bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncogenic Transformation of NIH 3T3 Fibroblasts by BCR-ABL Oncoprotein Requires the IL-3 Receptor.
Authors: Tao Wenjing , Lin Hui , Sun Tong , Samanta Ajoy K. , Arlinghaus Ralph B. 
Published: October 2019

Abstract
Bcr-Abl is a leukemia-inducing protein, which causes oncogenic transformation of myeloid progenitors in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) and lymphoid progenitors in Ph+ acute lymphoid leukemia (ALL). Oncogenic transformation of hematopoietic cells by the Bcr-Abl oncoprotein directly involves the activation Jak2 tyrosine kinase and the Stat5 transcription factor. Both proteins are normally linked to the IL-3/GM-CSF receptors for growth and survival. Since fibroblastic cells are not targets of BCR-ABL induced oncogenesis, we determined whether forced expression of the IL-3 receptor would allow oncogenic transformation of NIH 3T3 fibroblasts known to be resistant to transformation by BCR-ABL. NIH 3T3 cells transduced with the human IL-3 receptor a and b chains were highly susceptible to oncogenic transformation by expression of BCR-ABL. Forced expression of both receptor chains but not either one alone allowed efficient foci formation of NIH 3T3 cells expressing BCR-ABL, and these cells formed colonies in soft agar whereas BCR-ABL positive NIH 3T3 cells lacking IL-3 receptor expression did not. The Bcr-Abl kinase inhibitor imatinib mesylate (1 mM) and the Jak kinase inhibitor AG490 (10 mM) strongly inhibited agar colony formation. A small molecule inhibitor of Jak2 kinase, 1,2,3,4,5,6-hexabromocyclohexane reported to be specific for Jak2 (Sandberg et al. J. Med. Chem, 2005)-significantly reduced the phosphorylation of Gab2 at the YxxM motif, which is needed for activation of the PI-3 kinase and Akt, two proteins that are part of the Bcr-Abl/Jak2 Network (Samanta et al. Cancer Res, 2006). These findings indicate that Bcr-Abl oncoprotein requires the IL-3 receptor/Jak2/Stat5 pathways for oncogenic transformation of NIH 3T3 fibroblasts, and may explain partially why Bcr-Abl oncogenesis is restricted to hematopoietic malignancies. Furthermore, this cell system in fibroblastic and other cell lineages will provide a model to probe the detailed steps that require IL-3 receptor and Jak2 for Bcr-Abl induced leukemia.
Environmental Factors Determine Lineage Fate in a Human Model of MLL-AF9 Leukemia.
Authors: Wei Junping , Mark Wunderlich , Fox Catherine , DiMartino Jorge F. , Mulloy James C. 
Published: October 2019

Abstract
The MLL gene is fused to over 30 different fusion partners by reciprocal translocations in human acute leukemias. Some fusion partners are associated almost exclusively with myeloid or lymphoid leukemias while others are found in both. The degree to which the fusion partner contributes to the lineage of the resulting leukemia remains a matter of controversy. Using a novel model system, we demonstrate that myeloid vs lymphoid differentiation of hematopoietic progenitors transformed by MLL-AF9 can be predictably driven by cytokine combinations in vitro and in vivo. The t(9;11)(p22;q23) MLL-AF9 fusion gene is commonly associated with M5 myeloid leukemia but approximately 5% of MLL-AF9 leukemia is B-lymphoid. Expression of MLL-AF9 in human CD34+ cells enables efficient modeling of acute myeloid, B-lymphoid and biphenotypic leukemia. The lineage of the resulting leukemia can be readily manipulated in vitro (by altering the growth factors) or in vivo (using B-lymphoid-biased NOD/SCID mice or myeloid-biased NOD/SCID that are transgenic for human SCF, GM-CSF and IL-3). The cytokines IL-3, IL-7 and FLT3L appear to exert the major effects on lineage fate determination in vitro. Through limiting dilution and clonality analyses, we find a complex relationship between different leukemia stem cell compartments, with some LSC demonstrating multipotentiality and others showing strict lineage commitment. Data indicate that these differences are primarily due to microenvironment effects, with the identity of the initial cell that is targeted by MLL-AF9 possibly playing a role. These results would argue against a deterministic role for the fusion partner in MLL leukemia. This human-based system should prove useful in addressing the mechanism of lineage promiscuity of MLL leukemias. It also affords us the unique ability to determine the susceptibility of the different LSC to standard chemotherapeutic compounds, in addition to identifying novel therapeutic strategies that may be effective in treating MLL leukemia.
The Identification and Genomic Analysis of microRNAs in Human Erythrocytes in Sickle Cell Diseases.
Authors: Chen Shao-Yin , Wang Yulei , Telen Marilyn I. , Chi Jen-Tsan A. 
Published: October 2019

Abstract
Erythrocytes are circulating blood cells responsible for efficient gas exchange in human body. Since mature erythrocytes are terminally differentiated cells without nuclei and organelles, it is commonly thought that they do not contain nucleic acids. In this study, we re-examined this issue and found that human mature erythrocytes, while lacking ribosomal and large-sized RNAs, possess abundant small-sized RNAs. Using a combination of microarray analysis, real-time RT-PCR and Northern blots we found that mature erythrocytes contained abundant and diverse microRNAs which were distinct from microRNAs observed in reticulocytes/leukocytes and contributed to the majority of the microRNA expression in whole blood. When we used microarrays to analyze erythrocytes from normal (HbAA) and homozygous sickle (HbSS) individulas, we noted dramatic a difference in their microRNA expression pattern. To investigate how this difference is associated with erythrocyte disease phenotypes, we found that the poor expression of miR-320 was responsible for the defective downregulation of its target gene CD71 in HbSS cells during terminal differentiation. Collectively, we have discovered significant microRNA expression in human mature erythrocytes, which enables the microarray analysis of erythrocyte property to provide insights into the human erythrocyte diseases.
Elevated Urinary Leukotriene E4 Levels Are Associated with Hospitalization for Pain in Children with Sickle Cell Disease.
Authors: Jennings Jeanine E. , Ramkumar Thiruvamoor , Mao Jingnan , Boyd Jessica , Castro Mario , Strunk Robert C. , DeBaun Michael R. 
Published: October 2019

Abstract
Introduction: Sickle cell disease (SCD) is associated with an inflammatory state. Luekotrienes are inflammatory mediators derived from arachidonic acid and produced by white blood cells in response to inflammatory stimuli. We tested two hypotheses among children with SCD:
Baseline leukotriene levels are elevated in SCD when compared to controls children without SCD, Baseline leukotriene levels are associated with an increased incidence rate of hospitalization for pain.
Methods: During routine clinical visits, baseline urinary leukotriene E4 (LTE4) levels were measured in children with SCD (cases) and age, and ethnic, matched children without SCD (controls). Medical records of the cases were reviewed to assess the frequency of hospitalization for pain within three years of entering the study.
Results: LTE4 levels were obtained in 71 cases and 22 controls. LTE4 levels were higher in the cases compared to controls (median LTE4: 100 vs.57 pg/mg creatinine); P < 0.001. After adjustment for age and diagnosis of asthma, a greater incidence rate of hospitalization for pain was observed among children with SCD in the highest tertile group when compared to the lowest tertile group (114 vs. 52 episodes per 100 patient-years, P=0.038).
Conclusion: LTE4 levels are elevated in children with SCD when compared to controls without SCD and are associated with an increased rate of hospitalizations for pain.
Complement Activation and Resistance within the Cerebrospinal Fluid Following Intraventricular Administration of Anti-CD20 in the Treatment of Recurrent CNS Lymphoma.
Authors: Kadoch Cigall , Shuman Marc A. , Rubenstein James L. 
Published: October 2019

Abstract
We recently conducted the first phase I dose escalation study of intraventricular rituximab (anti-CD20 antibody) in patients with recurrent central nervous system (CNS) non-Hodgkin’s lymphoma (NHL). The goals of this study have been to define the safety and pharmacokinetics of intraventricular rituximab monotherapy and to gain insight into the molecular basis of rituximab efficacy and resistance in the treatment of high-grade lymphomas. We observed a rapid lymphocytotoxic effect of intraventricular rituximab administration in six out of ten subjects treated, resulting in four complete responses at the completion of five weeks of therapy. Cytologic responses were evident within one hour of rituximab treatment and were not likely related to the action of corticosteroids as these were held stable, tapered or withheld in the week before intrathecal therapy. Three potential mechanisms have been proposed to explain the basis for rituximab efficacy in the treatment of NHL:
direct induction of apoptosis; complement-dependent cytotoxicity (CDC); antibody dependent cellular cytotoxicity (ADCC).
Given the rapid rate of response detected in the leptomeningeal compartment and the relative paucity of Fc-receptor bearing natural killer cells detected in the CSF, we tested the hypothesis that complement activation is responsible for the rapid rituximab-mediated tumor cell lysis which we observed. Pretreatment gene expression profile analysis of meningeal lymphoma cells isolated from CSF demonstrated that RNA levels of expression of CD46, CD55, and CD59 were similar in both responding and non-responding patients. However microarray analysis suggested a possible correlation between low levels of complement receptor 2 (CD21) and immediate rituximab resistance. We focused on the potential generation of C3a anaphylatoxin in the CSF after rituximab administration as C3 is the central component in the classical and alternative complement pathways. Quantitative measurement of C3a concentration in CSF by ELISA demonstrated rapid activation of the complement cascade within one hour of intrathecal anti-CD20 antibody administration. C3a concentrations increased between three-to-eight-fold up to peak concentrations greater than 300 ng/ml. These findings were confirmed by immunoblot analysis of C3a in CSF. Acquired rituximab resistance was associated with marked decreases in the magnitude of complement activation in two patients who initially had exhibited complete responses to intraventricular rituximab monotherapy. These results suggest a mechanistic basis for the rapid lymphocytoxic effects observed and provide a possible explanation for the development of acquired rituximab resistance.
Efficacy and Safety of YM155 in Relapsed/Refractory Non-Hodgkin’s Lymphoma Patients Enrolled in a Phase I Study.
Authors: Papadopoulos Kyriakos , Mita Alain , Antonio Scott , Lewis Lionel D. , Reddy N.J. , Till Elizabeth , Mahany J.J. , Keating Anne , Seiz Amanda , Bartels Pamela , Tolcher Anthony 
Published: October 2019

Abstract
Background: YM155 is a member of a novel class of compounds called survivin suppressants that target survivin. Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin over-expression has been reported in a variety of tumor cells including lymphoma. A Phase I dose escalation study of YM155 was conducted to evaluate safety, tolerability and antitumor activity in patients with solid tumors or non-Hodgkin’s lymphoma (NHL).
Methods: Patients with solid tumors or NHL with no other treatments options were eligible for this Phase I study and received YM155 in escalating doses ranging from 1.8 – 6 mg/m2/day as a 168 hour (7 day) continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until either disease progression or toxicity. 41 patients were enrolled into the study including 5 patients with NHL (2 diffuse large B-cell lymphoma [DLBCL], 1 each small lymphocytic B-cell, follicular [FL] and anaplastic large cell lymphoma). This report focuses solely on the patients with NHL. All 5 NHL patients had at least 2 prior treatment regimens (range: 2 – 7) including stem cell transplant in two patients (DLBCL, FL) and one patient who received 2 investigational therapies. Three patients were considered refractory to the treatment regimen given just prior to study entry (DLBCL, anaplastic large cell, FL).
Results: All 5 NHL patients were male with a mean age of 56 (range: 46 – 64). They were all dosed at the maximum tolerated dose (MTD) of 4.8 mg/m2/day. The most common adverse events reported, regardless of relationship to YM155, were URI (3/5) and arthralgia, fever, hypomagnesemia, mucositis peripheral edema and rash (2/5). The majority of adverse events were Grade 1 or 2 with 3 events reported as Grade 4: Klebsiella bacteremia, neutropenia and hypokalemia. Three patients (60%) (2 DLBCL and FL) had partial response (PR) to YM155 as assessed by independent review using both RECIST and 1999 Cheson criteria. One responder (DLBCL) had a PR after 2 cycles, completed a total of 5 cycles and proceeded to stem cell transplant. This patient has no evidence of disease at 3 years. A second responder (DLBCL) had a PR after 12 cycles and received a total of 26 cycles (∼ 1.5yrs) before disease progression. The third responder (FL) had a PR after 14 cycles, has maintained a prolonged PR for ∼ 2 years and continues to receive YM155 in a long-term extension study.
Conclusion: Based upon the objective responses, the tolerability and safety profile observed in this Phase I study in 5 NHL patients, a Phase II study in refractory DLBCL has been initiated.
Survival in Follicular Lymphoma: The Stanford Experience, 1960–2003.
Authors: Tan Daryl , Rosenberg Saul A. , Levy Ronald , Lavori Philip , Tibshirani Robert , Hoppe Richard T. , Warnke Roger , Advani Ranjana , Natkunam Yasodha , Yuen Alan , Horning Sandra J. 
Published: October 2019

Abstract
Background: Recent data from retrospective and prospective studies indicate an improvement in the overall survival (OS) of follicular lymphoma (FL) patients (pt). We sought to evaluate survival data in FL pt managed at our institution and to analyze their presenting features, management and disease course.
Methods: Previously untreated FL (grades 1 and 2) pt referred from 1960–2003 and followed at Stanford were identified from the Lymphoma Database for this retrospective study. Data were reviewed for quality and consistency of coding for histology (pathology reviewed at Stanford) and treatment courses. Four eras were defined by date of diagnosis 1 (1960–75, n=180); 2 (1976–86, n=426); 3 (1987–96, n=471); and 4 (1997–2003, n=257). Patient (age, gender) and disease (stage, histology) characteristics, management (time from diagnosis to referral, time to first treatment, courses/types of treatment), and outcomes (progression-free survival [PFS], OS, transformation) were evaluated, overall and with respect to era.
Results: The OS for the 1334 FL pt in the dataset was 12.6 years (yr). Age (median = 49 yr), gender (54% male) and stage (83% III-IV) did not differ across the eras. Median OS improved from 11.2 yr [95% CI 10.2,12.1] in eras 1 and 2 (1960–86) to 18.4 yr [95% CI 14.5,22.4] in eras 3 and 4 (1986–2003), p<0.001. Greatest gains were observed in pt less than 60 yr old and in advanced stage disease. OS was not different in eras 3 and 4 (p=0.56) but median follow-up is just 5 yr in era 4. Although treatment varied over the eras, PFS was no longer for the later eras (3 and 4) compared to early eras (1 and 2), p=0.73. Initial therapy was more likely to be deferred in the later eras: 16%, 44%, 59%, 60% for eras 1, 2, 3 and 4, respectively. Rituximab use, as expected, varied over the eras: 1 (1% pt), 2 (8% pt), 3 (23% pt), 4 (42% pt). The incidence of transformation was similar over the eras and OS after transformation was significantly longer if patients were chemotherapy-naive at transformation (p<0.001).
Conclusions: OS of patients with FL managed at Stanford University significantly improved in the 1986–2003 eras, particularly among younger and advanced stage patients. This improvement was not associated with longer PFS after the first course of treatment or differences in the incidence of histologic transformation. Application of a time-variant Cox regression model is in progress to better understand the contributions of treatment, particularly rituximab, as well as other factors in these patients.
Improved Survival of Intravascular Large B-Cell Lymphoma (IVLBCL) by Rituximab Containing Combination Chemotherapies.
Authors: Shimada Kazuyuki , Matsue Kosei , Yamamoto Kazuhito , Ichikawa Naoaki , Okamoto Masataka , Niitsu Nozomi , Kosugi Hiroshi , Tsukamoto Norifumi , Murase Takuhei , Miwa Hiroshi , Asaoku Hideki , Kikuchi Ako , Matsumoto Morio , Saburi Yoshio , Masaki Yasufumi , Kashimura Makoto , Yamaguchi Motoko , Nakamura Shigeo , Naoe Tomoki , Tomohiro Kinoshita 
Published: October 2019

Abstract
Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) with poor prognosis. Recently, the addition of rituximab to CHOP regimen has significantly improved the outcome of DLBCL. However, the efficacy of rituximab in IVLBCL remains unclear.
Objective and Patients: To evaluate the usefulness of rituximab in IVLBCL, 70 patients who were diagnosed as IVLBCL between 1999 and 2007 from the 16 participating centers were retrospectively analyzed. Patient characteristics were as follows: median age, 68 yrs (range, 34 to 88 yrs); sex, M/F 56%/44%; LDH > UNL, 99%; stage III/IV, 100%; extranodal site > 1, 81%; PS > 1, 84%; IPI: H-I/H, 97%. Sixty four of 70 patients received anthracycline containing chemotherapies. In 64 patients, 43 (67%) and 21 (33%) patients received rituximab containing chemotherapies (R-chemo) and chemotherapies without rituximab (chemo), respectively. There was no significant difference between the two groups in terms of various clinical variables.
Results: The complete response rate (%CR) was significantly higher in the R-chemo group than in the chemo group (90% vs. 55%, P = 0.0003). With a median follow up time of 24 months (range, 2 to 88 months) in living patients, 2-year progression-free and overall survival (OS) rates were significantly higher in the R-chemo group than in the chemo group (63% vs. 32%, 71% vs. 39%, P = 0.015 and 0.01, respectively). In univariate analysis, age, LDH, the number of extranodal site, PS and platelet count were not significant prognostic factor, while the use of rituximab was favorably associated with OS (HR, 0.33; 95% CI, 0.13 to 0.88; P = 0.015). Grade 3 hypoxia due to the infusion of rituximab was observed in one of 43 patients (2%). Grade 3 or 4 non-hematologic adverse events were observed in the 3 of 43 (7%) patients and 3 of 21 (14%) patients, respectively. Treatment related death was observed in 3 patients. Two in the R-chemo group died of HBV reactivation and tuberculosis, and one in the chemo group died of sepsis. Eight of 43 and 12 of 21 patients in the each group died at the time point of the study, respectively, and the most major cause of death was primary disease (6 and 11 patients, respectively).
Conclusion: Our data strongly suggested that the addition of rituximab to chemotherapies significantly improved the %CR and survival in IVLBCL without significant increase in toxicities. Thus, prospective clinical trials of rituximab-containing chemotherapies for IVLBCL are warranted.
Primary Diffuse Large B-Cell Lymphoma of the Colon: Surgery for Local Disease Control Does Not Improve Outcome.
Authors: Katipamula Rajini , Ristow Kay , Colgan Joseph P. , Habermann Thomas M. , Johnston Patrick B. , Inwards David J. , Markovic Svetomir N. , Micallef Ivana N. , Porrata Luis F. , White William L. , Witzig Thomas E. , Ansell Stephen M. 
Published: October 2019

Abstract
Purpose: Primary colorectal large B-cell lymphoma is rare and accounts for less than 1% of all malignancies in the colon. Standard treatment for limited stage diffuse large B-cell lymphomas (DLBCL) includes systemic therapy combined with involved field radiation therapy. However, radiation therapy may often not be feasible in patients with primary colon lymphoma. For primary DLBCL of the colon particularly the cecum, surgical resection prior to the administration of systemic chemotherapy has been considered to improve local control. The goal of this study was therefore to determine whether surgical resection improves the outcome of patients with primary DLBCL of the colon.
Methods: Clinical information and outcomes on all the patients with primary DLBCL of the colon seen at Mayo Clinic, Rochester, between January 1980 and June 2005 were retrospectively reviewed.
Results: There were 28 patients identified with primary colon DLBCL. Pre-existing conditions like colon polyps, Crohn’s disease and diverticulosis were uncommon. The most common presenting symptom was bleeding per rectum seen in 13 patients (46.5%). Other symptoms included abdominal pain, diarrhea and anemia. All patients had early stage disease (stage1–22 patients, stage2–6 patients) at diagnosis. Of the 28 patients, 16 underwent initial surgery followed by chemotherapy, 7 were treated with chemotherapy alone, and 5 patients had inadequate data to determine time to progression or overall survival. Chemotherapy was anthracycline based, with the most common regimen being CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone). There was no difference in overall survival or time to progression between the 16 patients who received combined modality therapy compared to the 7 patients who received chemotherapy alone. Of the 16 patients who underwent surgical resection followed by chemotherapy, all 5 patients who relapsed, relapsed at other sites in the colon. Conclusion: Surgery as part of combined modality therapy did not appear to improve the outcome of patients with primary DLBCL of the colon. Systemic chemotherapy with an anthracycline-based regimen in combination with rituximab is therefore likely to be sufficient treatment for these patients. Follow-up for these patients should include a colonoscopy to monitor for recurrences at other sites in the colon.