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Biganzoli L.,Sandro Pitigliani Medical Oncology Unit | Di Vincenzo E.,Cardiologic Unit | Jiang Z.,307 Hospital | Lichinitser M.,Modality | And 15 more authors.
Annals of Oncology | Year: 2012

Background: There are limited data on treatment outcomes in the growing population of elderly patients with locally recurrent/metastatic breast cancer (LR/mBC). To gain information on first-line bevacizumab combined with chemotherapy in the elderly, we analyzed data from the ATHENA trial in routine oncology practice. Patients and methods: Patients with human epidermal growth factor receptor-2-negative LR/mBC received firstline bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We carried out a subgroup analysis of safety and efficacy in patients aged ≥70 years. Possible correlations between tolerability and baseline comorbidities or Eastern Cooperative Oncology Group status were explored. Results: Bevacizumab was combined with single-agent paclitaxel in 46% of older patients. Only hypertension and proteinuria were more common in older than in younger patients (grade ≥3 hypertension: 6.9% versus 4.2%, respectively; grade ≥3 proteinuria: 4.0% versus 1.5%, respectively). Grade ≥3 arterial/venous thromboembolism occurred in 2.9% versus 3.3%, respectively. Further analysis revealed no relationship between baseline presence and severity of hypertension and risk of developing hypertension during bevacizumab-containing therapy. Median time to progression was 10.4 months in patients aged ≥70 years. Conclusions: These findings suggest that bevacizumab-containing therapy is tolerable and active in patients aged ≥70 years. Hypertension was more common than in younger patients but was manageable. We find no evidence precluding the use of bevacizumab in older patients, including those with hypertension, although age may influence chemotherapy choice. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Chang N.,University of Western Ontario | Li L.,University of Western Ontario | Hu R.,University of Nevada, Reno | Shan Y.,University of Western Ontario | And 9 more authors.
Aging Cell | Year: 2010

Dysfunction of PTEN-induced kinase 1 (PINK1) or DJ-1 promotes neuronal death and is implicated in the pathogenesis of Parkinson's disease, but the underlying mechanisms remain unclear. Given the roles of N-methyl-d-aspartate receptor (NMDAr)-mediated neurotoxicity in various brain disorders including cerebral ischemia and neurodegenerative diseases, we investigated the effects of PINK1 and DJ-1 on NMDAr function. Using protein overexpression and knockdown approaches, we showed that PINK1 increased NMDAr-mediated whole-cell currents by enhancing the function of NR2A-containing NMDAr subtype (NR2ACNR). However, DJ-1 decreased NMDAr-mediated currents, which was mediated through the inhibition of both NR2ACNR and NR2B-containing NMDAr subtype (NR2BCNR). We revealed that the knockdown of DJ-1 enhanced PTEN expression, which not only potentiated NR2BCNR function but also increased PINK1 expression that led to NR2ACNR potentiation. These results indicate that NMDAr function is differentially regulated by DJ-1-dependent signal pathways DJ-1/PTEN/NR2BCNR and DJ-1/PTEN/PINK1/NR2ACNR. Our results further showed that the suppression of DJ-1, while promoted NMDA-induced neuronal death through the overactivation of PTEN/NR2BCNR-dependent cell death pathway, induced a neuroprotective effect to counteract DJ-1 dysfunction-mediated neuronal death signaling through activating PTEN/PINK1/NR2ACNR cell survival-promoting pathway. Thus, PINK1 acts with DJ-1 in a common pathway to regulate NMDAr-mediated neuronal death. This study suggests that the DJ-1/PTEN/NR2BCNR and DJ-1/PTEN/PINK1/NR2ACNR pathways may represent potential therapeutic targets for the development of neuroprotection strategy in the treatment of brain injuries and neurodegenerative diseases such as Parkinson's disease. © 2010 The Authors Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Xu B.,Peking Union Medical College | Jiang Z.,307 Hospital | Kim S.-B.,University of Ulsan | Yu S.,Huazhong University of Science and Technology | And 6 more authors.
Breast Cancer | Year: 2011

Background: The primary objective of this multicenter, open-label, randomized, parallel, phase II selection trial was to compare the objective tumor response to biweekly (every 2 weeks) gemcitabine/paclitaxel, gemcitabine/carboplatin, and gemcitabine/cisplatin as first-line treatment for metastatic breast cancer. Patients and methods: Eligible patients with stage IV disease who relapsed after anthracycline failure were randomly assigned in a 1:1:1 ratio to gemcitabine (2,500 mg/m2) plus paclitaxel 150 mg/m 2 (n = 49); plus carboplatin, area under the curve = 2.5 mg/mL × min (n = 47); or plus cisplatin 50 mg/m 2 (n = 51). Study therapy continued up until a maximum of 8 cycles and follow-up continued for 24 months. Results: All patients were analyzed for efficacy and one patient was excluded from the safety analyses. The objective response was 26.5% [95% confidence interval (CI) 14.9-41.1] for gemcitabine/paclitaxel, 17.0% (95% CI 7.6-30.8) for gemcitabine/carboplatin, and 15.7% (95% CI 7.0-28.6) for gemcitabine/cisplatin. The adjusted odds ratio for tumor response was 0.33 (95% CI 0.10-1.06), P = 0.063 for gemcitabine/carboplatin versus gemcitabine/paclitaxel; 0.26 (95% CI 0.08-0.86), P = 0.027 for gemcitabine/cisplatin versus gemcitabine/paclitaxel; and 0.77 (95% CI 0.24-2.52), P = 0.671 for gemcitabine/cisplatin versus gemcitabine/carboplatin. There were no significant differences in overall survival or progression-free survival (P > 0.05). Grade 3 or 4 drug-related adverse events varied between groups and the majority of deaths (94.9%; 74/78) were related to disease progression. Conclusions: The gemcitabine-based treatments had comparable activity and tolerability. Similar survival characteristics and different toxicity profiles suggested that gemcitabine-platinum may be evaluated further in patients after anthracycline failure. © The Japanese Breast Cancer Society 2011.

Liu B.,University of Western Ontario | Li L.,University of Western Ontario | Zhang Q.,Georgia Regents University | Chang N.,University of Western Ontario | And 9 more authors.
Stroke | Year: 2010

BACKGROUND AND PURPOSE-: Downregulation of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is thought to be a novel neuroprotective strategy in ischemic stroke, but the underlying mechanisms remain unclear. In this study, we aimed to validate the use of PTEN regulation of γ-aminobutyric acid subtype A receptors (GABAARs) as a molecular target for the treatment of ischemic stroke. Because suppression of GABAARs contributes to ischemic neuron death, describing the intracellular signaling that interacts with GABAARs in ischemic neurons would provide a molecular basis for novel stroke therapies. METHODS-: We measured surface GABAAR expression by immunocytochemical labeling and surface protein biotinylation assay. Knockdown and overexpression approaches were used to test the effects of PTEN on the expression and function of GABA ARs. Neuronal death was detected in both in vitro and in vivo stroke models. RESULTS-: The knockdown and overexpression approaches provided the first evidence that PTEN negatively regulated membrane expression and function of GABAARs in rat hippocampal neurons. Importantly, we demonstrated that a PTEN inhibitor prevented the reduction of surface GABAARs in injured hippocampal neurons subjected to oxygen-glucose deprivation, an in vitro insult that mimics ischemic injury, whereas a GABAAR antagonist significantly reduced this PTEN inhibitor-induced neuroprotection in both the in vitro and in vivo ischemic stroke models. CONCLUSIONS-: Our study provides direct evidence that downregulation of PTEN protects against ischemic neuron death by preserving GABAAR function. Targeting this pathway may be an effective strategy for development of selective, potent stroke treatments. © 2010 American Heart Association, Inc.

Di G.-H.,Beijing Institute of Radiation Medicine | Di G.-H.,Shandong Academy of Sciences | Liu Y.,Beijing Institute of Radiation Medicine | Lu Y.,307 Hospital | And 3 more authors.
PLoS ONE | Year: 2014

Human mesenchymal stem cells (hMSCs) are currently investigated for a variety of therapeutic applications. However, MSCs isolated from primary tissue cannot meet clinical grade needs and should be expanded in vitro for several passages. Although hMSCs show low possibility for undergoing oncogenic transformation, they do, similar to other somatic cells, undergo cellular senescence and their therapeutic potential is diminished when cultured in vitro. However, the role of senescent MSCs in tumor progression remains largely elusive. In the current study, by establishing senescent human umbilical cord mesenchymal stem cells (s-UCMSCs) through the replicative senescence model and genotoxic stress induced premature senescence model, we show that s-UCMSCs significantly stimulate proliferation and migration of breast cancer cells in vitro and tumor progression in a co-transplant xenograft mouse model compared with 'young' counterparts (defined as MSCs at passage 5, in contrast to senescent MSCs at passage 45). In addition, we identified IL-6, a known pleiotropic cytokine, as a principal mediator for the tumor-promoting activity of s-UCMSCs by induction of STAT3 phosphorylation. Depletion of IL-6 from s-UCMSCs conditioned medium partially abrogated the stimulatory effect of s-UCMSCs on the proliferation and migration of breast tumor cells. © 2014 Di et al.

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