Breast cancer consists of several intrinsic molecular subtypes, providing the basis for clinical treatment decisions. Lately, it is becoming increasingly recognized that factors other than the intrinsic cancer characteristics, such as immune components’ activity in the tumor microenvironment, have important effects on treatment choices and efficacy. bioSyntagma has developed a method, the Molecular Fingerprint (mPrint®), that enables multiplexed analysis of spatially defined regions in formalin-fixed, paraffin-embedded (FFPE) tumor samples allowing for analysis of the gene signatures unique to the tumor microenvironment. This method was applied to molecularly defined sets of breast cancers and used to evaluate four different tumor regions of interest (ROIs): 1) viable carcinoma proper (>90% cancer cells), 2) fibrotic tumor center (sparse cellularity), 3) interface between viable tumor and inflammatory component (tumor and inflammatory microenvironment) and 4) tissue away from the tumor (normal breast tissue). This was compared to the whole tissue scrapes from each patient block. Each ROI and tissue scrape was analyzed by high throughput qPCR for a panel of 248 genes using SmartChip technology (Takara Bio, USA). Sequential tissue slices from each patient were also analyzed using immunohistochemistry (IHC) for three targets and investigated for correlation with qPCR results for validation of the method. Overall, reasonable concordance was observed in general expression trends between selected IHC and RNA expression. qPCR data were further analyzed using hierarchical clustering analysis and showed that morphologically defined ROI’s cluster completely differently than traditional clustering of entire tissue scrapes. Notably, patient clustering based on morphological regions was independent of the intrinsic cancer subtype, as determined by molecular profiling of whole tissue scrapes, as well as independent of trends in Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI). These findings suggest that current methods of patient stratification based on whole tumor molecular subtyping may be inferior to stratification based on molecular characteristics of the tumor microenvironment. Citation Format: Colleen Ziegler, Isaiah Slemons, Chris DeSilva, Barbara Witkowski, Alain Mir, Sangeetha Anandakrishnan, Andrew Farmer, Elma Contreras, David Richardson, Semir Vranic, Zoran Gatalica, Dmitry N. Derkach. Novel method for patient stratification in breast carcinoma based upon spatial analysis of tumor microenvironment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B094. doi:10.1158/1535-7163.TARG-19-B094

We study a class of distributed optimization problems of minimizing the sum of potentially non-differentiable convex objective functions (without requiring strong convexity). A novel approach to the analysis of asynchronous distributed optimization is developed. An iterative algorithm based on dual decomposition and block coordinate ascent is implemented in an edge based manner. We extend available results in the literature by allowing multiple and potentially overlapping blocks to be updated at the same time with non-uniform probabilities assigned to different blocks. Sublinear convergence with probability one is proved for the algorithm under the aforementioned weak assumptions. A numerical example is provided to illustrate the effectiveness of the algorithm.

Value iteration is a method to generate optimal control inputs for generic nonlinear systems and cost functions. Its implementation typically leads to approximation errors, which may have a major impact on the closed-loop system performance. We talk in this case of approximate value iteration (AVI). In this paper, we investigate the stability of systems for which the inputs are obtained by AVI. We consider deterministic discrete-time nonlinear plants and a class of general, possibly discounted, costs. We model the closed-loop system as a family of systems parameterized by tunable parameters, which are used for the approximation of the value function at different iterations, the discount factor and the iteration step at which we stop running the algorithm. It is shown, under natural stabilizability and detectability properties as well as mild conditions on the approximation errors, that the family of closed-loop systems exhibit local practical stability properties. The analysis is based on the construction of a Lyapunov function given by the sum of the approximate value function and the Lyapunov-like function that characterizes the detectability of the system. By strengthening our conditions, asymptotic and exponential stability properties are guaranteed.

Most emulation-based results in networked control systems rely on a bound on the maximal allowable transmission interval (MATI) under which stability is preserved. However, having only such a MATI condition can lead to conservative results, as large values of transmission intervals may only occur sporadically, while the typical transmission interval is much smaller. In this paper, we therefore propose, in addition to the existence of a MATI, to also impose a bound on the average allowable transmission interval, expressed in terms of a reverse average dwell-time (RADT) condition on the transmission intervals. We provide joint conditions on the RADT and the MATI such that stability of the NCS can still be guaranteed, which can, in addition, lead to significant higher values of the MATI itself. The strengths of these new results are illustrated on a numerical example, showing a 484% improvement of the MATI, while still guaranteeing stability.

We propose a novel triggering policy to implement state-feedback controllers for nonlinear systems via packet-based communication networks. The idea is to generate transmissions between the plant and the controller only when a state-dependent rule has been satisfied for a given amount of time. We refer to this new paradigm as event-holding control, in which a clock variable is thus only running when a state-dependent criterion is verified. This is different from time-regularized event-triggered control, where the clock variable keeps running after each transmission instant until it is reset to zero at the moment a state-based condition is verified. We approach the problem of designing an event-holding controller via emulation. We first synthesize a state-feedback law, which stabilizes the closed-loop system in the absence of the communication network. We then design the event-holding triggering mechanism under a set of general assumptions. The results are applied to two case studies consisting of linear systems and a class of nonlinear systems controlled by backstepping. We also provide a numerical backstepping control example, which demonstrates that the event-holding behaviour can reduce the number of transmissions.

Most extremum-seeking control approaches focus solely on the problem of finding the extremum of some unknown, steady-state performance map. However, many industrial applications also have to deal with constraints on operating conditions due to, e.g., actuator limitations, limitations on design or tunable system parameters, or constraints on measurable signals. These constraints, which can be unknown a-priori, may conflict with the otherwise optimal operational condition, and should be taken into account in performance optimization. In this work, we propose a sampled-data extremum-seeking approach for optimization of constrained dynamical systems using barrier function methods, where both the objective function and the constraint function are available through measurement only. We show that, under the assumption that initialization does not violate constraints, the interconnection between a constrained dynamical system and optimization algorithms that employ barrier function methods is stable, the constraints are satisfied, and optimization is achieved. We illustrate the results by means of a numerical example.

geopolitical the definitions. The concept of the book consists of seven chapters: Introduction , Model and Theory , Several Geopolitical Approaches in the Recent Past , Classical Geopolitical Assumptions , Classical Geopolitical Theories, Applications of the Model, Setting the Course for a Rejuvenated Geopolitics , and Annex: Classical Geopolitical Concepts / Theories , Notes and Index . Following an overview of the development of geopolitics, the book introduces us to the history of geopolitics, but also its directions and scholars along two lines. The first line would be an organic, reflected by German concern about scientific laws, which contributed to the survival of states in an increasingly volatile world, with his two scholars Friedrich Ratzel and Rudolf Kjellén. Another would be the geostrategic British and North American interest, through the depicted geographical position of states and regions as a condition of foreign action with Alfred Thayer Mahan, Halford Mackinder, and Nicholas Spykman as their standard bearers. After World War II, these classical directions were exposed to great influence by the alleged connection with General Karl Haushofer and his geopolitical school in Munich as well as the aggression of Adolf Hitler, both directions in promoting war and racism. The book is structured to follow three main goals: first, purpose; constructed classical geopolitical model, second, objective; by its construction it outlines the usefulness and legitimacy of classical geopolitics as an important model of international relations, third, access; listed three ways that will show the benefit of classical geopolitics. Phil Kelly separates the model from theory and its application. Theory and the model are different, first, the theory is part of the second, the model. It lists sixty theories in our geopolitical model. These theories can be used to interpret actions and policies in the field of international relations

OBJECTIVE The aim of this study was to assess the relationship between the use of neuroenhancing substances, exam anxiety and academic performance among first-year Bosnian-Herzegovinian (BH) university students. METHODS In a cross-sectional study, an ad hoc questionnaire was delivered to a sample of BH first-year university students. The following data were collected: socio-demographic features, consumption of neuroenchancing substances, the Westside Test Anxiety Scale (WTAS) and academic performance. RESULTS A total of 214 students were included. Consumption of lifestyle substances, coffee, energy drinks, nicotine, alcohol, and marijuana, for the purpose of neuroenhancement increased during the week before the exams. OTC cognitive enhancer use was reported by 31.0%, and of benzodiazepines by 1.5% of students. No psycostimulants were used. A high to extremely high exam WTAS score was reported in 38.3% students. The exam WTAS score was positively correlated with consumption of coffee (rho=0.31; P<0.001), energy drinks (rho=0.18; P=0.009), and nicotine (rho=0.22; P=0.001), and negatively correlated with last exam grade (rho=-0.33; P<0.001). The exam WTAS score was a significant independent predictor (OR=0.55; 95% CI 0.31 to 0.97, P=0.039) for self-assessed academic performance. Self-assessed academic performance was positively correlated with last exam grade (rho=0.15; P=0.043). CONCLUSIONS Although first-year BH university students do not seem to use either prescription or illicit psycostimulants, the consumption of nicotine, alcohol, and marijuana is worrying. However, the consumption of these neuroenhancing substances seems not to be related to better self-assessed academic performance. Finally, exam anxiety seems to be a significant problem among BH first-year university students.

SUMMARY This review article is focused on the impact of antioxidants and prooxidants on health with emphasis on the type of antioxidants that should be taken. Medical researchers suggest that diet may be the solution for the control of chronic diseases such as cardiovascular complications, hypertension, diabetes mellitus, and different cancers. In this survey, we found scientific evidence that the use of antioxidants should be limited only to the cases where oxidative stress has been identified. This is often the case of specific population groups such as postmenopausal women, the elderly, infants, workers exposed to environmental pollutants, and the obese. Before starting any supplementation, it is necessary to measure oxidative stress and to identify and eliminate the possible sources of free radicals and thus increased oxidative stress.

Abstract Background: Many destructive and immunotherapeutic modalities have been used for the management of plantar warts; however, an optimal treatment with high efficacy and absent or low recurrence has not been explored to date. Tuberculin purified protein derivative (PPD) shown promising results for treatment of viral warts without ablation. Aim of Study: To evaluate the efficacy and safety of intralesional (IL) PPD in the treatment of plantar warts. Patients and Methods: Twenty patients with plantar warts were included in this study and divided into two equal groups; group I was treated using IL tuberculin PPD every 2 weeks, group II was treated with IL saline every 2 weeks, till complete clearance or for a maximum of 3 sessions. The patients were followed-up for a period of 6 months. Results: There was a statistically highly significant im-provement in the therapeutic group compared with control group. This modality was well tolerated, with no remarkable side effects and no recurrence in cured patients during follow up period. A significant positive correlation existed between the number of sessions and treatment response. There was a significant negative correlation between the number of lesions and response to treatment. Conclusion: Intralesional PPD is safe and effective treat-ment alternative for the treatment of plantar warts even if they are recalcitrant or multiple, with no post-procedural downtime and better results and patient satisfaction.

We propose a novel strategy to construct optimal controllers for continuous-time nonlinear systems by means of linear-like techniques, provided that the optimal value function is differentiable and quadratic-like. This assumption covers a wide range of cases and holds locally in general. The proposed strategy avoids solving the Hamilton-Jacobi-Bellman (HJB) equation, that is a nonlinear partial differential equation, which is known to be hard or impossible to solve. Instead, the HJB equation is replaced with an easy-solvable state- dependent Lyapunov matrix equation without introducing any approximation. We achieve this exploiting a linear-factorization of the underlying nonlinear system and a policy-iteration algorithm (PI) to yield a linear-like PI for nonlinear systems. The proposed control strategy solves optimal nonlinear control problems in an exact, yet still linear-like manner. We prove optimality of the resulting solution and illustrate the results via two examples.

Background Lung cancer is the leading cause of cancer-related death worldwide, with 5-year overall survival less than 15%. Therefore, it is essential to find biomarkers for early detection and prognosis. Aberrant DNA methylation is a common feature of human cancers and its utility is already recognized in cancer management. The aim of this study was to explore the diagnostic and prognostic value of the promoter methylation status of the ASC/TMS1/PYCARD and MyD88 genes, key adaptor molecules in the activation of the innate immune response and apoptosis pathways. Methods A total of 50 non-small cell lung cancer (NSCLC) patients were enrolled in the study. Methylation of bisulphite converted DNA was quantified by pyrosequencing in fresh frozen malignant tissues and adjacent non-malignant tissues. Associations between methylation and lung function, tumor grade and overall survival were evaluated using receiver-operating characteristics (ROC) analysis and statistical tests of hypothesis. Results Methylation level of tested genes is generally low but significantly decreased in tumor tissues (ASC/TMS1/PYCARD, P<0.0001; MyD88, P<0.0002), which correlates with increased protein expression. Three CpG sites were identified as promising diagnostic marker candidates; CpG11 (-63 position) in ASC/TMS1/PYCARD and CpG1 (-253 position) and 2 (-265 position) in MyD88. The association study showed that the methylation status of the ASC/TMS1 CpG4 site (-34 position) in malignant and non-malignant tissues is associated with the overall survival (P=0.019) and the methylation status of CpG8 site (-92 position) is associated with TNM-stage (P=0.011). Conclusions The methylation status of the ASC/TMS1/PYCARD and MyD88 promoters are promising prognostic biomarker candidates. However, presented results should be considered as a preliminary and should be confirmed on the larger number of the samples.

Organizations in today’s extremely competitive environment need to devote significant time, energy as well as human and financial resources to the measurement of their efficiency, in order to increase their profit, reduce costs, better plan their assets and manage their budgets, as well as to improve budget controls and risk assessment. Therefore, they need performance models, including the Balanced Scorecard. Primarily intended for profit organizations, the Balanced Scorecard is today used in the public sector, as well. This paper presents the research into the utilization of the Balanced Scorecard in the public sector, examining whether the performance of higher education institutions may be improved by the design and utilization of the Balanced Scorecard model.