Assessing risk of breast cancer in an ethnically South-East Asia population (results of a multiple ethnic groups study)

10.1186/1471-2407-12-529BMC Cancer12-BCMA

Lack of association between mutations of gene-encoding mitochondrial D310 (displacement loop) mononucleotide repeat and oxidative stress in chronic dialysis patients in Taiwan

<p>Abstract</p> <p>Background</p> <p>Mitochondria (mt) are highly susceptible to reactive oxygen species (ROS). In this study, we investigated the association between a region within the displacement loop (D-loop) in mtDNA that is highly susceptible to ROS and oxidative stress markers in chronic dialysis patients. We enrolled 184 chronic dialysis patients and 213 age-matched healthy subjects for comparison. Blood levels of oxidative stress markers, such as thiobarbituric acid reactive substances (TBARS) and free thiol, and the mtDNA copy number were determined. A mononucleotide repeat sequence (CCCC...CCCTCCCCCC) between nucleotides 303 and 316-318 (D310) was identified in mtDNA.</p> <p>Results</p> <p>Depending on alterations in the D310 mononucleotide repeat, subjects were categorized into 4 subgroups: 7-C, 8-C, 9 or 10-C, and T-to-C transition. Oxidative stress was higher in chronic dialysis patients, evidenced by higher levels of TBARS and mtDNA copy number, and a lower level of free thiol. The distribution of 7-C, 8-C, and 9-10C in dialysis and control subjects was as follows: 7-C (38% <it>vs. </it>31.5%), 8-C (35.3% <it>vs. </it>43.2%), and 9-10C (24.5% <it>vs. </it>22.1%). Although there were significant differences in levels of TBARS, free thiol, and the mtDNA copy number in the D310 repeat subgroups (except T-to-C transition) between dialysis patients and control subjects, post hoc analyses within the same study cohort revealed no significant differences.</p> <p>Conclusion</p> <p>Although oxidative stress was elevated in chronic dialysis patients and resulted in a compensatory increase in the mtDNA copy number, homopolymeric C repeats in the mtDNA region (D310), susceptible to ROS, were not associated with oxidative stress markers in these patients.</p

Synergy between inhibitors of androgen receptor and MEK has therapeutic implications in estrogen receptor-negative breast cancer

Introduction: Estrogen receptor-negative (ER-) breast cancer is a heterogeneous disease with limited therapeutic options. The molecular apocrine subtype constitutes 50% of ER-tumors and is characterized by overexpression of steroid response genes including androgen receptor (AR). We have recently identified a positive feedback loop between the AR and extracellular signal-regulated kinase (ERK) signaling pathways in the molecular apocrine subtype. In this feedback loop, AR regulates ERK phosphorylation through the mediation of ErbB2 and, in turn, ERK-CREB1 signaling regulates the transcription of AR in molecular apocrine cells. In this study, we investigated the therapeutic implications of the AR-ERK feedback loop in molecular apocrine breast cancer.Methods: We examined a synergy between the AR inhibitor flutamide and the MEK inhibitor CI-1040 in the molecular apocrine cell lines MDA-MB-453, HCC-1954 and HCC-202 using MTT cell viability and annexin V apoptosis assays. Synergy was measured using the combination index (CI) method. Furthermore, we examined in vivo synergy between flutamide and the MEK inhibitor PD0325901 in a xenograft model of the molecular apocrine subtype. The effects of in vivo therapies on tumor growth, cell proliferation and angiogenesis were assessed.Results: We demonstrate synergistic CI values for combination therapy with flutamide and CI-1040 across three molecular apocrine cell lines at four dose combinations using both cell viability and apoptosis assays. Furthermore, we show in vivo that combination therapy with flutamide and MEK inhibitor PD0325901 has a significantly higher therapeutic efficacy in reducing tumor growth, cellular proliferation and angiogenesis than monotherapy with these agents. Moreover, our data suggested that flutamide and CI-1040 have synergy in trastuzumab resistance models of the molecular apocrine subtype. Notably, the therapeutic effect of combination therapy in trastuzumab-resistant cells was associated with the abrogation of an increased level of ERK phosphorylation that was developed in the process of trastuzumab resistance.Conclusions: In this study, we demonstrate in vitro and in vivo synergies between AR and MEK inhibitors in molecular apocrine breast cancer. Furthermore, we show that combination therapy with these inhibitors can overcome trastuzumab resistance in molecular apocrine cells. Therefore, a combination therapy strategy with AR and MEK inhibitors may provide an attractive therapeutic option for the ER-/AR+ subtype of breast cancer

Impact of Visual Repetition Rate on Intrinsic Properties of Low Frequency Fluctuations in the Visual Network

BACKGROUND: Visual processing network is one of the functional networks which have been reliably identified to consistently exist in human resting brains. In our work, we focused on this network and investigated the intrinsic properties of low frequency (0.01-0.08 Hz) fluctuations (LFFs) during changes of visual stimuli. There were two main questions to be discussed in this study: intrinsic properties of LFFs regarding (1) interactions between visual stimuli and resting-state; (2) impact of repetition rate of visual stimuli. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed scanning sessions that contained rest and visual stimuli in various repetition rates with a novel method. The method included three numerical approaches involving ICA (Independent Component Analyses), fALFF (fractional Amplitude of Low Frequency Fluctuation), and Coherence, to respectively investigate the modulations of visual network pattern, low frequency fluctuation power, and interregional functional connectivity during changes of visual stimuli. We discovered when resting-state was replaced by visual stimuli, more areas were involved in visual processing, and both stronger low frequency fluctuations and higher interregional functional connectivity occurred in visual network. With changes of visual repetition rate, the number of areas which were involved in visual processing, low frequency fluctuation power, and interregional functional connectivity in this network were also modulated. CONCLUSIONS/SIGNIFICANCE: To combine the results of prior literatures and our discoveries, intrinsic properties of LFFs in visual network are altered not only by modulations of endogenous factors (eye-open or eye-closed condition; alcohol administration) and disordered behaviors (early blind), but also exogenous sensory stimuli (visual stimuli with various repetition rates). It demonstrates that the intrinsic properties of LFFs are valuable to represent physiological states of human brains

MicroRNA profiling in ischemic injury of the gracilis muscle in rats

<p>Abstract</p> <p>Background</p> <p>To profile the expression of microRNAs (miRNAs) and their potential target genes in the gracilis muscles following ischemic injury in rats by monitoring miRNA and mRNA expression on a genome-wide basis.</p> <p>Methods</p> <p>Following 4 h of ischemia and subsequent reperfusion for 4 h of the gracilis muscles, the specimens were analyzed with an Agilent rat miRNA array to detect the expressed miRNAs in the experimental muscles compared to those from the sham-operated controls. Their expressions were subsequently quantified by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) to determine their expression pattern after different durations of ischemia and reperfusion. In addition, the expression of the mRNA in the muscle specimens after 4 h of ischemia and reperfusion for 1, 3, 7, and 14 d were detected with the Agilent Whole Rat Genome 4 × 44 k oligo microarray. A combined approach using a computational prediction algorithm that included miRanda, PicTar, TargetScanS, MirTarget2, RNAhybrid, and the whole genome microarray experiment was performed by monitoring the mRNA:miRNA association to identify potential target genes.</p> <p>Results</p> <p>Three miRNAs (miR-21, miR-200c, and miR-205) of 350 tested rat miRNAs were found to have an increased expression in the miRNA array. Real-time RT-PCR demonstrated that, with 2-fold increase after 4 h of ischemia, a maximum 24-fold increase at 7 d, and a 7.5-fold increase at 14 d after reperfusion, only the miR-21, but not the miR-200c or miR-205 was upregulated throughout the experimental time. In monitoring the target genes of miR-21 in the expression array at 1, 3, 7, 14 d after reperfusion, with persistent expression throughout the experiment, we detected the same 4 persistently downregulated target genes (<it>Nqo1</it>, <it>Pdpn</it>, <it>CXCL3</it>, and <it>Rad23b</it>) with the prediction algorithms miRanda and RNAhybrid, but no target gene was revealed with PicTar, TargetScanS, and MirTarget2.</p> <p>Conclusions</p> <p>This study revealed 3 upregulated miRNAs in the gracilis muscle following ischemic injury and identified 4 potential target genes of miR-21 by examining miRNAs and mRNAs expression patterns in a time-course fashion using a combined approach with prediction algorithms and a whole genome expression array experiment.</p

saeRS and sarA Act Synergistically to Repress Protease Production and Promote Biofilm Formation in Staphylococcus aureus

Mutation of the staphylococcal accessory regulator (sarA) limits biofilm formation in diverse strains of Staphylococcus aureus, but there are exceptions. One of these is the commonly studied strain Newman. This strain has two defects of potential relevance, the first being mutations that preclude anchoring of the fibronectin-binding proteins FnbA and FnbB to the cell wall, and the second being a point mutation in saeS that results in constitutive activation of the saePQRS regulatory system. We repaired these defects to determine whether either plays a role in biofilm formation and, if so, whether this could account for the reduced impact of sarA in Newman. Restoration of surface-anchored FnbA enhanced biofilm formation, but mutation of sarA in this fnbA-positive strain increased rather than decreased biofilm formation. Mutation of sarA in an saeS-repaired derivative of Newman (P18L) or a Newman saeRS mutant (ΔsaeRS) resulted in a biofilm-deficient phenotype like that observed in clinical isolates, even in the absence of surface-anchored FnbA. These phenotypes were correlated with increased production of extracellular proteases and decreased accumulation of FnbA and/or Spa in the P18L and ΔsaeRS sarA mutants by comparison to the Newman sarA mutant. The reduced accumulation of Spa was reversed by mutation of the gene encoding aureolysin, while the reduced accumulation of FnbA was reversed by mutation of the sspABC operon. These results demonstrate that saeRS and sarA act synergistically to repress the production of extracellular proteases that would otherwise limit accumulation of critical proteins that contribute to biofilm formation, with constitutive activation of saeRS limiting protease production, even in a sarA mutant, to a degree that can be correlated with increased enhanced capacity to form a biofilm. Although it remains unclear whether these effects are mediated directly or indirectly, studies done with an sspA::lux reporter suggest they are mediated at a transcriptional level

Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer

Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of £301 359. This equated to £6500 per life years gained and £7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of £430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer

Partnership disengagement from primary community care networks (PCCNs): A qualitative study for a national demonstration project

<p>Abstract</p> <p>Background</p> <p>The Primary Community Care Network (PCCN) Demonstration Project, launched by the Bureau of National Health Insurance (BNHI) in 2003, is still in progress. Partnership structures in PCCNs represent both contractual clinic-to-clinic and clinic-to-hospital member relationships of organizational aspects. The partnership structures are the formal relationships between individuals and the total network. Their organizational design aims to ensure effective communication, coordination, and integration across the total network. Previous studies have focused largely on how contractual integration among the partnerships works and on its effects. Few studies, however, have tried to understand partnership disengagement in PCCNs. This study explores why some partnerships in PCCNs disengage.</p> <p>Methods</p> <p>This study used a qualitative methodology with semi-structured questions for in-depth interviews. The semi-structured questions were pre-designed to explore the factors driving partnership disengagement. Thirty-seven clinic members who had withdrawn from their PCCNs were identified from the 2003-2005 Taiwan Primary Community Care Network Lists.</p> <p>Results</p> <p>Organization/participant factors (extra working time spend and facility competency), network factors (partner collaboration), and community factors (health policy design incompatibility, patient-physician relationship, and effectiveness) are reasons for clinic physicians to withdraw or change their partnerships within the PCCNs.</p> <p>Conclusions</p> <p>To strengthen partnership relationships, several suggestions are made, including to establish clinic and hospital member relationships, and to reduce administrative work. In addition, both educating the public about the concept of family doctors and ensuring well-organized national health policies could help health care providers improve the integration processes.</p