Acute cholestatic hepatitis caused by amoxicillin/ clavulanate

Amoxicillin/clavulanate is a synthetic penicillin that is currently commonly used,especially for the treatment of respiratory and cutaneous infections.In general,it is a well-tolerated oral antibiotic.However,amoxicillin/clavulanate can cause adverse effects,mainly cutaneous,gastrointestinal,hepatic and hematologic,in some cases.Presented here is a case report of a 63-yearold male patient who developed cholestatic hepatitis after recent use of amoxicillin/clavulanate.After 6 wk of prolonged use of the drug,he began to show signs of cholestatic icterus and developed severe hyperbilirubinemia(total bilirubin>300 mg/L).Diagnostic investigation was conducted by ultrasonography of the upper abdomen,serum tests for infection history,laboratory screening of autoimmune diseases,nuclear magnetic resonance(NMR)of the abdomen with bile duct-NMR and transcutaneous liver biopsy guided by ultrasound.The duration of disease was approximately 4 mo,with complete resolution of symptoms and laboratory changes at the end of that time period.Specific treatment was not instituted,only a combination of anti-emetic(metoclopramide)and cholestyramine for pruritus.

Analysis of PTEN Methylation Pattern by Pyrosequencing in Renal Cell Carcinoma

Objectives: We aimed to determine the frequency of PTEN (phosphatase with tensin homology deleted in chromosome 10) hypermethylation in renal cell carcinoma (RCC) and its impact on overall (OS) and disease-free survival (DFS). The association between PTEN hypermethylation and clinic and pathologic factors was also analyzed. Materials and Methods: The authors analyzed 137 patients who had undergone a radical or partial nephrectomy between 1997 and 2011. The methylation pattern was quantified individually at multiple CpG islands that are located on the exon 1 of PTEN gene by pyrosequencing. Results: Mean follow-up was 32.3 months. PTEN hypermethylation was detected with a low frequency (3.6%). There were no deaths or disease recurrence among patients with PTEN hypermethylation. Determining the association between PTEN hypermethylation and clinical and pathological factors was not possible due to the low frequency observed. Conclusion: The results show that the methylation of promoter CpG sites in PTEN is relatively infrequent in renal carcinogenesis and has no prognostic impact on survival.

Expression of Multidrug Resistance ATP-Binding Cassette(ABC)Transporters in Canine Mammary Tumors

Mammary neoplasms are the most common tumors in female dogs. They are usually treated using solely surgical mastectomy—which is recognized as unsatisfactory in many cases. Given this, the benefits of chemotherapy in dogs with mammary cancer need to be further explored. Some drugs that can be used for treating canines with mammary tumors may be substrates of uptake and/or efflux transporters such as the ATP-binding cassette (ABC) transporters. Unfortunately, very little is known regarding the pathobiology of such proteins in canine tumors, including mammary cancer. Accordingly, this study was designed to characterize the expression of ABC transporters P-glycoprotein, MRP1, and MRP2 and their relation with clinicopathologic factors in order to allow a better understanding of their influence in canine mammary cancer. P-glycoprotein was expressed in tumors from 55.8% of patients, while MRP1 and MRP2 were expressed in 37.2% and 39.5% of tumors, respectively. P-glycoprotein expression showed to be related with regional lymph node spread (P = 0.0038), as well as with tumor grade (P = 0.0353) and with a shorter survival (P = 0.0245). MRP1 revealed a strong association with a higher histological grade (P < 0.0001) and overall survival (P = 0.0002). Additionally, MRP1 was determined as prognostic indicator independent of lymph node status using Cox proportional-hazards regression multivariate analysis (P = 0.0216). No relations between MRP2 and clinicopathologic features were observed. We have found that P-glycoprotein and MRP1 are expressed in highly aggressive canine mammary tumors and are related with poor prognosis. Our results suggest that they may play a significant role in the course of canine mammary cancer progression and be promising candidate markers for a validation study on therapy outcome.

Snai-1 and Epithelial-Mesenchymal Transition-Related Protein Immunoexpression in Canine Mammary Carcinomas

Epithelial-mesenchymal transition (EMT) is defined as switching of polarized epithelial cells to a migratory fibroblastoid phenotype. EMT is known to be involved in the progression and metastasis of various cancers in humans, but this specific process is still little explored in the veterinary literature. The aim of this research was to evaluate the expression of EMT-related proteins in canine mammary carcinomas (CMCs). The expression of six EMT-related proteins in 94 CMCs of female dogs was evaluated by immunohistochemistry using a tissue array method. Additionally, clinicopathological characteristics were compared with the expression of EMT-related proteins. Loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins were observed in CMCs. Loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins were observed, particularly in tumors with evidence of stromal invasion;however, significance was only observed between the S100A4 and vascular invasion. In addition, Snai-1 nuclear immunoexpression was significantly related to E-cadherin loss. In conclusion, loss of epithelial proteins and/or the acquisition of mesenchymal proteins are associated with EMT and may have an important role in the evaluation of CMC patients. The unique immunoexpression pattern of Snai-1 could help to distinguish between an adenoma and a non-metastatic carcinoma and seems to be related to conversion of myoepithelial cells to a complete mesenchymal-like phenotype. Loss of E-cadherin and cytokeratin and change of immunoexpression pattern of Snai-1, N-cadherin, S100A4 and MMP-2 indicate the occurrence of EMT in canine mammary carcinomas and should result in an en bloc resection or a close follow-up.

Immunoexpression of Cathepsin D and S100A4 Protein and Their Molecular Subtyptes in Canine Mammary Carcinomas

Cathepsin D (CD), a lysosomal protease, and S100A4 protein, a calcium binding motif, are considered to be involved in metastasis in various human cancers. No data regarding such proteins are available for canine mammary carcinomas (CMCs). Accordingly, their expression in association with known factors of prognosis was investigated in this study. For that, 66 surgically resected CMCs were submitted to an immunohistochemical evaluation using anti CD, S100A4 protein, HER2, estrogen receptor α, cytokeratin 5, and p63 antibodies, further characterizing the tumors' molecular subtype. An increase in S100A4 immunoexpression by neoplastic luminal mammary cells was associated with an infiltrative tumor mode of growth, consequently leading us to conclude that S100A4 protein could be related to progression in CMCs. Additionally, the occurrence of the luminal A molecular subtype was associated with the complex histotype in CMCs. Although we have demonstrated that changes in S100A4 protein immunoexpression occurs in CMCs, further studies are needed to determine whether this represents important independent biomarkers for CMCs.

Computing a Predictor Set Influence Zone through a Multi-Layer Genetic Network to Explore the Role of Estrogen in Breast Cancer

Modeling inter-relationships of genes over a specific genetic network is one of the most challenging studies in systems biology. Among the families of models proposed one commonly used is the discrete stochastic, based on conditionally independent Markov chains. In practice, this model is estimated from time sequential sampling, usually obtained by microarray experiments. In order to improve the accuracy of the estimation method, we can use biological knowledge. In this paper, we decided to apply this idea to study the role of estrogen in breast cancer proliferation. The n-influence zone of a set S of genes in a given multi-layer genetic network is a set L of genes regulated, directly or indirectly, by genes in S, after at most n-1 layers. In this manuscript we describe a new approach for computing the n-influence zone of S through the estimation of a multi-layer genetic network from gene expression time series, measured by microarrays, and biological knowledge. Using seed genes related to cell proliferation, our method was able to add to the third layer of the network other genes related to this biological function and validated in the literature. Using a set of genes directly influenced by estrogen, we could find a new role for cell adhesion genes estrogen dependent. Our pipeline is user-friendly and does not have high system requirements. We believe this paper could contribute to improve the data mining for biologists in microarray time series.

一氧化氮合成酶、环氧化酶-2、硝基酪氨酸及血管生成与软骨肉瘤预后的相关性研究

背景：免疫组织化学标记物有助于肿瘤诊断及预后评估。通过对硝基酪氨酸分析及采用一氧化氮合成酶1（NOS1）、一氧化氮合成酶2（NOS2）、一氧化氮合成酶3（NOS3）检测分析可了解一氧化氮（NO）与肿瘤的相关性。NO与超氧阴离子反应产生的过氧亚硝酸对基因有毒性作用，过氧亚硝酸传递一个硝基基团到酪氨酸的苯环上形成硝基酪氨酸。细胞内硝基酪氨酸的积累说明过氧亚硝酸持续生成。NO刺激所生成的环氧化酶-2（COX-2）与肿瘤内新生血管水平相关，研究表明新生血管影响肿瘤预后，免疫组化标记CD34可表示微血管生成，从而被用于预测肿瘤预后。本研究检测上述标记物在软骨肉瘤中的表达并分析与软骨肉瘤分级和预后的相关性。方法：101例软骨肉瘤患者肿瘤组织样本采用甲醛固定，组织样本采用免疫组织化学染色，指标为：NOS1、NOS2、NOS3、COX-2、硝基酪氨酸和CD34。5例正常软骨样本作为对照。研究分析患者特征、手术变量、肿瘤分级与这些指标的相关性。使用Kaplan—Meier多变量统计学方法分析生存曲线及生存率。结果：硝基酪氨酸、COX-2和CD34与组织学分级有明显相关性（p=0．022，p=0．014，p=0．028），但与总体预后无相关性（p=0．064，p=0．143，p=0．581）。NOS2阳性表达常预示较高的局部复发率（p=0．038）。NOS1、NOS2阳性表达预示较低的生存率（p=0．007，p〈0．001）。通过多变量分析处理，NOS2的表达被证实可作为局部复发率的独立预后判断因素；NOS1、NOS2的表达作为因变量，它们单独或复合阳性表达常与较低的总生存率有关（p=0．046，p=0．004）[危险率，3．17（95％置信区间，1．0-9．8）和5．58（95％置信区间，1．7-18．0）]。