The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression

ST6GAL1: A key player in cancer

Aberrant glycosylation is a universal feature of cancer cells and there is now overwhelming evidence that glycans can modulate pathways intrinsic to tumour cell biology. Glycans are important in all of the cancer hallmarks and there is a renewed interest in the glycomic profiling of tumours to improve early diagnosis, determine patient prognosis and identify targets for therapeutic intervention. One of the most widely occurring cancer associated changes in glycosylation is abnormal sialylation which is often accompanied by changes in sialyltransferase activity. Several sialyltransferases are implicated in cancer, but in recent years ST6 β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) has become increasingly dominant in the literature. ST6GAL1 catalyses the addition of α2,6-linked sialic acids to terminal N-glycans and can modify glycoproteins and/or glycolipids. ST6GAL1 is upregulated in numerous types of cancer (including pancreatic, prostate, breast and ovarian cancer) and can promote growth, survival and metastasis. The present review discusses ST6GAL in relation to the hallmarks of cancer, and highlights its key role in multiple mechanisms intrinsic to tumour cell biology

Design and fabrication of a meso-scale stirling engine and combustor.

Power sources capable of supplying tens of watts are needed for a wide variety of applications including portable electronics, sensors, micro aerial vehicles, and mini-robotics systems. The utility of these devices is often limited by the energy and power density capabilities of batteries. A small combustion engine using liquid hydrocarbon fuel could potentially increase both power and energy density by an order of magnitude or more. This report describes initial development work on a meso-scale external combustion engine based on the Stirling cycle. Although other engine designs perform better at macro-scales, we believe the Stirling engine cycle is better suited to small-scale applications. The ideal Stirling cycle requires efficient heat transfer. Consequently, unlike other thermodynamic cycles, the high heat transfer rates that are inherent with miniature devices are an advantage for the Stirling cycle. Furthermore, since the Stirling engine uses external combustion, the combustor and engine can be scaled and optimized semi-independently. Continuous combustion minimizes issues with flame initiation and propagation. It also allows consideration of a variety of techniques to promote combustion that would be difficult in a miniature internal combustion engine. The project included design and fabrication of both the engine and the combustor. Two engine designs were developed. The first used a cylindrical piston design fabricated with conventional machining processes. The second design, based on the Wankel rotor geometry, was fabricated by through-mold electroforming of nickel in SU8 and LIGA micromolds. These technologies provided the requisite precision and tight tolerances needed for efficient micro-engine operation. Electroformed nickel is ideal for micro-engine applications because of its high strength and ductility. A rotary geometry was chosen because its planar geometry was more compatible with the fabrication process. SU8 lithography provided rapid prototypes to verify the design. A final high precision engine was created via LIGA. The micro-combustor was based on an excess enthalpy concept. Development of a micro-combustor included both modeling and experiments. We developed a suite of simulation tools both in support of the design of the prototype combustors, and to investigate more fundamental aspects of combustion at small scales. Issues of heat management and integration with the micro-scale Stirling engine were pursued using CFD simulations. We found that by choice of the operating conditions and channel dimensions energy conversion occurs by catalysis-dominated or catalysis-then-homogeneous phase combustion. The purpose of the experimental effort in micro-combustion was to study the feasibility and explore the design parameters of excess enthalpy combustors. The efforts were guided by the necessity for a practical device that could be implemented in a miniature power generator, or as a stand-alone device used for heat generation. Several devices were fabricated and successfully tested using methane as the fuel

Helsingin hotellien kannattavuuden kehittäminen benchmarkkauksen avulla

Opintojemme aikana tutustuimme kolmeen toimintamalliin, joiden näimme olevan sidoksissa katetuottolaskennan kolmeen osa-alueeseen: myynnin lisäämiseen, katteen parantamiseen ja kiinteiden kustannusten alentamiseen. Yksi toimintamalleista oli lentoyhtiöiden käytössä, toi-nen osa kansainvälistä kehitysprojektia ja kolmas oli käytössä hotelleissa Suomen ulkopuolel-la. Huomasimme, ettei mitään näistä toimintamalleista oltu vielä hyödynnetty Helsingin alueen hotelleissa, minkä vuoksi päätimme lähteä tutkimaan opinnäytetyössämme niiden soveltu-vuutta kyseisen alueen toimipaikoissa. Tämän opinnäytetyön tavoitteena on benchmarkkauksen avulla tuoda esille toimintatapoja, joilla uskomme olevan vaikutusta kannattavuuden paranemiseen Helsingin hotelleissa. Tavoitteena on selvittää, kuinka toimivina Helsingin alueen hotellien ylin johto ne näkee. Työn tietoperustassa perehdytään toimintaympäristön nykytilaan ja käsitellään kannattavuuteen liittyvät keskeisimmät asiat. Kannattavuuden parantamisen osalta työ on rajattu koskemaan myynnin lisäämistä, myyntihinnan korotusta ja kiinteiden kustannusten pienentämistä. Osana tietoperustaa esitellään benchmarkkauksen kohteena olevat toimintamallit, jotka ovat The Plusgrade –sovellusalusta, Geneva Transport Card ja automatisoitu sisäänkirjautuminen. Opinnäytetyön tutkimusongelma on, voidaanko Helsingin hotellien kannattavuutta parantaa tässä opinnäytetyössä esitettyjen benchmarkattujen toimintamallien avulla. Tutkimusongelma on täsmennetty vielä alaongelmiksi. Niiden avulla pyritään löytämään vastaus siihen, kuinka toimiviksi nämä toimintatavat tutkimukseen osallistuneissa hotelleissa nähdään. Lisäksi selvitetään, miksi toimintatavat eivät toimisi tutkimukseen osallistuneissa hotelleissa ja mitä haasteita toimintatapoihin liittyy. Tutkimusstrategiaksi tässä työssä valikoitui kvalitatiivinen tutkimus ja sen tutkimusmetodiksi teemahaastattelu. Tutkimusta varten haastateltiin viittä Helsingin alueella toimivaa hotellinjohtajaa. Haastattelut tehtiin helmi-maaliskuussa vuonna 2016. Tutkimustuloksista ilmeni, että The Plusgrade -sovellusalustaa voitaisiin hyödyntää lähes ainoastaan kausiluontoisesti eikä sen kannattavuudesta oltu varmoja. Geneva Transport Card sai varovaisimman vastaanoton, koska sille ei nähty varsinaista tarvetta, rahoitus olisi haastavaa ja käyttöönotto edellyttäisi laajaa yhteistyötä eri toimijoiden välillä. Automatisoitu sisäänkirjautuminen sen sijaan kiinnosti haastateltavia eniten kaikesta kolmesta toimintamallista, sillä kyseessä on lähitulevaisuudessa tapahtuva muutos

Екатеринбургская неделя. 1890. № 13

Background: Androgen steroid hormones are key drivers of prostate cancer. Previous work has shown that androgens can drive the expression of alternative mRNA isoforms as well as transcriptional changes in prostate cancer cells. Yet to what extent androgens control alternative mRNA isoforms and how these are expressed and differentially regulated in prostate tumours is unknown. Methods: Here we have used RNA-Seq data to globally identify alternative mRNA isoform expression under androgen control in prostate cancer cells, and profiled the expression of these mRNA isoforms in clinical tissue. Results: Our data indicate androgens primarily switch mRNA isoforms through alternative promoter selection. We detected 73 androgen regulated alternative transcription events, including utilisation of 56 androgen-dependent alternative promoters, 13 androgen-regulated alternative splicing events, and selection of 4 androgen-regulated alternative 3′ mRNA ends. 64 of these events are novel to this study, and 26 involve previously unannotated isoforms. We validated androgen dependent regulation of 17 alternative isoforms by quantitative PCR in an independent sample set. Some of the identified mRNA isoforms are in genes already implicated in prostate cancer (including LIG4, FDFT1 and RELAXIN), or in genes important in other cancers (e.g. NUP93 and MAT2A). Importantly, analysis of transcriptome data from 497 tumour samples in the TGCA prostate adenocarcinoma (PRAD) cohort identified 13 mRNA isoforms (including TPD52, TACC2 and NDUFV3) that are differentially regulated in localised prostate cancer relative to normal tissue, and 3 (OSBPL1A, CLK3 and TSC22D3) which change significantly with Gleason grade and  tumour stage. Conclusions: Our findings dramatically increase the number of known androgen regulated isoforms in prostate cancer, and indicate a highly complex response to androgens in prostate cancer cells that could be clinically important

RNA splicing and splicing regulator changes in prostate cancer pathology

This work was supported by Prostate Cancer UK (PG12-34 and S13-020), the J.G.W. Patterson Foundation and the Special Trustees of the RVI