bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression Pattern and Prognostic Impact of Vascular Endothelial Growth Factors VEGF and VEGF-C and Their Receptors Flt-1, KDR and Flt-4 in Peripheral T-Cell Lymphomas.
Authors: Jørgensen Judit M. , Sørensen Flemming B. , Bendix Knud , Nielsen Johan L. , Funder Anette D. , Tainola Tapio , Karkkainen Marika , Sørensen Annette B. , Pedersen Finn S. , Kühle Astrid V. , d’Amore Francesco 
Published: October 2019

Abstract
The vascular endothelial growth factor family (VEGF, VEGF-B, -C and -D) is the main regulator of angiogenesis and lymphangiogenesis via their receptors, Flt-1, KDR and Flt-4. The aim of the present study was to estimate the microvascular density and investigate the expression of VEGF, VEGF-C and its receptors Flt-1, KDR and Flt-4 in peripheral T-cell lymphomas (PTCL).
Material and methods: Microvessel density (MVD) was determined after CD34 immunohistochemical (IH) staining of endothelial cells in pre-therapeutic lymph-node biopsies from 107 cases of PTCL (64 unspecified, 1 angiocentric, 10 angioimmunoblastic and 32 anaplastic large cell T/0). 44 of these cases (28 unspecified, 1 angiocentric, 4 angioimmunoblatic and 11 anaplastic large cell T/0) were investigated for expression of angiogenic molecules, VEGF, VEGF-C and their receptors by IH at protein level. Furthermore, VEGF and VEGF-C mRNA expression was detected by non-isotopic ′in situ′ hybridization. The angiogenic scores were correlated to pre-therapeutic clinical parameters, treatment response and survival.
Results: Tumoral expression of VEGF, VEGF-C and of their receptors was detected in the majority of the PTCL biopsies investigated (VEGF mRNA: 73%, VEGF protein: 95%; VEGF-C mRNA: 79%; VEGF-C protein: 79%; Flt-1 and KDR: 100%; Flt-4: 26%). All biopsies contained VEGF, Flt-1 and KDR positive vessels and VEGF-C was also widely expressed by the endothelial cells (3 negative cases), while endothelial Flt-4 expression was detected only in 43% of cases. High MVD scores correlated with an advanced clinical stadium (Ann Arbor) (p=0.047). A strong diffuse VEGF mRNA expression significantly correlated with a poorer overall survival (p=0.0015) as compared to focal or negative ISH signal. The predictive value of this parameter persisted at multivariate level independently of the International Prognostic Index (HR: 3.95, p=0.012, Cox regression).
Conclusion: VEGF, VEGF-C and their receptors are expressed by both lymphoma and endothelial cells in the majority of PTCL cases. VEGF expression seems to have an adverse impact on survival. Larger studies of angiogenesis/lymphangiogenesis in PTCL are needed to clarify the biological role of these molecules and identify possible therapeutic targets.
Hfe Acts in Hepatocytes To Prevent Hemochromatosis.
Authors: Muckenthaler Martina U. , Vujic-Spasic Maja , Kiss Judit , Herrmann Thomas , Galy Bruno , Gröne Herrmann-Josef , Stremmel Wolfgang , Hentze Matthias W. 
Published: October 2019

Abstract
Hereditary hemochromatosis (HH) is a prevalent, potentially fatal disorder hallmarked by intestinal iron hyperabsorption, hyperferremia and hepatic iron overload. In both humans and mice, type I HH is associated with mutations in the ubiquitously expressed HFE/Hfe gene. To understand the molecular mechanism(s) underlying HH and to identify the cell type in which Hfe acts to prevent HH we generated mice with tissue-specific Hfe ablations. We demonstrate that hepatocyte-specific Hfe deficiency fully recapitulates the phenotype observed in Hfe−/− mice with severe liver iron accumulation, reduced splenic iron content, increased Tf saturation, hyperferremia and reduced hepcidin expression. These findings unambiguously and directly show that Hfe acts in hepatocytes to prevent hemochromatosis.
MicroRNA-155 Promotes Myeloid Proliferation and Is Overexpressed in Acute Myeloid Leukemia.
Authors: Rao Dinesh S. , O’Connell Ryan M. , Chaudhuri Aadel A. , Boldin Mark , Taganov Konstantin , Nicoll John , Paquette Ronald , Baltimore David 
Published: October 2019

Abstract
Recent discoveries have implicated microRNAs, which are small 22–24 nucleotide long RNA molecules, as important regulators of many cellular processes, including differentiation and development. The microRNA-155 (miR-155) is known to be overexpressed in subsets of B-cell neoplasms and is thought to be important in the activation and function of B-lymphocytes. Here, we show that miR-155 is signficantly overexpressed in human acute myeloid leukemia and that its overexpression is most consistently seen in acute myelomonocytic leukemia. These findings led us to investigate the effects of overexpression of miR-155 in hematopoietic cells. By utilizing retroviral infection and transfer of murine bone marrow, we introduced miR-155 overexpressing hematopoietic stem cells into lethally irradiated recipient mice. Following reconstitution of hematopoietic organs, the mice demonstrated a profound myeloproliferative condition in the bone marrow characterized by replacement of the marrow by proliferating and dysplastic myelomonocytic cells. In addition, extramedullary hematopoiesis was observed in the spleen and examination of the peripheral blood revealed anemia and thrombocytopenia. To begin to explore the mechanisms whereby miR-155 overexpression results in this myeloproliferative phenotype, we utilized computational methods to identify targets predicted to be regulated by miR-155. This revealed several genes that have previously been implicated in myeloid development and neoplasia, which were confirmed to be targets of miR-155 by reverse-transcription/quantitative polymerase chain reaction (RT/QPCR) and by downregulation of luciferase protein upon fusion of the luc gene with the respective 3′ untranslated regions. These studies show a hitherto uncharacterized role of miR-155 in myeloid development and proliferation. Importantly, these findings lay the groundwork for understanding the complex regulatory networks underlying myeloid development in the context of microRNAs, and may point to new therapeutic opportunities in the treatment of myeloid malignancies.
Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance.
Authors: Kantarjian Hagop M. , Hochhaus Andreas , Cortes Jorge , Martinelli Giovanni , Bhalla Kapil N. , Giles Francis J. , Ossenkoppele Gert , Gattermann Norbert , Haque Ariful , Gallagher Neil , Baccarani Michele , le Coutre Philipp 
Published: October 2019

Abstract
Background: Nilotinib is a novel, selective BCR-ABL inhibitor, designed to bind the ATP-binding site of BCR-ABL protein with higher affinity than imatinib. It is more potent than imatinib (IC50 <30 nM) against wild-type BCR-ABL and active against 32/33 imatinib-resistant BCR-ABL mutants.
Methods: This open-label study was designed to evaluate the safety and efficacy of nilotinib in patients (pts) with Philadelphia (Ph+) imatinib-resistant or -intolerant CML-CP. Planned nilotinib dose was 400 mg twice daily (BID) with escalation to 600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR) determined on the conventional intent-to-treat patient population. Cytogenetic response (CyR) was assessed by bone marrow karyotyping; peripheral blood FISH was used if a marrow sample cannot be obtained.
Results: This analysis includes data from 320 pts who received at least 6 months of nilotinib therapy (70.6% imatinib-resistant; 29.4% imatinib-intolerant). The median age was 58 years, the median duration of CML was 57.3 months, and 50.3% were males. Treatment with nilotinib is ongoing in 188 pts (58.8%) and 132 pts (41.3%) discontinued the treatment [51 (15.9%) for disease progression, 51 (15.9%) for adverse events (AE)]. The median duration of nilotinib exposure was 341 (1–624) days and the median average dose intensity was 792.1 mg/d (47.9–1111.6 mg/d). The dose was escalated to 600 mg BID in only 51 pts (15.9%). Complete hematological remission (CHR) at baseline was reported in 114 pts. Of the remaining 206 pts, 157 (76.2%) achieved CHR in 1 month. MCyR was observed in 180 pts (56.3%): 128/320 pts (40.0%) had complete cytogenetic response (CCyR). The median time to CHR and to first MCyR was 1.0 and 2.8 months, respectively. The median duration of MCyR has not been reached. Minor and Minimal CyR was seen in 22 (6.9%) and 42 (13.1%) patients respectively. The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (27%), neutropenia (30%), anemia (9%), and asymptomatic serum lipase elevation (15%).
Conclusion: The present study confirms nilotinib is an effective therapeutic option in CML-CP pts with imatinib-resistance or -intolerance, with an acceptable safety and tolerability profile. With longer follow up, cytogenetic response continues to increase and no change in safety profile has been observed on nilotinib therapy.
MMY-3002: A Phase 3 Study Comparing Bortezomib-Melphalan-Prednisone (VMP) with Melphalan-Prednisone (MP) in Newly Diagnosed Multiple Myeloma.
Authors: Miguel J.F. San , Schlag R. , Khuageva N. , Shpilberg O. , Dimopoulos M. , Kropff M. , Spicka I. , Petrucci M. , Samoilova O. , Dmoszynska A. , Abdulkadyrov K. , Schots R. , Jiang B. , Palumbo A. , Mateos M. , Liu K. , Cakana A. , Van de Velde H. , Richardson P. 
Published: October 2019

Abstract
Background: In a phase 1/2 trial of VMP in 60 newly diagnosed MM patients (median age 75 years), the CR/nCR rate was 43%, with 32% CR; the 3-year survival was 85% (Mateos et al, Blood 2006; Mateos et al, EHA/IMW 2007). MMY-3002 is a phase 3 study comparing VMP with standard MP in patients with previously untreated MM who are not candidates for high-dose chemotherapy/stem-cell transplant.
Methods: Approximately 680 patients were randomized to VMP or MP and stratified according to baseline β2-microglobulin and albumin, and geographic region. Eligibility criteria required the presence of measurable disease, KPS ≥60% and hematology/chemistry laboratory values meeting predefined criteria. Patients in the VMP arm received intravenous bortezomib 1.3mg/m2 twice weekly (weeks 1, 2, 4, 5) for four 6-week cycles (8 doses per cycle), followed by once weekly (weeks 1, 2, 4, 5) for five 6-week cycles (4 doses per cycle) in combination with oral melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4 of each cycle. Patients in the MP arm received 9 6-week cycles of MP once daily on days 1–4. For both groups, treatment continued for a maximum of 9 cycles (54 weeks) unless disease progression or unacceptable treatment-related toxicity occurred. The primary endpoint was time to progression (TTP), and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate, time to and duration of response, and safety.
Results: Between December 2004 and September 2006, 682 patients from 151 centers in 22 countries across Europe, North and South America, and Asia were randomized. The median age was 71 years with 30% of patients aged ≥75 years. Fifty percent were male and 88% were of Caucasian origin. Median KPS was 80%, and 34% of patients had KPS ≤70%. Sixty-three percent had IgG myeloma, 25% had IgA myeloma, and 8% had light-chain disease. Bone involvement with >10 lytic bone lesions was reported in 27% of patients, 33% had β2-microglobulin >5.5mg/L, and 60% had albumin <35g/L. The study population therefore included a high proportion of patients with advanced disease and high-risk factors. The Independent Data Monitoring Committee is scheduled to review data from a pre-planned interim analysis to determine whether TTP was significantly longer with VMP vs MP and therefore whether the protocol-specified statistical boundary for the primary endpoint has been reached.
Conclusion: Efficacy and safety analyses will be reported at the meeting.
Small-Molecule XIAP Antagonist Restores Caspase-9-Mediated Apoptosis in XIAP-Positive Diffuse Large B-Cell Lymphoma Cells.
Authors: Cillessen Saskia A.G.M. , Reed John C. , Pinilla Clemencia , Meijer Chris J.L.M. , Hooijberg Erik , Hess Corine J. , Castricum Kitty C.M. , Kortman Pim , Ossenkoppele Gert J. , Oudejans Joost J. 
Published: October 2019

Abstract
Clinical outcome in patients with diffuse large B-cell lymphomas (DLBCL) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including XIAP. XIAP suppresses apoptosis through inhibiting active caspases-3, -7 and -9. In this study we investigated if the small-molecule XIAP antagonist 1396–12 induces cell death in cultured lymphoma cells of DLBCL patients and whether it is possible to predict whether a DLBCL will be sensitive to the XIAP antagonist. Treatment with this XIAP antagonist resulted in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy refractory and responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal center B-cells from healthy donors. XIAP antagonist-sensitive cases were characterized by high expression levels of XIAP and relatively low expression levels of Bcl-2. In addition, we found that XIAP antagonist sensitive lymphomas are characterized by constitutive caspase-9 activation and that the apoptosis inducing effect of the XIAP antagonist depends on this constitutive caspase 9 activity. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in DLBCL cells by restoring caspase 9 mediated apoptosis and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers suggesting the possibility of pre-defining patients most likely to benefit from XIAP antagonist therapy.
Treatment with hERG1 K+ Channel Inhibitors Reduces Acute Myeloid Leukemia Cell Lines Engraftment into Nonobese Diabetic/Severe Combined Immunodeficient Mice and Prolongs Survival of Injected Mice.
Authors: Pillozzi Serena , De Lorenzo Emanuele , Masselli Marika , Crociani Olivia , Cilia Emanuele , Torre Eugenio , Mugnai Antonio , Becchetti Andrea , Arcangeli Annarosa 
Published: October 2019

Abstract
hERG1 K+ channels are expressed in a broad range of human leukemic cell lines and primary acute myeloid and lymphoid leukemias (Pillozzi S, et al Leukemia16:1791–1798, 2002; Smith GA, et al, JBC227:18528–18534, 2002). hERG1 activity is necessary for leukemia cell proliferation as well as migration in response to angiogenic factors (VEGF). This effect can be traced back to the assembly of a macromolecular signaling complex on the plasma membrane of leukemia cells. Such complex comprises hERG1 channels, the beta1 subunit of integrin adhesion receptors and the VEGF receptor 1, FLT-1. In vivo experiments in NOD/SCID mice injected with AML cells showed that herg1 over-expression confers a greater malignancy, witnessed by a higher bone marrow (BM) angiogenesis, and a stronger leukemia blast exit into the peripheral blood (PB) and into extramedullary organs. What is more, herg1 expression in AML patients correlates with a higher probability of relapse and shorter survival periods (Pillozzi S et al, Blood110:1238–1250, 2007). On the whole we can conclude that hERG1 channel expression in AML represent a progression factor and can be envisaged as a novel target for therapy. We tested this latter hypothesis in NOD/SCID mice injected with AML cell lines expressing hERG1 channels at various extent, and treating injected mice with a selective hERG1 inhibitor, E4031. E4031 was administered i.p. starting one week after inoculum, at the dose of 20 mg/kg, daily for two weeks. In a first set of experiments mice were sacrificed after a total 3 weeks after inoculum. It emerged that E4031 reduced both BM engraftment and PB invasion of AML cells. In particular, BM angiogenesis was significantly lower in mice treated with E4031. In a second set of experiments, mice were treated as above and the survival time was measured. It emerged that E4031 treatment prolonged survival compared with the control-treated group. We have developed a monoclonal antibody against an extracellular loop of hERG1 channels. The immunoreactivity and activity on hERG1 channels of such antibody was first tested in leukaemia cells. Treatment of NOD/SCID mice injected with AML cell lines with this antibody is ongoing.
Phase I Study of Sapacitabine, an Oral Nucleoside Analogue, in Patients with Advanced Leukemias or Myelodysplastic Syndromes (MDS).
Authors: Kantarjian Hagop , Garcia-Manero Guillermo , Faderl Stefan , Cortes Jorge , Estrov Zeev , Boone Patricia , Stuart Iain , Westwood Robert , Green Simon , Chiao Judy H. , Plunkett Willilam 
Published: October 2019

Abstract
Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to cause irreparable single-strand DNA breaks and as a result induce G2 cell cycle arrest, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg twice daily (b.i.d.) x 7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTDs of two dosing schedules, b.i.d. x 7 days orally every 21 days or b.i.d. x 3 days per week for 2 weeks every 21 days. The secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC.
Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which ≤2/6 patients experienced a DLT during the first treatment cycle.
Results: Forty-seven patients received sapacitabine, including 35 treated with the 7-day schedule and 12 treated with the 3-day per week schedule. Median age was 65 (range: 36 – 91). The majority of patients had AML (n=36) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 – 6). Cytogenetic abnormalities were present in 27; 30 had relapsed disease or were refractory to cytarabine or high-dose cytarabine regimens. MTD was reached at 375 mg b.i.d. on the 7-day schedule, and 475 mg b.i.d. on the 3-day per week x 2 schedule. DLTs consist of abdominal pain/small bowel obstruction (n=1), neutropenic colitis (n=2) and diarrhea (n=3). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included fatigue, nausea, vomiting, diarrhea, anorexia, cough, dyspnea, and abdominal pain, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 11 patients of 42 evaluable (9 AML, 2 MDS) had a reduction in bone marrow blast counts to ≤ 5% including 2 CRs, 2CRs with incomplete recovery of platelets, 1 CR of extramedullary disease, and 1 PR of extramedullary disease. 5/11 had relapse-resistance disease on prior cytarabine.
Conclusion: The MTD of sapacitabine is 375 mg b.i.d. by the 7-day schedule and 475 mg b.i.d. by the 3-day per week schedule. The predominant DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS.
SGN-33, Lintuzumab, Demonstrates Anti-Leukemic Activity in Preclinical Models of AML.
Authors: Sutherland May S.K. , Yu Changpu , Morris-Tilden Carol , Lewis Timothy S. , Miyamoto Jamie B. , McEarchern Julie A. , Oflazoglu Ezogelin , Gerber Hanspeter , Sievers Eric L. , Grewal Iqbal S. , Law Che-Leung 
Published: October 2019

Abstract
SGN-33 is a humanized IgG1 antibody with signaling properties that also mediates effector functions including Antibody-Dependent Cellular Cytotoxicity (ADCC). SGN-33 targets CD33, a sialoadhesion family member expressed on acute myeloid leukemia (AML) cells, eliciting complete remissions in some AML patients. In the laboratory, SGN-33 mediates natural killer (NK) cell lysis of both multi-drug resistant (MDR- positive) and MDR-negative AML cell lines. Additionally, SGN-33 significantly increases survival in SCID mouse disseminated models of MDR-negative and MDR- positive AML. Immunomodulatory compounds such as thalidomide and its analog, lenalidomide (Revlimid®), have been shown to enhance NK cell function and anti-cancer activity. In particular, Revlimid in combination with rituximab demonstrated greater tumor cell killing compared to the antibody alone. Given these reports, we investigated whether thalidomide or lenalidomide would enhance the anti-tumor effects of SGN-33. In vitro, lenalidomide augmented NK function in a dose-dependent fashion, manifested as significant increases in perforin expression. Thalidomide and lenalidomide enhanced ADCC activity (% maximal specific lysis) while having no significant effects on tumor cell levels of CD33. In vivo, treatment of SCID mice with lenalidomide resulted in a 2-fold increase in the absolute numbers of lymphocytes (including NK cells). In vivo studies evaluating the efficacy of the combination of SGN-33 and lenalidomide in SCID mouse models of AML are in progress. In summary, our studies demonstrate the anti-leukemic activity of SGN-33 against MDR-positive AML cell lines, suggesting that this unconjugated anti-CD33 antibody may yield benefit in clinical settings where other therapies fail due to the MDR phenotype of the tumor cells. Additionally, agents augmenting immunologic effector function might provide clinical benefit in combination with SGN-33. The combination of SGN-33 and lenalidomide is now being evaluated in a clinical trial.