bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Impact of Mutations in the Nucleophosmin (NPM1) and of the FMS-Related Tyrosine Kinase 3 (FLT3) Genes in Elderly Patients with Acute Myeloid Leukemia (AML) Treated with Intensive Chemotherapy
Authors: Etienne Anne , Borel Cecile , Reutenauer Sarah , Olschwang Sylviane , Mozziconacci Marie-Joelle , Delabesse Eric , Demur Cecile , Prebet Thomas , Huguet Francoise , Charbonnier Aude , Recher Christian , Vey Norbert 
Published: April 2020

Abstract
AML is a heterogeneous disease and the actual most reliable prognostic factor is the karyotype. Mutations of NPM1 and FLT3 constitute the most frequent molecular genetic alterations in patients with AML. Their prognostic impact is now well recognized, especially in young patients with intermediate prognosis karyotype. However few studies have focused on elderly patients. We retrospectively studied the prevalence of NPM1 mutation and FLT3 internal tandem duplications (ITD) and its association with complete remission (CR) and survival in 86 patients aged 61 years or older treated between 1996 and 2007 for acute non promyelocytic leukemia with intermediate karyotype in the Institut Paoli-Calmettes, Marseille, and the university hospital of Toulouse. All patients received intensive induction chemotherapy (“3+7” regimen). Median age was 70 years (range, 61–79). The median follow-up of surviving patients was 34 months. 44 patients (51%) had NPM1 mutation and 21 had FLT3-ITD (24%). In the NPM1 mutated group, there were significantly more: female patients, absence of antecedent hematologic disorder, de novo AML, and low CD34 expression. In the FLT3-ITD group, there were significantly more: female patients, increased white blood cell counts and peripheral blood blasts. Overall CR rate was 67%; median disease free survival (DFS) and overall survival (OS) were 11 and 10 months, respectively. CR rate was negatively associated with a poor performans status and a high score previously described including assessment of comorbidities (Etienne et al., Cancer2007; 109(7):1376–83). CR rate was 57% versus 72% for patients with FLT3-ITD compared to patients with wild-type FLT3 (p 0.2), and 64% versus 71% for the NPM1 mutated group compared with the NPM1 non-mutated group (p 0.5). Median OS was 6 months versus 12 months for patients with FLT3-ITD mutation versus wild type patients (p = 0.04). Median OS was 9 months for patients with NPM1 mutation and did not differ from non-mutated patients. No significant difference in term of CR rate and OS was found between the 29 patients carrying NPM1 mutation without FLT3-ITD and the 57 other patients without NPM1 mutation or with FLT3-ITD. Median DFS was 21 months versus 9 months for these two groups, respectively (p 0.2). These results confirm the prognostic impact of FLT3-ITD in our series of old patients with AML. Unlike young patients, NPM1 mutated elderly patients have a similar outcome than NPM1 wild type patients. The absence of prognostic impact of NPM1 mutation without FLT3-ITD has to be validated on larger prospective cohort. FLT3 status should be taken into account for treatment choices in elderly patients.
Identification of Novel Activities of Immunomodulatory Drugs: Cytoskeleton Reorganization through Modulation of Rho GTPases
Authors: Xu Yibing , Li JianWu , Ferguson Greg , Mercurio Frank , Khambatta Gody , Morrison Lisa , Lopez-Girona Antonia , Corral Laura G , Webb David , Bennett Brydon L. , Xie Weilin 
Published: April 2020

Abstract
Immunomodulatory drugs including the IMiDs®, lenalidomide, and pomalidomide represent a novel class of compounds that have both anti-cancer and anti-inflammatory properties. While many studies have demonstrated that IMiDs have broad in vitro and in vivo biological activities including antiangiogenesis, inhibition of TNFa expression, enhancement of antitumor immunity, and induction of IL-2 in T cells, the molecular mechanism through which these drugs exert their effects is largely undefined. In primary human monocytes, IMID1 selectively activated RhoA and Rac1, but not Cdc42 or Ras. Importantly, the activation of these GTPases occurred immediately following treatment with IMID1 in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that IMID1enhanced F-actin formation, stabilized microtubules, and increased monocyte cell migration, all of which were blocked by selective inhibitors of ROCK1, a downstream effector of RhoA or Rac1. Finally, we demonstrated that IMID1 was able to regulate the activity of Rho GTPases and formation of F-actin in primary human T cells similarly as it did in monocytes, and showed that the activation of RhoA was essential for IMID1-induced IL-2 expression in T cells. In conclusion, these studies demonstrate a novel and acute molecular activity from IMiDs mediated via Rho GTPases. Activation of Rho by IMiDs and the resulting effect on cytoskeletal reorganization may represent a critical mechanism by which IMiDs function as therapeutic immunomodulatory agents.
Crystal Structure of Von Willebrand Factor (VWF) A1 Domain in Complex with Aptamer ARC1172, An Inhibitor of VWF-Platelet Binding
Authors: Huang Ren-Huai , Fremont David , Tuley Elodee A , Diener John L , Schaub Robert G , Sadler J. Evan 
Published: April 2020

Abstract
ARC1779 is a modified 40-mer oligonucleotide aptamer that binds with high affinity to the VWF A1 domain and blocks VWF binding to platelet GPIb-alpha. When given intravenously to volunteers and assayed ex vivo, ARC1779 dose-dependently inhibits VWF activity and prolongs the PFA-100 closure time with EC90 values of 2–3 μg/ml. ARC1779 also inhibits carotid artery thrombosis induced by electrical injury in nonhuman primates. These properties suggest that ARC1779 may be useful to prevent or treat platelet-dependent thrombosis in acute coronary syndromes, percutaneous coronary intervention procedures, or thrombotic thrombocytopenic purpura. To characterize this aptamer-VWF interaction, we determined the crystal structure of a complex between recombinant VWF domain A1 (residues 497–705, mature subunit numbering) expressed in E. coli and ARC1172, a 41-mer DNA oligonucleotide with the sequence 5′-GGC GTG CAG TGC CTT CGG CCG TGC GGT GCC TCC GTC ACG CC-invdT-3′. ARC1779 was derived from ARC1172 by adding modifications to prevent digestion by nucleases, and both aptamers bind VWF A1 with the same affinity. Crystals of the complex belonged to space group P212121 and diffracted to 2.4 angstroms. The A1 domain (Figure) has essentially the same structure as observed previously in isolation or bound to GPIb-alpha, botrocetin, bitiscetin, or Fab NMC4. Therefore, aptamer binding does not substantially alter the conformation of the VWF A1 domain. ARC1172 consists of three short helical segments and three connecting loops. Nucleotides C32-C40 interact with two segments G23-G26 and G2-G6 to form a 9-basepair helix with an interruption in one strand. The interruption comprises residues C7-T22, which protrude to form a 3-basepair helix between G11-C13 and G17-C19. The loop of ARC1172 composed of nucleotides G26-C32 makes extensive contacts with VWF A1 residues in helix alpha-4 (yellow) and alpha-5 (orange) and loop betaD-alpha4. For example, the side chains (shown in Figure) of Q625, Q628, R632 and Y637 participate in numerous hydrogen bonds and salt-bridges with ARC1172 (e.g., Q625 contacts C29), and R632 is buried within a deep pocket of the aptamer. Botrocetin occupies a similar interface on VWF A1, which accounts for the ability of ARC1172 or ARC1779 to block botrocetininduced platelet aggregation. In addition, nucleotide T10 extends toward helix alpha3 (lime green) and obstructs residue K599, which is required for binding to platelet GPIbalpha. The results provide a structural explanation for many of the functional properties of aptamers ARC1172 and ARC1779.
Figure Figure
A Phase II Study of the Purine Nucleoside Phosphorylase (PNP) Inhibitor RO5092888 (BCX-4208) in Patients with Moderate to Severe Chronic Plaque Psoriasis: Safety, Tolerability and Lymphocyte Effects
Authors: Gomes Joseph P , Georgy Angela , Passe Sharon , Farid Adrienne , Bantia Shanta , Wolff Gerhard 
Published: April 2020

Abstract
Introduction: PNP is a purine-metabolizing enzyme that catalyzes the phosphorolysis of 2′-deoxyguanosine [dGuo] to guanine and deoxyribose-1-phosphate. In T-cells, PNP inhibition leads to accumulation of deoxyguanosine triphosphate (dGTP), triggering apoptotic cell death. Chronic-plaque type psoriasis (psoriasis) is an autoimmune disorder, in which T-cells contribute, at least in part, to the manifestations and maintenance of the disease. Therefore, targeting T-cells may be a beneficial treatment strategy. Since for chronic inflammatory diseases the safety of potential immunosuppressive drugs is a major consideration, we conducted this study to investigate safety and tolerability of oral RO5092888 (BCX-4208) in patients with moderate to severe chronic plaque psoriasis.
Methods: This was a randomized, double-blind, placebo-controlled, dose-ranging study. Sixty-six patients 18 to 70 years old were randomized into one of three groups: placebo, 20mg/d or 120mg/d. The study was conducted from August 2007 to June 2008. Patients received study drug over six weeks and were observed over an additional 4 weeks. Assessments for safety included tracking of adverse events (AEs) including infections; vital signs; ECGs; chemistry panel; LFTs; hematologic parameters including peripheral blood (PB) lymphocyte subsets CD3+, CD4+, CD8+, CD56+, CD20+; and urinalysis.
Results: 65 of the 66 enrolled patients were analyzed. One serious AE was observed in the 20mg/d group, a deep vein thrombosis (DVT) in a patient with a history of DVTs, and was considered unrelated to study drug. The percentage of patients experiencing at least one adverse event (AE) of any grade was placebo: 33% (7/21), 20mg: 41% (9/22), and 120mg: 59% (13/22). During treatment, two infections occurred in the placebo group (influenza and sinusitis), one in the 20mg group (nasopharyngitis), and 4 in the 120mg group (2-upper respiratory tract infections, 1 bronchitis, and 1 otitis externa). Reductions in PB lymphocytes and subsets were observed (Table 1). Nine patients showed decreased levels of CD4+ lymphocytes, below 350 cells/μL (20mg/d, 3; 120mg/d, 6).
Conclusion: Daily oral administration of 20 mg or 120 mg of RO5092888 for up to 6 weeks demonstrated adequate safety and tolerability. Reductions in PB T cells, T cell subsets and B cells were observed. Further investigation of RO5092888 is warranted in both T-cell and B-cell diseases.
Lymphocyte subpopulation Mean Nadir (% change from baseline) Placebo (n=21) 20 mg (n=22) 120 mg (n=22) CD3+ 24.0 30.6 47.5 CD4+ 23.6 28.9 44.9 CD8+ 26.1 31.8 53.9 CD20+ 37.5 42.6 64.2 CD56+ 40.1 47.7 72.6
Table 1
VWF-Cleaving Protease ADAMTS13 Reduces Brain Injury Following Ischemic Stroke in Mice: Essential Role for VWF in Stroke
Authors: Zhao Bing-Qiao , Chauhan Anil kumar , Patten Ian S. , Dockal Michael , Scheiflinger Friedrich , Wagner Denisa D. 
Published: April 2020

Abstract
Ischemic stroke is the second leading cause of death and disability. The only approved therapy available is recombinant tissue plasminogen activator (tPA), but its use remains limited. Therefore, there is a need for an alternative drug. Platelets and their adhesion receptors play a crucial role in modulating infarct size during ischemic stroke. ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) is a plasma metalloprotease that cleaves von Willebrand factor (VWF) an important adhesion molecule for platelets at sites of vascular injury. In patients, an increase in circulating levels of VWF and a decrease in ADAMTS13 activity are considered risk factors for ischemic stroke. By using genetically-modified mice we have previously shown that ADAMTS13 down regulates both thrombosis and inflammation and recombinant human ADAMTS13 down regulates platelet thrombi in injured arterioles. All these processes were dependent on VWF. We therefore hypothesize that ADAMTS13 has a protective role after ischemic stroke. In this study, we show that VWF deficiency or VWF heterozygosity in mice reduces infarct volume by two-fold after focal cerebral ischemia compared to wild-type (WT) in the middle cerebral artery occlusion (MCAO) stroke model. Furthermore, infusion of recombinant human VWF in WT mice not only accelerates thrombosis in the ferric-chloride injured artery model, but also increases infarct volume compared to vehicle-treated controls. These findings suggest an essential role of VWF in modulating infarction after stroke. We also show that ADAMTS13 deficiency in mice results in approximately 20% larger infarcts after cerebral ischemia compared to WT. The larger infarcts observed in ADAMTS13 deficient mice were due to VWF because mice deficient in both ADAMTS13 and VWF had infarct sizes similar to VWF deficient mice. Importantly, infusion of r-human ADAMTS13 immediately before reperfusion (two hour after occlusion) significantly reduced infarct volume (106.2 ± 9.7 mm3 vs 75.8 ± 6.9 mm3, P&lt;0.05). Of note, we observed that ADAMTS13 protein was induced in the ischemic penumbra region of brain after ischemic stroke. Our findings reveal an important role for VWF in modulating infarct volume after ischemic stroke. In addition, recombinant-ADAMTS13 could become a new therapeutic agent for stroke therapy.
Confirmation of the Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Relapsed or Refractory Mantle-Cell Lymphoma: Results of An International Study (NHL-003)
Authors: Zinzani Pier Luigi , Witzig Thomas E. , Vose Julie M. , Reeder Craig B. , Buckstein Rena , Haioun Corinne , Bouabdallah Reda , Polikoff Jonathan , Guo Pingshan , Ervin-Hayes Annette , Pietronigro Dennis , Zeldis Jerome B. , Czuczman Myron S. 
Published: April 2020

Abstract
Introduction: Mantle-cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma (NHL) that typically responds to initial chemo-immunotherapy, but with a relatively short duration of response (DR) and progression-free survival (PFS) when treated with conventional chemotherapy agents. Although the overall survival (OS) of MCL has improved, most patients are not cured and new agents are needed. A sub-analysis of a recent phase II trial (NHL-002) investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL, demonstrated a promising overall response rate (ORR) of 53% with a median DR of 11.9 months. A confirmatory international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed/refractory aggressive NHL that had received at least one prior treatment and had measurable disease. In this report, we analyze the current results from the MCL patients enrolled in this trial.
Methods: Patients with relapsed or refractory MCL and measurable disease ≥2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression.
Results: This report focuses on the 39 MCL patients that were enrolled and evaluable for response assessment. Median age was 66 (33–82) years and 29 (74%) patients were male. Median time from diagnosis to lenalidomide treatment was 3.4 (0.4–9) years. Patients had received a median of 3 (1–8) prior treatments, and 23% (9/39) of patients had received prior bortezomib treatment. The ORR with lenalidomide was 41% (16/39), including 13% (5/39) complete response (CR)/unconfirmed CR, and 28% (11/39) partial responses. Ten (26%) patients had stable disease. The most common grade 3 or 4 adverse events were neutropenia (51%) and thrombocytopenia (25%), anemia (13%), fatigue (10%) and febrile neutropenia (10%).
Conclusion: These results confirm that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects.
Inhibitors of Heat Shock Protein 72 Induction Enhance Apoptosis Induced by Hsp90 Inhibitors
Authors: Davenport Emma , Zeisig Athanasia , Wiseglass Lauren , Moore Hannah E. , Hockley Sarah L. , Gonzalez David , Smith Emma , Sharp Swee , Workman Paul , Morgan Gareth J , Davies Faith 
Published: April 2020

Abstract
Exposure of myeloma cells to Hsp90 inhibitors (eg 17-AAG) or proteasome inhibitors (eg Bortezomib) results in a time-dependent induction of heat shock protein 72 (Hsp72), protecting cells from drug-induced apoptosis. Hsp72 is a member of the heat shock protein 70 (Hsp70) family and enables cells to cope with harmful aggregations of proteins during and after stress, protecting cells from apoptosis in addition to acting as a chaperone for proteins such as immunoglobulin. We show that inhibition of Hsp72 upregulation induced by these anti-myeloma drugs, by either inhibitors of Hsp70 induction or siRNA, increases susceptibility of myeloma cells to drug-induced apoptosis. This provides a rationale for using such inhibitors in combination with anti-myeloma drugs. A number of commercially available inhibitors of Hsp70 induction, including KNK437 and triptolide, were used to inhibit stress-induced upregulation of Hsp72. Combining Hsp90 inhibitors (Hsp90i) with these compounds increased cell death to 73% from 33% when Hsp90i were used alone. Cell cycle analysis indicated that combining these compounds with Hsp90 inhibitors overcame the G2 growth arrest induced by Hsp90 inhibitors and increased the proportion of cells in sub G1, indicative of apoptosis. Analysis of their anti-proliferative effects demonstrated that, in H929 cells, Hsp90 inhibitor/triptolide combinations had additive effects whilst in U266 cells their effects were synergistic. To determine the underlying mechanisms responsible for the effects of the combination, key proteins involved in endoplasmic reticulum (ER) stress, Unfolded Protein Response and caspase-dependent and independent signalling pathways were analysed. We show that ER stress signalling through IRE1 and PERK pathways, measured by cleavage of XBP1 and induction of CHOP, were initiated earlier and sustained longer, when cells were treated with the combination. Similarly, analysis of caspase-dependent and independent signalling demonstrated that the combination induced early cleavage of caspases 9, 8 and 3 which was sustained. Nuclear translocation of AIF, the caspase-independent cell death signal, was strongly induced suggestive of strong activation of this pathway. We demonstrate that death induced by triptolide or its combination with 17-AAG is p53-independent using of a panel of myeloma cell lines. To confirm our findings, we used lentiviral siRNA constructs targeting the inducible forms of Hsp70 and then analysed response to Hsp90 inhibitors. These experiments confirm the results generated using the chemical inhibitors of Hsp70 expression. In conclusion, inhibiting drug-induced Hsp72 expression appears to overcome cellular resistance to Hsp90 inhibitors, supporting the clinical development of Hsp70 inhibitors and their combination with Hsp90 and proteasome inhibitors.
NK Cell Anti-Tumor Immune Responses Are Impaired by Sorafenib but Not by Sunitinib
Authors: Krusch Matthias , Schlicke Manuela , Salih Julia , Baessler Tina , Kanz Lothar , Salih Helmut 
Published: April 2020

Abstract
Natural killer (NK) cells play an important role in the surveillance of tumors by exerting cellular cytotoxicity and also due to their ability to secrete immunoregulatory cytokines. A variety of intracellular kinases like PI3K, MAPKs or STAT molecules are involved in the regulation of NK cell functions. Therefore, treatment of tumor patients with small molecule inhibitors targeting various protein kinases may also largely affect NK cell anti-tumor reactivity. The multikinase inhibitors Sunitinib (SUTENT®) and Sorafenib (NEXAVAR®) have been approved for the treatment of patients with metastatic Renal Cell Carcinoma (RCC), and are now also being evaluated in various other tumor entities including AML. Both compounds target, among others, PDGF receptors, VEGF receptors, Flt3 and c-kit. Sorafenib additionally inhibits the MAPK pathway members B-RAF and c-RAF. Here we report that Sorafenib but not Sunitinib substantially reduces NK cell cytotoxicity as revealed by analysis of cell surface CD107a expression as a surrogate marker for mobilization of cytolytic granules on NK cells from ten healthy donors. In line, pharmacological levels of Sorafenib but not Sunitinib largely reduced lysis of several solid tumor and leukemia cell lines by primary NK cells, and this inhibitory effect of Sorafenib occurred concentration dependently. Furthermore, Sorafenib but not Sunitinib concentration dependently impaired NK cell IFN-γ production in coculture experiments with different tumor cell lines. Since Sorafenib, in contrast to Sunitinib, also potently inhibits RAF which is involved in MAPK activation we determined the influence of the two compounds on ERK phosphorylation which is important for the activation of NK cell anti-tumor reactivity. While Sunitinib had no effect, Sorafenib, alike the specific MEK inhibitor PD98059, markedly reduced ERK phosphorylation in NK cells. Taken together, out results indicate that NK cell-mediated anti-tumor immune responses are impaired by Sorafenib but not by Sunitinib via inhibition of signaling pathways crucial for NK cell effector functions. Thus, Sunitinib is exquisitely suitable in diseases and for therapeutic approaches which rely on a sufficient anti-tumor immune response like e.g. allogenic stem cell transplantation in AML or immunotherapeutic approaches in RCC patients.
Efficient Binding, but Moderate Modulation, of Human Dendritic Cell Functions by Milatuzumab, a Humanized Anti-CD74 Monoclonal Antibody
Authors: Chen Xiaochuan , Chang Chien-Hsing , Goldenberg David 
Published: April 2020

Abstract
Milatuzumab (hLL1, Immunomedics, Inc.), a humanized anti-CD74 immunoglobulin-G monoclonal antibody (MAb), has been shown to have therapeutic activity against CD74-expressing B-cell malignancies in vitro and in xenografts models, and is in clinical evaluation as a therapeutic MAb for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Since it is unclear whether this MAb has any effects on human antigen-presenting cells that express CD74, we investigated the binding efficiency, viability, and functional modulation of human dendritic cells (DC), the professional and most potent antigen-presenting cells, exposed to milatuzumab. We found that milatuzumab bound efficiently with B cells, monocytes, and different subsets of blood DCs including myeloid DC1 (BDCA-1+), myeloid DC2 (BDCA-3+) and plasmacytoid DC (BDCA-2+) in human PBMC, as well as with monocyte-derived immature DCs, but not LPS-matured DCs. The side-by-side comparative cytotoxicity assay showed that milatuzumab, in the presence of a second antibody for cross-linking (GAH, the F(ab′)2 of goat anti-human IgG Fcgamma-specific), dramatically reduced the cell viability of Daudi B-lymphoma cells, but did not influence the cell viability or induce apoptosis in monocyte-derived DCs, even at high concentations up to 50 μg/ml. At the concentrations ranging from 0.05 to 5 μg/ml, milatuzumab upregulated the expression of the antigen-presenting molecule, HLA-DR, and costimulatory molecules, CD54 and CD86, in human monocyte-derived DCs in a moderate, but dose-dependent manner, suggesting that milatuzumab could enhance DC constitutive maturation. Although this effect was not reflected by an enhanced T-cell expansion, as shown by unaltered CFSE-low, -medium, and –high peaks in total and CD4+ and CD4− T cells, milatuzumab-treated DCs could moderately promote the differentiation of CD4+ naïve T cells toward more Th1 effector cells, suggesting that milatuzumab can modulate DC functions, inducing the polarization and differentiation of functional Th cells. These data highlight the prospects of milatuzumab as a novel immunotherapeutic agent that possesses not only direct anti-proliferative effects against CD74+ hematological malignancies, but also some regulatory effects on DC-mediated immune functions, and no cytotoxic effect on DCs.