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1.
Am J Hematol ; 95(12): 1572-1577, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32918335

RESUMO

There are multiple intravenous (IV) iron formulations available, of which several may be administered as single-dose infusions such as low-molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. However, administration of ferumoxytol as a single-dose infusion is off-label as it is approved as a two-dose series. Previous studies of ferumoxytol alone support the effectiveness and safety of the single-dose regimen, but there is a paucity of data directly comparing single-dose ferumoxytol to other single-dose IV iron formulations. This multicenter cohort study sought to affirm the safety and effectiveness of single-dose ferumoxytol compared to single-dose LMWID. Overall, 906 patients who received single-dose LMWID (n = 439) or ferumoxytol (n = 467) were identified, of whom 351 met criteria for the primary effectiveness endpoint defined as median change in hemoglobin (Hb), hematocrit (Hct), and ferritin 8 to 12 weeks from baseline. All 906 patients were included for the secondary analysis evaluating the incidence of adverse events (AE) and requirement of additional IV iron infusions. Median change in Hb (LMWID 0.5 g/dL; ferumoxytol 0.8 g/dL; P = .24), Hct (LMWID 1.1%; ferumoxytol 1.25%; P = .89), and ferritin (LMWID 87 ng/dL; ferumoxytol 71 ng/dL; P = .47) was not significantly different between groups. Both groups experienced similar rates of AEs (LMWID 2.3%; ferumoxytol 2.8%; P = .63). The LMWID patients more frequently required additional IV iron infusions (LMWID 28.5%; ferumoxtyol 16.1%; P < .001). These findings support that single-dose ferumoxytol is effective and safe, and that patients may require fewer additional infusions compared to patients who received LMWID.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Óxido Ferroso-Férrico/administração & dosagem , Deficiências de Ferro , Complexo Ferro-Dextran/administração & dosagem , Adulto , Idoso , Anemia Ferropriva/sangue , Feminino , Óxido Ferroso-Férrico/efeitos adversos , Hematócrito , Hemoglobinas/metabolismo , Humanos , Ferro/sangue , Complexo Ferro-Dextran/efeitos adversos , Masculino , Pessoa de Meia-Idade
2.
J Clin Neurosci ; 73: 162-167, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31987634

RESUMO

Myxopapillary ependymomas (MPE) are WHO Grade I ependymomas that annually occur in 0.05-0.08 per 100,000 people. Surgical resection is the recommended first line therapy. Due to the rarity of the disease, there is a relatively poor understanding of the use of radiotherapy (RT) in managing this disease. The National Cancer Database (NCDB) was analyzed for patterns of care foradult MPE diagnosed between 2002 and 2016. Of 753 qualifying cases, the majority of patients underwent resection (n = 617, 81.9%). A relatively small portion received RT (n = 103, 13.3%) with most receiving RT post-operatively (n = 98, 95.1%). The likelihood of patients to undergo resection and RT was associated with patient age at diagnosis (p = 0.002), tumor size (p < 0.001), and race (p = 0.017). Chemotherapy was not widely utilized (0.27% of patients). One limitation of our analysis is that there was no data on progression free survival (PFS), an important outcome given the high survival rate in this disease. Surgery remains the primary means to manage adult MPE. For spinal MPE, it is understood that gross total resection (GTR) should be attempted whenever possible as GTR has been associated with improved PFS in several studies. The impact of RT on overall survival (OS) is indeterminate given the 1.6% death rate in the cohort. Analyses of the impact of RT on PFS in a larger database would be beneficial for determining an algorithm for post-operative and definitive RT in this disease entity.


Assuntos
Ependimoma/radioterapia , Oncologia/tendências , Neoplasias da Medula Espinal/radioterapia , Adulto , Algoritmos , Ependimoma/tratamento farmacológico , Ependimoma/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sistema de Registros , Estudos Retrospectivos , Neoplasias da Medula Espinal/tratamento farmacológico , Neoplasias da Medula Espinal/mortalidade , Taxa de Sobrevida , Estados Unidos
3.
Mol Cancer Res ; 16(10): 1447-1453, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29991528

RESUMO

The aggressive nature and inherent therapeutic resistance of glioblastoma multiforme (GBM) has rendered the median survival of afflicted patients to 14 months. Therefore, it is imperative to understand the molecular biology of GBM to provide new treatment options to overcome this disease. It has been demonstrated that the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is an important regulator of the endoplasmic reticulum (ER) stress response. PERK signaling has been observed in other model systems after radiation; however, less is known in the context of GBM, which is frequently treated with radiation-based therapies. To investigate the significance of PERK, we studied activation of the PERK-eIF2α-ATF4 pathway in GBM after ionizing radiation (IR). By inhibiting PERK, it was determined that ionizing radiation (IR)-induced PERK activity led to eIF2α phosphorylation. IR enhanced the prodeath component of PERK signaling in cells treated with Sal003, an inhibitor of phospho-eIF2α phosphatase. Mechanistically, ATF4 mediated the prosurvival activity during the radiation response. The data support the notion that induction of ER stress signaling by radiation contributes to adaptive survival mechanisms during radiotherapy. The data also support a potential role for the PERK/eIF2α/ATF4 axis in modulating cell viability in irradiated GBM.Implications: The dual function of PERK as a mediator of survival and death may be exploited to enhance the efficacy of radiation therapy.Visual Overview: http://mcr.aacrjournals.org/content/16/10/1447/F1.large.jpg Mol Cancer Res; 16(10); 1447-53. ©2018 AACR.


Assuntos
Fator 4 Ativador da Transcrição/genética , Fator de Iniciação 2 em Eucariotos/genética , Glioblastoma/radioterapia , Tolerância a Radiação/genética , eIF-2 Quinase/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Retículo Endoplasmático/efeitos da radiação , Estresse do Retículo Endoplasmático/genética , Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Lentivirus/genética , Fosforilação/efeitos da radiação , Radiação Ionizante , Transdução de Sinais/efeitos da radiação , Transfecção
4.
Clin Cancer Res ; 23(10): 2556-2564, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-27815359

RESUMO

Purpose: Non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) have poor median survival. NSCLC and GBM overexpress glucose regulated protein 78 (GRP78), which has a role in radioresistance and recurrence. In this study, we determined the effect of anti-GRP78 antibody and the combined effect of the anti-GRP78 antibody with ionizing radiation (XRT) on NSCLC and GBM cell lines both in vitro and in vivoExperimental Design: NSCLC and GBM cancer cell lines were treated with anti-GRP78 antibodies and evaluated for proliferation, colony formation, cell death, and PI3K/Akt/mTOR signaling. The efficacy of anti-GRP78 antibodies on tumor growth in combination with XRT was determined in vivo in mouse xenograft models.Results: GBM and NSCLC cells treated with anti-GRP78 antibodies showed attenuated cell proliferation, colony formation, and enhanced apoptosis. GBM and NSCLC cells treated with anti-GRP78 antibodies also showed global suppression of PI3K/Akt/mTOR signaling. Combining antibody with XRT resulted in significant tumor growth delay in both NSCLC and GBM heterotopic tumor models.Conclusions: Antibodies targeting GRP78 exhibited antitumor activity and enhanced the efficacy of radiation in NSCLC and GBM both in vitro and in vivo GRP78 is a promising novel target, and anti-GRP78 antibodies could be used as an effective cancer therapy alone or in combination with XRT. Clin Cancer Res; 23(10); 2556-64. ©2016 AACR.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Proteínas de Choque Térmico/antagonistas & inibidores , Recidiva Local de Neoplasia/tratamento farmacológico , Animais , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/imunologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Proteínas de Choque Térmico/imunologia , Humanos , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Oncotarget ; 7(2): 2080-92, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26716508

RESUMO

Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Estresse do Retículo Endoplasmático/efeitos da radiação , Glioblastoma/patologia , Receptor Notch1/metabolismo , Fator 6 Ativador da Transcrição/genética , Apoptose/efeitos da radiação , Western Blotting , Proliferação de Células/efeitos da radiação , Chaperona BiP do Retículo Endoplasmático , Citometria de Fluxo , Glioblastoma/radioterapia , Humanos , RNA Mensageiro/genética , Radiação Ionizante , Reação em Cadeia da Polimerase em Tempo Real , Receptor Notch1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
6.
J Nucl Med ; 57(12): 1991-1997, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27445290

RESUMO

Cancer-specific targeting sparing normal tissues would significantly enhance cancer therapy outcomes and reduce cancer-related mortality. One approach is to target receptors or molecules that are specifically expressed on cancer cells. Peptides as cancer-specific targeting agents offer advantages such as ease of synthesis, low antigenicity, and enhanced diffusion into tissues. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum stress chaperone that regulates the unfolded protein response and is overexpressed in various cancers. In this study, we evaluated GIRLRG peptide that specifically targets GRP78 for cancer-specific binding (in vitro) and noninvasive tumor imaging (in vivo). METHODS: GIRLRG peptide was modeled into the GRP78 ATPase domain using computational modeling. Surface plasmon resonance studies were performed to determine the affinity of GIRLRG peptide to GRP78 protein. GIRLRG was conjugated with PEG to prolong its circulation in mice. Tumor binding efficacy of PEG-GIRLRG peptide was evaluated in nude mice bearing heterotopic cervical (HT3), esophageal (OE33), pancreatic (BXPC3), lung (A549), and glioma (D54) tumors. Nano-SPECT/CT imaging of the mice was performed 48 and 72 h after injection with 111In-labeled PEG-GIRLRG or PEG-control peptide. Post-SPECT biodistribution studies were performed 96 h after injection of the radiolabeled peptides. RESULTS: Using molecular modeling and surface plasmon resonance, we identified that GIRLRG was binding with an affinity constant of 2.16 × 10-3 M in the ATPase domain of GRP78. GIRLRG peptide specifically bound to cervical, lung, esophageal, and glioma cells. SPECT imaging revealed that 111In-PEG-GIRLRG specifically bound to cervical, esophageal, pancreatic, lung, and brain tumors. Post-SPECT biodistribution data also validated the SPECT imaging results. CONCLUSION: GIRLRG peptide specifically binds to the ATPase domain of GRP78. Radiolabeled PEG-GIRLRG could be used to target various cancers. Further studies would be required to translate PEG-GIRLRG peptide into the clinic.


Assuntos
Adenocarcinoma/metabolismo , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Polietilenoglicóis/química , Células A549 , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenosina Trifosfatases/metabolismo , Sequência de Aminoácidos , Animais , Chaperona BiP do Retículo Endoplasmático , Feminino , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Humanos , Camundongos , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Especificidade por Substrato
7.
Cancer Res ; 75(17): 3442-5, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26130648

RESUMO

Radiation-induced lymphopenia (RIL) is associated with treatment of different tumors (lung, colon, pancreas, breast, sarcomas, and glioblastoma). It is a significant clinical problem affecting the survival of cancer patients. The biologic mechanisms leading to RIL are not clearly understood. In this study, we established a mouse model of RIL representing therapeutic clinical regimen for lung cancer. Flow cytometry was used to analyze circulating levels of T and B cells and bone marrow (BM) stem cells. We found that fractionated radiation to the thorax significantly reduced circulating T and B cells as well as BM stem cells. Ex-vivo irradiation of blood and autologous reinjection to mice also significantly induced lymphopenia. Furthermore, we found that mobilization of stem cells from the BM and autologous stem cell transplant rescued RIL in mice. Overall, our results suggest that RIL has not only direct effect on circulating lymphocytes, but also has indirect effect on circulating lymphocytes as well as stem cells in the nonirradiated BM. These results open a new window for investigating the direct and indirect biologic mechanisms leading to RIL, and provide a preclinical basis to test the effect of stem cell transplantation for treatment of RIL in cancer patients.


Assuntos
Transplante de Medula Óssea , Neoplasias Pulmonares/radioterapia , Linfopenia/imunologia , Radioterapia/efeitos adversos , Animais , Células da Medula Óssea/efeitos da radiação , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfopenia/etiologia , Linfopenia/terapia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/patologia , Células-Tronco/efeitos da radiação
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