Microcystins: measuring human exposure and the impact on human health

Abstract

Context: Freshwater cyanobacterial toxins, microcystins, may be a contributing factor to the development of hepatocellular cancer and colorectal cancer.

Objectives: This review summarizes the toxicity data, exposure routes and the methodologies available to determine exposure to elucidate the relationship to liver and colorectal cancer.

Methods: Literature searches were conducted using Medline, PubMed and Web of Science.

Results: There is evidence of human poisonings resulting from exposure to microcystins, however current methods rely on targeted approaches only suitable for acute exposure. No methods exist for the determination of chronic exposure to microcystins.

Conclusions: With the growing evidence of exposure to microcystins and the possible links to cancer, methods to measure medium to long-term human exposure are needed. The identification and validation of candidate biomarkers are key to undertaking urgently required epidemiological studies.     

A specific autoantibody against a novel tumour-association antigen derived from human DNA-topoiomerase I is a potential biomarker for early diagnosis and favourable prognosis in patients with colorectal carcinoma

Abstract

Context: We previously reported a novel tumour associated antigen (TTA) with molecular weight around 48?kDa and identified the novel TTA as a fragment derived from human DNA-topoiomerase I (TOP1). We termed the novel TAA as TOPO48 and termed autoantibody against the TAA as anti-TOPO48 autoantibody.

Objective: To explore the clinical significance of anti-TOPO48 autoantibody in patients with colorectal carcinoma (CRC).

Materials and methods: Serum levels of the autoantibody in patients with CRC or benign tumours and healthy volunteers were measured with a specific ELISA.

Results: CRC patients at early stage had higher frequency of positive levels of the autoantibody and CRC patients with positive autoantibody levels had higher overall survival rate than those with negative autoantibody levels.

Conclusion: The autoantibody is a potential biomarker for early diagnosis and favourable prognosis of CRC.     

Epigenetic biomarkers in colorectal cancer: premises and prospects

Context: Colorectal cancer is one of the most common cancers worldwide. Epigenetic alterations play an important role in the pathogenesis of the colorectal cancer.

Objective: This review has focused on the most recent investigations, which has suggested potential epigenetic biomarkers in colorectal cancer.

Methods: Evidences were achieved by searching online medical databases including Google scholar, Pubmed, Scopus and Science Direct.

Results: Extensive studies have indicated that aberrant epigenetic modifications could serve as potential biomarkers for diagnosis, prognosis and prediction of colorectal cancer.

Conclusion: Advances in aberrant epigenetic modifications can open new avenues for exploration of reliable and robust biomarkers to improve the management of CRC patients.     

Circulating RNA: looking at the liver through a frosted glass

Abstract

Context: The evaluation of the liver condition, based on serum enzymatic activity and biopsies, is insufficient. Therefore, it is a priority to find a correlation between circulating RNAs and liver damage.

Methods: Publications were retrieved by the search terms “circulating RNA AND liver”.

Results: Although differences exist between studies, a profile of RNAs that repeatedly appeared as indicators of liver damage was identified.

Discussion: We highlight those circulating RNAs useful to diagnostic, and discuss the transport mechanisms.

Conclusion: Several studies have proven that circulating RNAs are useful to establish a diagnostic and a prognosis of liver diseases.     

Lectin adhesion proteins (P-, L- and E-selectins) as biomarkers in colorectal cancer

Context: Selectins probably participate in the interactions between platelets and other inflammatory cells in cancer invasion and metastasis formation. We assessed a potential relationship of P-, L- and E-selectin in colorectal cancer (CRC) patients in relation to tumour advancement according to TNM classification, and tumour location.

Materials and methods: The study group was composed of 53 CRC patients and 25 healthy subjects. Plasma levels of soluble P-, L- and E-selectins were measured using the immunoenzymatic method with Quantikine kits (R&D Systems, Minneapolis, MN).

Results: The mean levels of all selectins were significantly higher in CRC patients compared to healthy controls. The highest level of sP-selectin was observed in patients with metastases to the liver (stage IV), and was significantly higher than in patients without metastases (stage I/II) and with lymph node metastases (stage III), p?=?.02. The highest levels of sL- and sE-selectin were observed in patients with lymph node metastasis. We also found sP-selectin to be the best predictor of CRC.

Conclusion: Our finding show possible involvement of tested selectins in CRC advancement and forming metastasis. Among sL- and E- selectins, P-selectin plays an important role in the progression of CRC and could be an attractive biomarker with clinical significance.     

Bulky DNA adduct levels in normal-appearing colon mucosa,and the prevalence of colorectal adenomas

Abstract

Purpose: Examine the association between bulky DNA adduct levels in colon mucosa and colorectal adenoma prevalence, and explore the correlation between adduct levels in leukocytes and colon tissue.

Methods: Bulky DNA adduct levels were measured using ³²P-postlabelling in biopsies of normal-appearing colon tissue and blood donated by 202 patients. Multivariable logistic regression was used to examine associations between DNA adducts, and interactions of DNA adduct-DNA repair polymorphisms, with the prevalence of colorectal adenomas. Correlation between blood and tissue levels of DNA adducts was evaluated using Spearman’s correlation coefficient.

Results: An interaction between bulky DNA adduct levels and XPA rs1800975 on prevalence of colorectal adenoma was observed. Among individuals with lower DNA repair activity, increased DNA adduct levels were associated with increased colorectal adenoma prevalence (OR?=?1.41 per SD increase, 95%CI: 0.92–2.18). Conversely, among individuals with normal DNA activity, an inverse association was observed (OR?=?0.60 per SD increase, 95%CI: 0.34–1.07). Blood and colon DNA adduct levels were inversely correlated (ρ?=??0.20).

Conclusions: Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.     

Biological significance of piRNA in liver cancer: a review

Abstract

Liver cancer is one of the most common and deadly cancers in the world. In recent years, non-coding RNA has been a hot topic in liver cancer research. piRNAs (PIWI-interacting RNAs) are a new type of small non-coding RNA, which are formed by the PIWI proteins interacting with RNA. The latest research shows that piRNA and PIWI proteins are abnormally expressed in various cancers, including pancreatic, colorectal, breast, etc. piRNA plays an important regulatory role in liver cancer. In this review, we discuss the biological function of piRNAs and new progress in the development of liver cancer, and new targets and ideas for piRNA and PIWI proteins in the diagnosis and treatment of liver cancer.     

血清CA72-4、CA199对结直肠癌的诊断价值及与肿瘤进展的关系研究

摘要 目的：探讨血清糖类抗原72-4（CA72-4）、糖类抗原199（CA199）对结直肠癌的诊断价值及与肿瘤进展的关系。方法：选取2016年7月到2018年7月期间在我院接受治疗的结直肠癌患者60例作为结直肠癌组,另选取同期在我院接受治疗的结直肠良性病变患者40例作为良性病变组,比较结直肠癌组、良性病变组血清CA72-4、CA199的水平,比较不同TNM分期、不同分化程度的结直肠癌患者血清CA72-4、CA199的水平,以病理诊断为金标准,分析血清CA72-4、CA199对结直肠癌的诊断价值。结果：结直肠癌组的血清CA72-4、CA199水平高于良性病变组（P<0.05）。TNM分期为III-IV期的结直肠癌患者的血清CA72-4、CA199水平高于I-II期的患者（P<0.05）,分化程度为低分化的结直肠癌患者的血清CA72-4、CA199水平高于中高分化的患者（P<0.05）。CA72-4联合CA199检测对结直肠癌的灵敏度高于CA72-4、CA199单独检测。结论：CA72-4与CA199联合检测对结直肠癌具有较高的诊断价值,且两指标的水平与结直肠癌的分化程度和TNM分期有关,可在一定程度上反映肿瘤进展情况。     

Serum methylation levels of TAC1. SEPT9 and EYA4 as diagnostic markers for early colorectal cancers: a pilot study

Abstract

Objective: To identify methylated genes in serum with diagnostic potentials for early colorectal cancer (CRC).

Methods: Serum methylation levels of up to 12 genes were measured in two sets of serum samples with the second set from 26 stage I CRC patients and 26 age/gender-matched controls.

Results: Serum methylation levels of TAC1, SEPT9, and EYA4 were significant discriminants between stage I CRC and healthy controls. Combination of TAC1 and SEPT9 rendered 73.1% sensitivity with 92.3% specificity.

Conclusion: Serum methylation levels of TAC1. SEPT9 and EYA4 may be useful biomarkers for early detection of CRC though a validation study is necessary.     

The role of the PTEN/mTOR axis in clinical response of rectal cancer patients

Background

Preoperative chemoradiotherapy has long been accepted as a method to improve survival and lifetime quality of rectal cancer patients. However, physiologic effects of these therapies largely depend on the resistance of cells to the radiation, type of chemotherapeutic agents and individual responses. As one of the signaling cascades involved in chemo- or radiation- resistance, the present study focused on several proteins involved in pTEN/Akt/mTOR pathway to explore their prognostic significance.

Materials and methods

Samples from advanced stage rectal cancer patients were analyzed to detect expression levels of pTEN/Akt/mTOR pathway related proteins pTEN, mLST8, REDD1, BNIP3, SAG and NOXA, together with p53, by RT-qPCR. Kaplan–Meier analysis was used to assess expression-survival relation and correlations among all proteins and clinicopathological features were statistically analyzed.

Results.

Except p53, none of the proteins showed prognostic significance. High p53 expression presented clear impact on overall survival and disease free survival. It was also significantly related to pathologic complete response. p53 showed high correlation to local recurrence as well. On the other hand, strong correlation was observed with PTEN expression and tumor response, but not with survival. High associations were also observed between mLST8/REDD1, PTEN and NOXA, confirming their role in the same cascade.

Conclusion

The contentious role of p53 as a prognostic biomarker in colorectal cancer was further affirmed, while PTEN and REDD1 could be suggested as potential candidates. Additionally, NOXA emerges as a conjunctive element for different signaling pathways.

     

Establishing population-based surveillance of diagnostic timeliness using linked cancer registry and administrative data for patients with colorectal and lung cancer

BackgroundDiagnostic timeliness in cancer patients is important for clinical outcomes and patient satisfaction but, to-date, continuous monitoring of diagnostic intervals in nationwide incident cohorts has been impossible in England.MethodsWe developed a new methodology for measuring the secondary care diagnostic interval (SCDI - first relevant secondary care contact to diagnosis) using linked cancer registration and healthcare utilisation data. Using this method, we subsequently examined diagnostic timeliness in colorectal and lung cancer patients (2014–15) by socio-demographic characteristics, diagnostic route and stage at diagnosis.ResultsThe approach assigned SCDIs to 94.4% of all incident colorectal cancer cases [median length (90th centile) of 25 (104) days] and 95.3% of lung cancer cases [36 (144) days]. Advanced stage patients had shorter intervals (median, colorectal: stage 1 vs 4 - 34 vs 19 days; lung stage 1&2 vs 3B&4 - 70 vs 27 days). Routinely referred patients had the longest (colorectal: 61, lung: 69 days) and emergency presenters the shortest intervals (colorectal: 3, lung: 14 days). Comorbidities and additional diagnostic tests were also associated with longer intervals.ConclusionThis new method can enable repeatable nationwide measurement of cancer diagnostic timeliness in England and identifies actionable variation to inform early diagnosis interventions and target future research.     

结直肠癌组织ANP32A、Ataxin-3、FHL1的表达及其与肝转移的关系研究

摘要 目的：探讨结直肠癌组织中酸性核磷蛋白32A（ANP32A）、Ataxin-3及4个半LIM结构域蛋白1（FHL1）的表达及其与肝转移的关系。方法：对120例结直肠癌患者癌组织和癌旁组织中ANP32A、Ataxin-3及FHL1蛋白水平进行检测,分析其阳性表达率。其中44例发生肝转移作为肝转移组,76例无肝转移作为无肝转移组,比较两组癌组织中ANP32A、Ataxin-3及FHL1蛋白阳性表达率,分析结直肠癌肝转移的影响因素,分析ANP32A、Ataxin-3、FHL1蛋白之间的相关性。结果：结直肠癌患者癌组织中ANP32A蛋白阳性表达率高于癌旁组织,Ataxin-3、FHL1蛋白阳性表达率低于癌旁组织（P<0.05）。经单因素分析显示肝转移组患者癌组织中ANP32A蛋白阳性表达率显著高于无肝转移组,Ataxin-3、FHL1蛋白阳性表达率显著低于无肝转移组（P<0.05）,肝转移组患者原发癌中低分化、原发癌浸润深度T3~T4、原发癌有淋巴结转移者构成比显著高于无肝转移组（P<0.05）。多因素Logistic回归分析显示,ANP32A蛋白阳性表达、原发癌中低分化、原发癌浸润深度T3~T4、原发癌有淋巴结转移是结直肠癌肝转移的危险因素（P<0.05）,Ataxin-3、FHL1蛋白阳性表达是结直肠癌肝转移的保护因素（P<0.05）。Spearman相关分析显示,结直肠癌患者癌组织中ANP32A阳性表达率与Ataxin-3、FHL1阳性表达率呈负相关（P<0.05）,Ataxin-3蛋白阳性表达率与FHL1蛋白阳性表达率呈正相关（P<0.05）。结论：ANP32A蛋白高表达,Ataxin-3、FHL1蛋白低表达与结直肠癌发生及肝转移有密切关系,且以上指标间具有一定相关性。结直肠癌肝转移受多种因素影响,临床诊治中可根据相关因素为患者制定针对性治疗方案。     

Progress in the search for circulating biomarkers of nonalcoholic fatty liver disease

Abstract

Context: The definitive standard for the diagnosis of nonalcoholic fatty liver disease (NAFLD) is clinico-pathological correlation, but frequently the only laboratory abnormality is an elevation of serum aminotransferases.

Objective: This has resulted in the search for more specific laboratory biomarkers.

Methods: The literature was searched for novel plasma/serum markers of NAFLD.

Results: Studies reviewed here included histologically-confirmed patients presenting some stage of NAFLD and monitored one or more novel serum/plasma biomarkers.

Conclusion: The most promising application of some of these novel biomarkers for the detection and quantification of NAFLD and particularly NASH appears to be in the combination of several into diagnostic panels.     

Validity of initial cancer diagnoses in the Diagnosis Procedure Combination data in Japan

BackgroundIn Japan, the Diagnosis Procedure Combination (DPC) data have been used as a nationwide administrative hospital discharge database for clinical studies. However, few studies have evaluated the validity of recorded diagnoses of cancer in the database.MethodsWe compared the DPC data with hospital-based cancer registries in Osaka Prefecture, Japan to assess the validity of the recorded cancer diagnoses in the DPC data. Fifteen types of cancer were included in the analysis. Cancer stage with tumor-node-metastasis (TNM) classification was assessed for eight cancer types with >400 patients. We evaluated concordance and positive predictive value of cancer diagnosis, and concordance of cancer stage between the DPC data and the hospital-based cancer registry.ResultsIn total, we identified 29,180 eligible patients. The five types of cancer with the highest number of patients were as follows: 6,765 (23.2 %) colorectal, 6,476 (22.2 %) stomach, 4,862 (16.7 %) breast, 4,445 (15.2 %) lung, and 2,257 (7.7 %) liver. Concordance of diagnosis ranged from 63.9 %–99.5 %, and twelve of the fifteen types of cancers had concordance of over 90 %. Positive predictive values of diagnosis ranged from 86.8 %–100 %. Regarding cancer stage, the overall degree of concordance was 67.2 % in all patients and the concordance was over 70 % in four types of cancers.ConclusionsThe DPC data had high validity of cancer diagnosis. However, the potential impact of the misclassifications and low concordance in cancer stage among specific type of cancers in the DPC data should be considered.     

结直肠癌组织RSK4、p53蛋白的表达及临床病理意义

目的:探讨结直肠癌组织中P90核糖体S6激酶4(RSK4)蛋白、p53蛋白的表达及其临床病理意义。方法:选取我院病理科2014年1月~2016年5月既往收集的结直肠癌手术后标本70例及同期结直肠癌癌旁组织30例,采用免疫组化染色检测两组标本中RSK4蛋白、p53蛋白的表达情况,并分析其与结肠癌患者临床病理特征的相关性。结果:结直肠癌组织中RSK4蛋白、p53蛋白的阳性表达率分别为20.00%、55.71%,而癌旁组织中RSK4蛋白、p53蛋白阳性表达率分别为53.33%、10.00%,两组比较差异均具有统计学意义(P0.05)。Ⅰ期+Ⅱ期、高分化和中分化结直肠癌组织RSK4蛋白的阳性表达率显著高于Ⅲ期、低分化结直肠癌(P0.05);Ⅰ期+Ⅱ期、浸润深度(T1、T2)、未发生淋巴结转移的结直肠癌组织中p53蛋白阳性表达率显著的低于Ⅲ期、浸润深度(T3、T4)、发生淋巴结转移的结肠癌组织(P0.05)。结论:结直肠癌组织中RSK4蛋白表达下调、p53蛋白表达上调,二者可能与结直肠癌的发生和发展有关,并可能作为结肠癌诊断和预后评估的参考指标。     

生物钟基因PER2在结直肠癌中的表达及意义

目的:探讨PER2基因表达水平和结直肠癌发生发展的关系。方法:收集203例在上海市第一人民医院接受根治性肠切除术结直肠癌患者的标本,通过实时定量PCR和免疫组织化学技术检测PER2在肿瘤组织和邻近正常组织中的表达水平,并对PER2的表达与患者的病理资料和临床预后的相关性进行统计学分析。结果:PER2在结直肠患者肿瘤组织的表达较正常组织减少(P0.001)。与PER2阳性患者相比,PER2阴性的结直肠癌患者有远处转移(P=0.026)、AJCC分期为IV期(P=0.011)的比例更高。结论:PER2基因在结直肠癌患者中存在低表达现象,其对于患者的AJCC分期评价以及了解患者有无远处转移有一定的参考价值。     

Correlation between CAT polymorphism and susceptibility to DMAc-induced abnormal liver function: a case-control study of Chinese population

Context: Acute or chronic exposure of N,N-dimethylacetamide (DMAc) is responsible for abnormal liver function. It appears that DMAc is mainly metabolized by cytochrome P450 in the liver and thereby produces reactive oxygen species (ROS). The elimination of ROS and the repairing of ROS-induced DNA damage are relevant to the ultimate toxicity of DMAc.

Objective: To investigate whether the polymorphisms in the CAT (rs564250, rs769214 and rs7943316), hOGG1 (rs2072668 and rs159153) and XRCC1 (rs25487 and rs1799782) genes are associated with susceptibility to DMAc-induced abnormal liver function in Chinese population.

Methods: Samples were obtained from 108 workers with DMAc-induced abnormal liver function and 108 workers with normal liver function.

Results: Subjects with the CAT rs769214 GA/GG genotypes had a reducing risk of abnormal liver function, which was more evident in the subgroups exposed to DMAc?<10?years, exposed to DMAc?<5?mg/m³, never smoked and never drank.

Conclusions: CAT rs769214 (-844?G?>?A) polymorphism may be associated with DMAc-induced abnormal liver function in Chinese population.     

Promotion of cancer metastasis: candidate validation using an iTRAQ-based approach

Evaluation of: Ghosh D, Li Z, Tan XF, Lim TK, Mao Y, Lin Q. RAQ based quantitative proteomics approach validated the role of calcyclin binding protein (CacyBP) in promoting colorectal cancer metastasis. Mol. Cell Proteomics 12(7), 1865–1880 (2013).

The use of iTRAQ-based relative quantification is demonstrated by Ghosh et al. to analyze the downstream effectors of a calcyclin-binding protein, which is proposed to promote colorectal cancer progression. These findings are reviewed and discussed in relation to the need to establish robust in vitro model cell lines for identification of cancer-specific pathways and to confirm the leads generated by proteomic analysis.     

Biochemical alterations induced by nickel oxide nanoparticles in female Wistar albino rats after acute oral exposure

Context: Nickel oxide (NiO) nanoparticles (NPs) with appropriate surface chemistry have been widely used for their potential new applications in biomedical industry. Increased usage of these NPs enhances the chance of exposure of personnel involved in the work place.

Objective: This study was designed to assess the ability of NiO NPs to cause biochemical alterations post-acute oral exposure in female Wistar rats.

Materials and methods: Rats were administered with 125, 250, and 500?mg/kg doses of NiO NPs for haematological, biochemical, and histopathological studies. Biodistribution patterns of NiO NPs in female Wistar rats were also monitored.

Results: NiO NPs caused significant (p?Conclusions: This study revealed that exposure to nanosized NiO particles at acute doses may cause adverse changes in animal biochemical profiles. Further, the in vivo studies on toxicity evaluation help in biomonitoring of the potential contaminants.