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1.
Clin Case Rep ; 11(12): e8267, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38033698

RESUMO

In this case report we present a very rare case of intramuscular cavernous hemangioma in the temporalis muscle which was successfully managed with surgical excision with no evidence of recurrence in follow-up.

2.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35817480

RESUMO

BACKGROUND: Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2Rß/γ+ natural killer (NK) cells and CD8+, CD4+ and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα+ regulatory T cells (Tregs) and IL-2Rα+ eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high Cmax likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα+ cells and suboptimal pharmacokinetics with high Cmax and short half-life. METHODS: TransCon IL-2 ß/γ was designed to optimally address these drawbacks. To abolish IL-2Rα binding yet retain strong IL-2Rß/γ activity, IL-2 ß/γ was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2Rα binding site. To improve pharmacokinetics, IL-2 ß/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 ß/γ, with sustained release of IL-2 ß/γ. IL-2 ß/γ was characterized in binding and primary cell assays while TransCon IL-2 ß/γ was studied in tumor-bearing mice and cynomolgus monkeys. RESULTS: IL-2 ß/γ demonstrated selective and potent human IL-2Rß/γ binding and activation without IL-2Rα interactions. TransCon IL-2 ß/γ showed slow-release pharmacokinetics with a low Cmax and a long (>30 hours) effective half-life for IL-2 ß/γ in monkeys. In mouse tumor models, TransCon IL-2 ß/γ promoted CD8+ T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 ß/γ induced robust activation and expansion of CD8+ T cells, NK cells and γδ T cells, relative to CD4+ T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 ß/γ enhanced proliferation and cytotoxicity of primary human CD8+ T cells, NK cells and γδ T cells. SUMMARY: TransCon IL-2 ß/γ is a novel long-acting prodrug with sustained release of an IL-2Rß/γ-selective IL-2. It has remarkable and durable pharmacodynamic effects in monkeys and potential for improved clinical efficacy and tolerability compared with aldesleukin. TransCon IL-2 ß/γ is currently being evaluated in a Phase 1/2 clinical trial (NCT05081609).


Assuntos
Neoplasias , Pró-Fármacos , Animais , Linfócitos T CD8-Positivos , Síndrome da Liberação de Citocina , Preparações de Ação Retardada/farmacologia , Células Endoteliais , Humanos , Interleucina-2/farmacologia , Subunidade alfa de Receptor de Interleucina-2 , Camundongos , Neoplasias/tratamento farmacológico , Pró-Fármacos/farmacologia
3.
Ann Maxillofac Surg ; 11(1): 17-20, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522648

RESUMO

INTRODUCTION: P16 is an independent and reliable surrogate for the detection of human papillomavirus (HPV) in oral squamous cell carcinoma (OSCC). The aim of this study was to assess the P16 expression as a marker for HPV infection in OSCC and its impact on the treatment outcome. METHODS AND MATERIALS: A cross-sectional study was conducted on patients with a definite diagnosis of OSCC. Patients were assigned into two groups with and without recurrence or metastasis. Tumour resection was performed in the same manner for all patients. P16 expression was evaluated by immunohistochemical staining. Independent t-test and Chi-square tests were used to find significant differences in age, gender, stage of the disease, tumour size, lymph node involvement, and P16 expression between the two groups. RESULTS: Of 50 patients, 37 did not show any recurrence or metastasis (group 1), while 13 had a relapse (group 2). There was no significant difference for age, gender distribution, stage of the disease, or lymph node involvement between the two groups (P > 0.05). A significant difference in tumour size was noted between the two groups (P = 0.001). The mean expression of P16 was 38.92 ± 24.36 in group 1 and 51.54 ± 33.63 in group 2. No significant difference was found between the two groups for the mean expression of P16 (P = 0.23). DISCUSSION: A review of the recent literature revealed that the HPV role in OSCC treatment is controversial. According to the results of this study, there was no significant difference in terms of P16 expression between OSCC patients with and without recurrence or metastasis.

4.
Arch Acad Emerg Med ; 8(1): e33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32259125

RESUMO

Penetrating orbital trauma (POT) consists of high and low velocity penetrating injuries that may lead to severe consequences such as visual impairment and globe tearing. It has been reported to make up 30% to 50% of all orbital injuries. POT requires a multidisciplinary approach due to complex orbital injury, which involves eye function, brain injury, and facial aesthetics. In this report, we presented a case of POT due to knife injury in which the knife blade was removed and bleeding was controlled, the patient's general condition after surgery was good, but the vision of the right eye was lost.

5.
AAPS J ; 20(4): 66, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29704129

RESUMO

With the recent advances in cancer immunotherapy, it is now evident that the antigen-specific activation of the patients' immune responses can be utilized for achieving significant therapeutic benefits. Novel molecules have been developed and promising advances have been achieved in cancer therapy. The recent success of cancer immunotherapy clearly reflects the novelty of the approach and importance of this class of therapeutics. Due to the nature of immunotherapy, i.e., harnessing the patient's immune system, it becomes critical to evaluate the important variables that can guide preclinical development, translational strategies, patient selection, and effective clinical dosing paradigms following single and combination therapies. To further boost the durability and efficacy profiles of IO (immuno-oncology) drugs following single agent therapy, novel combination therapies are being sought. Combination strategies have become critical for enhancing the anti-tumor immunity in broader cancer indications. Comprehensive methods are being developed to quantify the synergistic combination effect profiles at various development phases. Further evaluation of the signaling and pathway components can potentially establish a unique "signature" characteristic for specific combination therapies following modulation of various immunomodulatory pathways. In this article, critical topics related to preclinical, translational, and clinical development of IO agents are discussed.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Desenvolvimento de Medicamentos/métodos , Imunoterapia/métodos , Oncologia Integrativa/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/uso terapêutico , Terapia Combinada/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Neoplasias/imunologia , Seleção de Pacientes , Pesquisa Translacional Biomédica/métodos , Resultado do Tratamento
7.
Cancer Res ; 71(3): 1029-40, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21245093

RESUMO

Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R-targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I- or IGF-II-driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of (18)F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Fator de Crescimento Insulin-Like II/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Neoplasias Experimentais/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Linhagem Celular , Feminino , Fluordesoxiglucose F18 , Humanos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/antagonistas & inibidores , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Knockout , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Fosforilação/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Isoformas de Proteínas , Compostos Radiofarmacêuticos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/antagonistas & inibidores , Receptor de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Oral Maxillofac Surg ; 68(11): 2765-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20708317

RESUMO

PURPOSE: The aim of this study was to assess the biomechanical stress tolerance of screws used in 9 fixation methods after bilateral sagittal split ramus osteotomy to determine which configuration leads to lesser force load on the cortical bone at fixation points. MATERIALS AND METHODS: A 3-dimensional computerized model of a human mandible with posterior teeth was generated. The bilateral sagittal split ramus osteotomy was virtually performed on this model. The separated model was assembled with 9 fixation methods: single screw, 2 screws one behind the other, 2 screws one below the other, 3 screws in an L configuration, 3 screws in an inverted backward L configuration, miniplate with 2 screws, miniplate with 4 screws, 2 parallel plates (upper + lower border), and square miniplate with 4 screws. Then, 75-, 135-, and 600-N vertical loads were applied on the posterior teeth of these models. The stress distribution on the screw sites on the buccal cortex was measured by the finite element method. RESULTS: In this model all the fixation methods withstood forces between 75 and 135 N. However, the single-screw and the 2-hole miniplate models showed that the stress distributions in the configurations were intolerable when 600 N of posterior force was applied. The results of this study indicated that the inverted backward L configuration with 3 bicortical screws was the most stable. CONCLUSION: Although this study indicated that the inverted backward L configuration with 3 bicortical screws was the most stable pattern, most of the patterns had adequate stability for clinical applications (mean, 125 N).


Assuntos
Parafusos Ósseos , Análise de Elementos Finitos , Mandíbula/cirurgia , Osteotomia/instrumentação , Dente Pré-Molar/fisiologia , Fenômenos Biomecânicos , Placas Ósseas , Simulação por Computador , Desenho de Equipamento , Humanos , Imageamento Tridimensional , Côndilo Mandibular/fisiologia , Teste de Materiais , Modelos Biológicos , Dente Molar/fisiologia , Procedimentos Cirúrgicos Ortognáticos/instrumentação , Estresse Mecânico , Tomografia Computadorizada por Raios X , Interface Usuário-Computador
9.
Artigo em Inglês | MEDLINE | ID: mdl-20382052

RESUMO

OBJECTIVE: The present study aimed to assess the occurrence of trigeminocardiac reflex (TCR) during Le Fort I osteotomies. STUDY DESIGN: This case-crossover study included 25 Le Fort I osteotomy candidates without systemically compromising conditions. Mean arterial blood pressure and pulse rate values were recorded before downfracture (DF) (MABP1, PR1), during DF (MABP2, PR2), and after DF (MABP3, PR3). The data were analyzed using repeated measure ANOVA tests (alpha = 0.05). RESULTS: PR1 and PR3 were significantly higher than PR2 (P < .001). MABP2 value was significantly lower compared with MABP1 and MABP3 values (P < .001). PR2 and MABP2 showed a mean decrease of 6.5% and 9.7% compared with PR1 and MABP1, respectively. CONCLUSION: Different values have been suggested for TCR. Considering the limitations, the present study may suggest a revision of the values or descriptions for TCR, at least in maxillofacial Le Fort I osteotomy.


Assuntos
Complicações Intraoperatórias , Osteotomia de Le Fort , Reflexo/fisiologia , Nervo Trigêmeo/fisiopatologia , Adolescente , Adulto , Análise de Variância , Estudos Cross-Over , Feminino , Frequência Cardíaca , Humanos , Masculino , Estatísticas não Paramétricas , Adulto Jovem
10.
Mol Cancer Ther ; 9(1): 145-56, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20053776

RESUMO

Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.3) was developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms of reduced immunogenicity and increased half-life to block Ang2 function. The 3.19.3 antibody potently binds Ang2 with an equilibrium dissociation constant of 86 pmol/L, leading to inhibition of Tie2 receptor phosphorylation in cell-based assays. In preclinical models, 3.19.3 treatment blocked blood vessel formation in Matrigel plug assays and in human tumor xenografts. In vivo studies with 3.19.3 consistently showed broad antitumor activity as a single agent across a panel of diverse subcutaneous and orthotopic xenograft models. Combination studies of 3.19.3 with cytotoxic drugs or anti-vascular endothelial growth factor agents showed significant improvements in antitumor activity over single-agent treatments alone with no apparent evidence of increased toxicity. Initial pharmacokinetic profiling studies in mice and nonhuman primates suggested that 3.19.3 has a predicted human half-life of 10 to 14 days. These studies provide preclinical data for 3.19.3 as a potential new antiangiogenic therapy as a single agent or in combination with chemotherapy or vascular endothelial growth factor inhibitors for the treatment of cancer.


Assuntos
Angiopoietina-2/imunologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Especificidade de Anticorpos/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Colágeno/metabolismo , Combinação de Medicamentos , Humanos , Laminina/metabolismo , Camundongos , Neovascularização Patológica/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Primatas , Ligação Proteica/efeitos dos fármacos , Proteoglicanas/metabolismo , Receptor TIE-2/metabolismo
11.
Invest New Drugs ; 28(5): 561-74, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19626278

RESUMO

Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to rituximab, in the Ramos lymphoma cell line. Also, mAb 1.5.3 mediated both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) similar to rituximab in human B-lymphoma lines. Interestingly, mAb 1.5.3 demonstrated superior ADCC compared to rituiximab when FcgammaRIIIa F/F allotype donors were profiled and superior cytolytic activity across multiple human B-lymphoma and chronic B-cell leukemia lines in an in vitro whole blood assay. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Ramos, Daudi, and Namalwa tumour xenograft models. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to rituximab in a primate pharmacodynamic (PD) model. These findings underscore the potential of mAb 1.5.3 to exhibit improved clinical activity in the treatment of B-cell malignancies compared to rituximab.


Assuntos
Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Linfoma de Células B/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Murinos , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Mapeamento de Epitopos , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Macaca fascicularis , Camundongos , Camundongos SCID , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/imunologia , Rituximab
12.
AAPS J ; 12(1): 33-43, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19924542

RESUMO

The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.


Assuntos
Anticorpos Monoclonais/farmacocinética , Animais , Afinidade de Anticorpos , Artrite Reumatoide/metabolismo , Medula Óssea/metabolismo , Encéfalo/metabolismo , Humanos , Articulações/metabolismo , Pulmão/metabolismo , Linfonodos/metabolismo , Baço/metabolismo , Distribuição Tecidual
13.
Anal Chem ; 79(21): 8176-84, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17922557

RESUMO

The cut point and detection limit of any immunogenicity assay are two of the most important quantities that define the adequacy of an assay for detecting anti-drug antibodies against therapeutic proteins. To date in the immunogenicity testing literature, only the type I (alpha) error (i.e., the false positive) rate of the assay has been considered for establishing cut points. The "sensitivity" of an immunogenicity assay is usually reported as the concentration of a monoclonal or polyclonal anti-drug antibody standard corresponding to the signal at the cut point. We propose that a more traditional and rigorous analytical chemistry definition of the detection capability be utilized wherein both type I and type II (beta, false negative) error rates are considered. Specifically, the Hubaux-Vos technique of calculating cut points and limits of detection from predication intervals on calibration curves is recommended as a statistically rigorous approach. The utility of using receiver-operator characteristic curves for managing the type I and II error rates of an immunogenicity assay is also presented. In addition, we illustrate how a soluble receptor, sMUC18, for the therapeutic mAb ABX-MA1 can result in false positives by Biacore methodology. This result suggests that immunogenicity confirmatory experiments must be carefully designed, preferably with a smaller type I and II error rate than in the primary screening if an acceptable limit of detection can be maintained.


Assuntos
Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Ressonância de Plasmônio de Superfície/métodos , Anticorpos Monoclonais Humanizados , Antígeno CD146/sangue , Calibragem , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/normas , Reações Falso-Negativas , Reações Falso-Positivas , Humanos , Interleucina-8/antagonistas & inibidores , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Ressonância de Plasmônio de Superfície/normas , Fatores de Tempo
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