Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase I study of RAD001 (everolimus), cetuximab, and irinotecan as second-line therapy in metastatic colorectal cancer (mCRC).

e15115 Background: The PI3K/AKT/mTOR pathway is frequently dysregulated in colorectal cancer (Cancer Res 2005;65:11227). In a phase I study in patients with advanced solid tumors, everolimus an oral mTOR inhibitor demonstrated clinical benefit including a partial response in pts with colorectal cancer (J Clin Oncol 2008;26:1603-10; J Clin Oncol 2008; 26:1588-95). METHODS This open-label, multicenter phase I study uses a Bayesian logistic model to identify feasible doses of everolimus + irinotecan + cetuximab. Adult pts with mCRC progressing despite prior 5-FU/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (XELOX) plus bevacizumab (if standard practice) were treated using a sequential dose escalation scheme (Table). Dose decisions were driven by the probability of dose-limiting toxicity (DLT) in the first 2 cycles. Dose level decisions were based on maximizing the probability that end-of-cycle-2 DLT rate would be within the targeted toxicity interval (20% to <35%) and minimizing the risk of over-dosing (< 5% risk of unacceptable toxicity and < 25% risk of excessive/unacceptable toxicity). RESULTS 18 pts were treated from April '07 to August '08, 5 pts at dose level A1 and 13 pts at dose level B1. Two DLTs (G3 rash on cycle 2 day 1 lasting > 7 days and G3 mucositis on cycle 1 day 14 lasting > 7 days, 1 pt each) were reported in 4 evaluable pts at dose level A1. No DLTs were reported in 7 evaluable patients at dose level B1. CONCLUSIONS At dose level B1 everolimus in combination with irinotecan and cetuximab was generally well tolerated. The study was stopped due to changes in clinical practice based on emerging data indicating that cetuximab has limited efficacy in mCRC patients with KRAS mutations and that efficacy data favors daily RAD001 over weekly dosing. Patients in this study were treated with cetuximab irrespective of KRAS status. [Table: see text] [Table: see text].
Wage Determination and Efficiency in Search Equilibrium

Using a simple search technology and the Nash bargaining solution, the paper derives the steady state equilibrium negotiated wage as a function of the equilibrium unemployment and vacancy rates. For this wage, the lifetime expected present discounted value of earnings of a new worker is compared with the social marginal product of a new worker. These are not generally equal implying inefficient incentives for labour mobility.
Exploring Variations in Contracting for Services Among American Local Governments

During the previous two decades, researchers have conducted an array of empirical studies of local government contracting for services. Some of the more recent findings have suggested that this form of privatization has become less politically controversial and more accepted as a service delivery approach. Do politics still matter when it comes to explaining patterns in local government contracting? The findings from this study indicate that the influence of political factors, such as demand for smaller government and public employee opposition to privatization, still help to account for variations in local government contracting, as they did during the 1980s and early 1990s. Contract management capacity is an important determinant of local government contracting.
Microarray-based classification and clinical predictors: on combined classifiers and additional predictive value

MOTIVATION In the context of clinical bioinformatics methods are needed for assessing the additional predictive value of microarray data compared to simple clinical parameters alone. Such methods should also provide an optimal prediction rule making use of all potentialities of both types of data: they should ideally be able to catch subtypes which are not identified by clinical parameters alone. Moreover, they should address the question of the additional predictive value of microarray data in a fair framework. RESULTS We propose a novel but simple two-step approach based on random forests and partial least squares (PLS) dimension reduction embedding the idea of pre-validation suggested by Tibshirani and colleagues, which is based on an internal cross-validation for avoiding overfitting. Our approach is fast, flexible and can be used both for assessing the overall additional significance of the microarray data and for building optimal hybrid classification rules. Its efficiency is demonstrated through simulations and an application to breast cancer and colorectal cancer data. AVAILABILITY Our method is implemented in the freely available R package 'MAclinical' which can be downloaded from http://www.stat.uni-muenchen.de/~socher/MAclinical
Host–Multi-Pathogen Warfare: Pathogen Interactions in Co-infected Plants

Studies of plant–pathogen interactions have historically focused on simple models of infection involving single host-single disease systems. However, plant infections often involve multiple species and/or genotypes and exhibit complexities not captured in single host-single disease systems. Here, we review recent insights into co-infection systems focusing on the dynamics of host-multi-pathogen interactions and the implications for host susceptibility/resistance. In co-infection systems, pathogen interactions include: (i) Competition, in which competing pathogens develop physical barriers or utilize toxins to exclude competitors from resource-dense niches; (ii) Cooperation, whereby pathogens beneficially interact, by providing mutual biochemical signals essential for pathogenesis, or through functional complementation via the exchange of resources necessary for survival; (iii) Coexistence, whereby pathogens can stably coexist through niche specialization. Furthermore, hosts are also able to, actively or passively, modulate niche competition through defense responses that target at least one pathogen. Typically, however, virulent pathogens subvert host defenses to facilitate infection, and responses elicited by one pathogen may be modified in the presence of another pathogen. Evidence also exists, albeit rare, of pathogens incorporating foreign genes that broaden niche adaptation and improve virulence. Throughout this review, we draw upon examples of co-infection systems from a range of pathogen types and identify outstanding questions for future innovation in disease control strategies.
Heritage Management and Control

ABSTRACT Tourism is one of the most important economic activities. Historical heritage has been identified by both administrators and the private sectors as major touristic assets. It has been a myth that the more heritages a country own, the better it would be. Some recent reports, however, revealed that heritages, in fact, could be a burden to the concerned government and the economy. This paper is to review the situation in Egypt in relation to the issues of discovering, preserving and commercializing of historical heritages. The results of this study are expected to contribute to the community, which has the gift of heritage, and heritage preservation of Egypt and to the improvement of our knowledge of the discipline of tourism.
Are Contributors Rational? Untangling Strategies of Political Action Committees

Empirical public choice literature and casual observation suggest that the behavior of political action committees is remarkably unsophisticated, meaning that PACs give to those legislators who would support their interests anyway. Thus it is suggested that contributor behavior deviates from rational behavior, which is a cornerstone of economic analysis. In this paper, a switching regression model is estimated that allows for strategies of PACs to vary for different contribution recipients. I analyze the behavior of farm PACs over three election cycles. In contrast to previous findings, I find that contributor behavior is not inconsistent with rational behavior. Contributors who attempt to influence the voting behavior of members of Congress give the most money to legislators whose constituency interest suggests that they are likely to be undecided on how to vote and PACs give less money to legislators who represent districts with larger farm populations because those legislators are likely to vote in contributor interests anyway.
Dividend Changes, Earnings Reports, And Share Prices: Some Australian Findings

Australian companies typically announce profit figures and dividend payouts at the same time. During the 60's and early 70's, profit and dividend changes were positively correlated, and were associated with significant share price changes, after abstracting from market effects. When profit and dividend reports gave conflicting signals, share prices tended to decline.
FOUR RUMOURS AND AN EXPLANATION

Our analysis of 2207 domestic news reports in a structured sample of UK “quality” (the Guardian, The Times, the Independent and the Telegraph) and mid-market (Daily Mail) newspapers, revealed journalists’ extensive use of copy provided by public relations sources and news agencies, especially the UK-based Press Association. A political economic explanation for this reliance on news stories produced “outside the newsroom”, draws inspiration from Gandy's notion of information subsidies and presents findings from a substantive content analysis of selected UK national newspapers, interviews with journalists working on national titles and news agencies, as well as detailed archival analysis of UK newspaper companies’ annual accounts across 20 years to deliver information about newspapers’ profitability, their expansive editorial pagination as well as the number of journalists they employ. The argument here is that this reliance on public relations and news agency copy has been prompted by the need for a relatively stable community of journalists to meet an expansive requirement for news in order to maintain newspapers’ profitability in the context of declining circulations and revenues.
Business Model Innovation and Strategy Making Nexus: Evidence from a Cross‐Industry Mixed‐Methods Study

Theory discussing how to define and frame the relationship between the strategy making process (SMP) and business model innovation (BMI) is still incipient in the academic literature. Thus, this study aims at investigating the relationship between SMP and BMI by addressing (1) when firms engage in BMI within the overall SMP, and (2) how firms design a new business model (BM) or improve their current BM within the overall SMP. The research questions are tackled by means of a mixed‐method research, combining (1) a quantitative survey on 138 firms involved in SMP and BMI (to understand when BM design and improvement occur) and (2) a qualitative multiple‐case study focused on four firms (to address how BM design and improvement evolve). The findings empirically validate the arguments that BM design and improvement are more likely to be positioned in the strategic alternatives implementation step of the SMP, and BM is related to strategy execution; on top of this, light is shed on the inherent dynamics of the BMI process for different types of BMI.
Managerial views about dividend policy in Pakistan

Purpose - Very little is known about the influences on dividend decisions in Pakistan, despite the importance of the market in the region and the nation's non-standard tax system. This study therefore aims to provide detailed evidence regarding this issue by examining the views of those charged with the decisions in practice. Design/methodology/approach - The study reports the findings from interviews with 23 Pakistani company officials about influences on their firms' dividend policies. A semi-structured interview document was used to guide the discussions. The interviewees chosen ensure that a wide spread of professional and industrial backgrounds were covered in the study. Findings - The results suggest that, despite differences in environmental idiosyncrasies, the dividend decision-making process in Pakistani companies is similar in many important respects to that in the USA and other developed markets. However, unlike in earlier studies, the interviewees suggested that past dividends do not influence current dividend levels in Pakistan and respondents were not reluctant to announce news of a dividend cut; instead, firms focus only on current earnings and company liquidity when deciding on a disbursement level. Originality/value - The study suggests that views about dividends in Pakistan differ from those reported in other markets in a number of important respects. Some, but not all of this evidence relates to the Pakistan taxation system, where until very recently share dividends (as with all capital gains) were tax exempt.
Interactive Runtime Verification

Monitoring is the study of a system at runtime, looking for input and output events to discover, check or enforce behavioral properties. Interactive debugging is the study of a system at runtime in order to discover and understand its bugs and fix them, inspecting interactively its internal state. Interactive Runtime Verification (i-RV) combines monitoring and interactive debugging. We define an efficient and convenient way to check behavioral properties automatically on a program using a debugger. We aim at helping bug discovery while keeping the classical debugging techniques and interactivity, which allow understanding and fixing bugs.
From the Japanese Association of Medical Sciences

The Japanese Society of Pathology (JSP) marked its 100th anniversary in 2011. The JSP now has 4,189 members in total, including 3,436 physicians and 272 dentists. Academic council members who play a central role in the activities of this society total 1,478, and the executive board, consisting of 20 board members, formulates JSP policies. Candidates for board membership who are elected based on the votes of academic council members are appointed by JSP members at the annual meeting, and their term of office is 2 years. The JSP holds two annual meetings per year, i.e., one in spring and the other in autumn. The latter is a special session. The JSP has a variety of tasks including the development and support of deserving physicians through the education of medical school students, studies aimed at the elucidation of pathological conditions, and pathological diagnosis in medical institutions. In addition, autopsy occupies an important position in the education of both medical students and residents. These aspects of pathological science are indispensable for the maintenance and improvement of the quality of medical science and medical care in Japan. Thus, we consider the role of the JSP to be very significant. On the other hand, as for the human resources needed to perform these tasks, there are 1,478 academic council members consisting of experienced pathologists, and 2,123 pathological diagnosis specialists. The latter have passed the specialist examination and been accredited by the JSP, and are now working in more than 640 hospitals nationwide. The human resources carrying out the responsibilities in these various fields of pathology are educated and trained mainly in about 80 medical schools throughout the nation. In general, each medical school has two pathology courses, and, currently, virtually all university hospitals have a pathology department or a diagnostic pathology laboratory. These pathology departments or laboratories generally have 5 staff members at most, having a much smaller size than their European or North American counterparts. This constitutes a significant weakness in the field of pathology in our nation, particularly in the implementation of research and diagnosis. Therefore, an increase in the size, i.e., the number of young physicians specializing in pathology, is strongly desired. However, in actuality, the age distribution of JSP members is disproportionately skewed toward middle or more advanced ages, while there are ever fewer young physicians among pathology specialists, resulting in a progressive aging trend within this specialty (Fig. 1). An overview of each area of pathology is provided below.
Soft-tissue response to silicone and poly-L-lactic acid implants with a periodic or random surface micropattern.

Tissue reaction to biomaterials is dependent on properties such as surface topography. The aim of this study was to evaluate the tissue reaction around implants with different surface topographies. We made coin-shaped silicone and poly-L-lactic acid (PLLA) implants with double-sided parallel microgrooves (depth 1.0 microm; width 10.0 microm) and random roughness on a micrometer scale. The control implants were smooth. These implants were inserted into subcutaneous pockets created on the flanks of goats. After 1, 3, or 12 weeks, the goats were sacrificed and the implants retrieved and histologically processed. Light microscopic evaluation revealed the formation of fibrous tissue capsules around all implant materials. The PLLA did not visibly degrade during the study period. Histomorphometric analyses were performed on capsule thickness, capsule quality, and on the implant-tissue interface quality. Compared with the silicone implants, the capsules around the PLLA implants showed significantly better capsule quality. Compared to the smooth implants, the capsules around the microgrooved implants were thicker, but the capsules around the roughened implants were thinner. However, randomly roughened implant surfaces generally elicited a stronger and more prolonged inflammatory reaction compared to smooth and microgrooved implant surfaces. We conclude that the application of microgrooves or random surface roughness to polymer implants apparently does not have beneficial effects on peri-implant tissue healing.
Machine perfusion or cold storage in deceased-donor kidney transplantation.

BACKGROUND Static cold storage is generally used to preserve kidney allografts from deceased donors. Hypothermic machine perfusion may improve outcomes after transplantation, but few sufficiently powered prospective studies have addressed this possibility. METHODS In this international randomized, controlled trial, we randomly assigned one kidney from 336 consecutive deceased donors to machine perfusion and the other to cold storage. All 672 recipients were followed for 1 year. The primary end point was delayed graft function (requiring dialysis in the first week after transplantation). Secondary end points were the duration of delayed graft function, delayed graft function defined by the rate of the decrease in the serum creatinine level, primary nonfunction, the serum creatinine level and clearance, acute rejection, toxicity of the calcineurin inhibitor, the length of hospital stay, and allograft and patient survival. RESULTS Machine perfusion significantly reduced the risk of delayed graft function. Delayed graft function developed in 70 patients in the machine-perfusion group versus 89 in the cold-storage group (adjusted odds ratio, 0.57; P=0.01). Machine perfusion also significantly improved the rate of the decrease in the serum creatinine level and reduced the duration of delayed graft function. Machine perfusion was associated with lower serum creatinine levels during the first 2 weeks after transplantation and a reduced risk of graft failure (hazard ratio, 0.52; P=0.03). One-year allograft survival was superior in the machine-perfusion group (94% vs. 90%, P=0.04). No significant differences were observed for the other secondary end points. No serious adverse events were directly attributable to machine perfusion. CONCLUSIONS Hypothermic machine perfusion was associated with a reduced risk of delayed graft function and improved graft survival in the first year after transplantation. (Current Controlled Trials number, ISRCTN83876362.)
The Australian Union Merger Wave Revisited

What factors explain the Australian trade union merger wave between 1991 and 1994? Existing explanations largely attribute it to the pro-amalgamation policy of the Australian Council of Trade Unions (ACTU) and other union leaders, and to declining union membership and decentralised bargaining. This paper reviews discussion of the causes of mergers and publicly available evidence upon them. It concludes that current explanations of the merger wave are an over-simplification. The effects of ACTU leadership, official union policy, and members’ views are complex and not uniform and require more disaggregated analysis. Also, there has been a tendency to overstate the importance of membership decline and decentralised bargaining and to overlook other environmental factors such as changing occupational structure. The paper cautions against the assumption that variables influencing ACTU policy also shape affiliate actions.
Critical factors and results of quality management: An empirical study

Quality management theory has been influenced by the contributions from quality leaders, standardized quality models and empirical research. This has helped identifiy a set of critical factors for successful quality management implementation, as a way to improve customer satisfaction and performance. This study reviews the literature in order to identify the critical factors and results of quality management, using a factor analysis and, starting from this analysis, we also create a scale that can be empirically tested from the answers provided by those responsible for quality in 106 certified firms.
TRIP-Br Links E2F to Novel Functions in the Regulation of Cyclin E Expression During Cell Cycle Progression and in the Maintenance of Genomic Stability

The TRIP-Br family of transcriptional regulators (TRIP-Br1 and TRIP-Br2)has been proposed to function at E2F-responsive promoters to integrate regulatorysignals provided by PHD zinc finger- and/or bromodomain-containing transcriptionfactors. To characterize the TRIP-Br “integrator” function(s), we have employeddecoy peptides (*Br1 and *Br2) to antagonize the interaction between TRIP-Br1 orTRIP-Br2 and the PHD zinc finger and/or bromodomain of other transcriptionfactors. Antagonism of the TRIP-Br integrator function elicits anti-proliferativeeffects through the transcriptional downregulation of a subset of E2F-responsive genesin vivo, and induces aberrant cyclin E accumulation, leading to Geminin deregulationand caspase-3-independent cellular sub-diploidization. The observed cyclin Ederegulation is attributed to the downregulation of Fbxw7, which encodes the Fbw7receptor subunit of the SCFFBW7 ubiquitin ligase (E3) responsible for targeting cyclinE for proteolysis. Fbxw7 is identified herein as an E2F-responsive and TRIP-Br coregulatedgene. Our results demonstrate a physiologic role for TRIP-Br in couplingE2F to novel functions in the regulation of cyclin E expression during cell cycleprogression to ensure the proper execution of DNA replication and the maintenance ofgenomic stability.
The Analysis of Determinants of Public Transport Demand in the City of Perugia

There are several ways to promote public transport demand. Perugia achieved a leading national position in the last decade by a tariff reform and by developing an integrated local public transport network that includes lifts and escalators. Since 1996, the number of passengers has continually increased, with an increase in demand of 41%. This paper has two objectives. The first is to identify the factors underlying the performance of local public transport in Perugia. To this end, an aggregate demand function is estimated for bus and urban railway trips in order to present evidence on demand elasticities with respect to the main attributes of local public transport and to the socio-demographic characteristics of its users. The second aim is to evaluate the impact of the tariff reform and the consequences of the introduction of cards and multi-ride tickets by estimating a system of own- and cross-price elasticities for different ticket types.