The Role of PME-1 in Cancer: Therapeutic Implication

Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis in human cells by reversibly affecting the phosphorylation of a variety of proteins. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by reversible demethylation and active site binding. Thus far, it is known that overexpression of PME-1 in human gliomas contributes to ERK pathway signaling, cell proliferation, and malignant progression. Whether PME-1-mediated PP2A inhibition promotes therapy resistance in gliomas is unknown. Specific PP2A targets regulated by PME-1 in cancers also remain elusive. Additionally, whether oncogenic function of PME-1 can be generalized to various human cancers needs to be investigated. This study demonstrated that PME-1 expression promotes kinase inhibitor resistance in glioblastoma (GBM). PME-1 silencing sensitized GBM cells to a group of clinically used indolocarbazole multikinase inhibitors (MKIs). To facilitate the quantitative evaluation of MKIs by cancer-cell specific colony formation assay, Image-J software-plugin ‘ColonyArea’ was developed. PME-1-silencing was found to reactivate specific PP2A complexes and affect PP2A-target histone deacetylase HDAC4 activity. The HDAC4 inhibition induced synthetic lethality with MKIs similar to PME-1 depletion. However, synthetic lethality by both approaches required co-expression of a pro-apoptotic protein BAD. In gliomas, PME-1 and HDAC4 expression was associated with malignant progression. Using tumor PME-1, HDAC4 and BAD expression based stratification signatures this study defined patient subgroups that are likely to respond to MKI alone or in combination with HDAC4 inhibitor therapies. In contrast to the oncogenic role of PME-1 in certain cancer types, this study established that colorectal cancer (CRC) patients with high tumor PME-1 expression display favorable prognosis. Interestingly, PME-1 regulated survival signaling did not operate in CRC cells. Summarily, this study potentiates the candidacy of PME-1 as a therapy target in gliomas, but argues against generalization of these findings to other cancers, especially CRC.PME-1:n vaikutukset syövässä ja niiden terapeuttinen potentiaali Proteiinifosfataasi 2A (PP2A)-entsyymillä on tärkeä rooli solun sisäisen signaloinnin säätelyssä sillä se defosforyloi lukuisia signalointi-proteiineja. Proteiinifosfataasi metyyliesteraasi-1 (PME-1)-entsyymi taas säätelee negatiivisesti PP2A:n aktiivisuutta demetyloimalla sitä. Ihmisen glioomassa PME-1:n korkea ilmentyminen lisää syöpää edistävän ERK-signalointireitin aktiivisuutta syöpäsoluissa, syöpäsolujen jakautumista ja edelleen syövän pahanlaatuisuutta. Toistaiseksi on vielä selvittämättä, edistääkö PME-1:n välittämä PP2A:n esto terapiaresistenssiä glioomassa. Lisäksi PME-1:n säätelemät spesifiset PP2A:n kohde-proteiinit syövässä ovat vielä tuntemattomia. Lisätutkimuksia myös kaivataan PME-1:n roolista eri syöpätyypeissä. Tämä tutkimus osoitti, että PME-1:n ilmentyminen lisää resistenssiä kinaasi-inhibiittoreille glioblastoomassa (GBM). PME-1-geenin hiljentäminen altisti GBM-solut indolokarbatsoli ryhmän multikinaasi-inhibiittoreille (MKI) jotka ovat kliinisessä kehityksessä muihin syöpätyyppeihin. Parantaaksemme MKI-yhdisteiden vaikutusten arviointia pesäkemuodostukseen syöpäsoluviljelmissä, kehitimme “ColonyArea” lisäosan Image-J-ohjelmaan. Osoitimme, että PME-1:n hiljentäminen lisää spesifisten PP2A-kompleksien aktiivisuutta ja säätelee PP2A:n kohdeproteiinia, histonideasetylaasia (HDAC4). Kuten PME-1:n hiljentäminen, myös HDAC4:n esto yhdessä MKI-yhdisteiden kanssa indusoi synteettistä letaalisuutta glioomasoluissa. Kumpikin mekanismi vaatii apoptoosia edistävän BAD-proteiinin ilmentymisen. PME-1:n ja HDAC4:n ilmentyminen korreloi gliooman etenemiseen. Kasvaimien PME-1, HDAC4 ja BAD ilmentymistasojen perusteella voitaisiinkin mahdollisesti erotella glioomapotilaat, jotka reagoivat MKI-terapiaan joko HDAC4-inhibiittoriterapian kanssa tai ilman. Päinvastoin kuin tietyissä muissa syöpätyypeissä, korkea PME-1:n ilmentyminen paransi potilaiden ennustetta paksusuolen syövässä. PME-1 ei lisännyt selviytymistä edistävien signalointireittien aktiivisuutta paksusuolen syöpäsoluissa. Yhteenvetona tämä tutkimus osoittaa PME-1:n olevan potentiaalinen lääkehoidon kohde gliooman hoidossa, mutta tämä löydös ei ole välttämättä yleistettävissä muiden syöpien, tai ei ainakaan paksusuolen syövän hoidossa.Siirretty Doriast

The Puzzling Bulge to Disk Nova Ratio in the Andromeda Galaxy (M31)

Novae in M31 are often associated with the bulge component of the light from this galaxy, i.e., more novae are assumed to be produced in the bulge of M31. But examining this from a population synthesis approach, one expects that evolved binaries in the disk should produce more novae. We strive to understand this bulge to disk nova ratio puzzle in M31 by exploring two scenarios. The nova rate normalized to the K-band luminosity for different galaxy Hubble types is approximately constant. We utilize this observed correlation to model the bulge and disk nova distribution. However, the decomposition of K light into bulge and disk does not yield a good match to the observed spatial distribution of novae in M31. Therefore, we conclude that the assumption that the nova rate follows total K light is too simple to explain the actual distribution of novae in this galaxy. Second, we examine the role of dust in the disk of M31 in extinction novae, possibly more so in the disk, which would increase the relative number of observed bulge novae compared to those in the disk. We construct a three dimensional multi-component dust model (uniform background, 10 kpc ring, 2 logarithmic spirals) and apply it to novae in the bulge and the disk of M31. With model parameters calibrated from infrared emission models, this results in hiding only ~ 1 % of the novae in the disk and 0.3-0.4 % in the bulge. We, therefore conclude that dust in M31 does not play a significant role in shrouding novae in the disk. In fact, the effect of the dust is not much higher for disk novae in comparison to bulge novae. Therefore, we conclude that the common assumption that \u27novae trace the K-band light\u27 is not supported by the detailed spatial models of novae in M31, and that extinction by dust is insufficient to resolve the puzzle of the relative scarcity of disk novae in M31

Cross Culturalism in Bharati Mukherjee's Jasmine

Multiculturalism is a burning issue today and the critical analysis of Bharati Mukherjee's selected novel Jasmine brings into focus the immigrant experience of the female's self of being a woman and being an immigrant woman. It also covers cross-cultural experiences such as the rootlessness, the identity issues and the assimilation of the protagonists in her novels. The present research paper analyses Bharati Mukherjee's Jasmine from a cross-cultural perspective. She is one of the renowned and established female writers of Indian diaspora in the United States. Her key objective is to explore and examine an impenetrable cross cultural awareness of those who connect with more than one culture. Her keen interest is to explore the plights and pains of South Asian immigrants in America and Canada and to bring about how immigrants face the problem of acculturation and cultural conflicts in adapted lands. Cultural alienation, displacement, survival and adjustment are the most frequent themes in her novels. Her own journey of life stretches across India, Canada and the United States. Almost her all novels reflect the themes of migration, exile, cultural alienation, assimilation and identity issues

App Review: Trello

This article focuses on using Trello, a collaborative project management tool

Investigation of azo-bond cleavage in Methyl Orange and Direct Yellow 12 using soybean peroxidase

Removal of dyes released in water by textile industries presents a major challenge for the researchers. Soybean peroxidase (SBP) has been widely explored for removal of a variety of toxic aromatics consisting of phenolic or anilino functional groups. Also, it has been known to possess the ability of azo-bond cleavage. This thesis was aimed to investigate azo-bond cleavage by SBP in the presence of hydrogen peroxide, if possible, in the absence of these functional groups. Direct Yellow 12 and azobenzene were chosen as a model compounds for this study. Experiments were conducted at a range of pHs, SBP and hydrogen peroxide to investigate the hypothesis. Enzymatic removal of p-anisidine and Methyl Orange (MO) and azo-bond cleavage of MO were also studied. Optimization of pH, hydrogen peroxide-to-substrate ratio and SBP activity were performed to achieve ≥95% removal of these substrates in 3 hours, analyzed using high-performance liquid chromatography. A time course study was conducted to calculate pseudo-first-order rate constants and half-lives for degradation of these compounds. Mass spectrometry analysis showed oligomerization of p-anisidine and for MO, evidence of azo-bond cleavage was obtained after the enzymatic treatment

Ultraluminous X-ray Sources in Andromeda Galaxy: Two Recent Discoveries and their Implications

Ultraluminous X-ray sources are believed to be associated with X-ray binaries, in which an accreting black hole generates X-ray luminosities in excess of 10 39 erg/s. The nature of the companion star and the underlying physics of the accretion process is not yet established with certainty. In particular, whether or not the accretion is super/sub Eddington is an open question, as is the mass of the companion star. We discuss the first two ULXs recently discovered in M31 and investigate the nature of their underlying sources. We present the X-ray observations for ULX-1 in detail and discuss its implications for its accretor. We also considered the positions of both ULX sources in the context of their hypothetical association with either High Mass X-ray Binaries and Low Mass X-ray Binaries. We construct a simple disk plus bulge model to test their association with starlight and use IR images from Spitzer to investigate their possible link to star formation. We find that the position of these two sources more strongly supports scenarios in which the companion is a high mass star. Using the data obtained with XMM-Newton, Swift and Chandra, we infer that the underlying source for ULX-1 is a 13 Msun black hole under the assumption that it is non-spinning. The combined study of X-ray properties and the spatial distribution presented in this thesis argue in favor of stellar mass black holes accreting at near Eddington rates from high mass companions

Comparison of Linear Method and Non Linear Method for Analysis of Heart Rate Variability using MatlabÂ

No Abstrac

Multi Round Selective Encryption using AES over Storage Cloud

Cloud computing is the re-incarnation of the client-server architecture. It is highly promising technology because of its unlimited resource provisioning and data storage services which help us in managing the data as per requirements. Due to the use of internet and vital remote servers to maintain the data and applications, the cloud computing environment becomes open for the attackers to attack on the user data and communication services. This paper mainly focuses on the user authentication and data security over the Broker Cloud Computing Paradigm by purposing new cryptographic technique named as Multi Round Selective Encryption using AES. Along with this, we compared our approach with existing cryptographic techniques as AES, Blowfish and Selective encryption to find out its pros and cons. The Multi Round Selective Encryption with AES is the best suitable technique where the file size is large because it gives fast execution by maintaining the encryption complexity as compared to selective encryption technique in public and hybrid cloud