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1.
J Agric Food Chem ; 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37917162

RESUMO

Osteoporosis (OP) is typically brought on by disruption of bone homeostasis. Excessive oxidative stress and mitochondrial dysfunction are believed to be the primary mechanisms underlying this disorder. Therefore, in order to restore bone homeostasis effectively, targeted treatment of oxidative stress and mitochondrial dysfunction is necessary. Cinnamaldehyde (CIN), a small molecule that acts as an agonist for the nuclear factor erythroid 2-related factor (Nrf2), has been found to possess antiapoptotic, anti-inflammatory, and antioxidant properties. We found that CIN, while rescuing apoptosis, can also reduce the accumulation of reactive oxygen species (ROS) to improve mitochondrial dysfunction and thus restore the osteogenic differentiation potential of BMSCs disrupted by hydrogen peroxide (H2O2) exposure. The role of CIN was preliminarily considered to be a consequence of Nrf2/HO-1 axis activation. The ovariectomized mice model further demonstrated that CIN treatment ameliorated oxidative stress in vivo, partially reversing OVX-induced bone loss. This improvement was seen in the trabecular microarchitecture and bone biochemical indices. However, when ML385 was concurrently injected with CIN, the positive effects of CIN were largely blocked. In conclusion, this study sheds light on the intrinsic mechanisms by which CIN regulates BMSCs and highlights the potential therapeutic applications of these findings in the treatment of osteoporosis.

2.
Exp Ther Med ; 18(4): 3037-3045, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31555387

RESUMO

NF-κB activating protein (NKAP) is a highly conserved protein involved in transcriptional repression, immune cell development, maturation, acquisition of functional competency and maintenance of hematopoiesis. In the present study, the function of NKAP in the progress of Ewing sarcoma (ES) was investigated. It was identified that NKAP is highly expressed in ES cells when compared with human mesenchymal stem cells (MSCs). NKAP was knocked-down in human ES cell lines A673 and RD-ES using small interfering (si)RNA transfection. The effectiveness of transfection was then verified using reverse transcription-quantitative PCR and western blot analysis to determine mRNA and protein levels, respectively. The results of the proliferation assays indicated that the knockdown of NKAP inhibited the proliferation and clonogenic abilities of human ES cells. Transwell assays further indicated that cell invasion and migration were significantly inhibited by NKAP knockdown, which may be mediated by downregulation of matrix metalloproteinase (MMP)-9 activity. Gain-of-function analysis also demonstrated the positive role NKAP played in the proliferation, invasion and migration of ES cells. Cell apoptosis was evaluated by flow cytometry, which identified that apoptotic cells were significantly increased when NKAP was silenced. In addition, downregulation of NKAP increased the levels of Bax and cleaved caspase 3, but decreased Bcl2 levels, which suggested that the mitochondrial apoptosis pathway was activated. To explore the action mechanism of NKAP, the status of the AKT signaling pathway in NKAP-silenced A673 and RD-ES cells was investigated. Results indicated that NKAP knockdown led to decreased phosphorylation of AKT and expression of cyclin D1, a down-stream effector of the AKT signaling pathway, suggesting inactivation of the AKT signaling pathway. In conclusion, the present study revealed that NKAP promoted the proliferation, migration and invasion of ES cells, at least partly, through the AKT signaling pathway, providing new approaches for the therapeutic application of NKAP in ES.

3.
Cancer Chemother Pharmacol ; 82(5): 803-814, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30128949

RESUMO

PURPOSE: This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-ixazomib. METHODS: After administration of a single 4.1-mg oral dose of [14C]-ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0-168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry. RESULTS: Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0-816 h time-proportional pooled plasma, ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0-35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active. CONCLUSIONS: Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of ixazomib. The inference of formation-rate-limited clearance of ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/urina , Compostos de Boro/sangue , Compostos de Boro/urina , Fezes/química , Glicina/análogos & derivados , Neoplasias/metabolismo , Administração Oral , Antineoplásicos/administração & dosagem , Área Sob a Curva , Biotransformação , Compostos de Boro/administração & dosagem , Radioisótopos de Carbono , Feminino , Glicina/administração & dosagem , Glicina/sangue , Glicina/urina , Humanos , Masculino , Metaboloma/efeitos dos fármacos , Neoplasias/tratamento farmacológico
4.
Nat Med ; 24(2): 186-193, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29334375

RESUMO

The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.


Assuntos
Neoplasias/tratamento farmacológico , Nucleosídeos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Humanos , Imidas/farmacologia , Camundongos , Neoplasias/genética , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/genética , Ligação Proteica , Pirazóis , Pirimidinas , Sulfetos , Ubiquitina/antagonistas & inibidores , Ubiquitina/química , Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/química , Enzimas Ativadoras de Ubiquitina/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
World J Surg Oncol ; 14(1): 155, 2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27255520

RESUMO

BACKGROUND: The purpose of this meta-analysis was to evaluate the clinical significance of diffusion-weighted imaging in assessing the status of axillary lymph nodes in patients with breast cancer. METHODS: We searched the PubMed, Cochrane, and EMBASE databases, selected studies by inclusion and exclusion criteria, and assessed the quality of selected studies. We explored the source of heterogeneity; calculated sensitivity, specificity, positive and negative likelihood ratios, and pretest probability. A summary receiver operating characteristic curve was performed. Student's t test was used to compare the different mean apparent diffusion coefficient values of different status lymph nodes. RESULTS: In selected 10 studies, a total of 801 patients and 2305 lymph nodes were included following inclusion criteria. All scores of the quality assessment of the included studies were greater than or equal to 10 points. The sensitivity was 0.89 (95 % CI 0.79-0.95), the specificity was 0.83 (95 % CI 0.71-0.91), the positive and negative likelihood ratios were 3.86 (95 % CI 2.75-5.41) and 0.17 (95 % CI 0.09-0.32), the pretest probabilities were 53 and 54 %, the area under the curve were 0.93 (95 % CI 0.90-0.95), respectively. The mean apparent diffusion coefficient value of metastatic lymph nodes was significantly lower than that of nonmetastatic axillary lymph nodes. CONCLUSIONS: Diffusion-weighted imaging is a promising tool to discriminate between metastatic and nonmetastatic axillary lymph nodes. Combined with the mean apparent diffusion coefficient value, it can quantitatively diagnose lymph node metastases. Conducting large-scale, high-quality researches can improve the clinical significance of diffusion-weighted imaging to distinguish metastatic and nonmetastatic axillary lymph nodes in patients with breast cancer and provide the evidence to assess the status of axillary lymph nodes.


Assuntos
Neoplasias da Mama/patologia , Linfonodos/patologia , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Metástase Linfática , Curva ROC
6.
J Pharm Biomed Anal ; 128: 226-235, 2016 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-27281578

RESUMO

Antibody-drug conjugates (ADCs) play an increasingly important role for targeted cancer treatment. One class of ADCs has attracted particular interest in drug development. These ADCs employ a cleavable chemistry linkage for drugs and utilize the reduced interchain disulfide cysteine residues for conjugation. In this work, a novel bioanalytical method for the quantification of a cleavable antibody-conjugated drug in plasma was developed, qualified, and implemented. This novel method significantly improves throughput by combining a microwave-assisted, enzymatic cleavage of conjugated drugs from ADCs with a 96-well based sample preparation procedure to immunocapture ADCs in plasma. The released drug is subsequently quantified using a LC/MS/MS method. Our results represent a high-throughput, generic, and sensitive quantification method for antibody-conjugated microtubule inhibitors (such as MMAE) for preclinical PK/PD studies. The linear range of the standard curve for antibody conjugated drug (MMAE) was from 2.01 to 2010ng/mL with an excellent linearity (r(2)>0.997). The intra-run precision was below 8.14% and accuracy was from -7.71% to -1.08%. No matrix effect or carryover was observed for this method. This method was successfully used to measure the level of conjugated drug in a preclinical PK/PD study in mice.


Assuntos
Imunoconjugados/análise , Imunoconjugados/farmacocinética , Animais , Azidas/química , Biotina/química , Catepsina B/química , Cromatografia Líquida de Alta Pressão , Enzimas/química , Feminino , Hidrólise , Camundongos , Camundongos SCID , Proteínas dos Microtúbulos/antagonistas & inibidores , Micro-Ondas , Oligopeptídeos/química , Propanolaminas/química , Controle de Qualidade , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
7.
World J Surg Oncol ; 14: 142, 2016 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-27159980

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a kind of rare neurogenic tumor. If associated with neurofibromatosis type 1, MPNST usually has a higher mortality. The aim of the article is to assess the imaging characteristics of MPNST and compare them with those of benign peripheral nerve sheath tumor (BPNST) to characterize this tumor. METHODS: Clinical and imaging data of six cases with MPNST and 28 cases with BPNST in our institution since 2011 were retrospectively reviewed. Thirty-three patients have available MR imaging data, and two patients of MPNST also accepted CT scan. One patient accepted CT scan only. Location, size, shape, signal or density, boundary, bone destruction, relation to adjacent nerve, contrast-enhanced features as well as some other signs were assessed and compared with statistical software. Student's t test was used for comparison of continuous variables. Fisher's exact test was used for analysis of nominal variable. A P value ≤0.05 was considered to be statistically significant. RESULTS: Differences existed between two groups in tumor size ((7.2 ± 3.3)cm in MPNST vs. (3.8 ± 1.4)cm in BPNST), unclear margin (4/6 in MPNST vs. 1/28 in BPNST), eccentricity to the nerve (1/6 in MPNST vs. 21/28 in BPNST), intratumoral lobulation (4/6 in MPNST vs. 2/28 in BPNST), peritumoral edema (3/6 in MPNST vs. 0 in BPNST), and peripheral enhancement (4/6 in MPNST (three of five MR, one CT) vs. 4/28 in BPNST). Bone destruction was observed in one MPNST. CONCLUSIONS: MR imaging is a valuable, non-invasive modality for the diagnosis of MPNST. Peripheral enhancement with non-cystic appearance or remarkable heterogeneous enhancement may be useful for differential diagnosis. Other imaging features such as large size (over 5 cm in diameter), ill-defined margin, intratumoral lobulation, peritumoral edema, and adjacent bone destruction are also supportive of MPNST.


Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasias de Bainha Neural/diagnóstico por imagem , Neoplasias de Bainha Neural/patologia , Neoplasias do Sistema Nervoso Periférico/diagnóstico por imagem , Neoplasias do Sistema Nervoso Periférico/patologia , Tomografia Computadorizada por Raios X/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
8.
Afr J Tradit Complement Altern Med ; 13(4): 176-183, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28852734

RESUMO

BACKGROUND: The current study was designed to evaluate the effect of Platycodin D (PD), triterpenoid saponins extracted from the roots of Platycodon grandiflorum (PG) on alcohol-induced fatty liver (AFL) and investigate the possible mechanism. METHODS AND MATERIALS: A rat model was set up by feeding ethanol and fish oil to experimental rats, which then were treated with PD of 10, 20, 30 mg/kg body weight/day for 4 weeks, respectively, whereafter, liver function enzymes, endotoxin of serum and liver lipid were assayed by biochemical methods, cytokines, histochemistry of hepatic tissue, the protein expression of CD14 and TLR4, the mRNA expression of MD-2, MyD 88 and TRAF-6 were assayed. RESULTS: Treatment with PD on AFL rats significantly decreased the levels of serum ALT, AST and TBIL, coefficient of liver index and the hepatic tissue contents of TG, additionally and dramatically decreased serum endotoxin levels, down-regulated MD-2 and CD14 levels, as well as the mRNA expression of TLR4, MyD88 and TRAF-6, accordingly suppressed NF-κB: p65 as well as endotoxin-mediated inflammatory factors such as TNF-α and IL-6. CONCLUSIONS: Treatment with PD effectively protects against AFL through anti-inflammatory and anti-endotoxic process, and the confirmed mechanism is that PD treatment ameliorate alcoholic-induced liver injury mainly via TLR4-MyD88-NF-K: B signal path in AFL rat. List of Abbreviations: AFL: alcoholic-induced fatty liver, CD14: cluster of differentiation 14, LPS: lipopolysaccharide, LBP: lipopolysaccharide-binding protein, TLR4: toll-like receptor 4, MD-2: molecule myeloid differential protein-2, MyD 88: myeloid differentiation primary response protein 88, TRAF-6: TNF-receptor associated factor-6, NF-κB: nuclear transcription factor kappa B, IL-6: interleukin-6, TNF-α: tumor necrosis factor-α, PG: Platycodon grandiflorum, PD: Platycodin D.


Assuntos
Álcoois/efeitos adversos , Anti-Inflamatórios/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Fígado Gorduroso/tratamento farmacológico , NF-kappa B/metabolismo , Platycodon/química , Saponinas/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Triterpenos/administração & dosagem , Animais , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , NF-kappa B/genética , Raízes de Plantas/química , Ratos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
World J Surg Oncol ; 12: 324, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25351104

RESUMO

CT findings in three cases with solitary fibrous tumors (SFTs) confirmed by histopathology and immunohistochemistry were reviewed retrospectively, and compared with pathological results. The three tumors were large, well-defined, and smooth contour masses and SFT consisted of solid components of two different densities. On enhanced CT scans, tumors were strongly enhancing, the multiple vascular shadows were seen within the tumor in the arterial phase. There is progressive enhancement from the arterial to the venous phase, and the tumor capsule can be observed. Histologically, the tumors are composed of spindle cells within a background of collagen stroma, and showed a wide range of growth patterns, alternating hypercellular (tumor cell-rich) and hypocellular (collagen-rich) areas. The diagnosis is confirmed by characteristic positive immunohistochemical staining for CD34.


Assuntos
Neoplasias Retroperitoneais/diagnóstico por imagem , Tumores Fibrosos Solitários/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Abdom Imaging ; 39(6): 1323-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24831155

RESUMO

PURPOSE: The purpose of this study was to investigate the imaging characteristics of solitary fibrous tumor (SFT) in the abdomen and pelvis. METHODS: Nine cases of SFT confirmed by surgery and pathology were retrospectively analyzed in terms of computed tomography (CT, eight cases) and magnetic resonance imaging (MRI, one case). RESULTS: SFT were located in the retroperitoneum (4/9), abdominal cavity (1/9), pelvis (4/9). Eight cases were single (8/9) and one case (1/9) with three tumors. The average tumor size of 11 lesions was 9.7 cm (4.7-20 cm). Nine tumors were round or ovoid, and two lesions were irregular. The CT value of the plain scans ranged from 33 to 43 Hounsfield units (HU, mean 37.6 HU) in five cases. Arterial-phase CT found solid parts demonstrate avid enhancement (eight cases) and five of them presented with multiple circuitous vessels along the periphery with a CT value of 68-89 HU (mean 76.6 HU). In the venous and delayed phases, enhancement was strengthened progressively. The CT values at venous (eight cases) and delayed phases (five cases) were 108-115 and 112-123 HU respectively, with averages of 109.8 and 114.8 HU. Patch or nodular no-enhanced areas were observed in eight cases during the enhanced phases. One case showed isointensity on T1-weighted images and high signal intensity on T2-weighted images accompanied by linear or curvilinear hypointense lines. Intense enhancements along with linear no-enhancement areas are seen in the arterial and venous phases. CONCLUSION: The possibility of SFT should be considered when a single or multiple masses with sharp border, inhomogeneous density or signal are detected, especially, with inhomogeneous intense enhancement in the arterial phase being maintained in the venous and delayed phases.


Assuntos
Neoplasias Abdominais/diagnóstico por imagem , Neoplasias Abdominais/patologia , Neoplasias Pélvicas/diagnóstico por imagem , Neoplasias Pélvicas/patologia , Tumores Fibrosos Solitários/diagnóstico , Cavidade Abdominal/diagnóstico por imagem , Cavidade Abdominal/patologia , Adulto , Idoso , Meios de Contraste , Feminino , Gadolínio DTPA , Humanos , Aumento da Imagem/métodos , Iohexol/análogos & derivados , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Pelve/diagnóstico por imagem , Pelve/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
11.
World J Gastroenterol ; 20(15): 4446-52, 2014 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-24764686

RESUMO

AIM: To characterize the clinical, radiological, endoscopic and pathological features of intestinal tuberculosis (ITB) and primary small intestinal lymphoma (PSIL). METHODS: This was a retrospective study from February 2005 to October 2012 of patients with a diagnosis of ITB (n = 41) or PSIL (n = 37). All patients with ITB or PSIL underwent computed tomography (CT) and pathological examination. Thirty-five patients with ITB and 32 patients with PSIL underwent endoscopy. These patients were followed for a further 18 mo to ascertain that the diagnosis had not changed. Clinical, endoscopic, CT and pathological features were compared between ITB and PSIL patients. RESULTS: Night sweating, fever, pulmonary TB and ascites were discovered significantly more often in ITB than in PSIL patients (P < 0.05), however, abdominal mass, hematochezia and intestinal perforation were found significantly more frequently in PSIL than in ITB patients (P < 0.05). Ring-like and rodent-like ulcers occurred significantly more often in ITB than in PSIL patients (P < 0.05), however, enterorrhagia and raised lesions were significantly more frequent in PSIL than in ITB patients (P < 0.05). The rate of granuloma was significantly higher in ITB than in PSIL patients (87.8% vs 13.5%, χ(2) = 43.050, P < 0.05), and the incidence of confluent granulomas with caseous necrosis was significantly higher in ITB than in PSIL patients (47.2% vs 0.0%, χ(2) = 4.034, P < 0.05). Multi-segmental lesions, mural stratification, mural gas sign, and intestinal stricture were more frequent in ITB than in PSIL patients (P < 0.05), however, a single-layer thickening of bowel wall, single segmental lesions, and intussusception were more common in PSIL than in ITB patients (P < 0.05). Necrotic lymph nodes, comb sign and inflammatory mass were more frequent in ITB than in PSIL patients (P < 0.05). The bowel wall enhancement in ITB patients was greater than that in PSIL patients (P < 0.05), while the thickening and lymph node enlargement in PSIL patients were higher than those in ITB patients (P < 0.05). CONCLUSION: Combined evaluation of clinical, radiological, endoscopic and pathological features is the key to differentiation between ITB and PSIL.


Assuntos
Neoplasias Intestinais/diagnóstico , Intestinos/patologia , Linfoma/diagnóstico , Tuberculose Gastrointestinal/diagnóstico , Adulto , Diagnóstico Diferencial , Endoscopia , Humanos , Inflamação , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
Drug Metab Lett ; 7(2): 96-104, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24484538

RESUMO

Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 µM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose.


Assuntos
Antineoplásicos/farmacocinética , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacocinética , Cálculos da Dosagem de Medicamento , Avaliação Pré-Clínica de Medicamentos , Modelos Biológicos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Aurora Quinase A/metabolismo , Azepinas/administração & dosagem , Azepinas/sangue , Células CACO-2 , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Cães , Feminino , Células HCT116 , Meia-Vida , Humanos , Infusões Subcutâneas , Fígado/metabolismo , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Camundongos Nus , Modelos Animais , Pan troglodytes , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Ratos Sprague-Dawley , Especificidade da Espécie , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Invest New Drugs ; 32(1): 160-70, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23817974

RESUMO

INTRODUCTION: This phase 1 study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, cerebrospinal fluid (CSF) distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285. METHODS: Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status ≤2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose (RP2D) were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors. RESULTS: Fifty-four patients were enrolled (median age 60; range, 35-76 years). The most common diagnoses were cancers of the colon (28 %), breast (17 %), and pancreas (9 %). Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD/RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast (median time of maximum concentration was 2-3 h), and mean half-life was 9 h. Steady-state average unbound CSF concentration (geometric mean 1.54 [range, 0.51-4.27] ng/mL; n = 5) at the RP2D was below the 50 % inhibitory concentration (9.3 ng/mL) for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease (12 weeks of nonprogression) in 13 patients. CONCLUSIONS: TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition.


Assuntos
Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/líquido cefalorraquidiano , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Receptores ErbB/antagonistas & inibidores , Hidroxibutiratos/líquido cefalorraquidiano , Hidroxibutiratos/farmacocinética , Neoplasias/líquido cefalorraquidiano , Neoplasias/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Demografia , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Feminino , Humanos , Hidroxibutiratos/administração & dosagem , Hidroxibutiratos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Receptor ErbB-2/metabolismo , Resultado do Tratamento
14.
Zhonghua Yi Xue Za Zhi ; 93(35): 2830-3, 2013 Sep 17.
Artigo em Chinês | MEDLINE | ID: mdl-24360184

RESUMO

OBJECTIVE: To develop a magnetic nanoparticles based magnetic resonance (MR) probe targeting CD40 mutant in the imaging of breast cancer cells in vitro. METHODS: For preparing an immunologically competent probe, monoclonal antibody was conjugated with ultrasmall superparamagnetic iron oxide (USPIO) particles basing on chemical cross-linking method.Its bioactivity was analyzed with flow cytometry, confocal microscopy and Prussian blue staining. The probe's cell MR imaging in vitro was conducted on breast cancer cells (M231) high expressing CD40 mutant. The signal data from different groups were collected and analyzed with one-way variance and least significant difference-t test. RESULTS: The molecular probe carrying nanoparticles and CD40 mutant antibody was constructed and separated successfully. The probe had similar magnetic property compared with original USPIO particles.It could recognize CD40 mutant on breast cancer cells (M231) with high specificity. MR cell imaging in vitro shows that T2 and T2(*) obviously shortened after probe binding with M231 cells and T2 weighted imaging become darker than control groups, the time of T2 is 5H6-USPIO (51.66 ± 5.31) , 5C11-USPIO (92.89 ± 4.72), USPIO (64.56 ± 3.85) ms. The T2 and T2(*) relaxation time of experiment group was shorter than control groups with statistical significance (P < 0.01) . CONCLUSION: MR molecular probe targeting CD40 mutant may bind with breast cancer cells (M231) to provide further in vivo animal MR imaging. And CD40 mutant is expected to provide a new target for MR molecular imaging of breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico , Imageamento por Ressonância Magnética , Antígenos CD40/genética , Linhagem Celular Tumoral , Feminino , Humanos , Magnetismo , Sondas Moleculares , Nanopartículas
15.
Zhonghua Wei Chang Wai Ke Za Zhi ; 16(5): 443-7, 2013 May.
Artigo em Chinês | MEDLINE | ID: mdl-23696400

RESUMO

OBJECTIVE: To investigate the value of CT and X-ray enterography in the diagnosis of small intestinal Crohn disease(CD). METHODS: Data of 39 CD cases confirmed by surgery and pathology who underwent CT and X-ray enterography were analyzed retrospectively. All the patients had complete CT data, 28 cases had X-ray intestinal barium meal data, and 18 had sinus tract enterography. RESULTS: CT enterography showed mural thickening(>4 mm) in 34(87.2%) patients, mural gas in 7(17.9%), mural edema in 7(17.9%), mural fat in 4(10.3%), increased enhancement of bowel wall(>10 HU) in 37(94.9%), multiple segmental lesions in 33(84.6%), single segmental lesions in 6(15.4%), mesenteric lymphadenopathy(>5 mm) in 13(33.3%), vascular bundle thickening in 9(23.1%), cellulitis in 12(30.8%), peritoneal abscess in 10(25.6%), phlegmon in 8(20.5%), incomplete intestinal obstruction in 14(35.9%), seroperitoneum in 22(56.4%), and fistulization in 4(10.3%). CT enterography did not demonstrate the change of mucosa such as strip ulcer or cobblestone. Among the 28 cases of small bowel X-ray enterography, 23 cases(82.1%) presented with multiple segmental lesions, 5(17.9%) with single segmental lesions, 18(64.3%) with strip ulcer, 16(57.1%) with cobblestones, 4(14.3%) with intestinal fistula, while no bowel wall and extraintestinal complication of CD disease was observed. Among the 18 cases of sinus tract enterography, 13 cases (72.2%) presented with intestinal fistula, 12(66.7%) with peritoneal abscess, 8(44.4%) with sinus tract. CONCLUSIONS: CT enterography can demonstrate exactly the diseased bowel wall and extraintestinal complication of CD disease, which is important to evaluate the extent of CD and guide the treatment, however strip ulcer and cobblestone sign cannot be demonstrated. The X-ray enterography is available to demonstrate the characteristic changes of CD such as trip ulcers and cobblestones, but is difficult to show the bowel wall and extraintestinal inflammatory mass and abscesses. The sinus tract enterography is easy to demonstrate the intestinal fistula and intra-abdominal abscess. Combination of these methods is more beneficial to guild the diagnosis and treatment.


Assuntos
Doença de Crohn , Tomografia Computadorizada por Raios X , Abscesso Abdominal , Doença de Crohn/diagnóstico , Humanos , Fístula Intestinal , Raios X
16.
Acta Radiol ; 54(3): 355-62, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23446748

RESUMO

BACKGROUND: Renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusion (Xp11.2/TFE RCC), and collecting duct carcinoma (CDC) are uncommon subtypes of renal cell carcinomas. PURPOSE: To investigate the multislice CT (MSCT) characteristics of these two tumor types. MATERIAL AND METHODS: Nine patients with Xp11.2/TFE RCC and 10 patients with CDC were studied retrospectively. MSCT was undertaken to investigate differences in tumor characteristics and enhancement patterns. RESULTS: All patients had single tumors centered in the renal medulla. Two patients with each tumor type had lymph node involvement and there was a single case of hepatic metastasis (Xp11.2/TFE RCC). The mean tumor diameter of Xp11.2/TFE RCC tumors was significantly larger than for CDC tumors. Two patients with Xp11.2/TFE RCC had cystic components as did eight patients with CDC (P < 0.05). Calcifications were present in six patients, each with CDC. Clear tumor boundaries were visible in two patients with CDC and in nine with Xp11.2/TFE RCC (P < 0.05). The density of Xp11.2/TFE RCC tumors was greater than that of CDC tumors, normal renal cortex, or medulla on unenhanced CT. Enhancement was higher with Xp11.2/TFE RCC than with CDC tumors during all phases. Xp11.2/TFE RCC enhancement was higher than in the renal medulla during cortical and medullary phase but lower than in normal renal medulla during the delayed phase. CDC tumor enhancement was lower than that for normal renal medulla during all enhanced phases. CONCLUSION: Both tumor types originated from the renal medulla. Distinguishing features included density on unenhanced CT, enhancement patterns, and capsule signs. Identifying these differences may aid diagnosis.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Análise de Variância , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Distribuição de Qui-Quadrado , Criança , Cromossomos Humanos Par 11/genética , Cromossomos Humanos X/genética , Feminino , Fusão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Estudos Retrospectivos , Translocação Genética
17.
World J Surg Oncol ; 11: 23, 2013 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-23356395

RESUMO

Choriocarcinoma usually arises in the uterus and gonads. Primary choriocarcinoma (PCC) in an extragenital organ is rare. When it occurs in the gastrointestinal tract, the stomach is the most common site. Only 12 cases of PCC of the colon have been reported in the world literature. Most cases were associated with adenocarcinoma. We report the case of a 36-year-old man with PCC of the colon and review the clinical characteristics of previously documented cases.


Assuntos
Coriocarcinoma/patologia , Neoplasias do Colo/patologia , Adulto , Humanos , Masculino , Prognóstico , Tomografia Computadorizada por Raios X
18.
Eur J Radiol ; 82(2): e76-80, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23079046

RESUMO

PURPOSE: To compare the differences between CT (Computed tomography) and DTS (digital tomosynthesis) in the X-ray radiation dose, and to analyze the sensitivity and specificity of each examination to check the suspected fractures and dislocations cases. METHODS: From May 2010 to February 2012, 46 patients suspected with fractures and/or dislocations were prospectively enrolled to do the CT and DTS examination on the basis of the results of DR examination. Patients were considered ineligible if they were pregnant or lactating (female subjects only). The Yangzhou Regional Ethical Review Board in Jiangsu province, China approved this study. All 46 patients signed the informed consent. To contrast radiation dose between CT and DTS group of the patients and make statistical analysis. Two experienced experts assess the image quality by I-III grade and make statistical analysis. Draw the ROC of reader A and B according to the golden standard of clinical diagnosis. RESULTS: The average effective dose of CT Group is 5.46 msv, while average effective dose of DTS group is 0.07 msv.There is significant statistical difference (t=22.89, p<0.01) between them. Calculate and compare the area under the ROC curve of reader A and B. The area of reader A by CT and DTS is 0.999 ± 0.005, 0.973 ± 0.022. The area of reader B is 0.961 ± 0.026, 0.944 ± 0.032. Both of them perform z test, and P>0.05. There is no significant difference. Assess the uniformity of two readers with Kappa test. The Kappa value of reader A and B is respectively 0.757 and 0.783. When the value is greater than 0.75, two readers' uniformity is considered well. The two readers' sensitivity and specificity in diagnosing hidden skeletal trauma with CT and DTS are respectively 97.06% (reader A), 96.97% (reader B); 91.67% (reader A), 84.62% (reader B). Use the χ(2) test to them, then get the same result: P>0.05. There is no statistical significant. CONCLUSION: Radiation dose of VolumnRAD DTS only account for 1.5% of CT, but its image can meet the requirements for clinical diagnosis. When fracture and/or dislocation is suspected with DR, VolumnRAD DTS can be recommended firstly as further checks.


Assuntos
Fraturas Ósseas/diagnóstico por imagem , Luxações Articulares/diagnóstico por imagem , Doses de Radiação , Intensificação de Imagem Radiográfica/métodos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Carga Corporal (Radioterapia) , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiometria , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
19.
Zhonghua Wei Chang Wai Ke Za Zhi ; 15(12): 1247-51, 2012 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-23268270

RESUMO

OBJECTIVE: To analyze the characteristics of intestinal tuberculosis(ITB) and primary small intestinal lymphoma(PSIL) in order to provide clue for the differential diagnosis. METHODS: Data of 24 cases of ITB and 23 cases of PSIL confirmed by surgery and pathology were retrospectively analyzed. The clinical features, endoscopic and CT scan were compared. All the patients had complete clinical and CT data. Twenty cases of ITB and 20 PSIL had complete endoscopic data. RESULTS: ITB was associated with significantly higher proportion of patients with fever(58.3% vs. 4.3%), night sweating(50.0% vs. 8.6%), pulmonary tuberculosis(54.2% vs. 4.3%) and ascites(54.2% vs. 21.7%) than PSIL(all P<0.05), and lower proportion of patients with abdominal mass (4.2% vs. 39.1%), hematochezia (8.3% vs. 47.8%), and perforation (0 vs. 39.1%)(all P<0.01). Endoscopic examination showed circumferential ulcer and rodent ulcer in 40% and 35% of the patients with ITB, and massive lesion and polypoid lesion in 55% of the patients with PSIL(P<0.05). Multi-segmental lesions, layered thickening, pneumatosis intestinalis, edematous ring, bowel lumen narrowing, hollow lymph nodes, and comb sign were more common in ITB(P<0.05), while single segmental lesions, eccentric thickening, and intussusception were more common in PSIL(P<0.05). The enhancement of intestinal wall of ITB were higher than that of PSIL(P<0.05), while the thickening and lymph nodes enlargement of PSIL were higher than that of ITB(P<0.05). CONCLUSION: The clinical characteristics differ between ITB and PSIL and the differential diagnosis can be made by combining endoscopy and CT.


Assuntos
Diagnóstico Diferencial , Neoplasias Intestinais/diagnóstico , Intestino Delgado/patologia , Linfoma/diagnóstico , Tuberculose Gastrointestinal/diagnóstico , Endoscopia , Humanos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
20.
Zhonghua Yi Xue Za Zhi ; 92(27): 1922-5, 2012 Jul 17.
Artigo em Chinês | MEDLINE | ID: mdl-23134968

RESUMO

OBJECTIVE: To explore the diagnostic features of collecting duct carcinoma (CDC). METHODS: A total of 7 CDC patients were retrospectively examined by multi-slice computed tomography (MSCT). The relevant diagnostic parameters were assessed. RESULTS: All lesions were located in renal medulla. Among them, infiltrations extended to renal calyx (n = 3) and cortex (n = 5). There were indistinct boundaries (capsule sign) on enhanced phase (n = 6) and pre-capsule (n = 1). On non-enhanced CT, CDC attenuation was greater than normal renal cortex or medulla (43.8 ± 5.3 vs 37.6 ± 5.1 or 32.6 ± 4.1, P < 0.05). The degree of enhancement was less than normal renal cortex and medulla during all enhanced phases (P < 0.05 or 0.01). Excellent consistency existed between CT appearances of CDC and pathological characteristics. CONCLUSION: Dynamic contrast enhanced-CT can show distinct imaging features of CDC correlated with pathological characteristics so as to allow a better differential diagnosis.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Tomografia Computadorizada Espiral , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
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