48 research outputs found
MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models
Macrophage migration inhibitory factor (MIF) is a ubiquitously expressed pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. We used a genetic approach to show that deletion of the MIF gene in mice has several major consequences for the proliferative and transforming properties of cells. MIF-deficient cells exhibit increased resistance to oncogenic transformation. The transformation defects associated with MIF deficiency can be overcome through concomitant inactivation of the p53 and Rb/E2F tumor suppressor pathways. We have produced compelling evidence that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 functionally antagonize each other in the cell. However, the involvement of MIF in p53 function is secondary to p53-independent mechanisms controlling protein stability, DNA damage checkpoints, and the integrity of the genome. Given the broad spectrum of cell types that normally express MIF and its elevated levels at sites of chronic inflammation, this pathway may be generic for many early stage tumors
Brain Miffed by Macrophage Migration Inhibitory Factor
Macrophage migration inhibitory factor (MIF) is a cytokine which also exhibits enzymatic properties like oxidoreductase and tautomerase. MIF plays a pivotal role in innate and acquired immunity as well as in the neuroendocrine axis. Since it is involved in the pathogenesis of acute and chronic inflammation, neoangiogenesis, and cancer, MIF and its signaling components are considered suitable targets for therapeutic intervention in several fields of medicine. In neurodegenerative and neurooncological diseases, MIF is a highly relevant, but still a hardly investigated mediator. MIF operates via intracellular protein-protein interaction as well as in CD74/CXCR2/CXCR4 receptor-mediated pathways to regulate essential cellular systems such as redox balance, HIF-1, and p53-mediated senescence and apoptosis as well as multiple signaling pathways. Acting as an endogenous glucocorticoid antagonist, MIF thus represents a relevant resistance gene in brain tumor therapies. Alongside this dual action, a functional homolog-annotated D-dopachrome tautomerase/MIF-2 has been uncovered utilizing the same cell surface receptor signaling cascade as MIF. Here we review MIF actions with respect to redox regulation in apoptosis and in tumor growth as well as its extracellular function with a focus on its potential role in brain diseases. We consider the possibility of MIF targeting in neurodegenerative processes and brain tumors by novel MIF-neutralizing approaches
Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial
Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter â„7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7-90·2) and in non-complete metabolic responders was 54·9% (40·5-67·3; HR 0·2, 95% CI 0·1-0·3, p<0·0001).Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.F Hoffmann-La Roche
Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety
PurposeThe GALLIUM study (ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101;G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P;CHOP);CVP;or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety.Patients and Methods: A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m(2) on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression.Results: Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68;95% CI, 0.54 to 0.87;P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63;95% CI, 0.46 to 0.88;CHOP: HR, 0.72;95% CI, 0.48 to 1.10;CVP: HR, 0.79;95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles.Conclusion: Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation
The outcome of renal ischemia-reperfusion injury is unchanged in AMPK-ÎČ1 deficient mice
AIM: Activation of the master energy-regulator AMP-activated protein kinase (AMPK) in the heart reduces the severity of ischemia-reperfusion injury (IRI) but the role of AMPK in renal IRI is not known. The aim of this study was to determine whether activation of AMPK by acute renal ischemia influences the severity of renal IRI. METHODS: AMPK expression and activation and the severity of renal IRI was studied in mice lacking the AMPK β1 subunit and compared to wild type (WT) mice. RESULTS: Basal expression of activated AMPK, phosphorylayed at αThr¹â·², was markedly reduced by 96% in AMPK-β1â»/â» mice. Acute renal ischaemia caused a 3.2-fold increase in α1-AMPK activity and a 2.5-fold increase in α2-AMPK activity (P<0.001) that was associated with an increase in AMPK phosphorylation of the AMPK-α subunit at Thr¹â·² and SerâŽâžâ”, and increased inhibitory phosphorylation of the AMPK substrate acetyl-CoA carboxylase. After acute renal ischemia AMPK activity was reduced by 66% in AMPK-β1â»/â» mice compared with WT. There was no difference, however, in the severity of renal IRI at 24-hours between AMPK-β1â»/â» and WT mice, as measured by serum urea and creatinine and histological injury score. In the heart, macrophage migration inhibitory factor (MIF) released during IRI contributes to AMPK activation and protects from injury. In the kidney, however, no difference in AMPK activation by acute ischemia was observed between MIFâ»/â» and WT mice. Compared with the heart, expression of the MIF receptor CD74 was found to be reduced in the kidney. CONCLUSION: The failure of AMPK activation to influence the outcome of IRI in the kidney contrasts with what is reported in the heart. This difference might be due to a lack of effect of MIF on AMPK activation and lower CD74 expression in the kidney
A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL
Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naĂŻve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD2 rates between arms, the log of the PFS hazard ratio decreased by 20.188 (95% confidence interval, 20.321 to 20.055; P 5 .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action
MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models-2
<p><b>Copyright information:</b></p><p>Taken from "MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models"</p><p>http://www.celldiv.com/content/2/1/22</p><p>Cell Division 2007;2():22-22.</p><p>Published online 19 Jul 2007</p><p>PMCID:PMC1941730.</p><p></p>carcinogen benzo[α]pyrene (B[α]P) in 100 Όl acetone topically on their backs once per week for 20 weeks. Skin tumors started to appear after week 14, and increased in number during the course of B[α]P treatment. MIFmice developed nearly twice as many tumors per mouse as MIFcontrols. Based on histological evaluation by a blinded pathologist, this primarily reflected an increase of non-invasive tumors. By contrast, the number of invasive tumors was similar between the genotypes. Likewise, we found no significant difference with respect to tumor size or vascularization. * = statistically significant with p < 0.01 in a Student's t-test
MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models-0
<p><b>Copyright information:</b></p><p>Taken from "MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models"</p><p>http://www.celldiv.com/content/2/1/22</p><p>Cell Division 2007;2():22-22.</p><p>Published online 19 Jul 2007</p><p>PMCID:PMC1941730.</p><p></p>carcinogen benzo[α]pyrene (B[α]P) in 100 Όl acetone topically on their backs once per week for 20 weeks. Skin tumors started to appear after week 14, and increased in number during the course of B[α]P treatment. MIFmice developed nearly twice as many tumors per mouse as MIFcontrols. Based on histological evaluation by a blinded pathologist, this primarily reflected an increase of non-invasive tumors. By contrast, the number of invasive tumors was similar between the genotypes. Likewise, we found no significant difference with respect to tumor size or vascularization. * = statistically significant with p < 0.01 in a Student's t-test
Brain Miffed by Macrophage Migration Inhibitory Factor
Macrophage migration inhibitory factor (MIF) is a cytokine which also exhibits enzymatic properties like oxidoreductase and tautomerase. MIF plays a pivotal role in innate and acquired immunity as well as in the neuroendocrine axis. Since it is involved in the pathogenesis of acute and chronic inflammation, neoangiogenesis, and cancer, MIF and its signaling components are considered suitable targets for therapeutic intervention in several fields of medicine. In neurodegenerative and neurooncological diseases, MIF is a highly relevant, but still a hardly investigated mediator. MIF operates via intracellular protein-protein interaction as well as in CD74/CXCR2/CXCR4 receptor-mediated pathways to regulate essential cellular systems such as redox balance, HIF-1, and p53-mediated senescence and apoptosis as well as multiple signaling pathways. Acting as an endogenous glucocorticoid antagonist, MIF thus represents a relevant resistance gene in brain tumor therapies. Alongside this dual action, a functional homolog-annotated D-dopachrome tautomerase/MIF-2 has been uncovered utilizing the same cell surface receptor signaling cascade as MIF. Here we review MIF actions with respect to redox regulation in apoptosis and in tumor growth as well as its extracellular function with a focus on its potential role in brain diseases. We consider the possibility of MIF targeting in neurodegenerative processes and brain tumors by novel MIF-neutralizing approaches
A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies
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