Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO)

Background: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator. Conclusions: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.

Micro-treatment options for components of organic fraction of MSW in residential areas

There is a growing interest in management of MSW through micro-treatment of organic fraction of municipal solid wastes (OFMSW) in many cities of India. The OFMSW fraction is high (> 80%) in many pockets within South Indian cities like Bangalore, Chikkamagalur, etc. and is largely represented by vegetable, fruit, packing and garden wastes. Among these, the last three have shown problems for easy decomposition. Fruit wastes are characterized by a large pectin supported fraction that decomposes quickly to organic acids (becomes pulpy) that eventually slow down anaerobic and aerobic decomposition processes. Paper fraction (newsprint and photocopying paper) as well as paddy straw (packing), bagasse (from cane juice stalls) and tree leaf litter (typical garden waste and street sweepings) are found in reasonably large proportions in MSW. These decompose slowly due to poor nutrients or physical state. We have examined the suitability of these substrates for micro-composting in plastic bins by tracking decomposition pattern and physical changes. It was found that fruit wastes decompose rapidly to produce organic acids and large leachate fraction such that it may need to be mixed with leachate absorbing materials (dry wastes) for good composting. Leaf litter, paddy straw and bagasse decompose to the tune of 90, 68 and 60% VS and are suitable for composting micro-treatment. Paper fractions even when augmented with 10% leaf compost failed to show appreciable decomposition in 50 days. All these feedstocks were found to have good biological methane potential (BMP) and showed promise for conversion to biogas under a mixed feed operation. Suitability of this approach was verified by operating a plug-flow type anaerobic digester where only leaf litter gathered nearby (as street sweepings) was used as feedstock. Here only a third of the BMP was realized at this scale (0.18 m(3) biogas/kg VS 0.55 m(3)/kg in BMP). We conclude that anaerobic digestion in plug-flow like digesters appear a more suitable micro-treatment option (2-10 kg VS/day) because in addition to compost it also produces biogas for domestic use nearby.

What does “futility” mean? An empirical study of doctors’ perceptions

Objective(s) To describe how doctors define and use the terms “futility” and “futile treatment” in end-of-life care. Design, Setting, Participants A qualitative study using semi-structured interviews with 96 doctors across a range of specialties who treat adults at the end of life. Doctors were recruited from three large Australian teaching hospitals and were interviewed from May to July 2013. Results Doctors’ conceptions of futility focused on the quality and chance of patient benefit. Aspects of benefit included physiological effect, weighing benefits and burdens, and quantity and quality of life. Quality and length of life were linked, but many doctors discussed instances when benefit was determined by quality of life alone. Most doctors described the assessment of chance of success in achieving patient benefit as a subjective exercise. Despite a broad conceptual consensus about what futility means, doctors noted variability in how the concept was applied in clinical decision-making. Over half the doctors also identified treatment that is futile but nevertheless justified, such as short-term treatment as part of supporting the family of a dying person. Conclusions There is an overwhelming preference for a qualitative approach to assessing futility, which brings with it variation in clinical decision-making. “Patient benefit” is at the heart of doctors’ definitions of futility. Determining patient benefit requires discussions with patients and families about their values and goals as well as the burdens and benefits of further treatment.

Just say no? The influence of personal goals, beliefs, psychosocial adjustment, and parental relationships in drug use by adolescents

The study in its entirety focused on factors related to adolescents decisions concerning drug use. The term drug use is taken here to include the use of tobacco products, alcohol, narcotics, and other addictive substances. First, the reasons given for drug use (attributions) were investigated. Secondly, the influence of personal goals, the beliefs involved in decision making, psychosocial adjustment including body image and involvement with peers, and parental relationships on drug use were studied. Two cohorts participated in the study. In 1984, a questionnaire on reasons for drug use was administered to a sample of adolescents aged 14-16 (N=396). A further questionnaire was administered to another sample of adolescents aged 14-16 (N=488) in 1999. The results for both cohorts were analyzed in Articles I and II. In Articles III and IV further analysis was carried out on the second cohort (N=488). The research report presented here provides a synthesis of all four articles, together with material from a further analysis. In a comparison of the two cohorts it was found that the attributions for drug use had changed considerably over the intervening fifteen-year period. In relation to alcohol and narcotics use an increase was found in reasons involving inner subjective experiences, with mention of the good feeling and fun resulting from alcohol and narcotics use. In addition, the goals of alcohol consumption were increasingly perceived as drinking to get drunk, and for its own sake. The attributions for the adolescents own smoking behavior were quite different from the attributions for smoking by others. The attributions were only weakly influenced by the participants gender or by their smoking habits, either in 1984 or 1999. In relation to participants own smoking, the later questionnaire elicited more mention of inner subjective experiences involving "good feeling. In relation to the perceived reasons for other people s smoking, it elicited more responses connected with the notion of "belonging. In the second sample, the results indicated that the levels of body satisfaction among adolescent girls are lower than those among adolescent boys. Overall, dissatisfaction with one's physical appearance seemed to relate to drug use. Girls were also found to engage in more discussions than boys; this applied to (i) discussion with peers (concerning both intimate and general matters), and (ii) discussion with parents (concerning general matters). However, more than a quarter of the boys (out of the entire population) reported only low intimacy with both parents and peers. If both drinking and smoking were considered, it seemed that girls in particular who reported drinking and smoking also reported high intimacy with parents and peers. Boys who reported drinking and smoking reported only medium intimacy with parents and peers. In addition, having an intimate relationship with one's peers was associated with a greater tendency to drink purely in order to get drunk. Overall, the results seemed to suggest that drug use is connected with a close relationship with peers and (surprisingly) with a close relationship with parents. Nevertheless, there were also indications that to some extent peer relationships can also protect adolescents from smoking and alcohol use. The results, which underline the complexity of adolescent drug use, are taken up in the Discussion section. It may be that body image and/or other identity factors play a more prominent role in all drug use than has previously been acknowledged. It does appear that in the course of planning support campaigns for adolescents at risk of drug use, we should focus more closely on individuals and their inner world. More research on this field is clearly needed, and therefore some ideas for future research are also presented.

Physicochemical studies on the gelation of hen's egg yolk: Delipidation of yolk plasma by treatment with phospholipase-C and extraction with solvents

A method for the delipidation of egg yolk plasma using phospholipase-C, n-heptane, and 1-butanol has been described. An aggregating protein fraction and a soluble protein fraction were separated by the action of phospholipase-C. The aggregating protein fraction freed of most of the lipids by treatment with n-heptane and 1-butanol was shown to be the apolipoproteins of yolk plasma, whereas the soluble proteins were identified as the livetins. Carbohydrate and the N-terminal amino acid analysis of these protein fractions are reported. A comparison of these protein fractions with the corresponding fractions obtained by formic acid delipidation of yolk plasma has been made. The gelation of yolk plasma by the action of phospholipase-C has been interpreted as an aggregation of lipoproteins caused by ionic interactions. The role of lecithin in maintaining the structural integrity of lipoproteins has been discussed.

Oncolytic Adenoviruses with Radiation Therapy for Treatment of Prostate Cancer

Prostate cancer is the most common cancer in males. Although many patients with localized disease can be cured with surgery and radiotherapy, advanced disease and especially castration resistant metastatic disease remains incurable, with a median life expectancy of less than 18 months. Oncolytic adenoviruses (Ads) are a new promising treatment against cancer due to their innate capacity to kill cancer cells. Viral replication in tumor cells leads to oncolysis and production of a multiplicity of new virions that are capable of further destroying cancerous tissue. Oncolytic Ads can be modified for tumor targeted infection and replication and be armed with therapeutic transgenes to maximize the oncolytic effect. Worldwide, clinical trials with oncolytic Ads have demonstrated good safety while the antitumor efficacy remains to be improved. Importantly, the best responses have been reported when oncolytic adenoviruses have been combined with standard cancer treatments, such as chemotherapy and radiation. Further, a challenge in many virotherapy approaches has been the monitoring of virus replication in vivo. Reporter genes have been extensively used as transgenes to evaluate the biodistribution of the virus and activity of specific promoters. However, these techniques are often limited to preclinical evaluation and not amenable to human use. The aim of the thesis was to find and develop new oncolytic Ads with maximum efficacy against metastatic, castration resistant prostate cancer and study them in vitro and in vivo combined to different forms of radiation therapy. Using combination therapy, we were aiming for better antitumor efficacy with reduced side effects. Capsid modified Ads for enhanced transduction were studied. Serotype 3 targeted chimera, Ad5/3, was found to have enhanced infectivity for prostate cancer and was used for developing new viruses for the study. Correlation between Ad-encoded marker peptide secretion and simultaneous viral replication was evaluated and the effects of radiotherapy on viral replication were studied in detail. We found that the repair of double strand breaks caused by ionizing radiation was inhibited by adenoviral proteins and led to autophagic cell death. Both subcutaneous models and intrapulmonary tumor models mimicking metastatic, aggressive disease were used in vivo. Virus efficacy was evaluated by intratumoral injections. Also, intravenous administration was evaluated to study the effectiveness in metastatic disease. Oncolytic adenovirus treatment led to significant tumor growth control and increased the survival rate of the mice. These results were further improved when oncolytic Ads were combined with radiation therapy. Oncolytic Ads expressing human sodium/iodide transporter (hNIS) as a transgene were evaluated for their oncolytic potency and for the functionality of hNIS in vitro and in vivo. Monitoring of viral replication was also assessed using different imaging modalities relative to clinical use. SPECT imaging of tumor-bearing mice was evaluated and combined with simultaneous CT-scanning to obtain important anatomical information on biodistribution, also in a three-dimensional form. It was shown that hNIS-expressing adenoviruses could harbour a bi-functional transgene allowing for localization and imaging of viral replication. Targeted radiotherapy was applied by systemic radioiodide administration and resulted in iodide accumulation into Ad-infected tumor. The combination treatment showed significantly enhanced antitumor efficacy in mice bearing prostate cancer tumors. In summary, the results presented above aim to provide new treatment modalities for castration resistant prostate cancer. Molecular insights were provided for better understanding of the benefits of combined radiation therapy and oncolytic adenoviruses, which will hopefully facilitate the translation of the approach into clinical use for humans.

A general treatment of two dimensional plane flows, for a micropolar fluid

In this paper we have studied the flow of a micropolar fluid, whose constitutive equations were given by Eringen, in two dimensional plane flow. In two notes, we have discussed the validity of the boundary condition v=a ω and its effect on the entire flow field. We have restricted our study to the case when Stokes' approximation is valid, i. e. slow motion for it is difficult to uncouple the equations in the most general case.

Tyttöjen kesken : Monikulttuurisuus ja sukupuolten tasa-arvo nuorisotyössä.

Among Girls Youth Work, Multiculturalism and Gender Equality Finland s increasingly multicultural society concerns younger generations in a very particular manner. Starting already in pre-school kindergartens, children from different cultural backgrounds share their everyday existence. The focus of this study is Finland s increasingly multicultural society that has challenged youth work professionals in particular and made them rethink questions related to content, basic values and goals of youth work. These reconsiderations include the following essential questions: which of these pedagogic principles are defined as Finnish, and under what kinds of circumstances would the youth workers be ready to negotiate about them. These questions, which are related to multiculturalism, are then linked to the girls position, status and gender equality. The research examines how gender equality is articulated in relation to multiculturalism and vice versa, in what contexts youth work-related questions are negoatiated in, and how these negotiations then relate to gender issues. The present study combines theoretical concepts and debates from both post-colonial and youth research, and has benefited greatly from previous research which has examined the everyday lives of young people with multicultural backgrounds and conceptualised the different meanings of age, ethnicity, culture and gender. Neither multiculturalism nor gender equality is, however, taken as a given concept in this study; rather the research focuses on how youth workers understand and define these concepts and how they are used. The emphasis has been on monitoring the varying consequences of different understandings and definitions in terms of everyday work and practices. The goal of this study has been to find typical ways of conceptualising multiculturalism, gender equality and the role of girls in the context of youth work. The focus of the research is not just the youth workers different views but also the notions of the girls themselves. These are then further analysed by examining the ways the girls negotiate their agency. Examples of how the girls agency is defined and the different forms of agency that are offered to the girls within the context of leisure time activities and youth work have been sought. The kind of agency the girls then assume is also examined. The data in this research is comprised of interviews with young people with multicultural backgrounds (n=39), youth workers (n=42) and of ethnographic fieldwork (2003 2005). The fieldwork concentrated on following different types of youth work activities that were targeted at girls with migrant backgrounds. These were organized both by selected municipalities and NGOs. The research shows that various questions related to multicultural issues have enhanced the visibility of gender equality in the field of youth work. The identification of gender-based inequality is especially closely linked to the position of girls from migrant backgrounds. These girls are a source of particular worry and the aim of the many activity groups for migrant girls is to educate them so that they can become equal Finnish citizens . The youth work itself is seen as gender-neutral and equality based. Equality in this context is defined as a purely quantitative concept, and the solution to any possible inequalities is thus the exact same treatment for everyone . The girls themselves seem mainly confused by the role that is offered to them. They would need a voice and the possibility to have an impact on the planning of youth work activities. They want to have their views heard. The role of the victim assigned to them is very confining and makes it difficult to act. At the same time the research shows how gender-sensitive youth work is seen to mean youth work with girls. Gender-sensitive work with boys is not really done or is done very little, even if many of the interviewees are of the opinion that the true materialization of gender equality would require boys to be taken into account too. The principle of gender equality should be shared by the entire youth work profession. Keywords Youth work, equality, multiculturalism, gender sensitivity, agency, girls, young people, sexuality

Effective treatment of infectious diseases: A nonlinear adaptive control theoretic approach

A nonlinear adaptive system theoretic approach is presented in this paper for effective treatment of infectious diseases that affect various organs of the human body. The generic model used does not represent any specific disease. However, it mimics the generic immunological dynamics of the human body under pathological attack, including the response to external drugs. From a system theoretic point of view, drugs can be interpreted as control inputs. Assuming a set of nominal parameters in the mathematical model, first a nonlinear controller is designed based on the principle of dynamic inversion. This treatment strategy was found to be effective in completely curing "nominal patients". However, in some cases it is ineffective in curing "realistic patients". This leads to serious (sometimes fatal) damage to the affected organ. To make the drug dosage design more effective, a model-following neuro-adaptive control design is carried out using neural networks, which are trained (adapted) online. From simulation studies, this adaptive controller is found to be effective in killing the invading microbes and healing the damaged organ even in the presence of parameter uncertainties and continuing pathogen attack.

A neuro-adaptive augmented optimal dynamic inversion approach for effective and efficient treatment of chronic myelogenous leukemia

Combining the advanced techniques of optimal dynamic inversion and model-following neuro-adaptive control design, an efficient technique is presented for effective treatment of chronic myelogenous leukemia (CML). A recently developed nonlinear mathematical model for cell dynamics is used for the control (medication) synthesis. First, taking a set of nominal parameters, a nominal controller is designed based on the principle of optimal dynamic inversion. This controller can treat nominal patients (patients having same nominal parameters as used for the control design) effectively. However, since the parameters of an actual patient can be different from that of the ideal patient, to make the treatment strategy more effective and efficient, a model-following neuro-adaptive controller is augmented to the nominal controller. In this approach, a neural network trained online (based on Lyapunov stability theory) facilitates a new adaptive controller, computed online. From the simulation studies, this adaptive control design approach (treatment strategy) is found to be very effective to treat the CML disease for actual patients. Sufficient generality is retained in the theoretical developments in this paper, so that the techniques presented can be applied to other similar problem as well. Note that the technique presented is computationally non-intensive and all computations can be carried out online.

Estramustine and its Derivatives in Potentiating Radiotherapy of Prostate Cancer

The purpose of this study was to deepen our knowledge of the combined use of estramustine and radiotherapy in the treatment of prostate cancer. Prostate cancer is a common disease, with a high variability between subjects in its malignant potential. In many cases, the disease is an incidental finding with little or no clinical significance. In other cases, however, prostate cancer may be an aggressive malignant disease, which, if the initial treatment fails, lacks an effective cure and may lead to severe symptoms, metastasis, and death despite all treatment. In many cases, the methods of treatment available at the moment provide cure or significant regression of symptoms, but often at the cost of considerable side effects. Estramustine, a cytostatic drug used for treating advanced cancer of the prostate, has been shown to inhibit prostate cancer progression and also to increase the sensitivity of cancer cells to radiotherapy. The goals of this study were, first, to find out whether it is possible to use either estramustine or an antibody against estramustine binding protein as carrier molecules for bringing therapeutic radioisotopes into prostate cancer cells, and, secondly, to gain more understanding of the mechanisms behind the known radiosensitising effect of estramustine. Estramustine and estramustine binding protein antibody were labelled with iodine-125 to study the biodistribution of these substances in mice. In the first experiment, both of the substances accumulated in the prostate, but radioiodinated estramustine also showed affinity to the liver and the lungs. Since the radiolabelled antibody was found out to accumulate more selectively to the prostate, we studied its biodistribution in nude mice with DU-145 human prostate cancer implants. In this experiment, the prostate and the tumour accumulated more radioactivity than other organs, but we concluded that the difference in the dose of radiation compared to other organs was not sufficient for the radioiodinated antibody to be advocated as a carrier molecule for treating prostate cancer. Mice with similar DU-145 prostate cancer implants were then treated with estramustine and external beam irradiation, with and without neoadjuvant estramustine treatment. The tumours responded to the treatment as expected, showing the radiation potentiating effect of estramustine. In the third experiment, this effect was found without an increase in the amount of apoptosis in the tumour cells, despite previous suggestions to the contrary. In the fourth experiment, we gave a similar treatment to the mice with DU-145 tumours. A reduction in proliferation was found in the groups treated with radiotherapy, and an increased amount of tumour hypoxia and tumour necrosis in the group treated with both neoadjuvant estramustine and radiation. This finding is contradictory to the suggestion that the radiation sensitising effect of estramustine could be attributed to its angiogenic activity.

Influence of substrate temperature and post-deposition heat treatment on the optical properties of SiO2 films

Silicon dioxide films are extensively used as protective, barrier and also low index films in multilayer optical devices. In this paper, the optical properties of electron beam evaporated SiO2 films, including absorption in the UV, visible and IR regions, are reported as a function of substrate temperature and post-deposition heat treatment. A comparative study of the optical properties of SiO2 films deposited in neutral and ionized oxygen is also made.