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Emerging studies are reporting associations between skeletal muscle abnormalities and survival in cancer patients. Cancer prognosis is associated with depletion of essential fatty acids in erythrocytes and plasma in humans. However the relationship between skeletal muscle membrane fatty acid composition and survival is unknown. This study investigates the relationship between fatty acid content of phospholipids in skeletal muscle and survival in cancer patients. Rectus abdominis biopsies were collected during cancer surgery from 35 patients diagnosed with cancer. Thin-layer and gas chromatography were used for quantification of phospholipid fatty acids. Cutpoints for survival were defined using optimal stratification. Median survival was between 450 and 500 days when patients had arachidonic acid (AA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in muscle phospholipid below the cut-point compared to 720–800 days for patients above. Cox regression analysis revealed that low amounts of AA, EPA and DHA are risk factors for death. The risk of death remained significant for AA [HR 3.5 (1.11–10.87), p = 0.03], EPA [HR 3.92 (1.1–14.0), p = 0.04] and DHA [HR 4.08 (1.1–14.6), p = 0.03] when adjusted for sex. Lower amounts of essential fatty acids in skeletal muscle membrane is a predictor of survival in cancer patients. These results warrant investigation to restore bioactive fatty acids in people with cancer.

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. HCMV proteins and DNA are detected in tumors and metastases, suggesting an association with increased invasion. We investigated HCMV infection in human breast cancer cell lines compared to fibroblasts, a component of tumors, and the role of platelet-derived growth factor receptor-α (PDGFRα). HCMV productively infected HEL299 fibroblasts and, to a lesser extent, Hs578T breast cancer cells. Infection of another triple-negative cell line, MDA-MB-231, and also MCF-7 cells, was extremely low. These disparate infection rates correlated with expression of PDGFRA, which facilitates HCMV uptake. Increasing PDGFRA expression in T-47D breast cancer and BCPAP thyroid cancer cells markedly increased HCMV infection. Conversely, HCMV infection decreased PDGFRA expression, potentially attenuating signaling through this receptor. HCMV infection of fibroblasts promoted the secretion of proinflammatory factors, whereas an overall decreased secretion of inflammatory factors was observed in infected Hs578T cells. We conclude that HCMV infection in tumors will preferentially target tumor-associated fibroblasts and breast cancer cells expressing PDGFRα. HCMV infection in the tumor microenvironment, rather than cancer cells, will increase the inflammatory milieu that could enhance metastasis involving lysophosphatidate.

Fahed A Elian,1 Ubah Are,1 Sunita Ghosh,2,3 Paulo Nuin,1 Tim Footz,1 Todd PW McMullen,4 David N Brindley,5,6 Michael A Walter1 1Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 2Department of Medical Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 3Department of Mathematical and Statistical Sciences, Faculty of Science, University of Alberta, Edmonton, AB, Canada; 4Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 5Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 6Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, CanadaCorrespondence: Michael A WalterDepartment of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, 8-32 Medical Sciences Building, Edmonton, AB, T6G 2H7, CanadaTel +1 (780) 492-3028Email mwalter@ualberta.caPurpose: Forkhead box Q1 (FOXQ1) has been shown to contribute to the development and progression of cancers, including ovarian and breast cancer (BC). However, research exploring FOXQ1 expression, copy number variation (CNV), and prognostic value across different BC subtypes is limited. Our purpose was to evaluate FOXQ1 mRNA expression, CNV, and prognostic value across BC subtypes.Materials and Methods: We determined FOXQ1 expression and CNV in BC patient tumors using RT-qPCR and qPCR, respectively. We also analyzed FOXQ1 expression and CNV in BC cell lines in the CCLE database using K-means clustering. The prognostic value of FOXQ1 expression in the TCGA-BRCA database was assessed using univariate and multivariate Cox’s regression analysis as well as using the online tools OncoLnc, GEPIA, and UALCAN.Results: Our analyses reveal that FOXQ1 mRNA is differentially expressed between different subtypes of BC and is significantly decreased in luminal BC and HER2 patients when compared to normal breast tissue samples. Furthermore, analysis of BC cell lines showed that FOXQ1 mRNA expression was independent of CNV. Moreover, patients with low FOXQ1 mRNA expression had significantly poorer overall survival compared to those with high FOXQ1 mRNA expression. Finally, low FOXQ1 expression had a critical impact on the prognostic values of BC patients and was an independent predictor of overall survival when it was adjusted for BC subtypes and to two other FOX genes, FOXF2 and FOXM1.Conclusion: Our study reveals for the first time that FOXQ1 is differentially expressed across BC subtypes and that low expression of FOXQ1 is indicative of poor prognosis in patients with BC.Keywords: transcription factors, mRNA expression, copy number variation, predictive marker

Ultrasonography for thyroid nodules is one of the most common imaging tests performed in the general population. Details from ultrasound reports guide biopsies and surgery. This study quantifies the completeness of these reports based on Thyroid Imaging and Reporting System (TI-RADS) criteria and considers their utility in predicting malignant disease.We retrospectively reviewed ultrasound reports for 329 thyroidectomy patients and extracted data elements using the TI-RADS criteria: nodule size, echogenicity, margins, vascularity, solid/cystic composition and the presence or absence of microcalcifications and the halo sign. We assessed the reports to determine whether individual or multiple criteria were associated with malignancy.More than 97% of reports document nodule size; however, more than 90% of the reports noted only 3 or fewer of the 6 remaining TI-RADS criteria. The presence of microcalcifications was the most sensitive marker of malignancy (90%), whereas the documentation of irregular margins was the most specific indicator of malignancy (88%). Overall it was clear that microcalcifications, hypoechogenicity, irregular margins and solid nodules were significantly more likely to be found in malignant neoplasms; their absence predicted benign disease. Because so few reports consistently documented all criteria, the overall ability of thyroid ultrasonography to discriminate between lowerand higher-risk nodules is limited.Although the accuracy of thyroid ultrasonography is good, few ultrasound reports contain the necessary information, as defined by TI-RADS, to predict malignancy and guide management. When reported, microcalcifications and/or irregular margins are the best predictors of malignancy.L’échographie des nodules thyroïdiens est l’une des épreuves d’imagerie les plus souvent effectuées dans la population générale. Les détails fournis par l’échographie guident les biopsies et la chirurgie. Cette étude quantifie l’exhaustivité des rapports d’échographie selon les critères TI-RADS (Thyroid Imaging and Reporting System) et en mesure l’utilité pour prédire les cancers.Nous avons passé en revue de façon rétrospective les rapports d’échographie de 329 patients ayant subi une thyroïdectomie et nous en avons extrait les éléments sous l’angle des critères TI-RADS : taille des nodules, échogénicité, marges, vascularité, composition solide c. kystique, présence ou absence de microcalcifications et signe du halo. Nous avons évalué les rapports afin de déterminer si certains critères individuels ou multiples pouvaient être associés au cancer.Plus de 97 % des rapports mentionnent la taille des nodules; mais, plus de 90 % des rapports ne font état que de 3 critères ou moins sur les 6 autres critères TI-RADS. La présence de microcalcifications a été le marqueur tumoral le plus sensible (90 %), tandis que la présence de marges irrégulières a été le marqueur tumoral le plus spécifique (88 %). Dans l’ensemble, les microcalcifications, l’hypoéchogénicité, les marges irrégulières et les nodules solides ont sans contredit été significativement plus susceptibles d’être observés en présence de malignité; et en revanche, leur absence permettait de prédire une maladie bénigne. Étant donné que si peu de rapports ont documenté avec constance tous les critères, la capacité globale de l’échographie de la thyroïde à distinguer entre nodules de risque faible et élevé est limitée.Même si la précision de l’échographie thyroïdienne est bonne, peu de rapports d’échographie renferment les renseignements nécessaires, selon les critères TI-RADS, pour prédire un cancer et orienter sa prise en charge. Lorsqu’elles sont signalées, les microcalcifications ou les marges irrégulières sont les meilleurs prédicteurs de cancer.

International audience; Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocytes metabolism and adipogenic differentiation. Mice carrying inactivating mutations in the Lpin1 gene display the characteristic features of human familial lipodystrophy. Very little is known on the roles of lipin-1 in human adipocyte physiology. Apparently fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. In this study, we performed a systematic histopathological, biochemical and gene expression analysis of adipose tissue biopsies from human patients harbouring LPIN1 biallelic inactivating mutations and affected by recurrent episodes of severe rhabdomyolysis. We also explored the adipogenic differentiation potential of human mesenchymal cell populations derived from lipin-1 defective patients. White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of the adipocyte size. Nevertheless the adipose tissue develops without obvious histological signs of lipodystrophy and with a normal qualitative composition of the storage lipids. The increased expression of key adipogenic determinants such as SREBP1, PPARG and PGC1A shows that specific compensatory phenomena can be activated in vivo in human adipocytes under deficiency of a functional lipin-1.

Epigenetic silencing of RASSF1A is frequently observed in numerous cancers and has been previously reported. The promoter region of RASSF1A is predicted to have 75 CpG sites, and very few studies demonstrate how the methylation of these sites affects expression. In addition, the expression relationship between RASSF1A and its downstream target, modulator of apoptosis 1 (MOAP-1), is poorly understood. In this study, we have explored the mRNA expression of RASSF1A, MOAP-1 and the well-characterized splice variant of RASSF1, RASSF1C, in cancer cell lines and primary tumors. We confirmed that the RASSF1A promoter is robustly methylated within a 32-CpG region in solid tumors and results in lower mRNA expression. The MOAP-1 promoter contains ~110 CpG sites, but was not found to be methylated in cancer cell lines when 19 predicted CpG sites were explored. Interestingly, MOAP-1 mRNA expression positively correlated with RASSF1A expression in numerous cancers, whereas RASSF1C expression remained the same or was increased in cell lines or tissues with epigenetic loss of RASSF1A. We speculate that MOAP-1 and RASSF1A may be more intimately connected than originally thought, and the expression of both are warranted in experimental designs exploring the biology of the RASSF1A/MOAP-1 molecular pathway.

We have investigated the thermotropic phase behavior of dipalmitoylphosphatidylcholine (DPPC) bilayers containing a series of cholesterol analogues varying in the length and structure of their alkyl side chains. We find that upon the incorporation of up to approximately 25 mol % of any of the side chain analogues, the DPPC main transition endotherm consists of superimposed sharp and broad components representing the hydrocarbon chain melting of sterol-poor and sterol-rich phospholipid domains, respectively. Moreover, the behavior of these components is dependent on sterol side chain length. Specifically, for all sterol/DPPC mixtures, the sharp component enthalpy decreases linearly to zero by 25 mol % sterol while the cooperativity is only moderately reduced from that observed in the pure phospholipid. In addition, the sharp component transition temperature decreases for all sterol/DPPC mixtures; however, the magnitude of the decrease is dependent on the sterol side chain length. With respect to the broad component, the enthalpy initially increases to a maximum around 25 mol % sterol, thereafter decreasing toward zero by 50 mol % sterol with the exception of the sterols with very short alkyl side chains. Both the transition temperature and cooperativity of the broad component clearly exhibit alkyl chain length-dependent effects, with both the transition temperature and cooperativity decreasing more dramatically for sterols with progressively shorter side chains. We ascribe the chain length-dependent effects on transition temperature and cooperativity to the hydrophobic mismatch between the sterol and the host DPPC bilayer (see McMullen, T. P. W., Lewis, R. N. A. H., and McElhaney, R. N. (1993) Biochemistry 32:516-522). Moreover, the effective stoichiometry of sterol/DPPC interactions is altered by a significantly large degree of hydrophobic mismatch between the sterol and the DPPC bilayer. Thus the short chain sterols appear to exhibit considerable immiscibility in gel state DPPC bilayers, effectively limiting their interaction with adjacent phospholipid molecules.

Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in blood plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through at least six G-protein coupled receptors to promote cell survival, proliferation and migration. The autotaxin/lysophosphatidate signaling axis is involved in wound healing and tissue remodeling, and it drives many chronic inflammatory conditions from fibrosis to colitis, asthma and cancer. In cancer, lysophosphatidate signaling promotes resistance to chemotherapy and radiotherapy, and increases both angiogenesis and metastasis. Research into autotaxin inhibitors is accelerating, both as primary and adjuvant therapy. Historically, autotaxin inhibitors had poor bioavailability profiles and thus had limited efficacy in vivo. This situation is now changing, especially since the recent crystal structure of autotaxin is now enabling rational inhibitor design. In this review, we will summarize current knowledge on autotaxin-mediated disease processes including cancer, and discuss recent advancements in the development of autotaxin-targeting strategies. We will also provide new insights into autotaxin as an inflammatory mediator in the tumor microenvironment that promotes cancer progression and therapy resistance.

We have investigated the comparative effects of the incorporation of increasing quantities of androstenol and cholesterol on the thermotropic phase behavior of aqueous dispersions of members of a homologous series of linear saturated diacyl PCs1 using high sensitivity DSC. We have also employed FTIR and 31P-NMR spectroscopy to study the comparative effects of androstenol and cholesterol incorporation on the organization of the host PC bilayer in both the gel and liquid-crystalline states. The effects of androstenol and cholesterol incorporation on the thermotropic phase behavior of shorter chain PCs like 14:0 PC are generally similar but not identical. The incorporation of either sterol progressively decreases the temperature and enthalpy, but not the cooperativity, of the pretransition and completely abolishes it at sterol concentrations above 5 mol%. Moreover, at sterol concentrations of 1 to 20-25 mol%, both androstenol and cholesterol incorporation produce DSC endotherms consisting of superimposed sharp and broad components, the former due to the hydrocarbon chain melting of sterol-poor and the latter to the melting of sterol-rich 14:0 PC domains. The temperature and cooperativity of the sharp component are reduced slightly with increasing concentration of androstenol or cholesterol, and the enthalpy of the sharp component decreases progressively and becomes zero at 20-25 mol% sterol. As well, at cholesterol or androstenol concentrations above 20-25 mol%, the enthalpy of the broad component also decreases linearly with increasing sterol incorporation and becomes zero at sterol levels of about 50 mol%. However, whereas cholesterol incorporation progressively increases the temperature of the broad component of the DSC endotherm, androstenol incorporation decreases the temperature of this component. In contrast, the effects of androstenol and cholesterol incorporation on the thermotropic phase behavior of the intermediate and longer chain PCs studied here are considerably different. Although the incorporation of cholesterol increases the main phase transition temperature of 16:0 PC slightly and decreases the phase transition of 18:0 PC and 21:0 PC, androstenol incorporation decreases the main phase transition temperatures of all three PCs rather markedly. Moreover, androstenol is less effective in reducing the enthalpy and cooperativity of the broad component of the DSC endotherm of 16:0 PC and especially 18:0 PC bilayers in comparison to cholesterol. Androstenol incorporation (> 5 mol%) also results in the appearance of a second, low temperature endotherm in the DSC traces of the intermediate and longer chain PC dispersions that is not observed in similar cholesterol/PC dispersions. FTIR and 31P-NMR results suggest that this endotherm arises from a temperature-induced dissolution of androstenol in the gel phase PC bilayers. This second endotherm occurs at lower androstenol concentrations and increases in area at a given androstenol level as the chain length of the host PC bilayer increases. We ascribe the increasing immiscibility of androstenol in both the gel and liquid-crystalline states of PC bilayers of increasing thickness to an increasing degree of hydrophobic mismatch between the androstenol molecule and the host phospholipid bilayer.

Introduction Aberrant expression of the embryonic stem cell marker Sox2 has been reported in breast cancer (BC). We previously identified two phenotypically distinct BC cell subsets separated based on their differential response to a Sox2 transcription activity reporter, namely the reporter-unresponsive (RU) and the more tumorigenic reporter-responsive (RR) cells. We hypothesized that Sox2, as a transcription factor, contributes to their phenotypic differences by mediating differential gene expression in these two cell subsets. Methods We used chromatin immunoprecipitation and a human genome-wide promoter microarray (ChIP-chip) to determine the promoter occupancies of Sox2 in the MCF7 RU and RR breast cancer cell populations. We validated our findings with conventional chromatin immunoprecipitation, quantitative reverse transcription polymerase chain reaction (qPCR), and western blotting using cell lines, and also performed qPCR using patient RU and RR samples. Results We found a largely mutually exclusive profile of gene promoters bound by Sox2 between RU and RR cells derived from MCF7 (1830 and 456 genes, respectively, with only 62 overlapping genes). Sox2 was bound to stem cell- and cancer-associated genes in RR cells. Using quantitative RT-PCR, we confirmed that 15 such genes, including PROM1 (CD133), BMI1, GPR49 (LGR5), and MUC15, were expressed significantly higher in RR cells. Using siRNA knockdown or enforced expression of Sox2, we found that Sox2 directly contributes to the higher expression of these genes in RR cells. Mucin-15, a novel Sox2 downstream target in BC, contributes to the mammosphere formation of BC cells. Parallel findings were observed in the RU and RR cells derived from patient samples. Conclusions In conclusion, our data supports the model that the Sox2 induces differential gene expression in the two distinct cell subsets in BC, and contributes to their phenotypic differences. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0470-2) contains supplementary material, which is available to authorized users.