direct effects of bortezomib on human platelets, we analyzed the effects of bortezomib for the activation of caspase-3 and mitochondrial potential in human platelets. We found that bortezomib did not directly induce apoptosis in human platelets. Our results demonstrate that bortezomib induces thrombocytopenia by inhibiting PPF but does not affect proliferation of megakaryocytes, endomitosis and platelet apoptosis. We believe this is the first report using human primary megakaryocytes to clarify the pathogenesis of thrombocytopenia caused by bortezomib therapy.
BMP4 and TGFbeta Differentially Regulate CD34+ Progenitor Development in Human Embryonic Stem Cells through SMAD-Dependent Pathway
Authors: Wang ZacK Z. , Bai Hao , Arzigian Melanie , Gao Yong-Xing , Wu Wen-Shu 
Published: October 2019

Abstract
Pluripotent stem cells derived from patients, including embryonic stem (ES) cells and “induced pluripotent stem” (iPS) cells, are a promising area of regenerative medical research. A major roadblock toward human clinical therapies using ES cells or iPS cells is to define the factors that direct ES cell differentiation into lineage specific cells. We previously established a simple and efficient human embryonic stem cell (hESC) differentiation system to generate CD34+/CD31+ progenitor cells that gave rise to hematopoietic and endothelial cells (Nat Biotech.25:317, 2007). To advance potential clinical application and to define the effects of growth factors on hematopoietic and vascular differentiation, we assessed hESC differentiation on human feeder cells in serum-free condition without intermediate embryoid body (EB) formation. We investigated the roles of BMPs, TGFbeta, VEGF, and FGF2 in directing hESC differentiation. Growth factors were added into culture at different time points to test their stage specific roles. Our study demonstrated that BMP proteins, including BMP2, BMP4, and BMP7, but not BMP9, had synergic effects to VEGF and FGF-2 on hESC differentiation to CD34+/CD31+ progenitor cells. BMP4 was essential to initial CD34+/CD31+ cell development, whereas VEGF and FGF2 promoted the differentiation in later stage, suggesting the sequential roles of BMP4, VEGF and FGF2 in directing hESC differentiation to CD34+/CD31+ progenitor cells. TGFbeta or activin promoted hESC differentiation into CD34+/CD31− cells that were unable to give rise to hematopoietic, endothelial, and smooth muscle cells. Furthermore, TGFbeta or activin activated Smad2/3 signaling, and suppressed BMP4-induced CD34+/CD31+ cells. Microarray analysis revealed that BMP4-induced CD34+ cells expressed hematopoietic, endothelial and smooth muscle genes, including GATA2, gamma globins, VE-Cad, KDR, CD31, Tie2, and aortic smooth muscle actin, whereas TGFbeta-induced CD34+ cells expressed pluripotent markers and endoderm markers, including Oct3/4, Sox2, and Nanog, HHEX, GATA6, and FoxA2. Both canonical BMP signaling (Smad1/5/8-dependent) and non-canonical BMP signaling (p38 MAPK and p42 ERK pathway) were activated by BMP4 in hESCs. Dorsomorphin specifically inhibited BMP4-mediated phosphorylation of Smad1/5/8, and blocked hESC differentiation into CD34+/CD31+ cells. In summary, BMPs and TGFbeta regulate distinct populations of CD34+ cells in hESCs. BMP-Smad1/5/8 pathway is critical for hematopoietic and vascular progenitor development.
Rare Polymorphisms Associated with Neonatal Alloimmune Thrombocytopenia (NATP) and New Mutations Identified in Platelet Glycoproteins (GP)
Authors: Peterson Julie A. , Gitter Maria , Kanack Adam , Curtis Brian , McFarland Janice , Aster Richard H. 
Published: October 2019

Abstract
Neonatal Alloimmune Thrombocytopenia (NATP) is caused by maternal immunization against alloantigens carried on paternal platelet glycoproteins (GP). Although common antigens and their corresponding antibodies can be reliably detected, about two-thirds of suspected cases of NATP go unresolved. We are investigating the extent to which maternal immunization against low frequency antigens not usually tested for contributes to the relatively low diagnostic yield in NATP evaluations. In the course of this work, we have identified eight previously undescribed amino acid substitutions located in four different platelet GPs (Table 1).
Table 1. Eight new mutations identified in platelet glycoproteins
Name Sta Kno Sol Brc Bec Aus Rou2 Rou1 GP IIIa IIb IIIa Ia IIIa Ibb IIb IIb Mutation K137Q T619M E628K E505V K646E D13H G790S T9A
The incidence of each mutation in the general population is less than 1.0%. Antigens Sta and Kno were each identified in fathers of suspected NATP cases and in the affected infants. In addition, maternal antibodies reacted with recombinant GPs modified to contain the relevant mutations, making it very likely that the antibodies were the cause of NATP in these instances. Antigen Sol was identified in the father and maternal antibody reacted strongly with paternal GPIIb/IIIa. However, the infant has not yet been typed. It is likely, but not certain that immunization against Sol caused NATP in this case. Mutation Brc was found in the father of an infant with possible NATP. However maternal serum failed to react with GPIa from father’s platelets and it was not possible to type the affected infant. Mutations Bec, Aus and Rou2 were identified in paternal DNA but the affected infants were negative for these mutations. Mutation Rou1 was identified in maternal DNA and could not have been an immunogen. It is highly likely that three of the eight new mutations (Sta, Kno, and Sol) caused maternal immunization leading to NATP. However, the other five (Bec, Aus, Brc, Rou1 and Rou2) appear to have been identified incidentally in the course of the NATP evaluations. Before concluding that maternal-fetal incompatibility for a rare antigen identified in the father is the immunogen responsible for triggering NATP these findings emphasize the importance of typing an affected infant to determine whether a low frequency antigen identified in the father was inherited. In addition it is necessary to confirm that maternal serum reacts with the suspected paternal antigen incorporated into a recombinant protein or carried on platelets from an unrelated individual.
Protein Synthesis Escapes mTORC1 Control and Constitutes a Promising Therapeutic Target in Acute Myeloid Leukemia.
Authors: Tamburini Jerome , Green Alexa Samantha , Bardet Valérie , Chapuis Nicolas , Willems Lise , Park Sophie , Uzunov Madalina , Ifrah Norbert , Dreyfus Francois , Mayeux Patrick , Lacombe Catherine , Bouscary Didier 
Published: October 2019

Abstract
The deregulation of translation, leading to a preferential translation of oncogene-related mRNAs, markedly contributes to the malignant phenotype in human cancers. The assembly of the eukaryotic translation Initiation Factor 4F (eIF4F) complex is limiting for malignancy-related translation events and is hence an attractive anticancer therapeutic target. The Mammalian Target Of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through eIF4E Binding Protein 1 (4E-BP1) phosphorylation. The mTORC1 inhibitor rapamycin has been developed as an anti-cancer agent but is of limited efficacy in the treatment of Acute Myeloid Leukemia (AML). We show in our study that in primary AML cells, 4E-BP1 phosphorylation is mTORC1-independent and is in fact controlled by the Pim- 2 serine/threonine kinase: neither the rapamycin derivate RAD001 nor Raptor siRNA inhibited 4E-BP1 phosphorylation contrary to siRNA-mediated Pim-2 knock-down. We utilized the 4E-BP1 mimetic 4EGI-1, as a direct inhibitor of translation in AML. In contrast to RAD001, 4EGI-1
totally inhibited eIF4F assembly; markedly decreased the proportion of polysome-bound c-Myc mRNA; and dramatically decreased the accumulation of oncogenic proteins that are regulated at the translational level.
Moreover, 4EGI-1 demonstrated potent anti-leukemic activity ex vivo in primary AML blast cells through a selective suppression of proteins implicated in proliferation and in anti-apoptotic mechanisms. Significantly, these effects occurred with a minimal degree of toxicity against normal hematopoietic processes. Our present results therefore strongly implicate an mTORC1-independent mechanism of deregulated synthesis of oncogenic proteins in human myeloid leukemogenesis. The direct inhibition of the eIF4F translation initiating complex, by 4EGI-1, by the recently developed eIF4E antisense oligonucleotides or by specific Pim-2 inhibitors when available, thus represents an attractive option for the development of new therapies for AML.
mTORC1 Activity Is Independent of PI3K/Akt but Controlled by AMPK in Acute Myeloid Leukemia.
Authors: Green Alexa Samantha , Tamburini Jerome , Willems Lise , Chapuis Nicolas , Park Sophie , Bardet Valérie , Foretz Marc , Viollet Benoit , Ifrah Norbert , Dreyfus Francois , Mayeux Patrick , Lacombe Catherine , Bouscary Didier 
Published: October 2019

Abstract
In most cancer models, the PI3K/Akt pathway controls the activity of the mammalian Target of Rapamycin Complex 1 (mTORC1) that regulates cell growth through the phosphorylation of P70S6K and 4E-BP1. In Acute Myeloid Leukemia (AML), both constitutive activation of PI3K (PI3K+) and of mTORC1 are detected. We previously reported in AML that PI3K activity is due to the expression of the p110d isoform of class Ia PI3K and is constitutive in 50% of samples at diagnosis. We show here in primary AML samples that the constitutive activity of mTORC1, detected by the phosphorylation of P70S6K on Thr389, is not due to PI3K/Akt activation. In PI3K+ samples, the specific inhibition of p110d with IC87114 does not inhibit mTORC1. Furthermore, a constitutive activity of mTORC1 is detected in almost all AML samples regardless of their PI3K/ Akt activation status. Similarly, the inhibition of ERK/MAPK activity with UO126 does not result in mTORC1 inhibition. Interestingly, in primary AML cells, we shows that mTORC1 is fully inhibited following leucine starvation as observed in non-transformed cells, suggesting that the kinase activity of mTOR is not deregulated and remains accessible to target inhibition. We thus focused on the links between the AMP kinase (AMPK) and mTORC1. AMPK is a physiological cellular energy sensor and becomes phosphorylated at Thr172 downstream of LKB1 in response to a decrease in cellular ATP levels. AMPK then controls multiple metabolic processes such as fatty acid oxidation, glucose production and protein synthesis. Interestingly, AMPK is usually unphosphorylated in cancer cells including AML and thereby represents a potential therapeutic target. We thus investigated the effects of metformin, a potent AMPK activator developed as an oral anti-diabetic drug, in primary AML cells. This compound induces a dose-dependent activation of AMPK that correlates with a decrease of mTORC1 activity. Primary AML blast cells cultured with metformin show a significant inhibition of proliferation, of clonogenic growth and apoptosis suggesting that AMPK may be an attractive anticancer therapeutic target in AML. However, as metformin may exerts AMPK-independent effects, we are producing a lentiviral construct expressing a constitutively activated AMPK mutant to more specifically determine the consequences of AMPK activation in mTORC1 signaling and blast cells survival.