Breast cancer-derived K172N,D301V mutations abolish Na/H exchanger regulatory factor 1 inhibition of platelet-derived growth factor receptor signaling

Na⁺/H⁺ exchanger regulatory factor 1 (NHERF1) is a scaffold protein known to interact with a number of cancer-related proteins. nherf1 Mutations (K172N and D301V) were recently identified in breast cancer cells. To investigate the functional properties of NHERF1, wild-type and cancer-derived nherf1 mutations were stably expressed in SKMES-1 cells respectively. NHERF1-wt overexpression suppressed the cellular malignant phenotypes, including proliferation, migration, and invasion. nherf1 Mutations (K172N and D301V) caused complete or partial loss of NHERF1 functions by affecting the PTEN/NHERF1/PDGFRβ complex formation, inactivating NHERF1 inhibition of PDGF-induced AKT and ERK activation, and attenuating the tumor-suppressor effects of NHERF1-wt. These results further demonstrated the functional consequences of breast cancer-derived nherf1 mutations (K172N and D301V), and suggested the causal role of NHERF1 in tumor development and progression.     

Synthesis and preliminary evaluation steroidal antiestrogen–geldanamycin conjugates

Three novel steroidal antiestrogen–geldanamycin conjugates were prepared using a convergent strategy. The antiestrogenic component utilized the 11β-(4-functionalized-oxyphenyl) estradiol scaffold, while the geldanamycin component was derived by replacement of the 17-methoxy group with an appropriately functionalized amine. Ligation was achieved in high yield using azide alkyne cyclization reactions. Evaluation of the products against two breast cancer cell lines indicated that the conjugates retained significant antiproliferative activity.     

3-Acyl-5-hydroxybenzofuran derivatives as potential anti-estrogen breast cancer agents: A combined experimental and theoretical investigation

We first report the application of 3-acyl-5-hydroxybenzofurans as a scaffold to develop potential drugs for breast cancer. Seven novel derivative compounds were synthesized by using a microwave-assisted synthesis method. Those compounds exhibited different antiproliferation against human breast cancer MCF-7 cells, with the best activity of IC₅₀ = 43.08 μM for compound 1. A Quantum Mechanics Polarized Ligand Docking (QPLD) study was carried out to investigate the binding interactions between these compounds and estrogen receptor alpha (ERα). The simulation results showed that the trend of receptor–ligand binding interactions was same as that of their antiproliferative activities. A detailed analysis indicated that compound 1 possesses the highest Van der Waals and hydrogen bond interactions compared to the other six compounds and better inhibitors are achievable by enhancing the hydrogen bond interactions. Based on these results, we addressed that 3-acyl-5-hydroxybenzofuran is an attractive scaffold for designing drugs against breast cancer.     

Carbonic anhydrase inhibitors that directly inhibit anion transport by the human Cl−/HCO3− exchanger,AE1

Carbonic anhydrases (CA, EC 4.2.1.1.) catalyze reversible hydration of CO₂ to HCO₃^?+H⁺. Bicarbonate transport proteins, which catalyze the transmembrane movement of membrane-impermeant bicarbonate, function in cooperation with CA. Since CA and bicarbonate transporters share the substrate, bicarbonate, we examined whether novel competitive inhibitors of CA also have direct inhibitory effects on bicarbonate transporters. We expressed the human erythrocyte membrane Cl^?/HCO₃^? exchanger, AE1, in transfected HEK293 cells as a model bicarbonate transporter. AE1 activity was assessed in both Cl^?/NO₃^? exchange assays, which were independent of CA activity, and in Cl^?/HCO₃^? exchange assays. Transport was measured by following changes of intracellular [Cl^?] and pH, using the intracellular fluorescent reporter dyes 6-methoxy-N-(3-sulfopropyl)quinolinium and 2′,7′-bis-(2-carboxyethyl)-5-(and-6)carboxyfluorescein, respectively. We examined the effect of 16 different carbonic anhydrase inhibitors on AE1 transport activity. Among these 12 were newly-reported compounds; two were clinically used non-steroidal anti-inflammatory drugs (celecoxib and valdecoxib) and two were anti-convulsant drugs (topiramate and zonisamide). Celecoxib and four of the novel compounds significantly inhibited AE1 Cl^?/NO₃^? exchange activity with EC₅₀ values in the range 0.22–2.8 μM. It was evident that bulkier compounds had greater AE1 inhibitory potency. Maximum inhibition using 40 μM of each compound was only 22–53% of AE1 transport activity, possibly because assays were performed in the presence of competing substrate. In Cl^?/HCO₃^? exchange assays, which depend on functional CA to produce transport substrate, 40 μM celecoxib inhibited AE1 by 62±4%. We conclude that some carbonic anhydrase inhibitors, including clinically-used celecoxib, will inhibit bicarbonate transport at clinically-significant concentrations.     

门诊患者医疗服务感受度影响因素研究

??????? 目的 了解门诊患者对就医服务感受度影响因素,以期提高患者满意度。 方法 现场问卷调查法、专家访谈法。 结果 患者在门诊过程中最为关注的就诊流程、等候时间、就医环境、医德医风四个因素,非常看重医护人员服务规范,服务流程便捷流畅。病情不同患者对等候时间要求不同,对医院熟悉程度与就诊环境感受度不同。结论 在门诊服务中为患者提供便捷流畅、规范化的服务,同时应注重患者的不同服务需求。     

The aluminium content of breast tissue taken from women with breast cancer

The aetiology of breast cancer is multifactorial. While there are known genetic predispositions to the disease it is probable that environmental factors are also involved. Recent research has demonstrated a regionally specific distribution of aluminium in breast tissue mastectomies while other work has suggested mechanisms whereby breast tissue aluminium might contribute towards the aetiology of breast cancer. We have looked to develop microwave digestion combined with a new form of graphite furnace atomic absorption spectrometry as a precise, accurate and reproducible method for the measurement of aluminium in breast tissue biopsies. We have used this method to test the thesis that there is a regional distribution of aluminium across the breast in women with breast cancer. Microwave digestion of whole breast tissue samples resulted in clear homogenous digests perfectly suitable for the determination of aluminium by graphite furnace atomic absorption spectrometry. The instrument detection limit for the method was 0.48 μg/L. Method blanks were used to estimate background levels of contamination of 14.80 μg/L. The mean concentration of aluminium across all tissues was 0.39 μg Al/g tissue dry wt. There were no statistically significant regionally specific differences in the content of aluminium. We have developed a robust method for the precise and accurate measurement of aluminium in human breast tissue. There are very few such data currently available in the scientific literature and they will add substantially to our understanding of any putative role of aluminium in breast cancer. While we did not observe any statistically significant differences in aluminium content across the breast it has to be emphasised that herein we measured whole breast tissue and not defatted tissue where such a distribution was previously noted. We are very confident that the method developed herein could now be used to provide accurate and reproducible data on the aluminium content in defatted tissue and oil from such tissues and thereby contribute towards our knowledge on aluminium and any role in breast cancer.     

自动乳腺全容积扫描联合乳腺钼靶摄影在乳腺疾病诊断中的价值

目的：探讨自动乳腺全容积扫描（automated breast volume scanner,ABVS）联合乳腺钼靶摄影在乳腺疾病诊断中的价值。方法：观察随访130例就诊我科的乳腺疾病患者,进行ABVS、传统超声和乳腺钼靶检查。结果：130例患者中ABVS的疾病单独诊断准确率为91．5％（119／130）,传统乳腺超声的单独诊断准确率为84．6％（110／130）,乳腺钼靶的单独诊断准确率为86．9％（113／130）,而ABVS联合乳腺钼靶应用的诊断准确率为95．4％（124／130）,明显优于两者单独应用,差异具有统计学意义（P〈0．05）。结论：ABVS是一种全新的乳腺检查方法,较传统乳腺超声、乳腺钼靶具有较高的疾病诊断准确率,而ABVS联合乳腺钼靶可以显著提高诊断的准确率,值得在临床推广。     

中国北方地区血清钙、维生素D水平与乳腺癌的相关性研究

目的:探讨中国北方地区血清钙、维生素D水平与乳腺癌及相关临床因素的关系.方法:选取2007年12月至2012年7月哈尔滨医科大学附属肿瘤医院794例女性乳腺癌患者及976例乳腺良性肿瘤患者,并以128例健康妇女为对照,取空腹血清采用原子吸收分光光度法检测三组血清钙含量,采用放免法检测三组中162例血清25(OH)D含量,结合相关临床资料进行分析.结果:乳腺癌组血清钙含量为2.26± 0.12 mmol/L,乳腺良性肿瘤组血清钙含量为2.26±0.09 mmol/L,正常对照组血清钙含量为2.25±0.24 mmol/L,经方差分析,三组总体均数差别无统计学意义(P＞0.05);乳腺癌患者的血清钙水平与年龄、TNM分期、BMI、绝经情况、乳腺癌家族遗传史无关(P＞0.05).乳腺癌组血清25(OH)D含量为41.91±7.55 ng/mL,乳腺良性肿瘤血清25(OH)D含量为54.62±7.48 ng/mL,正常对照组血清25(OH)D含量为56.15±8.87 ng/mL,经方差分析,乳腺癌患者血清25(OH)D含量低于乳腺良性肿瘤组,差别有统计学意义(P＜0.05),乳腺良性肿瘤组与正常对照组差别无统计学意义(P＞0.05);乳腺癌患者的维生素D水平与年龄、TNM分期、BMI、绝经情况有关(P＜0.05),而与乳腺癌家族遗传史无关(P＞0.05).结论:中国北方地区的乳腺癌患者血清钙水平与乳腺良性肿瘤患者无明显差异.乳腺癌患者的维生素D水平低于乳腺良性肿瘤患者,并且与年龄、TNM分期、BMI、绝经情况有关.维生素D水平降低可能与乳腺癌的发生有关,高水平的维生素D可能会降低女性患乳癌的风险.     

靶向治疗乳腺癌骨转移的研究进展

本文对双磷酸盐、狄诺塞麦、Sagopilone等特异性靶向药物在乳腺癌骨转移靶向治疗中的作用机制、临床应用、临床疗效等方面的相关研究进展情况进行了简要阐述。双磷酸盐在抑制骨转移和非骨转移中发挥作用,狄诺塞麦可能成为双磷酸盐的合理替代物,尤其在双磷酸盐治疗效果不佳的病人中,而新型抗癌药物Sagopilone、骨唾液酸蛋白抑制剂亦可通过多种机制参与乳腺癌转移过程,具有抑制骨转移的巨大潜力。     

Shift work,circadian gene variants and risk of breast cancer

Circadian (clock) genes have been linked with several functions relevant to cancer, and epidemiologic research has suggested relationships with breast cancer risk for variants in NPAS2, CLOCK, CRY2 and TIMELESS. Increased breast cancer risk has also been observed among shift workers, suggesting potential interactions in relationships of circadian genes with breast cancer. Relationships with breast cancer of 100 SNPs in 14 clock-related genes, as well as potential interactions with shift work history, were investigated in a case–control study (1042 cases, 1051 controls). Odds ratios in an additive genetic model for European-ancestry participants (645 cases, 806 controls) were calculated, using a two-step correction for multiple testing: within each gene through permutation testing (10,000 permutations), and correcting for the false discovery rate across genes. Interactions of genotypes with ethnicity and shift work (<2 years vs ≥2 years) were evaluated individually. Following permutation analysis, two SNPs (rs3816360 in ARNTL and rs11113179 in CRY1) displayed significant associations with breast cancer and one SNP (rs3027188 in PER1) was marginally significant; however, none were significant following adjustment for the false discovery rate. No significant interaction with shift work history was detected. If shift work causes circadian disruption, this was not reflected in associations between clock gene variants and breast cancer risk in this study. Larger studies are needed to assess interactions with longer durations (>30 years) of shift work that have been associated with breast cancer.