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1.
Gynecol Minim Invasive Ther ; 13(1): 53-55, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487618

RESUMO

Pseudoaneurysm formation often occurs when there is inadequate sealing at an arterial puncture site. We present the case of a 27-year-old primigravida with rheumatic heart disease and a history of mitral valve replacement on anticoagulants who experienced recurrent episodes of postpartum hemorrhage (PPH). Despite conservative management and adjustments to anticoagulant therapy, the bleeding persisted. Further investigations revealed a small pseudoaneurysm originating from the left uterine artery. Bilateral uterine artery embolization (UAE) using polyvinyl alcohol particles was successfully performed. The patient's condition improved, and she was discharged on a carefully regulated medication regimen. This case highlights the importance of considering rare causes of PPH in high-risk patients, such as uterine artery pseudoaneurysm. Anticoagulants could be a potential contributor of its spontaneous rupture. Prompt diagnosis and appropriate intervention, such as UAE, can effectively manage PPH and prevent adverse outcomes.

2.
Mol Cancer Ther ; 15(4): 548-59, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26832798

RESUMO

The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V(600E)) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAF(V600) (E)-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G(186D)) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548-59. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Ratos
3.
Clin Cancer Res ; 21(1): 49-59, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25320355

RESUMO

PURPOSE: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. EXPERIMENTAL DESIGN: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. RESULTS: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER(+)/high-proliferative breast cancer showed antitumor activity. CONCLUSIONS: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER(+)/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Sirolimo/análogos & derivados , Adulto , Idoso , Animais , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Humanos , Pessoa de Meia-Idade , Receptor IGF Tipo 1 , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/imunologia , Receptores de Somatomedina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Discov ; 3(7): 742-50, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23614898

RESUMO

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinase Quinase Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Mutação , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
5.
Am J Physiol Renal Physiol ; 292(4): F1291-301, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17164399

RESUMO

In unilateral ureteral obstruction (UUO), the kidney is characterized by increased fibrosis and apoptosis. Both transforming growth factor-beta (TGF-beta) and ANG II have been implicated, and ANG II may mediate its effects through TGF-beta. Previous studies demonstrated amelioration of renal damage when either TGF-beta or ANG II has been individually targeted. In this study, we sought to determine whether combining 1D11 (monoclonal antibody to TGF-beta) and an ACE inhibitor, enalapril, would be more effective in UUO than either individual treatment, as has been shown in diabetic and glomerulonephritic models. Rats underwent UUO and were given either control monoclonal antibody, 1D11 or enalapril, or 1D11/enalapril combination, for 14 days. Kidneys were harvested and examined for fibrosis [trichrome; collagen (real-time PCR, Sircol assay) and fibroblast-specific protein expression (immunohistochemistry), apoptosis (TUNEL), macrophage infiltration (immunohistochemistry), and TGF-beta expression (real-time PCR and tubular localization with immunohistochemistry)]. UUO was found to induce fibrosis, apoptosis, macrophage infiltration, and TGF-beta expression in the obstructed kidney. Administration of either 1D11 or enalapril individually significantly decreased all these changes; when 1D11 and enalapril were combined, there was little additive effect, and the combination did not provide full protection against damage. The results demonstrate that, for the most part, combination therapy is not additive in UUO. This could be due to the continued presence of a physical obstruction or to biochemical differences between UUO and other renal disease models. Furthermore, it suggests that other targets may be amenable to pharmacological manipulation in UUO.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Enalapril/administração & dosagem , Fator de Crescimento Transformador beta/imunologia , Obstrução Ureteral/tratamento farmacológico , Animais , Apoptose/fisiologia , Colágeno/biossíntese , Quimioterapia Combinada , Fibrose , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Ativação de Macrófagos/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
6.
Arthritis Rheum ; 50(4): 1319-31, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15077316

RESUMO

OBJECTIVE: Diffuse systemic sclerosis (SSc; scleroderma) is a debilitating disease characterized by excessive dermal fibrosis with later progression to internal organs. In addition to the fibrotic component, major aspects of the disease include vascular or circulatory involvement and immune dysregulation evidenced by inflammatory cells in affected tissues and production of autoantibodies. Many animal models resembling this disease have been studied, including genetic models in mice and chickens, challenge with chemicals such as bleomycin or vinyl chloride to induce fibrosis, and models of graft-versus-host (GVH)-induced disease using certain strains of mice with differences in minor histocompatibility loci. The present studies were undertaken to determine if alteration of the induction of GVH-induced scleroderma could result in a model that more fully represented the human condition. METHODS: Disease was induced by injection of spleen cells from B10.D2 mice into BALB/c mice deficient in mature T and B cells (recombination-activating gene 2 targeted). Dermal thickening, collagen deposition, vasoconstriction, and parameters of immunity were analyzed. RESULTS: Similar to the human disease, this modified GVH model of SSc demonstrated evidence of dermal thickening, particularly in the extremities, progressive fibrosis of internal organs, vasoconstriction and altered expression of vascularity markers in skin and internal organs, early immune activation, inflammation in skin and internal organs, and autoantibody generation. CONCLUSION: This modified model of GVH-induced SSc exhibits all major components of human disease and is likely to contribute to better understanding of the disease mechanisms and, ultimately, improved treatments for patients.


Assuntos
Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/imunologia , Camundongos Knockout , Escleroderma Sistêmico/imunologia , Animais , Linfócitos B/citologia , Tecido Conjuntivo/imunologia , Tecido Conjuntivo/patologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares , Escleroderma Sistêmico/patologia , Linfócitos T/citologia
7.
Kidney Int ; 65(1): 106-15, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14675041

RESUMO

BACKGROUND: Transforming growth factor-beta (TGF-beta) modulates immune/inflammatory cells, promotes extracellular matrix (ECM) accumulation, and is increased in fibrotic organs. Here we report the effects of administering a puromycin aminonucleoside nephropathy (PAN)-specific TGF-beta neutralizing antibody on glomerulosclerosis in vivo. METHODS: Adult male Sprague-Dawley rats underwent uninephrectomy (Nx) followed by intraperitoneal PAN at weeks 2, 6, 7 and 8. Rats were treated with either high (5 mg/kg body weight) (N= 9) or low (0.5 mg/kg body weight) (N= 7) dose TGF-beta antibody intraperitoneally three times weekly until sacrifice at week 10. A PAN untreated control group (N= 7) was dosed with an isotype specific, null antibody. The nephrectomy samples were studied as normal kidney control (NL) (N= 5). Rats undergoing left kidney Nx (N= 5) only were also included as age-matched control. Renal function and morphology were assessed, and molecular studies performed. RESULTS: Systolic blood pressure was increased in parallel over time in all groups (at 10 weeks, control 137 +/- 10 mm Hg; high 129 +/- 4 mm Hg; low 137 +/- 3 mm Hg) (P= NS). Both TGF-beta antibody treatments decreased renal cortex mRNA expressions similarly for TGF-beta1, TGF-beta2, and collagen III (TGF-beta1, control 0.36 +/- 0.02 mm Hg; high 0.19 +/- 0.01 mm Hg; low 0.19 +/- 0.02 mm Hg; P < 0.01 low and high vs. control; TGF-beta2, control 0.38 +/- 0.03 mm Hg; high 0.19 +/- 0.02 mm Hg; low 0.20 +/- 0.03 mm Hg; P < 0.01 low and high vs. control; and collagen III, control 0.33 +/- 0.01 mm Hg; high 0.14 +/- 0.01 mm Hg; low 0.19 +/- 0.01 mm Hg; P < 0.01 low and high vs. control; P < 0.05 low vs. high, data expressed as mRNA normalized density units vs. 18S RNA). However, only low dose TGF-beta antibody improved renal function and sclerosis measured by serum creatinine and creatinine clearance (serum creatinine, control 2.3 +/- 0.5 mg/dL; high 2.5 +/- 0.5 mg/dL; low 0.8 +/- 0.1 mg/dL; P < 0.05 low vs. control and high; creatinine clearance, control 0.44 +/- 0.11 mL/min; high 0.70 +/- 0.26 mL/min; low 1.34 +/- 0.30 mL/min; P < 0.05 low vs. control, P= NS vs. high). In parallel, sclerosis index (0 to 4+ scale) was improved in low dose (control 2.67 +/- 0.27; high 2.37 +/- 0.30; low 1.78 +/- 0.24; P < 0.05 low vs. control). This improved function and structure was linked to decreased glomerular infiltrating macrophages (0 to 4+ score, control 2.3 +/- 0.2; high 1.8 +/- 0.4; low 0.8 +/- 0.1; P < 0.01 low vs. control; P < 0.05 low vs. high; P= NS high vs. control). Further, plasminogen activator inhibitor-1 (PAI-1) mRNA expression in renal cortex was attenuated after low dose TGF-beta antibody treatment compared to control and high dose group (PAI-1/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio, NL 0.18 +/- 0.003; control 0.45 +/- 0.03; high 0.40 +/- 0.04; low 0.23 +/- 0.01; P < 0.05 low vs. control and high). Matrix metalloproteinase-9 (MMP-9) activity was maintained at higher levels in kidneys of the low dose TGF-beta antibody-treated group. CONCLUSION: These results show an in vivo dose-response with an agent that blocks the biologic activity of TGF-beta. Higher dose of TGF-beta antibody was without beneficial effect, suggesting that TGF-beta-mediated effects on PAI-1 and macrophage influx are bimodal and closely regulated. Given that both antibody doses reduced the expression of TGF-beta isoforms and collagen III production, but only low dose ameliorated histologic sclerosis, it appears that pharmacologic effects of anti-TGF-beta antibody on matrix synthesis and degradation are not equivalent.


Assuntos
Glomerulosclerose Segmentar e Focal/terapia , Imunoterapia , Fator de Crescimento Transformador beta/imunologia , Animais , Antibióticos Antineoplásicos , Anticorpos/farmacologia , Colágeno/metabolismo , Creatinina/metabolismo , Relação Dose-Resposta Imunológica , Expressão Gênica , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Proteinúria/induzido quimicamente , Proteinúria/patologia , Proteinúria/terapia , Puromicina Aminonucleosídeo , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/genética , Aumento de Peso
8.
J Am Soc Nephrol ; 14(2): 377-88, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12538738

RESUMO

TGF-beta is believed to play a central role in the development of Cyclosporin A (CsA)-induced nephropathy. This study investigated the effects of 1D11, a murine pan-specific TGF-beta-neutralizing monoclonal antibody, in an ICR mouse model of chronic CsA nephropathy. Mice were administered a low-salt diet (0.01% sodium) for 1 wk followed by CsA treatment (30 mg/kg, subcutaneously, daily) for 4 wk. 1D11 was administered (2.5 mg/kg, intraperitoneally, 3 times/wk) beginning immediately after the termination of CsA dosing and continued through 8 wk. CsA caused extensive renal histopathologic alterations, including tubular damage, interstitial infiltrates and fibrosis, deposition of collagen III, and apoptosis of tubular epithelial cells. 1D11 ameliorated the CsA-induced histopathologic alterations, with significant reduction in collagen III expression and deposition. Additionally, elevated levels of mRNA encoding TGF-beta1 and TGF-beta2 were significantly reduced. 1D11 also protected tubular epithelial cells from apoptosis by 48% (P < 0.05). In contrast, 13C4 (a control antibody) had no significant effect on any of the endpoints described above. Importantly, the effects of 1D11 on the CsA-induced morphologic alterations were followed by a reduction in serum creatinine level when compared with CsA mice treated with 13C4 (13C4, 0.45 +/- 0.09; 1D11, 0.30 +/- 0.08; P < 0.05) after 8 wk of treatment. Endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), nitrotyrosine, and tissue hypoxia were examined by immunostaining using specific antibodies. eNOS was significantly reduced in the endothelium of arterioles in the kidneys of mice treated with CsA, whereas iNOS was induced in the cortical tubules. Tissue hypoxia was found in both the arterioles and tubules, whereas nitrotyrosine was localized in the tubules. Administration of 1D11 improved tissue hypoxia and reduced nitrotyrosine formation. Moreover, the reciprocal changes in iNOS and eNOS expression were normalized by 1D11. This study demonstrates that 1D11 administration ameliorated morphologic alterations and preserved renal function in the context of existing chronic CsA nephropathy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Ciclosporina , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Fator de Crescimento Transformador beta/imunologia , Animais , Apoptose/efeitos dos fármacos , Doença Crônica , Proteínas da Matriz Extracelular/metabolismo , Rim/patologia , Rim/fisiopatologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Fator de Crescimento Transformador beta/metabolismo
9.
Am J Physiol Regul Integr Comp Physiol ; 283(3): R757-67, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12185011

RESUMO

This study examined the role of transforming growth factor-beta (TGF-beta) in the development of hypertension and renal disease in 9-wk-old male Dahl salt-sensitive (Dahl S) rats fed an 8% NaCl diet for 3 wk. The rats received an intraperitoneal injection of a control or an anti-TGF-beta antibody (anti-TGF-beta Ab) every other day for 2 wk. Mean arterial pressure was significantly lower in Dahl S rats treated with anti-TGF-beta Ab (177 +/- 3 mmHg, n = 12) than in control rats (190 +/- 4 mmHg, n = 17). Anti-TGF-beta Ab therapy also reduced proteinuria from 226 +/- 20 to 154 +/- 16 mg/day. Renal blood flow, cortical blood flow, and creatinine clearance were not significantly different in control and treated rats; however, medullary blood flow was threefold higher in the treated rats than in the controls. Despite the reduction in proteinuria, the degree of glomerulosclerosis and renal hypertrophy was similar in control and anti-TGF-beta Ab-treated rats. Renal levels of TGF-beta1 and -beta2, alpha-actin, type III collagen, and fibronectin mRNA decreased in rats treated with anti-TGF-beta Ab. To examine whether an earlier intervention with anti-TGF-beta Ab would confer additional renoprotection, these studies were repeated in a group of 6-wk-old Dahl S rats. Anti-TGF-beta Ab therapy significantly reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in this group of rats. The results indicate that anti-TGF-beta Ab therapy reduces blood pressure, proteinuria, and the renal injury associated with hypertension.


Assuntos
Anticorpos Monoclonais/farmacologia , Hipertensão Renal/terapia , Fator de Crescimento Transformador beta/imunologia , Anestesia , Animais , Pressão Sanguínea , Colágeno Tipo III/genética , Fibronectinas/genética , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/terapia , Hipertensão Renal/patologia , Glomérulos Renais/patologia , Masculino , Proteinúria/terapia , Ratos , Ratos Endogâmicos Dahl , Circulação Renal , Cloreto de Sódio na Dieta/farmacologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta1 , Fator de Crescimento Transformador beta2
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