bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fenretinide enhances rituximab-induced cytotoxicity against B-cell lymphoma xenografts through a caspase-dependent mechanism
Authors: Gopal Ajay K. , Pagel John M. , Hedin Nathan , Press Oliver W. 
Published: December 2003

AbstractThe anti-CD20 monoclonal antibody rituximab induces remission in 40% to 60% of patients with indolent B-cell lymphoma, but virtually all patients have relapses. We evaluated the efficacy of concurrent administration of another biologic agent, N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide) with rituximab against a variety of human B-cell lymphoma cell lines (Ramos, DHL-4, and FL-18) in vivo. Concurrent 4HPR and rituximab administration prevented tumor progression of lymphoma-bearing mice in a minimal disease model (rituximab + 4HPR, 100% progression free; rituximab alone, 37.5% progression free, P = .01; 4HPR alone, 12.5% progression free, P &lt; .01; controls, 0% progression free, P &lt; .01). Combinations of 4HPR + rituximab exceeded the predicted 50% additive rate of disease control from each agent alone (P = .038). Administering 4HPR and rituximab to mice with established tumors induced complete responses (CRs) in 80% of animals compared with 20% to 40% CRs using either agent alone (P = .07), resulting in significantly improved survival. Tumors harvested from 4HPR + rituximab-treated mice displayed elevated caspase activation compared with untreated controls (P = .02). Adding a broad-spectrum caspase inhibitor in vivo fully abrogated the antitumor effects of 4HPR + rituximab (P = .05). These results establish the efficacy of 4HPR/rituximab combinations, confirm their caspase-mediated mechanism of action, and offer the potential for disease control with minimal toxicity for patients with B-cell malignancies. (Blood. 2004;103:3516-3520)
Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines
Authors: Cosmi Lorenzo , Liotta Francesco , Angeli Roberta , Mazzinghi Benedetta , Santarlasci Veronica , Manetti Roberto , Lasagni Laura , Vanini Vittorio , Romagnani Paola , Maggi Enrico , Annunziato Francesco , Romagnani Sergio 
Published: December 2003

AbstractT-cell clones generated from both CD4+CD25+ and CD8+CD25+ human thymocytes were assessed for their ability to suppress the proliferative response to allogeneic stimulation of type 1 T-helper (Th1) or type 2 T-helper (Th2) clones derived from autologous CD4+CD25- thymocytes. Both CD4+ and CD8+ T-regulatory (Treg) cells completely suppressed the proliferation of Th1 clones but exhibited significantly lower suppressive activity on the proliferation of Th2 clones. The partial suppressive effect on Th2 cells was further reduced by the addition in culture of interleukin-4 (IL-4), whereas it was increased in the presence of an anti–IL-4 monoclonal antibody (mAb). The suppressive activity on Th2 clones was also completely inhibited by the addition of IL-7, IL-9, and IL-15 but not of IL-2, whereas the suppressive effect on Th1 clones was only reverted by the addition of IL-15. Of note, Th2 clones expressed significantly higher amounts of mRNA for IL-4 receptor (IL-4R) and IL-9R α chains than Th1 clones, whereas the expression of mRNA for IL-2R, IL-7R, and IL-15R α chains was comparable. Taken together, these findings demonstrate that Th2 cells have a lower susceptibility than Th1 cells to the suppressive activity of human CD25+ regulatory thymocytes, because they are able to produce, and to respond to, growth factors distinct from IL-2, such as IL-4 and IL-9. (Blood. 2004; 103:3117-3121)
Missense or splicing mutation? The case of a fibrinogen Bβ-chain mutation causing severe hypofibrinogenemia
Authors: Asselta Rosanna , Duga Stefano , Spena Silvia , Peyvandi Flora , Castaman Giancarlo , Malcovati Massimo , Mannucci Pier Mannuccio , Tenchini Maria Luisa 
Published: December 2003

Abstract
The genetic basis of severe hypofibrinogenemia was analyzed in a 57-year-old Italian woman. She turned out to be a compound heterozygote for a novel putative missense mutation (Leu172Gln) and a previously described nonsense mutation (Arg17Stop) in the fibrinogen Bβ-chain gene. The pathogenetic role of Leu172Gln was analyzed by in vitro expression of the mutant recombinant protein in COS-1 cells. These experiments demonstrated that mutant Bβ-Leu172Gln fibrinogen was normally assembled and secreted. Inspection of the nucleotide sequence surrounding the mutation suggested a possible role on pre–messenger RNA (mRNA) splicing. Production of the mutant transcript in HeLa cells confirmed that the mutation activates a cryptic acceptor splice site in exon 4, resulting in a truncated Bβ chain, lacking approximately 70% of the C-terminal region. This represents the first exonic splicing mutation identified in the fibrinogen genes. These findings strengthen the importance to analyze potentially pathogenetic nucleotide variations at both the protein and the mRNA level. (Blood. 2004; 103:3051-3054)
High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia
Authors: Kantarjian Hagop , Talpaz Moshe , O'Brien Susan , Garcia-Manero Guillermo , Verstovsek Srdan , Giles Francis , Rios Mary Beth , Shan Jianqin , Letvak Laurie , Thomas Deborah , Faderl Stefan , Ferrajoli Alessandra , Cortes Jorge 
Published: December 2003

Abstract
Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] &lt; 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = .0005), major molecular response (QPRC &lt; 0.05%; P = .00001), and complete molecular response (undetectable BCR-ABL; P = .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004; 103:2873-2878)
Macrophage activation and Fcγ receptor-mediated signaling do not require expression of the SLP-76 and SLP-65 adaptors
Authors: Nichols Kim E , Haines Kathleen , Myung Peggy S , Newbrough Sally , Myers Erin , Jumaa Hassan , Shedlock Devon J , Shen Hao , Koretzky Gary A 
Published: December 2003

AbstractThe Src-homology 2 domain-containing, leukocyte-specific phosphoprotein of 76 kDa (SLP-76) is a hematopoietic adaptor that plays a central role during immunoreceptor-mediated activation of T lymphocytes and mast cells and collagen receptor-induced activation of platelets. Despite similar levels of expression in macrophages, SLP-76 is not required for Fc receptor for immunoglobulin G (IgG; FcγR)-mediated activation. We hypothesized that the related adaptor SLP-65, which is also expressed in macrophages, may compensate for the loss of SLP-76 during FcγR-mediated signaling and functional events. To address this hypothesis, we examined bone marrow-derived macrophages (BMM) from wild-type (WT) mice or mice lacking both of these adaptors. Contrary to our expectations, SLP-76−/− SLP-65−/− BMM demonstrated normal FcγR-mediated activation, including internalization of Ig-coated sheep red blood cells and production of reactive oxygen intermediates. FcγR-induced biochemical events were normal in SLP-76−/− SLP-65−/− BMM, including phosphorylation of phospholipase C and the extracellular signaling-regulated kinases 1 and 2. To determine whether macrophages functioned normally in vivo, we infected WT and SLP-76−/− SLP-65−/− mice with sublethal doses of Listeria monocytogenes (LM), a bacterium against which the initial host defense is provided by activated macrophages. WT and SLP-76−/− SLP-65−/− mice survived acute, low-dose infection and showed no difference in the number of liver or spleen LM colony-forming units, a measure of the total body burden of this organism. Taken together, these data suggest that neither SLP-76 nor SLP-65 is required during FcγR-dependent signaling and functional events in macrophages.
Mouse bone marrow contains large numbers of functionally competent neutrophils
Authors: Boxio Rachel , Bossenmeyer-Pourié Carine , Steinckwich Natacha , Dournon Christian , Nüße Oliver 
Published: December 2003

AbstractThe mouse has become an important model for immunological studies including innate immunity. Creating transgenic mice offers unique possibilities to study gene-function relationships. However, relatively little is known about the physiology of neutrophils from wild-type mice. Do they behave like human neutrophils, or are there species-specific differences that need to be considered when extrapolating results from mice to humans? How do we isolate neutrophils from mice? For practical reasons, many studies on mouse neutrophils are done with bone marrow cells. However, human bone marrow neutrophils appear to be heterogeneous and functionally immature. We have isolated and compared neutrophils from mouse bone marrow and from peripheral blood obtained by tail bleeding. Using the same Percoll® density gradient for both preparations, we have obtained morphologically mature neutrophils from bone marrow and blood. Both cell populations responded to formylmethionyl-leucyl-phenylalanine (fMLF) with primary and secondary granule release and superoxide production. Quantitative analysis of our data revealed minor differences between cells from bone marrow and blood. Superoxide production and primary granule release were stimulated at lower fMLF concentrations in blood neutrophils. However, the amplitude and the kinetics of maximal responses were similar. The principal difference was the lifespan of the two cell populations. Bone marrow cells survived significantly longer in culture, which may suggest that they are receiving antiapoptic signals that are absent in the blood. Our data suggest that mice have a large reservoir of functionally competent neutrophils in their bone marrow. This reservoir may be needed to replace circulating neutrophils rapidly during infection.
p38 activation through Toll-like receptors modulates IFN-γ-induced expression of the Tap-1 gene only in macrophages
Authors: Cecil Alicia A , Klemsz Michael J 
Published: December 2003

AbstractAlthough interferon-γ (IFN-γ) induces the transporter associated with antigen processing (Tap)-1 expression in macrophages, cooperation with lipopolysaccharide signaling through Toll-like receptor 4 (TLR4) accelerates the kinetics and increases the overall levels of this gene. In this report, we show that peptidoglycan signaling through TLR2 and bacterial CpG DNA signaling through TLR9 are functionally equivalent at synergizing with IFN-γ in regulating Tap-1 expression in macrophages. Activation of the p38 mitogen-activated protein kinase is necessary for this response, which correlates with increased phosphorylation of signal transducer and activator of transcription-1 on serine 727. Activation of p38, however, is not sufficient, as this signaling event does not affect the response to IFN-γ in HeLa cells. The cooperation between these different signaling pathways also requires membrane fluidity. These data suggest that macrophages possess an ability to coordinate the signaling between the IFN-γ and TLR receptors.
End-stage differentiation of neutrophil granulocytes in vivo is accompanied by up-regulation of p27kip1 and down-regulation of CDK2, CDK4, and CDK6
Authors: Klausen Pia , Bjerregaard Malene Digmann , Borregaard Niels , Cowland Jack Bernard 
Published: December 2003

AbstractThe in vivo expression profiles of cell-cycle proteins regulating G1-to-S-phase transition were determined in three neutrophil precursor populations from human bone marrow: myeloblasts (MBs) and promyelocytes (PMs); myelocytes (MCs) and metamyelocytes (MMs); and band cells (BCs) and segmented neutrophil cells (SCs) and in mature polymorphonuclear neutrophils (PMNs) from peripheral blood. Complete cell-cycle arrest was observed in BCs/SCs and PMNs. Cyclins D1, D2, and D3 were found to be down-regulated during granulopoiesis, whereas a slight increase of cyclin E was seen. In contrast, cyclin-dependent kinase (CDK)2, -4, and -6 were down-regulated from the MC/MM stages and onward. The transcript levels of CDK2, -4, and -6 were concurrently down-regulated. As the only CDK inhibitor, p27kip1 protein and mRNA expression were up-regulated in MCs/MMs and reached peak levels in PMNs. Protein expression of retinoblastoma protein and the related pocket proteins p107 and p130 was down-regulated from the MC/MM stages and onward. This is the first report to describe expression levels of cell-cycle proteins during granulopoiesis in vivo, and it strongly contrasts the observations made in cell-culture systems in vitro.
Impact of Hospital Procedure Volume on Surgical Operation and Long-Term Outcomes in High-Risk Curatively Resected Rectal Cancer: Findings From the Intergroup 0114 Study
Authors: Meyerhardt Jeffrey A. , Tepper Joel E. , Niedzwiecki Donna , Hollis Donna R. , Schrag Deborah , Ayanian John Z. , O'Connell Michael J. , Weeks Jane C. , Mayer Robert J. , Willett Christopher G. , MacDonald John S. , Benson Al B. , Fuchs Charles S. 
Published: December 2003

Purpose Prior studies have demonstrated superior outcomes after a curative surgical resection of rectal cancer at hospitals where the volume of such surgeries is high. However, because these studies often lack detailed information on tumor and treatment characteristics as well as cancer recurrence, the true nature of this relation remains uncertain. Patients and Methods We studied a nested cohort of 1,330 patients with stage II and stage III rectal cancer participating in a multicenter, adjuvant chemoradiotherapy trial. We analyzed differences in rates of sphincter-preserving operations, overall survival, and cancer recurrence by hospital surgical volume. Results We observed a significant difference in the rates of abdominoperineal resections across tertiles of hospital procedure volume (46.3% for patients resected at low-volume, 41.3% at medium-volume, and 31.8% at high-volume hospitals; P < .0001), even after adjustment for tumor distance from the anal verge. However, this higher rate of sphincter-sparing operations at high-volume centers was not accompanied by any increase in recurrence rates. Hospital surgical volume did not predict overall, disease-free, recurrence-free, or local recurrence-free survival. However, among patients who did not complete the planned adjuvant chemoradiotherapy (270 patients), those who underwent surgery at low-volume hospitals had a significant increase in cancer recurrence (adjusted hazard ratio, 1.94; 95% CI, 1.01 to 3.72; P = .04 for the trend) and a nonsignificant trend toward increased overall mortality (P = .08) and local recurrence (P = .10). In contrast, no significant volume-outcome relation was noted among patients who did complete postoperative therapy. Conclusion Using prospectively recorded data, we found that hospital surgical volume had no significant effect on rectal cancer recurrence or survival when patients completed standard adjuvant therapy. Sphincter-preserving surgery was more commonly performed at high-volume centers.
Group II Rhabdomyosarcoma and Rhabdomyosarcomalike Tumors: Is Radiotherapy Necessary?
Authors: Schuck Andreas , Mattke Adrian C. , Schmidt Bernhard , Kunz Denise S. , Harms Dieter , Knietig Robert , Treuner Joern , Koscielniak Ewa 
Published: December 2003

Purpose In the prospective Cooperative Soft Tissue Sarcoma Study Group (CWS) 81, 86, 91, and 96 trials, radiotherapy was omitted in some patients with rhabdomyosarcoma and rhabdomyosarcoma-like tumors within Intergroup Rhabdomyosarcoma Study (IRS) group II. This analysis evaluates whether subgroups can be defined for which radiotherapy is not necessary. Patients and Methods Two hundred three patients who were registered between January 1981 and December 1998 were eligible for evaluation. Radiotherapy was given depending on tumor location, histology, and whether a secondary complete resection could be performed. The recommended radiation doses ranged from 32 to 54 Gy. Results One hundred ten patients did receive and 93 patients did not receive radiotherapy. The calculated local control after 5 years was 83% with and 65% without radiotherapy (P < .004). Event-free survival (EFS) at 5 years was 76% and 58%, respectively (P < .005). Overall survival (OS) at 5 years was 84% and 77% (P = not significant). The differences in local control were significant for the subgroups of irradiated patients with favorable histology, favorable site, and initial tumor size of less than 5 cm. A trend for improved local control with irradiation was observed for patients with unfavorable site, unfavorable histology, and large primary tumors. EFS was significantly improved for irradiated patients who had unfavorable histology, both favorable and unfavorable tumor sites, and small initial tumors. OS was significantly improved for patients with unfavorable histology through radiation. Conclusion Local control and EFS in group II patients are improved with radiotherapy. No subgroup could be defined for which the omission of radiotherapy produced outcome equivalent to that of patients who were irradiated.
Phase I Trial of Combined-Modality Therapy for Localized Esophageal Cancer: Escalating Doses of Continuous-Infusion Paclitaxel With Cisplatin and Concurrent Radiation Therapy
Authors: Brenner Baruch , Ilson David H. , Minsky Bruce D. , Bains Manjit S. , Tong William , Gonen Mithat , Kelsen David P. 
Published: December 2003

Purpose To define the maximum-tolerated dose (MTD) of paclitaxel when given as a weekly 96-hour infusion with cisplatin and radiotherapy for patients with esophageal cancer. Patients and Methods Thirty-four patients with locally advanced esophageal cancer and three patients with local recurrence or positive resection margins were treated. Weekly paclitaxel doses of 10, 20, 30, 40, 60, and 80 mg/m2, given as a continuous 96-hour infusion, were administered with weekly cisplatin, 30 mg/m2 on day 1, weeks 1 to 6, and concurrent radiation (50.4 Gy). Plasma paclitaxel steady-state levels were measured. Results Dose-limiting toxicity, defined as a treatment break longer than 2 weeks for toxicity, occurred in one patient in the 80-mg/m2/wk dose level. Major causes for any (including ≤ 2 weeks) treatment breaks were mediport complications and neutropenic fever, which occurred mostly at that dose level. At a paclitaxel dose of 60 mg/m2/wk, myelosuppression, mostly neutropenia, was relatively mild and transient; stomatitis, esophagitis, diarrhea. and peripheral neuropathy were uncommon and usually of grade 2 or less. Therefore, the MTD was established at 60 mg/m2/wk. The mean steady-state concentration of paclitaxel at the MTD was 17.2 nmol/L. Complete (R0) resection was possible in 16 (73%) of 22 patients who underwent subsequent surgery, and the pathologic complete response rate was 24%. Conclusion Weekly, 96-hour infusion of paclitaxel 60 mg/m2/wk, given with concurrent cisplatin and radiotherapy, is a safe and tolerable regimen for patients with localized esophageal cancer. Preliminary efficacy data are encouraging. This regimen is the basis of ongoing Radiation Therapy Oncology Group phase II randomized trials in esophageal and gastric cancers.
Phase I Study of the Humanized Antiepidermal Growth Factor Receptor Monoclonal Antibody EMD72000 in Patients With Advanced Solid Tumors That Express the Epidermal Growth Factor Receptor
Authors: Vanhoefer Udo , Tewes Mitra , Rojo Federico , Dirsch Olaf , Schleucher Norbert , Rosen Oliver , Tillner Joachim , Kovar Andreas , Braun Ada H. , Trarbach Tanja , Seeber Siegfried , Harstrick Andreas , Baselga José 
Published: December 2003

Purpose To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). Patients and Methods This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. Results Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000 . Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. Conclusion Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.