Human disease and drug pharmacology, complex as real life

In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-torefuse argument that is spurring the development of multitarget therapies.

Uma experiência didática de corrosão usando colorimetria visual

In this paper, a simple and rapid method of evaluating galvanized steel sheet corrosion in a CuSO4 solution, as an experimentation proposal for corrosion teaching. Galvanized steel corrosion is present in tanks and tubing by leading of natural or industrial waters which contain soluble copper compounds. This was the rationale for choosing the Cu2+ ions solution as an oxidizing agent. The method principle is based on visual colorimetry because the used oxidant has an intense blue color. Thus, a change in its concentration as a result of the corrosive process can be followed by a color intensity change in the solution thereby allowing evaluation of the corrosion rate.

Images of imagination : an aesthetic approach to education

Visual art practice has generally been described as a lonely affair, thinking about what an artist has experienced in the outside world. This study is an inquiry into a visual art practice of another kind: the relational one. The research purpose is twofold. The first purpose is to shed light on a visual artist’s conceptions of art, education and scholarship. The second purpose is to by reasoning on imagination and a rhizomatic formation interpret the relations created between art, multimodality and literacy learning as an aesthetic approach to education. By inquiry into a specific collaborated long-term art practice, the study conveys how the meaning making elements of an arts based learning practice gradually transform an artist’s and a teacher’s concepts of art education to an aesthetic approach to education. In the art practice examined the typical Finnish rye bread and a poem have represented a cultural theme that has been elaborated through art conventions. The poem and the rye bread have in the art practice been articulated as cultural representations of as well as symbolic projections on the Swedishspeaking minority culture in Finland. The study connects art informed inquiry to a hermeneutic research rationale where the research reasoning is generated through a rhizomatic alliance between empiric data and theories. The reasoning is constructed as an interpretation pattern that expands throughout the study. The study arguments that the rhizome as an aesthetic formation can be appropriate to refer to when articulating arts based meaning making and when creating arts based educational strategies, dialogues, aesthetic learning and multimodal literacy in education. The study investigates an aesthetic approach to research in education, which means that the art practice surveyed is interpreted through articulation appropriate to poetic aspects of art, education and research.

Emancipating and developing learning activity: Systemic intervention and re-instrumentation in higher education.

The central theme of this thesis is the emancipation and further development of learning activity in higher education in the context of the ongoing digital transformation of our societies. It was developed in response to the highly problematic mainstream approach to digital re-instrumentation of teaching and studying practises in contemporary higher education. The mainstream approach is largely based on centralisation, standardisation, commoditisation, and commercialisation, while re-producing the general patterns of control, responsibility, and dependence that are characteristic for activity systems of schooling. Whereas much of educational research and development focuses on the optimisation and fine-tuning of schooling, the overall inquiry that is underlying this thesis has been carried out from an explicitly critical position and within a framework of action science. It thus conceptualises learning activity in higher education not only as an object of inquiry but also as an object to engage with and to intervene into from a perspective of intentional change. The knowledge-constituting interest of this type of inquiry can be tentatively described as a combination of heuristic-instrumental (guidelines for contextualised action and intervention), practical-phronetic (deliberation of value-rational aspects of means and ends), and developmental-emancipatory (deliberation of issues of power, self-determination, and growth) aspects. Its goal is the production of orientation knowledge for educational practise. The thesis provides an analysis, argumentation, and normative claim on why the development of learning activity should be turned into an object of individual|collective inquiry and intentional change in higher education, and why the current state of affairs in higher education actually impedes such a development. It argues for a decisive shift of attention to the intentional emancipation and further development of learning activity as an important cultural instrument for human (self-)production within the digital transformation. The thesis also attempts an in-depth exploration of what type of methodological rationale can actually be applied to an object of inquiry (developing learning activity) that is at the same time conceptualised as an object of intentional change within the ongoing digital transformation. The result of this retrospective reflection is the formulation of “optimally incomplete” guidelines for educational R&D practise that shares the practicalphronetic (value related) and developmental-emancipatory (power related) orientations that had been driving the overall inquiry. In addition, the thesis formulates the instrumental-heuristic knowledge claim that the conceptual instruments that were adapted and validated in the context of a series of intervention studies provide means to effectively intervene into existing practise in higher education to support the necessary development of (increasingly emancipated) networked learning activity. It suggests that digital networked instruments (tools and services) generally should be considered and treated as transient elements within critical systemic intervention research in higher education. It further argues for the predominant use of loosely-coupled, digital networked instruments that allow for individual|collective ownership, control, (co-)production, and re-use in other contexts and for other purposes. Since the range of digital instrumentation options is continuously expanding and currently shows no signs of an imminent slow-down or consolidation, individual and collective exploration and experimentation of this realm needs to be systematically incorporated into higher education practise.

Derivação biliopancreática com preservação gástrica videolaparoscópica: sistematização técnica

BACKGROUND: The authors describe a videolaparoscopic technical variation of biliopancreatic diversion, and its rationale, as well as its preliminary results.They operated on 12 female patients, age between 26 and 49 years, BMI range 47,4 and 59,5kg/m². There were no intraoperative complications; operative time ranged from 2 to 4,5 hours; discharge in the 3rd. postoperative day. Liquid dietetic recommendations in the early period, and normal diet after the first week. One patient was readmmitted after 1 week with abdominal pain because of excessive ingestion of food; there was deep venous trombosis in one patient. Follow-up showed loss of excess weight of 27,4% after four months. Initial results of the described operation sugests it may be a good alternative to morbid obesity surgical treatment; it is strongly required a multidisciplinar pre and postoperative treatment program.

Situational awareness concept in a multinational collaboration environment : challenges in the information sharing framework

Technological capabilities are built to support different types of collaboration, and this gives the justification to widely observe, how activity environments are influenced by technology. Technology as an enabler can be addressed from different perspectives, other than merely technological. Dynamic, evolving environment is at the same time interesting but also challenging. As a multinational collaboration environment, the maritime surveillance is an good example of time critical and evolving environment, where technological solutions enable new ways of collaboration. Justification for the inspiration to use maritime environment as the baseline for understanding the challenges in creating and maintaining adequate level of situational awareness, derives from the complexity of the collaboration and information sharing environment elements, needed to be taken into account, when analyzing criticalities related to decision making. Situational awareness is an important element supporting decision making, and challenges related to it can also be observed in the maritime environment. This dissertation describes the structures and factors involved in this complex setting, found from the case studies that should be taken into account when trying to understand, how these elements affect the activities. This dissertation focuses on the gray area that is between a life threatening situation and normal everyday activities. From the multinational experimentation series case studies, MNE5 and MNE6 it was possible to observe situations that were not life threatening for the participants themselves, but not also basic every day activities. These case studies provided a unique possibility to see situations, where gaining of situational awareness and decision making are challenged with time critical crisis situations. Unfortunately organizations do not normally take the benefit from the everyday work to prepare themselves for possible emerging crisis situations. This dissertation focuses on creating a conceptual model and a concept that supports organizations – also outside the maritime community – to improve their ability to support gaining of situational awareness from the individual training level, all the way to changes in organizational structures in aiming for better support for decision making from the individual level to the highest decision making level. Quick changes and unpredictability are reality in organizations and organizations do not have the possibility to control all the factors that affect their functioning. Since we cannot be prepared for everything, and predict every crisis, individual activities inside teams and as a part of organizations, need to be supported with guidance, tools and training in order to support acting in challenging situations. In fact the ideology of the conceptual model created, lies especially in the aim of not controlling everything in beforehand, but supporting organizations with concrete procedures to help individuals to react in different, unpredictable situations, instead of focusing on traditional risk prevention and management. Technological capabilities are not automatically solutions for functional challenges; this is why it is justified to broaden the problem area observation from the technological perspective. This dissertation demonstrates that it is possible to support collaboration in a multinational environment with technological solutions, but it requires the recognition of technological limitations and accepting the possible restrictions related to technological innovations. Technology should not be considered value per se, the value of technology should be defined according to the support of activities, including strategic and operational environment evaluation, identification of organizational elements, and taking into account also the social factors and their challenges. Then we are one step closer to providing technological solutions that support the actual activities by taking into account the variables of the activity environment in question. The multidisciplinary view to approach the information sharing and collaboration framework, is derived especially from the complexity of decision making and building of situational awareness, since they are not build or created in vacuity, but in the organizational framework by the people doing it with the technological capabilities, enabled by the organizational structures. Introduced case studies were related to maritime environment, but according to the research results, it is valid to argue, that based on the lessons learned it is possible to create and further develop conceptual model and to create a general concept to support a wider range of organizations in their attempt to gain better level of situational awareness (SA) and to support decision making. To proof the versatile usage of the developed concept, I have introduced the case study findings to the health care environment and reflected the identified elements from the trauma center to the created concept. The main contribution to complete this adventure is the presented situational awareness concept created in the respect to NATO concept structure. This has been done to tackle the challenge of collaboration by focusing on situational awareness in the information sharing context by providing a theoretical ground and understanding, of how these issues should be approached, and how these elements can be generalized and used to support activities in other environments as well. This dissertation research has been a several year evolving process reflecting and affecting presented case studies and this learning experience from the case studies has also affected the goals and research questions of this dissertation. This venture has been written from a retro perspective according to ideology of process modeling and design rationale to present to the reader how this entire journey took place and what where the critical milestones that affected the end result, conceptual model. Support in a challenging information sharing framework can be provided with the right type of combination of tools, procedures and individual effort. This dissertation will provide insights to those with a new approach to war technology for the organizations to gain a better level of awareness and to improve the capabilities in decision making. This dissertation will present, from the war technology starting point, a new approach and possibility for the organizations to create a better level of awareness and support for decision making with the right combination of tools, procedures and individual effort.

Software and Code Finder: making research outputs visible

Poster at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Ischemia and fibrosis: the risk mechanisms of hypertensive heart disease

Mechanisms underlying risk associated with hypertensive heart disease (HHD) and left ventricular hypertrophy (LVH) are discussed in this report and provide a rationale for understanding this very common and important cause of death from hypertension and its complications. Emphasized are impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis from increased collagen deposition intramurally and perivascularly. Each is exacerbated by aging and, perhaps, also by increased dietary salt intake. These functional and structural changes promote further endothelial dysfunction, altered coronary hemodynamics, and diastolic as well as systolic ventricular contractile function in HHD. The clinical endpoints of HHD include angina pectoris (with or without atherosclerosis of the epicardial coronary arteries), myocardial infarction, cardiac failure, lethal dysrhythmias, and sudden death. The major concept to be derived from these alterations is that not all that is clinically recognized as LVH is true myocytic hypertrophy and structural remodeling. Other major co-morbid changes occur that serve to increase cardiovascular risk including impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis.

A priori estimation of accuracy and of the number of wells to be employed in limiting dilution assays

The use of limiting dilution assay (LDA) for assessing the frequency of responders in a cell population is a method extensively used by immunologists. A series of studies addressing the statistical method of choice in an LDA have been published. However, none of these studies has addressed the point of how many wells should be employed in a given assay. The objective of this study was to demonstrate how a researcher can predict the number of wells that should be employed in order to obtain results with a given accuracy, and, therefore, to help in choosing a better experimental design to fulfill one's expectations. We present the rationale underlying the expected relative error computation based on simple binomial distributions. A series of simulated in machina experiments were performed to test the validity of the a priori computation of expected errors, thus confirming the predictions. The step-by-step procedure of the relative error estimation is given. We also discuss the constraints under which an LDA must be performed.

Long-chain n-3 fatty acids and inflammation: potential application in surgical and trauma patients

Lipids used in nutritional support of surgical or critically ill patients have been based on soybean oil, which is rich in the n-6 fatty acid linoleic acid (18:2n-6). Linoleic acid is the precursor of arachidonic acid (20:4n-6). In turn, arachidonic acid in cell membrane phospholipids is the substrate for the synthesis of a range of biologically active compounds (eicosanoids) including prostaglandins, thromboxanes, and leukotrienes. These compounds can act as mediators in their own right and can also act as regulators of other processes, such as platelet aggregation, blood clotting, smooth muscle contraction, leukocyte chemotaxis, inflammatory cytokine production, and immune function. There is a view that an excess of n-6 fatty acids should be avoided since this could contribute to a state where physiological processes become dysregulated. One alternative is the use of fish oil. The rationale of this latter approach is that fish oil contains long chain n-3 fatty acids, such as eicosapentaenoic acid. When fish oil is provided, eicosapentaenoic acid is incorporated into cell membrane phospholipids, partly at the expense of arachidonic acid. Thus, there is less arachidonic acid available for eicosanoid synthesis. Hence, fish oil decreases production of prostaglandins like PGE2 and of leukotrienes like LTB4. Thus, n-3 fatty acids can potentially reduce platelet aggregation, blood clotting, smooth muscle contraction, and leukocyte chemotaxis, and can modulate inflammatory cytokine production and immune function. These effects have been demonstrated in cell culture, animal feeding and healthy volunteer studies. Fish oil decreases the host metabolic response and improves survival to endotoxin in laboratory animals. Recently clinical studies performed in various patient groups have indicated benefit from this approach.

Peruskoulun yläkouluvalinnat Turussa. Perheiden yläkouluvalintojen rakentuminen äitien puheissa ja toimissa

Tutkimuksessa tarkastellaan peruskoulun yläkouluvalintoja Turussa. Tarkastelun keskiössä ovat vuonna 1997 syntyneiden turkulaislasten vanhempien yläkouluvalintaa koskeva yleinen sekä omaan lapseen kiinnittyvä puhe ja toimijuus paikallisessa institutionaalisessa kouluvalintatilassa sekä vanhempien lapsen koulutukseen ja kouluvalintaan liittämät perustelut, merkitykset, arvot ja arvostukset. Tämän lisäksi tutkimuksessa tarkastellaan puheesta ja toimista rakentuvia perheiden kouluvalintastrategioita, joita peilataan äitien koulutuksellisiin ja sosiaalisiin resursseihin sekä paikalliseen toimintapolitiikkaan. Tutkimus ei kerro ainoastaan paikallisessa kontekstissa tapahtuvista kouluvalinnoista, vaan laajemmin yhteiskunnassa vallitsevista hierarkioista ja arvoista sekä koulutukseen ja sosioekonomiseen asemaan linkittyvistä normatiivisista toimintatavoista. Tutkimuksessa käytetään haastattelu- ja kyselyaineistoja. Aineistot kerättiin osana kahta laajempaa Suomen Akatemian rahoittamaa Helsingin ja Turun yliopistojen kanssa yhteistyössä tehtyä tutkimusprojektia Vanhemmat ja kouluvalinta – Perheiden koulutusstrategiat, eriarvoistuminen ja paikalliset koulupolitiikat suomalaisessa peruskoulussa (VAKOVA) 2009–2012 sekä Parents and School Choice. Family Strategies, Segregation and School Policies in Chilean and Finnish Basic Schooling (PASC) 2010–2013. Tutkimusaineistot koostuvat 87 turkulaisäidin haastattelusta ja kyselyaineistosta. Kyselyaineiston analyysissä on käytetty kuvailevia tilastollisia menetelmiä, ja sitä käytetään ensisijaisesti taustoittamaan haastatteluaineistoa. Haastatteluaineiston analyysi perustuu pääasiallisesti teema-analyysiin, mutta toimija-asema-analyysin osalta myös diskursiiviseen lähestymistapaan. Haastatteluaineiston pohjalta esiin nousseiden lasten koulutusta ja kouluvalintoja koskevien kuvausten perusteella perheiden yläkouluvalinnat jaettiin kolmeen erityyppiseen valintastrategiaan: perinteiseen lähikouluvalintastrategiaan (n=41), ambivalenttiseen kouluvalintastrategiaan (n=23) ja päämäärätietoiseen kouluvalintastrategiaan (n=23). Jokainen kolmesta strategiasta piti sisällään kahdenlaista toimijuutta kouluvalintakentällä. Ryhmittely kouluvalintastrategioittain ja toimija-asemittain perustui äitien puhetapaan kouluvalinnoista ja yleisemmin koulutukseen liitetyistä merkityksistä ja arvoista sekä konkreettiseen toimintaan kouluvalinnan suhteen. Lähikouluvalintastrategiaa suosivien jälkeläiset siirtyivät koulunsa yleisluokalle. Perheet toimivat valintakentällä kaupungin rajaavan toimintapolitiikan ohjaamina, jolloin kouluvalinta näytti passiiviselta. Osoitteenmukaiseen kouluun siirtymistä perusteltiin praktisilla syillä; koulumatkan pituudella, kulkuyhteyksillä ja lapsen kaverisuhteilla. Hyvinvointivaltion edellytykseksi nähtiin kaikille taattu samanvertainen koulutus ja edelleen luotettiin perinteistä peruskoulua määrittävään mahdollisuuksien tasa-arvoon. Koulutuksen yhdeksi tärkeäksi tehtäväksi nähtiin lapsen kasvattaminen hyvinvoivaksi ja onnelliseksi. Vanhempien toiminta oli perinteisen kouluvalintastrategian mukaista. Ambivalenttista kouluvalintastrategiaa käyttävistä perheistä toiminta kouluvalintakentällä oli kahtalaista. Äidit joko harkitsivat kouluvalintoja tai vertailivat kouluja ja niihin pääsymahdollisuuksia realistisesti tasapainoillen ohjaavan ja mahdollistavan toimintapolitiikan välimaastossa. Tärkeintä oli olla tietoinen kaupungin kouluvalintapolitiikasta sekä siitä, että valinnoilla voi olla merkitystä jälkikasvun koulupolulle. Eri vaihtoehtojen punnitsemisen jälkeen päädyttiin useimmin lähikoulun painotettuun opetukseen. Lapsen peruskoulutusta haluttiin rikastaa painotetulla opetuksella ja hänen toivottiin pääsevän motivoituneeseen ja oppimismyönteiseen koululuokkaan. Valintoja tehtiin paikallisen toimintapolitiikan puitteissa lapsen parasta toivoen. Koulutuksen tehtäväksi nähtiin lapsen intellektuaalinen kasvu kiedottuna koulutuksen tuottamaan hyvinvointiin ja onnellisuuteen. Perheiden valintastrategiaksi muodostui ambivalenttinen strategia motivoituneen oppimisympäristön löytämiseksi. Päämäärätietoista kouluvalintastrategiaa käyttävät vanhemmat hyödynsivät aktiivisesti erilaisia reittejä tiettyihin yläkouluihin pääsemiseksi. Ennakoivien perheiden lapset olivat opiskelleet sellaisessa alakoulussa, joka ei kuulunut yläkoulun oppilasalueelle, mutta takasi lapselle reitin suosittuun yläkouluun. Määrätietoisten perheissä havahduttiin valintoihin puolestaan yläkouluun siirryttäessä, jolloin koulupaikkaa haettiin sopivimman painotetun opetuksen ja koulun maineen mukaan pois lähiyläkoulusta. Lähikoulu -periaate koettiin epäoikeudenmukaiseksi, sillä lapsella tulee olla oikeus toteuttaa omia kykyjään ja lahjakkuuttaan valikoidussa oppilasryhmässä ja perheillä mahdollisuus valita lapsen koulu. Paikallinen toimintapolitiikka ei näyttänyt rajaavan vanhempien kouluvalintoja. Koulutuksen tarkoitukseksi nähtiin intellektuaalinen kasvu ja akateemissivistävä tehtävä. Päämäärätietoisen kouluvalintavalintastrategian tavoitteena oli perheelle sopivan habituksen takaaminen. Paikallinen toimintapolitiikka mahdollisti vanhempien erilaisten kouluvalintastrategioiden rakentumisen ohjaten ensisijaisesti lähiyläkouluun, mutta samalla mahdollistaen koulun valinnan toissijaisen haun kriteerein. Kouluvalintastrategioihin ja toimintatapaan kouluvalintakentällä kytkeytyi vanhempien koulutukseen liittämät arvot sekä kulttuuriset ja sosiaaliset resurssit ja se, miten niitä käytettiin.

Consequences of cerebroventricular insulin injection on renal sodium handling in rats: effect of inhibition of central nitric oxide synthase

In the present study, we investigated the effects of acute intracerebroventricular (icv) insulin administration on central mechanisms regulating urinary sodium excretion in simultaneously centrally NG-nitro-L-arginine methylester (L-NAME)-injected unanesthetized rats. Male Wistar-Hannover rats were randomly assigned to one of five groups: a) icv 0.15 M NaCl-injected rats (control, N = 10), b) icv dose-response (1.26, 12.6 and 126 ng/3 µL) insulin-injected rats (N = 10), c) rats icv injected with 60 µg L-NAME in combination with NaCl (N = 10) or d) with insulin (N = 10), and e) subcutaneously insulin-injected rats (N = 5). Centrally administered insulin produced an increase in urinary output of sodium (NaCl: 855.6 ± 85.1 Δ%/min; 126 ng insulin: 2055 ± 310.6 Δ%/min; P = 0.005) and potassium (NaCl: 460.4 ± 100 Δ%/min; 126 ng insulin: 669.2 ± 60.8 Δ%/min; P = 0.025). The urinary sodium excretion response to icv 126 ng insulin microinjection was significantly attenuated by combined administration of L-NAME (126 ng insulin: 1935 ± 258.3 Δ%/min; L-NAME + 126 ng insulin: 582.3 ± 69.6 Δ%/min; P = 0.01). Insulin-induced natriuresis occurred by increasing post-proximal sodium excretion, despite an unchanged glomerular filtration rate. Although the rationale for decreased urinary sodium excretion induced by combined icv L-NAME and insulin administration is unknown, it is tempting to suggest that perhaps one of the efferent signals triggered by insulin in the CNS may be nitrergic in nature.

The fallacy of racial pharmacogenomics

Personalized pharmacogenomics aims to use individual genotypes to direct medical treatment. Unfortunately, the loci relevant for the pharmacokinetics and especially the pharmacodynamics of most drugs are still unknown. Moreover, we still do not understand the role that individual genotypes play in modulating the pathogenesis, the clinical course and the susceptibility to drugs of human diseases which, although appearing homogeneous on the surface, may vary from patient to patient. To try to deal with this situation, it has been proposed to use interpopulational variability as a reference for drug development and prescription, leading to the development of "race-targeted drugs". Given the present limitations of genomic knowledge and of the tools needed to fully implement it today, some investigators have proposed to use racial criteria as a palliative measure until personalized pharmacogenomics is fully developed. This was the rationale for the FDA approval of BiDil for treatment of heart failure in African Americans. I will evaluate the efficacy and safety of racial pharmacogenomics here and conclude that it fails on both counts. Next I shall review the perspectives and the predicted rate of development of clinical genomic studies. The conclusion is that "next-generation" genomic sequencing is advancing at a tremendous rate and that true personalized pharmacogenomics, based on individual genotyping, should soon become a clinical reality.

Coping with genetic diversity: the contribution of pathogen and human genomics to modern vaccinology

Vaccine development faces major difficulties partly because of genetic variation in both infectious organisms and humans. This causes antigenic variation in infectious agents and a high interindividual variability in the human response to the vaccine. The exponential growth of genome sequence information has induced a shift from conventional culture-based to genome-based vaccinology, and allows the tackling of challenges in vaccine development due to pathogen genetic variability. Additionally, recent advances in immunogenetics and genomics should help in the understanding of the influence of genetic factors on the interindividual and interpopulation variations in immune responses to vaccines, and could be useful for developing new vaccine strategies. Accumulating results provide evidence for the existence of a number of genes involved in protective immune responses that are induced either by natural infections or vaccines. Variation in immune responses could be viewed as the result of a perturbation of gene networks; this should help in understanding how a particular polymorphism or a combination thereof could affect protective immune responses. Here we will present: i) the first genome-based vaccines that served as proof of concept, and that provided new critical insights into vaccine development strategies; ii) an overview of genetic predisposition in infectious diseases and genetic control in responses to vaccines; iii) population genetic differences that are a rationale behind group-targeted vaccines; iv) an outlook for genetic control in infectious diseases, with special emphasis on the concept of molecular networks that will provide a structure to the huge amount of genomic data.

Early responses of the STAT3 pathway to platinum drugs are associated with cisplatin resistance in epithelial ovarian cancer

Cisplatin resistance remains one of the major obstacles when treating epithelial ovarian cancer. Because oxaliplatin and nedaplatin are effective against cisplatin-resistant ovarian cancer in clinical trials and signal transducer and activator of transcription 3 (STAT3) is associated with cisplatin resistance, we investigated whether overcoming cisplatin resistance by oxaliplatin and nedaplatin was associated with the STAT3 pathway in ovarian cancer. Alamar blue, clonogenic, and wound healing assays, and Western blot analysis were used to compare the effects of platinum drugs in SKOV-3 cells. At an equitoxic dose, oxaliplatin and nedaplatin exhibited similar inhibitory effects on colony-forming ability and greater inhibition on cell motility than cisplatin in ovarian cancer. Early in the time course of drug administration, cisplatin increased the expression of pSTAT3 (Tyr705), STAT3α, VEGF, survivin, and Bcl-XL, while oxaliplatin and nedaplatin exhibited the opposite effects, and upregulated pSTAT3 (Ser727) and STAT3β. The STAT3 pathway responded early to platinum drugs associated with cisplatin resistance in epithelial ovarian cancer and provided a rationale for new therapeutic strategies to reverse cisplatin resistance.