Blending process assessment and employees competencies assessment in very small entities

The ISO/IEC 29110 series aims to provide Very Small Entities (VSEs) with a set of standards based on subsets of existing standards. Process capability determination does not seem suitable for a VSE in terms of return on investment. Our approach proposes to move the viewpoint away from process and to the human resources. We propose a blended assessment model using the ISO/IEC 15504 for the level 1, but based on competency assessment for higher capability levels

Tumor tissue levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and outcome following adjuvant chemotherapy in premenopausal lymph node-positive breast cancer patients: A retrospective study

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that high tumor tissue levels of TIMP-1 are associated with no or limited clinical benefit from chemotherapy with CMF and anthracyclines in metastatic breast cancer patients. Here, we extend our investigations to the adjuvant setting studying outcome after adjuvant chemotherapy in premenopausal lymph node-positive patients. We hypothesize that TIMP-1 high tumors are less sensitive to chemotherapy and accordingly that high tumor tissue levels are associated with shorter survival.</p> <p>Methods</p> <p>From our original retrospectively collected tumor samples we selected a group of 525 pre-menopausal lymph node-positive patients (adjuvant treatment: CMF, 324 patients; anthracycline-based, 99 patients; no adjuvant chemotherapy, 102 patients). TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. TIMP-1 was analyzed as a continuous variable and as a dichotomized one using the median TIMP-1 concentration as a cut point between high and low TIMP-1 groups. We analyzed the benefit of adjuvant CMF and anthracyclines in univariate and multivariable survival models; endpoints were disease-free (DFS) and overall survival (OS).</p> <p>Results</p> <p>In this selected cohort of high-risk patients, and in the subgroup of patients receiving no adjuvant therapy, TIMP-1 was not associated with prognosis. In the subgroup of patients treated with anthracyclines, when analyzed as a continuous variable we observed a tendency for increasing TIMP-1 levels to be associated with shorter DFS (multivariable analysis, HR 1.75, 95% CI 1.00-3.07, P = 0.05) and a significant association between increasing TIMP-1 and shorter OS in both univariate (HR 3.52, 95% CI 1.54-8.06, P = 0.003) and multivariable analyses (HR 4.19, 95% CI 1.67-10.51, P = 0.002). No statistically significant association between TIMP-1 and DFS was observed in the CMF-treated patients although high TIMP-1 was associated with shorter OS when analyzed as a dichotomized variable (HR 1.64, 95% CI 1.02-2.65, P = 0.04).</p> <p>Conclusion</p> <p>In the subgroup of patients receiving adjuvant chemotherapy we found an association between shorter survival after treatment in TIMP-1 high patients compared with TIMP-1 low patients, especially in patients receiving anthracycline-based therapy. This suggests that high tumor tissue levels of TIMP-1 might be associated with reduced benefit from classical adjuvant chemotherapy. Our findings should be validated in larger prospective studies.</p

TIMP-1 Induces an EMT-Like Phenotypic Conversion in MDCK Cells Independent of Its MMP-Inhibitory Domain

Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) regulate epithelial-mesenchymal transition (EMT) critical for the development of epithelial organs as well as cancer cell invasion. TIMP-1 is frequently overexpressed in several types of human cancers and serves as a prognostic marker. The present study investigates the roles of TIMP-1 on the EMT process and formation of the lumen-like structure in a 3D Matrigel culture of MDCK cells. We show that TIMP-1 overexpression effectively prevents cell polarization and acinar-like structure formation. TIMP-1 induces expression of the developmental EMT transcription factors such as SLUG, TWIST, ZEB1 and ZEB2, leading to downregulation of epithelial marker and upregulation of mesenchymal markers. Importantly, TIMP-1′s ability to induce the EMT-like process is independent of its MMP-inhibitory domain. To our surprise, TIMP-1 induces migratory and invasive properties in MDCK cells. Here, we present a novel finding that TIMP-1 signaling upregulates MT1-MMP and MMP-2 expression, and potentiates MT1-MMP activation of pro-MMP-2, contributing to tumor cell invasion. In spite of the fact that TIMP-1, as opposed to TIMP-2, does not interact with and inhibit MT1-MMP, TIMP-1 may act as a key regulator of MT1-MMP/MMP-2 axis. Collectively, our findings suggest a model in which TIMP-1 functions as a signaling molecule and also as an endogenous inhibitor of MMPs. This concept represents a paradigm shift in the current view of TIMP-1/MT1-MMP interactions and functions during cancer development/progression

TGF-β1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Metastasis is the main factor responsible for death in breast cancer patients. Matrix metalloproteinases (MMPs) and their inhibitors, known as tissue inhibitors of MMPs (TIMPs), and the membrane-associated MMP inhibitor (RECK), are essential for the metastatic process. We have previously shown a positive correlation between MMPs and their inhibitors expression during breast cancer progression; however, the molecular mechanisms underlying this coordinate regulation remain unknown. In this report, we investigated whether TGF-β1 could be a common regulator for MMPs, TIMPs and RECK in human breast cancer cell models.</p> <p>Methods</p> <p>The mRNA expression levels of TGF-β isoforms and their receptors were analyzed by qRT-PCR in a panel of five human breast cancer cell lines displaying different degrees of invasiveness and metastatic potential. The highly invasive MDA-MB-231 cell line was treated with different concentrations of recombinant TGF-β1 and also with pharmacological inhibitors of p38 MAPK and ERK1/2. The migratory and invasive potential of these treated cells were examined in vitro by transwell assays.</p> <p>Results</p> <p>In general, TGF-β2, TβRI and TβRII are over-expressed in more aggressive cells, except for TβRI, which was also highly expressed in ZR-75-1 cells. In addition, TGF-β1-treated MDA-MB-231 cells presented significantly increased mRNA expression of MMP-2, MMP-9, MMP-14, TIMP-2 and RECK. TGF-β1 also increased TIMP-2, MMP-2 and MMP-9 protein levels but downregulated RECK expression. Furthermore, we analyzed the involvement of p38 MAPK and ERK1/2, representing two well established Smad-independent pathways, in the proposed mechanism. Inhibition of p38MAPK blocked TGF-β1-increased mRNA expression of all MMPs and MMP inhibitors analyzed, and prevented TGF-β1 upregulation of TIMP-2 and MMP-2 proteins. Moreover, ERK1/2 inhibition increased RECK and prevented the TGF-β1 induction of pro-MMP-9 and TIMP-2 proteins. TGF-β1-enhanced migration and invasion capacities were blocked by p38MAPK, ERK1/2 and MMP inhibitors.</p> <p>Conclusion</p> <p>Altogether, our results support that TGF-β1 modulates the mRNA and protein levels of MMPs (MMP-2 and MMP-9) as much as their inhibitors (TIMP-2 and RECK). Therefore, this cytokine plays a crucial role in breast cancer progression by modulating key elements of ECM homeostasis control. Thus, although the complexity of this signaling network, TGF-β1 still remains a promising target for breast cancer treatment.</p

The prognostic role of matrix metalloproteinases MMP-2 and -9 and their tissue inhibitors TIMP-1 and -2 in primary breast carcinoma

Abstract Breast carcinoma is a heterogeneous disease with a prognosis that varies from excellent to very poor. Traditional tumour parameters and biological factors that are also predictive for treatment response are used in determining breast carcinoma prognosis and selecting appropriate treatment. Gelatinases MMP-2 and MMP-9 have been shown to associate with tumour progression. Their tissue inhibitors TIMP-1 and -2 are multifunctional molecules that have been suggested as prognostic markers in some previous reports. In the present work, the expression and prognostic value of gelatinases MMP-2 and MMP-9 and their tissue inhibitors TIMP-1 and -2 were assessed in primary breast carcinoma. The material consisted of a total of 416 patients. Tissue expression of TIMP-1 and -2 was analysed in a population of 203 patients using immunohistochemistry. Circulating gelatinases and their inhibitors were studied using ELISA in two different populations of 71 at preoperative state and 213 patients at pre- and postoperative state. High expression of TIMP-1 immunoreactive protein positively correlated with high histological grade of the tumour and associated with aggressive disease course in grade 2–3 subpopulation. High preoperative plasma TIMP-1 was prognostic for relapse in a modern patient series after a median follow-up time of 18 months. TIMP-1 as a continuous variable was prognostic in Cox regression univariate analysis, and was an independent prognostic variable superior to nodal status in multivariate analysis. High preoperative serum TIMP-1 was an independent prognostic variable for poor disease-specific survival, and TIMP-1 was found to maintain its prognostic value when assessed independently with different ELISA analyses, and was not very sensitive for preanalytical conditions. In addition, low circulating preoperative serum MMP-2 was observed to associate with high stage and positive nodal status in breast carcinoma. These results indicate that circulating TIMP-1 may be a potential new marker of worsened prognosis in breast carcinoma, although careful validation of assay platforms and identification of the sources of physiological variation are needed before it can be adopted into clinical decision-making

Software process capability and maturity determination:BOOTSTRAP methodology and its evolution

Abstract Software process assessment and improvement came under the spotlight in the discussion of software engineering when the Software Engineering Institute published the maturity model for software process capability determination in 1987. Since then, several new approaches and standards have been developed. This thesis introduces a European software process assessment and improvement methodology called BOOTSTRAP, which was initially developed in an ESPRIT project starting from lean and kaizen philosophy. The focus is on the evolution of methodology and how it was developed, using an experimental research approach. The work covers also enhancements to the methodology investigated in the SPICE, PROFES and TAPISTRY projects. The enhancements expand the original methodology into new specific application areas, keep it compliant with new quality standards and certification, improve the efficiency of the assessment method, enhance the focus from process to product and strengthen improvement monitoring and support. To address these areas, the new BOOTSTRAP methodology releases offer tailored and enhanced assessment reference models and enhanced assessment and improvement methods. The new features also facilitate more frequent and even continuous assessments with software measurement-based indicators. The thesis explains the origin and features of BOOTSTRAP software process assessment and improvement methodology and how it was developed for professional use. The discussion starts with the evolution of the methodology. Then the new trends and demands are introduced and new features of the BOOTSTRAP methodology described. The conclusion discusses how the methodology developed to be able successfully to support professional software process assessment, to align it with the evolution of software engineering, to adopt the features and requirements of the underlying standards in order to conform to the requirements set by ISO 15504 standard and to become validated in practice.Tiivistelmä Ohjelmistoprosessin arvioinnista ja parantamisesta tuli ohjelmistotekniikan keskeinen kiinnostuksen kohde kun Carnegie-Mellon yliopiston ohjelmistotekniikan instituutti SEI julkaisi kypsyysmallinsa ohjelmistoprosessin kyvykkyyden arviointiin vuonna 1987. Siitä lähtien maailmalla on syntynyt lukuisa määrä uusia malleja ja standardeja tälle alueelle. Tässä väitöskirjassa esitellään eurooppalainen ohjelmistoprosessin arviointi- ja parantamismenetelmä BOOTSTRAP, joka kehitettiin alun perin Euroopan unionin ESPRIT tutkimusohjelman rahoittamassa projektissa lähtien japanilaisesta ohut-ajattelusta (Lean) ja sen jatkuvan parantamisen periaatteesta (Kaizen). Esitys keskittyy menetelmän kehittymiseen ja siihen miten menetelmä käytännössä kehitettiin käyttäen kokeellista tutkimustapaa teollisessa ympäristössä. Työ kattaa myös alkuperäiseen menetelmään tehdyt laajennukset, jotka syntyivät yhteistyössä SPICE, PROFES ja TAPISTRY projekteissa tehdyn tutkimuksen tuloksena. Tehdyt laajennukset mahdollistavat menetelmän käytön uusilla sovellusalueilla, takaavat menetelmän yhteensopivuuden alan laatu- ja sertifiointistandardien kanssa, parantavat menetelmän tehokkuutta, laajentavat menetelmän käyttöaluetta prosessin arvioinnista sisältämään myös tuotteen kehittämisen arvioinnin ja vahvistavat parantamisen seurantaa ja tukemista. Toteuttaakseen näiden uusien ominaisuuksien vaatimukset uudet BOOTSTRAP menetelmän julkistukset tarjoavat räätälöityjä ja laajennettuja mallikuvauksia arviointien tekemiseksi sekä entistä täydellisempiä lähestymistapoja arviointien suorittamiselle ja parantamiselle. Menetelmän uudet ominaisuudet mahdollistavat myös usein toistuvien arviointien suorittamisen ja jopa jatkuvan arvioinnin ohjelmisto-mittauksia hyödyntäen. Väitöskirjassa kuvataan yksityiskohtaisesti BOOTSTRAP menetelmän lähtö-kohdat ja ominaisuudet ja se kuinka menetelmä onnistuttiin kehittämään ammattimaiseen ohjelmistoprosessin arviointiin ja parantamiseen sopivaksi. Ensin kuvataan menetelmän kehittyminen ja sitten edetään alan uusien kehitystrendien ja vaatimusten esittelyyn siihen kuinka BOOTSTRAP menetelmä uudet ominaisuudet vastaavat näihin vaatimuksiin. Yhteenvedossa osoitetaan kuinka kehittämisessä onnistuttiin saamaan aikaan uusi menetelmä, joka sopii ammattimaiseen ohjelmistoprosessin arviointiin, vastaa kaikilta osin alan kehittymisen vaatimuksia, sisältää alan standardien vaatimukset täyttävät käytännössä koestetut ominaisuudet, jotka takaavat menetelmän vastaavuuden ISO 15504 standardin vaatimuksiin

Hoidosta hautaan:lääketieteellisen hoidon aiheuttamat kuolemat ja niiden tutkinta

Tiivistelmä Hoitokuolemalla tarkoitetaan kuolemaa, johon johtanut tapahtumaketju on alkanut lääketieteellisestä hoidosta. Potilasturvallisuuden kannalta kuolema on vakavin haittatapahtuma. Hoitokuolemien määristä ei ole olemassa tarkkoja tilastotietoja, mihin vaikuttaa muun muassa määritelmien vaihtelevuus. Suomessa epäily hoitokuolemasta edellyttää oikeuslääketieteellistä kuolemansyynselvitystä, minkä lisäksi tutkinta jakaantuu eri viranomaisille valvonta-, oikeus- ja vahinkoprosesseihin. Oikeuslääketieteellisen ruumiinavausaineiston ja kuolintodistusten perusteella hoidon osuutta kuolemassa epäillään usein, mutta hoitokuolemaksi luokiteltuja tapauksia on suhteellisen vähän. Suurin osa niistä liittyy lääkehoitoon ja suuririskisiksi tiedettyihin toimenpiteisiin. Varsinaisten hoitovirheiden aiheuttamat kuolemat ovat todellisuudessa todennäköisesti aiempaa arvioitua harvinaisempia. Hoitokuolemaepäilyjen oikeuslääketieteellinen selvittäminen on tärkeää, jotta voidaan edistää potilasturvallisuutta sekä varmistaa vainajien, omaisten ja hoitohenkilökunnan oikeusturvan toteutuminen

Using ISO 15504 Compliant Assessment Combined with Goal-oriented Measurement for Process Improvement at Dräger Medical Technology

Software Process Assessment techniques are extensively used in software industry in order to determine the processes capability and to start process improvement activities. In this paper, we are showing how an ISO 15504 compliant assessment method can be used to detect weaknesses in the software development process and how the suggested changes can be used as the basis for a process improvement program. The effect of implemented process changes is monitored and controlled by an accompanying measurement program according to the GQM paradigm. The presented approach has been applied in an industrial project at Dräger Medical Technology. Costs in terms of effort needed to start and implement the improvement activities and benefits in form of a higher maturity of changed processes are presented in order to show the successfulness of the approach

The incidence of iatrogenic deaths in the Finnish cause-of-death statistics:a retrospective study

Abstract Purpose: An adverse event in health care leading to death is a significant event when assessing patient safety. This study was designed in order to assess, how many iatrogenic deaths are registered in Finland annually, and what type of treatment they are mostly related to. Methods: Material was collected using cause of death-statistics that includes “manner of death”-classification in Finland in 2014–2015. Results: There were 350 cases that met the criteria of the study. In a majority of the cases (264, 75%), a medico-legal autopsy was performed. This represents only 1.4% of all medicolegal autopsies during the study period in Finland. The cases were most often related to medication (30%) or known high-risk procedures such as gastrointestinal surgery (23%) and cardiothoracic surgery (11%). Only 12% of the cases had no prior significant medical history. Patient characteristics were somewhat different among the surgical disciplines, probably reflecting treatment practices. Conclusions: Deaths that are classified as iatrogenic are mostly related to known high-risk surgery or medication. Further studies are needed to assess the true incidence of malpractice among this material