RESUMO
The revised International Prognostic Index (R-IPI) is an important prognostic tool in diffuse large B cell lymphoma (DLBCL); however, outcomes can vary markedly within R-IPI groups, and additional prognostic markers are needed. We conducted a prospective observational study to evaluate the circulating immature myeloid (IM) cell subsets and cytokine profiles of 31 patients with newly diagnosed DLBCL before and after chemoimmunotherapy. Among circulating IM cells, myeloid-derived suppressor cells (MDSCs) were the predominant cell type (73.8% ± 26%). At baseline, circulating monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) were predominantly mutually exclusive. Patients with DLBCL clustered into three distinct immunotypes according to MDSC levels and subtype predominance: M-MDSChigh, PMN-MDSChigh, and MDSClow. The M-MDSChigh immunotype was associated with the germinal center B cell-like (GCB) subtype and elevated serum IL-8 and MIP-1α levels. PMN-MDSChigh was associated with the non-GCB subtype and elevated IL-8, MCP-1, IP-10, TNFα, and IL-1Ra levels. Standard chemoimmunotherapy partially reduced M-MDSC distribution across the MDSClow and M-MDSChigh groups. By contrast, among the MDSClow and PMN-MDSChigh groups, PMN-MDSCs persisted after treatment. Two high-risk patients with non-GCB DLBCL and MDSClow immunotype experienced early disease recurrence within 12 months of treatment completion. This study demonstrates that distinct types of MDSCs are associated with subtypes of DLBCL. MDSC levels are dynamic and may be associated with disease status. Persistence of PMN-MDSCs among high-risk patients with DLBCL may be associated with early relapse.
Assuntos
Linfoma Difuso de Grandes Células B , Células Supressoras Mieloides , Humanos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Células Supressoras Mieloides/metabolismo , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Prognóstico , Inflamação/patologia , Adulto , Estudos Prospectivos , Idoso de 80 Anos ou mais , Citocinas/sangue , Imunoterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Angiosarcoma (AS) is a rare and aggressive vascular neoplasm with very poor prognosis. Patients with extensive cutaneous AS who are not surgical candidates have very limited options since there is no standard treatment. Treatment options include radiation, chemotherapy, and angiogenesis inhibitor with varying success rates. Here, we report a case an 88 year old patient with extensive scalp angiosarcoma having biopsy proven remission with bevacizumab and radiotherapy without undergoing surgery.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linfoma de Célula do Manto , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Piperidinas , Pirazóis/agonistas , Pirazóis/farmacologia , Pirimidinas/agonistas , Pirimidinas/farmacologiaRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. FACS panels from Figures 2D and 4D, as well as FACS panels from Figures 1C and 6C appear similar to each other. Also, panels from figures 1C and 6C appear similar to panels from Figures 1E and 4F of the article published by Hua-Xin Liang, Li-Bo Sun and Nai-Jie Liu in Biomedicine & Pharmacotherapy 109 (2019) 1032-1040 https://doi.org/10.1016/j.biopha.2018.10.122 and Figures 1D, 3E, 6C and 7A of the article published by Fangxi Xue, Zhaoxia Liu, Jian Xu, Xiaoguang Xu, Xingtian Chen and Feng Tian in Biomedicine & Pharmacotherapy 109 (2019) 1951-1959 https://doi.org/10.1016/j.biopha.2018.11.029. Given the comments of Dr Elisabeth Bik regarding this article "As previously described by Christopher , the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains", the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request.
Assuntos
Glucose/metabolismo , MicroRNAs/metabolismo , Oxigênio/metabolismo , Substâncias Protetoras/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Saponinas/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células Ganglionares da Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Young fit patients with mantle cell lymphoma (MCL) are commonly treated with induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT). Induction regimens with modifications of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and/or incorporation of high-dose cytarabine (HDAC) appear more effective than R-CHOP alone. PATIENTS AND METHODS: We adopted a modification of the Nordic protocol using standard, rather than higher dose R-CHOP, alternating with HDAC (rituximab plus HDAC), for 3 cycles each or, for patients already treated with R-CHOP alone before referral for AHCT, an additional 2 cycles of rituximab plus HDAC. We herein report our experience with 28 patients treated with this regimen who proceeded to AHCT, and compare their outcomes with patients treated with either standard-dose R-CHOP (n = 38) or R-HCVAD/MA (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate, and cytarabine; n = 21), before AHCT. RESULTS: With a median follow-up duration of 26 months, our data show that this modification of the Nordic regimen is a highly effective pre-AHCT first-line therapy for MCL (3-year progression-free and overall survival rates of 69% and 75%, respectively). CONCLUSION: By using a less intense induction, this regimen can serve as a platform for combined use of novel agents, with less risk of additive toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Célula do Manto/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
High molecular weight kininogen (HK) is an abundant, multi-domain plasma protein that circulates in plasma primarily in its single chain form. Proteolytic cleavage of HK by plasma kallikrein releases the vasoactive nanopeptide bradykinin (BK), and converts HK into two-chain HK (HKa). BK appears to have pro-angiogenic activity, most likely mediated through binding to B1 and B2 receptors on endothelial cells. Conversely, HKa and its domain 5, but not (single chain) HK, have potent anti-angiogenic activity comparable to other endogenous angiogenesis inhibitors. The mechanism by which HKa exerts its anti-angiogenic activity remains controversial, but appears to involve binding to cell surface tropomyosin and induction of apoptosis of proliferating endothelial cells. A role for tropomyosin in mediating the anti-angiogenic signals of other anti-angiogenic proteins such as endostatin and histidine-proline-rich glycoprotein (HPRG) has also been reported. Here we review the physiological importance of high molecular weight kininogen in angiogenesis, with emphasis on the mechanism(s) by which this activity is mediated.
Assuntos
Cininogênio de Alto Peso Molecular/farmacologia , Neovascularização Patológica/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Sequência de Aminoácidos , Inibidores da Angiogênese/química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacologia , Humanos , Cininogênio de Alto Peso Molecular/química , Cininogênio de Alto Peso Molecular/metabolismo , Dados de Sequência Molecular , Calicreína Plasmática/metabolismoRESUMO
High-molecular-weight kininogen (HK) is an abundant plasma protein that plays a central role in activation of the kallikrein-kinin system. Cleavage of HK by plasma kallikrein results in release of the nonapeptide bradykinin (BK), leaving behind cleaved high-molecular-weight kininogen (HKa). Previous studies have demonstrated that HKa induces apoptosis of proliferating endothelial cells and inhibits angiogenesis in vivo, activities mediated primarily through its domain 5. However, the mechanisms by which these effects occur are not well understood. Here, we demonstrate that HKa induces apoptosis of endothelial cells cultured on gelatin, vitronectin, fibronectin, or laminin but not collagen type I or IV. The ability of HKa to induce endothelial-cell apoptosis is dependent on the generation of intracellular reactive oxygen species and associated with depletion of glutathione and peroxidation of endothelial-cell lipids, effects that occur only in cells cultured on matrix proteins permissive for HKa-induced apoptosis. Finally, the ability of HKa to induce endothelial-cell apoptosis is blocked by the addition of reduced glutathione or N-acetylcysteine. These studies demonstrate a unique role for oxidant stress in mediating the activity of an antiangiogenic polypeptide and highlight the importance of the extracellular matrix in regulating endothelial-cell survival.
Assuntos
Apoptose/fisiologia , Células Endoteliais/metabolismo , Matriz Extracelular/metabolismo , Cininogênio de Alto Peso Molecular/metabolismo , Neovascularização Fisiológica/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Bradicinina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/citologia , Proteínas da Matriz Extracelular/metabolismo , Sequestradores de Radicais Livres/farmacologia , Glutationa/farmacologia , Humanos , Calicreínas/metabolismo , Cininogênio de Alto Peso Molecular/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
Heme oxygenase catalyzes the regiospecific oxidation of hemin to biliverdin IXalpha with concomitant liberation of CO and iron by three sequential monooxygenase reactions. The alpha-regioselectivity of heme oxygenase has been thought to result from the regioselective oxygenation of the heme alpha-meso position at the first step, which leads to the reaction pathway via meso-hydroxyheme IXalpha and verdoheme IXalpha intermediates. However, recent reports concerning heme oxygenase forming biliverdin isomers other than biliverdin IXalpha raise a question whether heme oxygenase can degrade meso-hydroxyhemin and isomers other than the alpha-isomers. In this paper, we investigated the stereoselectivity of each of the two reaction steps from meso-hydroxyhemin to verdoheme and verdoheme to biliverdin by using a truncated form of rat heme oxygenase-1 and the chemically synthesized four isomers of meso-hydroxyhemin and verdoheme. Heme oxygenase-1 converted all four isomers of meso-hydroxyhemin to the corresponding isomers of verdoheme. In contrast, only verdoheme IXalpha was converted to the corresponding biliverdin IXalpha. We conclude that the third step, but not the second, is stereoselective for the alpha-isomer substrate. The present findings on regioselectivities of the second and the third steps have been discussed on the basis of the oxygen activation mechanisms of these steps.