Discovering New Markets for an Industrial Product – International Market Selection Approach

Tämän tutkielman tavoitteena oli määrittää uuden markkinan valinnan perusteita teolliselle tuotteelle. Tutkielma keskittyi jo tunnettuihin kansainvälisen markkinavalinnan lähestymistapoihin ja pyrki soveltamaan yhtä menetelmää käytäntöön tutkielman empiria osassa case-tutkimuksen avulla. Tutkimusote oli tutkiva, eksploratiivinen ja perustui sekundääri analyysiin. Käytetyt tiedon lähteet olivat suureksi osin sekundäärisiä tuottaen kvalitatiivista tietoa. Kuitenkin haastatteluita suoritettiin myös. Kattava kirjallisuus katsaus tunnetuista teoreettisista lähestymistavoista kansainväliseen markkinavalintaan oli osa tutkielmaa. Kolme tärkeintä lähestymistapaa esiteltiin tarkemmin. Yksi lähestymistavoista, ei-järjestelmällinen, muodosti viitekehyksen tutkielman empiria-osalle. Empiria pyrki soveltamaan yhtä ei-järjestelmällisen lähestymistavan malleista kansainvälisessä paperiteollisuudessa. Tarkoituksena oli tunnistaa kaikkein houkuttelevimmat maat mahdollisille markkinointitoimenpiteille tuotteen yhdellä loppukäyttöalueella. Tutkielmassa päädyttiin käyttämään ilmastollisia olosuhteita, siipikarjan päälukua sekä siipikarjan kasvuprosenttia suodattimina pyrittäessä vähentämään mahdollisten maiden lukumäärää. Tutkielman empiria-osa kärsi selkeästi relevantin tiedon puutteesta. Siten myös tutkielman reliabiliteetti ja validiteetti voidaan jossain määrin kyseenalaistaa.

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

Background: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Methods: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. Conclusions: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.)

Photocontrolled DNA Binding of a Receptor-Targeted Organometallic Ruthenium(II) Complex

A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as"tumor-targeting devices" since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium-peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV-vis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(η6-p-cym)Ru(bpm)(H2O)]2+, reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, 5′dCATGGCT and 5′dAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptide-oligonucleotide hybrid, Phac-His-Gly-Met-linker-p5′dCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids.

Procurement and inventory management in product ramp down

Tuotteiden elinkaaret elektroniikkateollisuudessa ovat lyhentyneet entisestään. Paineet uusien kehittyneempien tuotteiden lanseeraamiselle ovat kasvaneet. Huonosti hoidettu tuotevaihto voi aiheuttaa merkittäviä kustannuksia yritykselle mikäli alasajon kustannusvaikutusta tulokseen aliarvioidaan. Työ käsittelee markkinoilta poistuvan tuotteen materiaalivirtojen hallintaa tuotevaihdon aikana. Lähtökohtana työssä oli kehittää toimintatapa miten tuotteen alasajon aikana tulisi toimia sekä mallintaa hankintaketju riskien ja pullonkaulojen löytämiseksi. Päätavoitteena oli materiaalivaraston arvon minimoiminen sekä ylijäämämateriaalien hyödyntäminen. Työn merkittävimpiä tuloksia oli hankintaketjun materiaalivirtojen seurantaan kehitetty Excel työkalu sekä alasajon liittyvien työvaiheiden kuvaaminen.

Product information management system design framework for production oriented company

Diplomityössä luodaan viitekehys tuotetiedonhallintajärjestelmän esisuunnittelua varten. Siinä on kolme ulottuvuutta: lisäarvontuotto-, toiminnallisuus- ja ohjelmistoulottuvuus. Viitekehys auttaa- tunnistamaan lisäarvontuottokomponentit, joihin voidaan vaikuttaa tiettyjen ohjelmistoluokkien tarjoamilla tuotetiedonhallintatoiminnallisuuksilla. Viitekehyksen järjestelmäsuunnittelullista näkökulmaa hyödynnetään tutkittavissa yritystapauksissa perustuen laskentamatriisin muotoon mallinnettuihin ulottuvuuksien välisiin suhteisiin. Matriisiin syötetään lisäarvontuotto- ja toiminnallisuuskomponenttien saamat tärkeydet kohdeyrityksessä suoritetussa haastattelututkimuksessa. Matriisin tuotos on tietyn ohjelmiston soveltuvuus kyseisen yrityksen tapauksessa. Soveltuvuus on joukko tunnuslukuja, jotka analysoidaan tulostenkäsittelyvaiheessa. Soveltuvuustulokset avustavat kohdeyritystä sen valitessa lähestymistapaansa tuotetiedonhallintaan - ja kuvaavat esisuunnitellun tuotetiedonhallintajärjestelmän. Viitekehyksen rakentaminen vaatii perinpohjaisen lähestymistavan merkityksellisten lisäarvontuotto- ja toiminnallisuuskomponenttien sekä ohjelmistoluokkien määrittämiseen. Määritystyö perustuu työssä yksityiskohtaisesti laadittujen menetelmien ja komponenttiryhmitysten hyödyntämiselle. Kunkin alueen analysointi mahdollistaa viitekehyksen ja laskentamatriisin rakentamisen yhdenmukaisten määritysten perusteella. Viitekehykselle on ominaista sen muunneltavuus. Nykymuodossaan se soveltuu elektroniikka- ja high-tech yrityksille. Viitekehystä voidaan hyödyntää myös muilla toimialoilla muokkaamalla lisäarvontuottokomponentteja kunkin toimialan intressien mukaisesti. Vastaavasti analysoitava ohjelmisto voidaan valita tapauskohtaisesti. Laskentamatriisi on kuitenkin ensin päivitettävä valitun ohjelmiston kyvykkyyksillä, minkä jälkeen viitekehys voi tuottaa soveltuvuustuloksia kyseiseen yritystapaukseen perustuen

Gaining momentum: New options and opportunities for the treatment of advanced melanoma.

Before 2011, patients with advanced or metastatic melanoma had a particularly poor long-term prognosis. Since traditional treatments failed to confer a survival benefit, patients were preferentially entered into clinical trials of investigational agents. A greater understanding of the epidemiology and biology of disease has underpinned the development of newer therapies, including six agents that have been approved in the EU, US and/or Japan: a cytotoxic T-lymphocyte antigen-4 inhibitor (ipilimumab), two programmed cell death-1 receptor inhibitors (nivolumab and pembrolizumab), two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib). The availability of these treatments has greatly improved the outlook for patients with advanced melanoma; however, a major consideration for physicians is now to determine how best to integrate these agents into clinical practice. Therapeutic decisions are complicated by the need to consider patient and disease characteristics, and individual treatment goals, alongside the different efficacy and safety profiles of agents with varying mechanisms of action. Long-term survival, an outcome largely out of reach with traditional systemic therapies, is now a realistic goal, creating the additional need to re-establish how clinical benefit is evaluated. In this review we summarise the current treatment landscape in advanced melanoma and discuss the promise of agents still in development. We also speculate on the future of melanoma treatment and discuss how combination and sequencing approaches may be used to optimise patient care in the future.

Mini invasive skeletal muscle biopsy technique with a tri-axial end cut needle.

OBJECTIVE: Skeletal Muscle Biopsy is a minor surgical procedure for the diagnosis of different neuromuscular pathological conditions and has recently gained popularity also in the research field of age-related muscular modifications and sarcopenia. Few studies focused on the application of mini-invasive muscular biopsy in both normal and pathological conditions. The aim of our study was to describe a mini invasive ultrasound-guided skeletal muscular biopsy technique in complete spinal cord injured (SCI) patients and healthy controls with a tri-axial end-cut needle. PATIENTS AND METHODS: Skeletal muscle biopsies were collected from 6 chronic SCI patients and 3 healthy controls vastus lateralis muscle with a tri-axial end cut needle (Biopince© - Angiotech). Muscle samples were stained for ATPase to determine fibers composition, moreover, gene expression of cyclooxygenase-1 (COX-1) and prostaglandin E2 receptor has been analyzed by Real Time RT-PCR. RESULTS: All the procedures were perfomed easily without failures and complications. Control tissue was macroscopically thicker than SCI one. Control specimen displayed an equal distribution of type I and type II fibers, while SCI sample displayed a prevalence of type II fibers SCI specimen displayed a significant reduction in COX-1 gene expression. This mini-invasive approach was easy, accurate and with low complication rate in performing skeletal muscle biopsy in both SCI patients and controls. CONCLUSIONS: This technique could be useful in conditions in which the overall quantity of specimen required is small like for molecular biology analysis. For histological diagnostic purposes and/or conditions in which the original tissue is already pathologically modified, this technique should be integrated with more invasive techniques.

Paediatric end-of-life care needs in Switzerland: current practices, and perspectives from parents and professionals. A study protocol.

AIM: To present a protocol for a multi-phase study about the current practice of end-of-life care in paediatric settings in Switzerland. BACKGROUND: In Switzerland, paediatric palliative care is usually provided by teams, who may not necessarily have specific training. There is a lack of systematic data about specific aspects of care at the end of a child's life, such as symptom management, involvement of parents in decision-making and family-centred care and experiences and needs of parents, and perspectives of healthcare professionals. DESIGN: This retrospective nationwide multicentre study, Paediatric End-of-LIfe CAre Needs in Switzerland (PELICAN), combines quantitative and qualitative methods of enquiry. METHODS: The PELICAN study consists of three observational parts, PELICAN I describes practices of end-of-life care (defined as the last 4 weeks of life) in the hospital and home care setting of children (0-18 years) who died in the years 2011-2012 due to a cardiac, neurological or oncological disease, or who died in the neonatal period. PELICAN II assesses the experiences and needs of parents during the end-of-life phase of their child. PELICAN III focuses on healthcare professionals and explores their perspectives concerning the provision of end-of-life care. CONCLUSION: This first study across Switzerland will provide comprehensive insight into the current end-of-life care in children with distinct diagnoses and the perspectives of affected parents and health professionals. The results may facilitate the development and implementation of programmes for end-of-life care in children across Switzerland, building on real experiences and needs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01983852.

Erforschung und Antworten auf den vorzeitigen Todeswunsch eines Patienten mit einer schweren fortgeschrittenen Krankheit [Exploring and Responding to a Wish to Hasten Death of a patient with Advanced Illness].

It is not uncommon for patients with an advanced disease to express a desire to their physician to hasten their death. Recent studies show that the motivation of such a desire is multifactorial and multidimensional, including depression, physical, psycho-social and spiritual suffering, fears about the process of dying and/or misunderstandings about the options for end-of-life care. The objective of this paper is to propose to the physician how to explore the dimensions of this request and some elements to answer it.

Development and initial validation of the Parental PELICAN Questionnaire (PaPEQu) - an instrument to assess parental experiences and needs during their child's end-of-life care.

AIM: To develop and test the Parental PELICAN Questionnaire, an instrument to retrospectively assess parental experiences and needs during their child's end-of-life care. BACKGROUND: To offer appropriate care for dying children, healthcare professionals need to understand the illness experience from the family perspective. A questionnaire specific to the end-of-life experiences and needs of parents losing a child is needed to evaluate the perceived quality of paediatric end-of-life care. DESIGN: This is an instrument development study applying mixed methods based on recommendations for questionnaire design and validation. METHOD: The Parental PELICAN Questionnaire was developed in four phases between August 2012-March 2014: phase 1: item generation; phase 2: validity testing; phase 3: translation; phase 4: pilot testing. Psychometric properties were assessed after applying the Parental PELICAN Questionnaire in a sample of 224 bereaved parents in April 2014. Validity testing covered the evidence based on tests of content, internal structure and relations to other variables. RESULTS: The Parental PELICAN Questionnaire consists of approximately 90 items in four slightly different versions accounting for particularities of the four diagnostic groups. The questionnaire's items were structured according to six quality domains described in the literature. Evidence of initial validity and reliability could be demonstrated with the involvement of healthcare professionals and bereaved parents. CONCLUSION: The Parental PELICAN Questionnaire holds promise as a measure to assess parental experiences and needs and is applicable to a broad range of paediatric specialties and settings. Future validation is needed to evaluate its suitability in different cultures.

Role of Aeromonas hydrophila flagella glycosylation in adhesion to Hep-2 cells, biofilm formation and immune stimulation.

Polar flagellin proteins from Aeromonas hydrophila strain AH-3 (serotype O34) were found to be O-glycosylated with a heterogeneous heptasaccharide glycan. Two mutants with altered (light and strong) polar flagella glycosylation still able to produce flagella were previously obtained, as well as mutants lacking the O34-antigen lipopolysaccharide (LPS) but with unaltered polar flagella glycosylation. We compared these mutants, altogether with the wild type strain, in different studies to conclude that polar flagella glycosylation is extremely important for A. hydrophila adhesion to Hep-2 cells and biofilm formation. Furthermore, the polar flagella glycosylation is an important factor for the immune stimulation of IL-8 production via toll receptor 5 (TLR5).

Offering planning process development: Bridging the Offering Gaps and Consolidating Top Priority Needs in Product Offering

The aim of this Thesis is to study how to manage the front-end of the offering planning process. This includes actual process development and methods to gather and analyze information to achieve the best outcome in customer oriented product offering. Study is carried out in two parts: theoretical part and company related part. Theoretical framework is created introducing different types of approaches to manage product planning processes. Products are seen as platforms and they are broken down to subsystems to show different parts of the development. With the help of the matrix-based approaches product platform related information is gathered and analyzed. In this kind of analysis business/market drivers and cus-tomer/competitor information are connected with product subsystems. This gives possibilities to study product gaps/needs and possible future ideas/scenarios in different customer segments. Company related part consists of offering planning process development in real company environment. Process formation includes documents and tools that guide planning from the information gathering to the prioritization and decision making.

Targeted ablation of gonadotropin dependent endocrine tumors in transgenic mice through their luteinizing hormone receptor (LHR)

Gonadal somatic cell and adrenocortical endocrine tumors are rare. The incidence of adrenocortical carcinomas is only 1-2/1000000 a year. However, they are aggressive, especially in adulthood and currently surgery is the only curative treatment. Cytotoxic agents are in use in advanced cancers, but side effects and multidrug resistance are often problems. Thus there is a need for novel curative treatment methods. In contrast, ovarian granulosa cell tumors and testicular Leydig cell tumors are usually benign, especially at a younger age. The aim of the present thesis was to study a novel targeted treatment method through luteinizing hormone/chorionic gonadotropin receptor (LHCGR) in a transgenic mouse tumor model. The cytotoxic agent was lytic peptide Hecate-CGbeta conjugate where 23 amino acid Hecate, a synthetic form of honeybee venom melittin, was conjugated to 15 amino acid fragment of human chorionic gonadotropin β subunit. Lytic peptides are known to act only on negatively charged cells, such as bacteria and cancer cells and hereby, due to hCGbeta fragment, the conjugate is able to bind directly to LHCGR bearing cancer cells, saving the healthy ones. The experiments were carried out in inhibin-alpha-Simian Virus 40-T-antigen transgenic mice that are known to express LHCGR-bearing gonadal tumors, namely Leydig and granulosa cell tumors by 100% penetrance. If the mice are gonadectomized prepubertally they form adrenocortical tumors instead. Transgenic and wild type mice were treated for three consecutive weeks with control vehicle, Hecate or Hecate-CGbeta conjugate. GnRH antagonist or estradiol was given to a group of mice with or without Hecate-CGbeta conjugate to analyze the additive role of gonadotropin blockage in adrenocortical tumor treatment efficacy. Hecate-CGbeta conjugate was able to diminish the gonadal and adrenal tumor size effectively in males. No treatment related side effects were found. Gonadotropin blockage through GnRH antagonist was the best treatment in female adrenal tumors. The mode of cell death by Hecate-CGbeta conjugate was proven to be through necrosis. LHCGR and GATA-4 were co-expressed in tumors, where the treatment down-regulated their expression simultaneously, suggesting their possible use as tumor markers. In conclusion, the present thesis showed that Hecate-CGbeta conjugate targets its action selectively through LHCGR and selectively kills the LHCGR bearing tumor cells. It works both in gonadal somatic and in ectopic LHCGR bearing adrenal tumors. These results establish a more general principle that receptors expressed ectopically in malignant cells can be exploited in targeted cytotoxic therapies without affecting the normal healthy cells.

Product Data Managemet as a Key Success Factor in After Sales Business

The objective of this master’s thesis is to define Larox´s Product Data present state and future development needs from after sales point of view. In particular the object was to investigate after sales needs, which data related to products need to be managed by using Product Data Management. Empirical material of thesis was collected mainly through interviews, benchmark visits, and personal experience. Among the interviewees were internal stakeholders who are closely related to the product process, as well as external stakeholders. Interviews revealed that each stakeholder group has deviating needs for product data management and that at present all the needs are not met to take the best possible way. The main requirement was availability of up-to-date information, which plays a key role in after sales business. At the end of study is concentrated to find development targets at Larox, especially from after sales point of view. In addition, consideration of how the product data management advantages can utilized in making internal processes more efficient. Development needs are collected together as project descriptions, whose headings are shown at the end of the study.

Pancreatic Cancer Cell Glycosylation Regulates Cell Adhesion and Invasion through the Modulation of a2b1 Integrin and E-Cadherin Function

In our previous studies we have described that ST3Gal III transfected pancreatic adenocarcinoma Capan-1 and MDAPanc-28 cells show increased membrane expression levels of sialyl-Lewis x (SLex) along with a concomitant decrease in α2,6-sialic acid compared to control cells. Here we have addressed the role of this glycosylation pattern in the functional properties of two glycoproteins involved in the processes of cancer cell invasion and migration, α2β1 integrin, the main receptor for type 1 collagen, and E-cadherin, responsible for cell-cell contacts and whose deregulation determines cell invasive capabilities. Our results demonstrate that ST3Gal III transfectants showed reduced cell-cell aggregation and increased invasive capacities. ST3Gal III transfected Capan-1 cells exhibited higher SLex and lower α2,6-sialic acid content on the glycans of their α2β1 integrin molecules. As a consequence, higher phosphorylation of focal adhesion kinase tyrosine 397, which is recognized as one of the first steps of integrin-derived signaling pathways, was observed in these cells upon adhesion to type 1 collagen. This molecular mechanism underlies the increased migration through collagen of these cells. In addition, the pancreatic adenocarcinoma cell lines as well as human pancreatic tumor tissues showed colocalization of SLex and E-cadherin, which was higher in the ST3Gal III transfectants. In conclusion, changes in the sialylation pattern of α2β1 integrin and E-cadherin appear to influence the functional role of these two glycoproteins supporting the role of these glycans as an underlying mechanism regulating pancreatic cancer cell adhesion and invasion