MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer

Cataloged from PDF version of article.Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Reaction rate reconstruction from biomass concentration measurement in bioreactors using modified second-order sliding mode algorithms

This paper deals with the estimation of unknown signals in bioreactors using sliding observers. Particular attention is drawn to estimate the specific growth rate of microorganisms from measurement of biomass concentration. In a recent article, notions of high-order sliding modes have been used to derive a growth rate observer for batch processes. In this paper we generalize and refine these preliminary results. We develop a new observer with a different error structure to cope with other types of processes. Furthermore, we show that these observers are equivalent, under coordinate transformations and time scaling, to the classical super-twisting differentiator algorithm, thus inheriting all its distinctive features. The new observers’ family achieves convergence to timevarying unknown signals in finite time, and presents the best attainable estimation error order in the presence of noise. In addition, the observers are robust to modeling and parameter uncertainties since they are based on minimal assumptions on bioprocess dynamics. In addition, they have interesting applications in fault detection and monitoring. The observers performance in batch, fed-batch and continuous bioreactors is assessed by experimental data obtained from the fermentation of Saccharomyces Cerevisiae on glucose.This work was supported by the National University of La Plata (Project 2012-2015), the Agency for the Promotion of Science and Technology ANPCyT (PICT2007-00535) and the National Research Council CONICET (PIP112-200801-01052) of Argentina; the Technical University of Valencia (PAID-02-09), the CICYT (DPI2005-01180) and AECID (A/024186/09) of Spain; and by the project FEDER of the European Union.De Battista, H.; Picó Marco, JA.; Garelli, F.; Navarro Herrero, JL. (2012). Reaction rate reconstruction from biomass concentration measurement in bioreactors using modified second-order sliding mode algorithms. Bioprocess and Biosystems Engineering. 35(9):1-11. https://doi.org/10.1007/s00449-012-0752-yS111359Aborhey S, Williamson D (1978) State amd parameter estimation of microbial growth process. Automatica 14:493–498Bastin G, Dochain D (1986) On-line estimation of microbial specific growth rates. Automatica 22:705–709Bastin G, Dochain D (1990) On-line estimation and adaptive control of bioreactors. Elsevier, AmsterdamBejarano F, Fridman L (2009) Unbounded unknown inputs estimation based on high-order sliding mode differentiator. In: Proceedings of the 48th IEEE conference on decision and control, pp 8393–8398Corless M, Tu J (1998) State and input estimation for a class of uncertain systems. Automatica 34(6):757–764Dabros M, Schler M, Marison I (2010) Simple control of specific growth rate in biotechnological fed-batch processes based on enhanced online measurements of biomass. Bioprocess Biosyst Eng 33:1109–1118Davila A, Moreno J, Fridman L (2010) Variable gains super-twisting algorithm: a lyapunov based design. In: American control conference (ACC), 2010, pp 968–973Dávila J, Fridman L, Levant A (2005) Second-order sliding-mode observer for mechanical systems. IEEE Transact Automatic Control 50(11):1785–1789De Battista H, Picó J, Garelli F, Vignoni A (2011) Specific growth rate estimation in (fed-)batch bioreactors using second-order sliding observers. J Process Control 21:1049–1055Dochain D (2001) Bioprocess control. Wiley, HobokenDochain D (2003) State and parameter estimation in chemical and biochemical processes: a tutorial. J Process Control 13(8):801–818Edwards C, Spurgeon S, Patton R (2000) Sliding mode observers for fault detection and isolation. Automatica 36(2):541–553Evangelista C, Puleston P, Valenciaga F, Fridman L (2012) Lyapunov designed super-twisting sliding mode control for wind energy conversion optimization. Indus Electron IEEE Transact. doi: 10.1109/TIE.2012.2188256Farza M, Busawon K, Hammouri H (1998) Simple nonlinear observers for on-line estimation of kinetic rates in bioreactors. Automatica 34(3):301–318Fridman L, Davila J, Levant A (2008) High-order sliding modes observation. In: International workshop on variable structure systems, pp 203–208Fridman L, Levant A (2002) Sliding mode control in engineering, higher-order sliding modes. Marcel Dekker, Inc., New York, pp 53–101Fridman L, Shtessel Y, Edwards C, Yan X (2008) Higher-order sliding-mode observer for state estimation and input reconstruction in nonlinear systems. Int J Robust Nonlinear Control 18(3–4):399–412Gauthier J, Hammouri H, Othman S (1992) A simple observer for nonlinear systems: applications to bioreactors. IEEE Transact Automatic Control 37(6):875–880Gnoth S, Jenzsch M, Simutis R, Lubbert A (2008) Control of cultivation processes for recombinant protein production: a review. Bioprocess Biosyst Eng 31(1):21–39Hitzmann B, Broxtermann O, Cha Y, Sobieh O, Stärk E, Scheper T (2000) The control of glucose concentration during yeast fed-batch cultivation using a fast measurement complemented by an extended kalman filter. Bioprocess Eng 23(4):337–341Kiviharju K, Salonen K, Moilanen U, Eerikainen T (2008) Biomass measurement online: the performance of in situ measurements and software sensors. J Indus Microbiol Biotechnol 35(7):657–665Levant A (1998) Robust exact differentiation via sliding mode technique. Automatica 34(3):379–384Levant A (2003) Higher-order sliding modes, differentiation and output-feedback control. Int J Control 76(9/10):924–941Lubenova V, Rocha I, Ferreira E (2003) Estimation of multiple biomass growth rates and biomass concentration in a class of bioprocesses. Bioprocess Biosyst Eng 25:395–406Moreno J, Alvarez J, Rocha-Cozatl E, Diaz-Salgado J (2010) Super-twisting observer-based output feedback control of a class of continuous exothermic chemical reactors. In: Proceedings of the 9th IFAC international symposium on dynamics and control of process systems, pp 719–724. Leuven, BelgiumMoreno J, Osorio M (2008) A Lyapunov approach to second-order sliding mode controllers and observers. In: Proceedings of the 47th IEEE conference on decision and control. Cancún, México, pp 2856–2861Moreno J, Osorio M (2012) Strict Lyapunov functions for the super-twisting algorithm. IEEE Transact Automatic Control 57:1035–1040Navarro J, Picó J, Bruno J, Picó-Marco E, Vallés S (2001) On-line method and equipment for detecting, determining the evolution and quantifying a microbial biomass and other substances that absorb light along the spectrum during the development of biotechnological processes. 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Medicinal importance of grapefruit juice and its interaction with various drugs

Grapefruit juice is consumed widely in today's health conscious world as a protector against cardiovascular diseases and cancers. It has however, been found to be an inhibitor of the intestinal cytochrome P – 450 3A4 system, which is responsible for the first pass metabolism of many drugs. The P – glycoprotein pump, found in the brush border of the intestinal wall which transports many of these cytochrome P – 450 3A4 substrates, has also been implicated to be inhibited by grapefruit juice. By inhibiting these enzyme systems, grapefruit juice alters the pharmacokinetics of a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on the calcium channel antagonist and the statin group of drugs. In the case of many drugs, the increased serum concentration has been found to be associated with increased frequency of dose dependent adverse effects. In this review, we have discussed the phytochemistry of grapefruit juice, the various drugs involved in the drug – grapefruit juice eraction with their mechanisms of action and have presented the clinical implications of these interactions

The Portuguese version of the Psychological Adjustment to Separation Test-Part A (PAST-A): a study with recently and non-recently divorced adults

Past research has demonstrated that divorced adults show more health problems and psychological distress than married adults. Considering the high prevalence rates of divorce among Western countries, new and robust measures should be developed to measure psychological distress after this specific transition in adulthood. The aim of this study was to adapt and validate a Portuguese version of the Psychological Adjustment to Separation Test-Part A (PAST-A; Sweeper and Halford in J Family Psychol 20(4):632–640, 2006). PAST-A is a self-report measure that assesses two key dimensions of separation adjustment problems: lonely-negativity and former partner attachment. Psychometric properties of the Portuguese version of PAST-A were assessed in terms of factor structure, internal consistency, and convergent and divergent validity, in an online convenience sample with divorced adults (N = 460). The PAST-A two-factor structure was confirmed by exploratory and confirmatory factor analyses, with each factor demonstrating very satisfactory internal consistency and good convergence. In terms of discriminant validity, the Portuguese PAST-A reveals a distinct factor from psychological growth after divorce. The results provided support for the use of the Portuguese PAST-A with divorced adults and also suggested that the explicative factors of the psychological adjustment to divorce may be cross-cultural stable. The non-existence of validated divorce-related well-being measures and its implications for divorce research are also discussed

Mortality differences by partnership status in England and Wales : the effect of living arrangements or health selection?

Sebastian Franke’s research was supported by the Economic and Social Research Council [ES/J500094/1] through the North West Doctoral Training Centre Social Statistics pathway (Ph.D. project: “Health, Mortality and Partnership Status: Protection or Selection”). The permission of the Office for National Statistics to use the Longitudinal Study is gratefully acknowledged, as is the help provided by staff of the Centre for Longitudinal Study Information and User Support (CeLSIUS). CeLSIUS is supported by the ESRC Census of Population Programme (Award Ref: ES/K000365/1).This paper investigates the relationship between partnership status and mortality in England and Wales. Using data from the Office for National Statistics Longitudinal Study (ONS LS) for the period between 2001 and 2011, we examine whether married people have lower mortality levels than unmarried individuals; whether individuals who cohabit have mortality levels similar to those of married or single persons; and how much the fact that married couples live with someone rather than alone explains their low mortality. Our analysis shows first that married individuals have lower mortality than unmarried persons. Second, men and women in pre-marital unions exhibit mortality levels similar to those of married men and women, whereas mortality levels are elevated for post-marital cohabitants. Third, controlling for household size and the presence of children reduces mortality differences between married and unmarried non-partnered individuals, but significant differences persist. The study supports both protection and selection theory. The increase in mortality differences by age group between never-married cohabitants and married couples is likely a sign of the long-term accumulation of health and wealth benefits of marriage. Similar mortality levels of cohabiting and married couples at younger ages suggest that healthier individuals are more likely to find a partner.PostprintPeer reviewe