Elevated Serum Vitamin B12 Levels in Association With Tumor Markers as the Prognostic Factors Predictive for Poor Survival in Patients With Hepatocellular Carcinoma

Elevated blood vitamin B₁₂ (VitB₁₂) level has recently been identified as a prognostic indicator for advanced cancer patients. The predictive value of blood VitB₁₂ for survival of patients with hepatocellular carcinoma (HCC) remains unclear. Our objective was to examine the determinants of elevated serum VitB₁₂ levels and their associations with prognosis of patients with HCC. The cohort study included 90 HCC patients who were consecutively admitted to the Chi-Mei Hospital, Taiwan, from April 2005 to December 2006. Nutrition and clinical pathological data were collected. Serum VitB₁₂ levels were determined by radioimmunoassay. Survival curves were calculated by the Kaplan–Meier method. Multivariate analysis of outcome predictors was assessed by Cox regression. Elevated serum VitB₁₂ levels of HCC patients were associated with reduced levels of albumin, hemoglobin, red blood cells count, and glutamate-pyruvate transaminase (GPT) ( P < 0.05). Serum VitB₁₂ levels were positively correlated with alpha-fetal protein (AFP) levels ( r = 0.623, P = 0.001) and tumor size ( r = 0.630, P = 0.001; Table 3). By univariate analysis, survival was significantly worse in patients with elevated serum AFP (> 200 μ g/l) and VitB₁₂ levels (> 1,500 ng/l; P < 0.05). In multivariate analysis, both elevated AFP (> 200 vs. < 20; HR 4.4; CI = 1.9–10.3, P = 0.001) and VitB₁₂ levels (> 699 vs. ≤ 699; HR = 2.88; CI = 1.26–6.6, P = 0.012) were found to be favorable predictive factors for HCC survival. This study shows that the determinants of elevated serum VitB₁₂ levels in HCC patients were in association with malnourishment, liver injuries, and tumor progression. Elevated VitB₁₂ levels in concurrence with AFP levels serve as the prognostic factors predictive for poor survival of HCC patients.     

Structure-activity relationship and enzyme kinetic studies on 4-aryl-1H-1,2,3-triazoles as indoleamine 2,3-dioxygenase (IDO) inhibitors

Previously, we have reported the design and synthesis of 4-aryl-1H-1,2,3-triazoles as inhibitors of indoleamine 2,3-dioxygenase (IDO), a promising therapeutic target of cancer. Here, we present the structure–activity relationship and enzyme kinetic studies on a series of 4-aryl-1H-1,2,3-triazoles. Three compounds (1, 6, 8) were found to possess more IDO inhibitory potency than the most commonly used 1-methyltryptophan. The results from the structure–activity relationship and molecular docking studies indicated that an electron-withdrawing group with low steric hindrance near the NH group of triazoles was necessary for the IDO inhibition.     

Metabolic Alterations Induced by Kudingcha Lead to Cancer Cell Apoptosis and Metastasis Inhibition

Abstract

Kudingcha is implicated in alleviating metabolic disorders in traditional Chinese medicine. However, the role of Kudingcha, one of the Ligustrum robustum species, in metabolic regulations and its antitumor activity in triple-negative breast cancer (TNBC) remains to be determined. Two breast cancer cell lines and immunocompetent and immunodeficient mice were used to evaluate the therapeutic effects of Kudingcha treatment. The production of reactive oxygen species (ROS) and glucose uptake were examined by flow cytometry. Metabolic shift was examined by metabonomics and western blot analysis. In this study, we found that aqueous extract of Kudingcha dose dependently inhibited cell growth and induced apoptosis in vitro and in vivo. Moreover, Kudingcha supplementation significantly reduced cancer metastasis. Kudingcha significantly inhibited glycolysis and glutamine metabolism. In addition, we demonstrated that the antitumor effects of Kudingcha were dependent on ROS production, which was increased by β-oxidation and oxidative phosphorylation. These findings provide a novel potential benefit of Kudingcha from targeting the cancer metabolism.     

雷公藤的化学成分及其提取物检验方法的分析

  目的  探讨雷公藤甲素（TPL）对三阴性乳腺癌细胞中乳腺癌易感基因1（BRCA1）表达影响及机制。  方法  用不同浓度TPL（12.5、25.0、50.0和100.0 nmol/L）处理携带野生型BRCA1基因的三阴性乳腺癌细胞株MDA-MB-468后,采用噻唑蓝（MTT）法检测细胞增殖情况、RT-PCR法检测BRCA1、ATM（ataxia telangiectasia mutated）和ATR （ATM and Rad3-related）mRNA表达水平、Western blot检测BRCA1、ATM、ATR蛋白及BRCA1蛋白磷酸化表达水平。  结果  不同浓度TPL处理后,MDA-MB-468细胞生长受到明显抑制,TPL 12.5、25.0、50.0、100.0 nmol/L剂量组MDA-MB-468细胞生长抑制率分别为13.3%、32.3%、42.9%、60.7%,抑制率与TPL呈浓度依赖性;与对照组比较,各剂量TPL组MDA-MB-468细胞BRCA1、ATM和ATR mRNA及蛋白表达水平均明显下调,呈剂量效应关系;TPL对MDA-MB-468细胞BRCA1中Ser-1524位点磷酸化作用具有明显抑制作用,并呈剂量效应关系。  结论  雷公藤甲素可诱导三阴性乳腺癌细胞凋亡,其机制可能与其抑制细胞中BRCA1表达及其磷酸化水平有关。     

Combined Genetic and Nutritional Risk Models of Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) presents clinical challenges due to unknown etiology, lack of treatment targets, and poor prognosis. We examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. We evaluated 18 DNA-repair nonsynonymous single nucleotide polymorphisms (nsSNPs) and dietary/nutritional intakes. Multivariate Adaptive Regression Splines models were used to select nutrients of interest and define cut-off values for logistic regression models. Our results suggest that TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and β-carotene). Combined analyses of these 6 nsSNPs and 3 micronutrients showed significant association with TNBC: odds ratios = 2.77 (95% confidence interval = 1.01–7.64) and 10.89 (95% confidence interval = 3.50–33.89) for 2 and at least 3 risk factors, respectively. To the best of our knowledge, this is the first study to suggest that multiple genetic and nutritional factors are associated with TNBC, particularly in combination. Our findings, if validated in larger studies, will have important clinical implication that dietary modulations and/or micronutrient supplementations may prevent or reverse TNBC phenotype, so tumors can be treated with less toxic therapeutic strategies, particularly in genetically susceptible women.     

32例三阴性乳腺癌患者易感基因胚系突变分析

目的:应用全外显子测序技术初步探讨三阴性乳腺癌(TNBC)患者易感基因突变情况。方法:收集本院就诊的32例TNBC患者,均经临床手术病理确诊。采集患者外周血提取基因组DNA进行全外显子组测序,通过生物信息学分析筛选与乳腺肿瘤相关的易感基因变异。结果:32例TNBC患者中14例检测到BRCA1/2罕见变异,明确致病性或可疑致病变异6例,突变携带频率为18.8%。其中BRCA1:c.5468-1_5474del和c.4749_4750del是较常见的突变;BRCA2:c.6027A>C为新的变异;BRCA2:c.3794G>T、c.7901T>A,BRCA1:c.4616T>C首次在中国人群中发现。除了BRCA1/2变异外,还检测到83个乳腺肿瘤易感基因变异,每个患者携带2.6个变异。2个以上患者携带的乳腺癌易感基因包括ALK、APC、CDH1、PTCH2、RB1CC1、RAD51D、RAD54L、TSC1等。结论:BRCA1/2是TNBC患者最重要的易感基因,其他与DNA损伤修复相关的基因突变可能与TNBC患者的表型有一定的相关性。     

Rutin as A Novel c-Met Inhibitory Lead for The Control of Triple Negative Breast Malignancies

Triple negative breast cancer (TNBC) has high metastatic and mortality potential and lacks effective and selective therapeutic options. Aberrant dysregulation of the receptor tyrosine kinase c-Met promotes TNBC progression, motility and survival and therefore considered a valid therapeutic target. Among various identified anticancer agents, plant polyphenols (PPs) including flavonoids, have been shown to be safe and proven for their antitumor activity through modulating diverse macromolecular targets. This study reports the bioassay-guided identification of the common flavonol glycoside rutin as breast cancer cell proliferation, migration and invasion inhibitor. The cell free Z′-LYTE kinase assay, Western blot and in silico docking experiments uncovered, for the first time, c-Met kinase as a potential mechanistic target for rutin-mediated anticancer effects on TNBC cell lines. Likewise, the intraperitoneal injection of rutin at 30 mg/kg, 3X/week, significantly reduced the growth of the TNBC MDA-MB-231/GFP orthotopic xenograft in nude mouse model. These results clearly designate the functional dietary flavonoid rutin as a potential lead for the prevention and control of c-Met-dependent breast malignancies.     

Serum Vitamin D Status and Breast Cancer Risk by Receptor Status: A Systematic Review

Background: The association between vitamin D status and breast cancer risk is equivocal. No systematic reviews or meta-analyses have examined this association stratified by receptor status. Our objective is to conduct a systematic review to answer the question, “Is there a relationship between lower serum/plasma vitamin D levels and increased risk of triple negative breast cancer (TNBC) specifically?” Methods: We systematically searched Embase and PubMed databases for published original research studies examining the risk of a breast cancer diagnosis according to vitamin D status. We excluded studies that did not provide risk estimates stratified by receptor status. Results: Fourteen studies met our criteria, including case-control, nested case-control, and case-series studies, reflecting the cumulative results of 13,135 breast cancer cases. When grouped by relevancy to TNBC, the proportion of analyses across all study types showing a significant association between vitamin D status and breast cancer diagnosis was 37% for non-TNBC analyses, 48% for analyses that included some TNBC cases, and 88% for TNBC analyses. Conclusions: Our results suggest that low vitamin D status may particularly increase the risk of TNBC, although more research is needed to determine if this association is causative. Women should be routinely screened for 25(OH)D deficiency.     

BRCA1 Polymorphisms and Breast Cancer Epidemiology in the Western New York Exposures and Breast Cancer (WEB) Study

Results of studies for the association of BRCA1 genotypes and haplotypes with sporadic breast cancer have been inconsistent. Therefore, a candidate single nucleotide polymorphism (SNP) approach was used in a breast cancer case‐control study to explore genotypes and haplotypes that have the potential to affect protein functions or levels. In a breast cancer case‐control study, genotyping of BRCA1 polymorphisms Q356R, D693N, and E1038G was performed on 1,005 cases and 1,765 controls. Unconditional, polytomous logistic regression and χ²‐tests were used to examine the associations of breast cancer with genotypes and haplotypes. In addition, interactions between genotype and smoking, benign breast disease, family history of breast cancer, body mass index (BMI), alcohol consumption, and hormonal risk factors, hormone receptor status, and breast cancer pathology were calculated also using logistic regression and χ². Although sporadic breast cancer was not associated with BRCA1 genotypes or haplotypes overall or by menopausal status, there was evidence of an interaction between the E1038G BRCA1 genotype, smoking, and BMI among premenopausal women (P for interaction = 0.01 and 0.045, respectively) and between E1038G and D693N BRCA1 genotypes and hormone therapy use among postmenopausal women (P for interaction = 0.01 and 0.02, respectively). There were no other associations found between BRCA1 genotypes and stage, histological grade, or nuclear grade. However, the D693N SNP was associated with the risk of triple negative breast cancer (odds ratio = 2.31 95% confidence interval 1.08–4.93). The BRCA1 variants studied may play a role in the etiology of triple negative breast cancer and may interact with environmental factors such as hormone therapy or smoking and increase sporadic breast cancer risk.     

U2依赖型mRNA剪接体与肝癌的相关性研究

目的 探讨U2依赖型mRNA剪接复合体相关基因多态性与肝癌的风险关联.方法 采用两阶段病例对照研究,筛查阶段采用Openarray中通量分型技术对U2依赖型mRNA剪接复合体的关键基因(U2AF1、U2AF2、SRSF1、SRSF2、SF3B1、SF3A1、SF1和PRPF40)的21个潜在功能标签SNP位点在筛查人群(武汉地区378例新发肝癌病例和461例非肿瘤对照)中进行基因分型;对筛查阶段得到的阳性位点进一步在验证人群(北京地区428例新发肝癌病例和647例非肿瘤对照)中采用TaqMan基因分型技术进行验证.采用加法交互模型分析吸烟/饮酒及遗传因素的交互作用.结果 两阶段人群中均观察到SF3A1基因的rs5994293与肝癌发病风险存在显著关联.合并分析显示,以携带TT基因型者为参照,携带G等位基因者的肝癌发病风险降低30%(OR=0.70,95%CI:0.58～0.84,FDR-P=0.000 5);合并阶段在HBsAg阴性者中观察到吸烟合并饮酒和rs5994293 TT基因型之间存在加法交互作用.结论 携带SF3A1 rs5994293 T等位基因可能增加肝癌发生风险,但仍需大样本研究及功能研究的验证.     

Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers

Background

Women with BRCA1 and BRCA2 mutation carriers are at substantially elevated risk of developing ovarian cancer. The aim of the meta-analysis is to clarify the role of risk-reducing salpingo-oophorectomy (RRSO) to reduce ovarian cancer risk and mortality in women with BRCA 1 and BRCA 2 mutation carriers.

Methods

Pubmed, Medline and Scopus were searched to select English-language articles. Two investigators independently extracted characteristics and results of selected studies. Articles were included only if prospective and if absolute numbers of ovarian cancer and death events were available or derivable from the test. Pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated using fixed effects model.

Results

Meta-analysis of 3 prospective studies demonstrated a significant risk reduction of ovarian cancer with RRSO in BRCA 1 and BRCA 2 mutation carriers, as well as benefit in all-causes mortality incidence.

Conclusions

It may be justified to recommend RRSO to reduce ovarian cancer risk and all-causes mortality in women with a mutation in BRCA 1 and BRCA 2.

     

Dairy Products and Cancer Risk in a Northern Sweden Population

Abstract

The role of dairy products in cancer is unclear. We assessed consumption of fermented milk, non-fermented milk, cheese, and butter, estimated from semi-quantitative food frequency questionnaires, in relation to prospective risk of breast, prostate, colorectal, smoking-, and obesity-related cancers in 101,235 subjects, including 12,552 cancer cases, in the population-based Northern Sweden Health and Disease Study. Most analyses (n?=?20) rendered null results. In men, we observed an increased prostate cancer risk among high-consumers of cheese (hazard ratio (HR) for highest vs. lowest quintile (Q5–Q1), 1.11; 95% CI, 0.97–1.27; P^trend?=?0.013). In women, high-consumers of cheese had a decreased risk of overall cancer (HR Q5–Q1, 0.95; 95% CI, 0.88–1.04; P^trend?=?0.039), smoking-related (HR Q5–Q1, 0.84; 95% CI, 0.72–0.97; P^trend ≤ 0.001), and colorectal cancers (HR Q5–Q1, 0.82; 95% CI, 0.63–1.07; P^trend?=?0.048). Butter yielded a weak decreased obesity-related cancer risk in women (HR Q5–Q1, 0.91; 95% CI, 0.81–1.02; P^trend?=?0.049). Fermented milk yielded HRs below zero in women, but with no clear linear associations. In conclusion, this study does not support any major adverse or beneficial effects of fermented milk, non-fermented milk, cheese, and butter in the diet from a cancer risk perspective.     

Curcumin analogues as possible anti-proliferative & anti-inflammatory agents

A series of novel curcumin analogues has been designed, synthesized and tested in vitro/in vivo as potential multi-target agents. Their anti-proliferative and anti-inflammatory activities were studied. Compounds 1b and 2b were stronger inhibitors of soybean lipoxygenase (LOX) than curcumin. Analogue 1b was also the most potent aldose reductase (ALR2) inhibitor. Two compounds, (1a and 1f) exhibited in vivo anti-inflammatory activity comparable to that of indomethacin, whereas derivative 1i exhibited even higher activity. The derivatives were also tested for their anti-proliferative activity using three different human cancer cell lines. Compounds 1a, 1b, 1d and 2b exhibited significant growth inhibitory activity as compared to curcumin, against all three cancer cell lines. Lipophilicity was determined as R_M values using RPTLC and theoretically. The results are discussed in terms of the structural characteristics of the compounds. Docking simulations were performed on LOX and ALR2 inhibitor 1b and curcumin. Compound 1b is well fitted in the active site of ALR2, binding to the ALR2 enzyme in a similar way to curcumin. Allosteric interactions may govern the LOX-inhibitor binding.     

Fish oil attenuates neurologic severity of antiphospholipid syndrome in a mice experimental model

Introduction: Murine experimental models of antiphospholipid syndrome (eAPLS) showed neurologic dysfunction and therapeutic effect of the anticoagulant enoxaparin is well established. Omega-3 fatty acids and curcumin, tested in neuroinflammation and auto-immunity diseases, might be interesting therapeutic candidates. The aim of this study was to evaluate the effects of these candidates on neurologic severity in eAPLS. Methods: One month after immunization of BALB/c mice with beta-2-glycoprotein I, daily treatments were initiated with enoxaparin (1?mg/kg), omega-3 fatty acids (0.5 g/kg), and curcumin (200?mg/kg) for 3 months. Results: Mortality was significantly decreased by enoxaparin and omega-3 treatments. Fish oil and curcumin group exhibited the highest mean of swimming behavior in forced swim test in surviving mice. Mice under omega-3 fatty acids or curcumin presented low anxiety-like behavior in the elevated plus-maze test. Cerebral histopathology revealed heavy inflammatory infiltrates in cortical and subcortical regions with vacuolization, swelling, and degeneration of astrocytes in the control group, with aggravation under curcumin; no infiltrate was retrieved in enoxaparin and omega-3 groups. Conclusion: Our study is the first to demonstrate a potential therapeutic effect of omega-3 fatty acids in eAPLS. Enoxaparin and omega-3 fatty acids combination would be interesting for further investigation.     

Synthesis and cytotoxic activity of novel 3-(1H-indol-3-yl)-1H-pyrazole-5-carbohydrazide derivatives

A series of novel 3-(1H-indole-3-yl)-1H-pyrazole-5-carbohydrazide derivatives 4Ia–n, 4IIa–b and 6 were prepared by hydrazinolysis of ethyl 3-(1H-indole-3-yl)-1H-pyrazole-5-carboxylate with hydrazine hydrate in excellent yields. These new compounds were fully characterized by spectroscopic methods, and the important intermediates 3Ie, 3IIc and 3IId were further confirmed by X-ray crystallography. All the new compounds were evaluated for their cytotoxic activity against 4 human cancer cell lines by MTT method. Some of them exhibited more potent antiproliferative activity against HepG-2, BGC823 and BT474 cell lines than the positive drug 5-fluorourcail. Flow cytometry analysis showed that 4Ik and 4Il arrested the cell cycle at S phase.     

BRCA1 R841W: A strong candidate for a common mutation with moderate phenotype

BRCA1 mutations cause increased risk for breast and ovarian cancer, frequently of early onset. Many different mutations occur in BRCA1, including several examples of recurrent mutations, each of which accounts for a significant number of families with heritable cancer predisposition. These common mutations have an etiological role in many breast and ovarian cancer cases and provide the opportunity to examine genotype-phenotype correlations and genotype-environment interactions in individuals with the identical BRCA1 lesion. We report a novel missense change in BRCA1, 2640 C→T (R841W), found in 3 cases from a subject group of 305 breast and 79 ovarian cancer cases from Orange County, CA. These are consecutive, population-based cases not selected for age or family history. In all three cases, there is a strong family history of breast, ovarian, or other cancers possibly related to a BRCA1 defect and family members showed a high concordance of cancer incidence with the presence of R841W. The age of cancer onset was not always distinct from typical sporadic cases. Testing of a sample of 413 unrelated individuals to examine the hypothesis that R841W might be a rare polymorphism detected one additional instance in a woman with breast cancer diagnosed at age 77 years, and cancer in one parent. R841W is likely to be an etiologically significant lesion with involvement in close to 1% (95% confidence interval 0–1.7%) of all breast and ovarian cancers in this population. © 1996 Wiley-Liss, Inc.     

Burden of Early-Stage Triple-Negative Breast Cancer in a US Managed Care Plan

ObjectiveTriple-negative breast cancer (TNBC) is a high-grade breast cancer with an aggressive clinical course. We examined the recurrence rate, health care utilization, and cost of early-stage TNBC in the US managed care setting.Study DesignA retrospective study using linked cancer registry, health care claims, and social administration databases.MethodsThis retrospective study used the Impact Intelligence Oncology Management cancer registry, linked to 1999-2009 administrative claims, from a national managed care health plan and also Social Security Administration mortality data. Patients with stage I-III TNBC and non-TNBC were followed from diagnosis to recurrence, disenrollment, or end of observation period. Risk-adjusted recurrence rate, health care utilization, and costs during the follow-up period were compared.ResultsA total of 1967 women (403 with TNBC) were included; 289 (14.7%) had local/distant recurrence during the follow-up period. Patients with TNBC were younger (53.68 vs. 56.16 years, P < .0001) and more likely to experience recurrence compared with non-TNBC (21.6% vs. 12.9%, P < .0001; adjusted hazard ratio = 2.11, P < .0001). In terms of adjusted annual health care utilization and costs, patients with TNBC had significantly higher numbers of hospitalizations (1.20 vs. 0.90, P = .001); hospitalization days (8.80 vs. 4.97, P < .0001); and emergency department (ED) visits (1.45 vs. 0.95, P = .009). They also had significantly higher inpatient costs (all-cause: $9154 vs. $5501; cancer-related: $5632 vs. $2869; P < .0001 for both); and ED costs (all-cause: $303 vs. $182, P = .003; cancer-related: $240 vs. $138, P = .012).ConclusionsThis study demonstrates that, compared with non-TNBC, early-stage TNBC is associated with higher rate of recurrence, resulting in increased health care utilization and costs.