Miracle-dz/UniFAR-FTUs huggingface dataset:
Randomized Phase II Multicenter Trial of Two Schedules of Lapatinib as First- or Second-Line Monotherapy in Patients with Advanced or Metastatic Non–Small Cell Lung Cancer

Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49
The mucopolysaccharidoses: a clinical review and guide to management.

The mucopolysaccharidoses are a group of inherited metabolic disorders caused by a deficiency of specific lysosomal enzymes. The enzyme deficiency results in interference with cellular function because of excess accumulation within the cells of partially degraded glycosaminoglycans (GAGS), which are also excreted to excess in the urine of affected patients. Although the mucopolysaccharidoses were first described clinically by Hunter in 1917, their biochemical basis was not fully elucidated until the 1950s and 1960s. More recently the molecular biology of many of the subtypes has been described.1 The ubiquitous nature of GAGS within the connective tissue of the body results in a wide range of clinical effects. The type of GAG stored depends on the specific enzyme deficiency and classification of the disorders is now based upon these deficiencies, rather than clinical features. The table outlines present day classification with details of the accumulating compounds and enzyme deficiencies, as well as the eponym used for each condition. Excellent accounts of the biochemical basis of the mucopolysaccharidoses are available and this area will not be considered further. In keeping with many other multisystem disorders affected patients are often under the Willink Biochemical care ofmany different clinicians and coordinaGenetics Unit, Royal tion of care can be difficult. A special clinic for Manchester Children's Hospital, Pendlebury, children with mucopolysacchardoses has been Manchester M27 4HA established in the Willink Biochemical Genetics Unit and this review outlines importCorrespondence to: Dr Wraith. ant management issues that occur with each
Protective immunity against toxoplasmosis in mice induced by single-dose immunization with rSAG1/2 protein released from poly(lactide-co-glycolide) microparticles

Triphasic sustained release of tachyzoite chimeric protein, rSAG1/2, from poly(lactide-co-glycolide) (PLG)-encapsulated rSAG1/2 (PLG-rSAG1/2) microparticles (MPs) is a promising characteristic for developing a single-dose vaccine against Toxoplasma gondii in domestic animals. In the present study, we aimed to evaluate whether single immunization with PLG-rSAG1/2 MPs in BALB/c mice would achieve effective immunity and protection against T. gondii. Peritoneal immunization of mice with a single dose of PLG-rSAG1/2 MPs enhanced serum IgG titers and lymphocyte proliferation in a triphasic model over a long 12-week period. In addition, 12 weeks after immunization, significant production of IFN-γ was also monitored in mice vaccinated with one dose of PLG-rSAG1/2 MPs. More importantly, the immunity induced by one dose of PLG-rSAG1/2 MPs protected 70% of mice (14/20) against a lethal subcutaneous challenge of 1 × 104 live tachyzoites of T. gondii (RH strain). In conclusion, a single dose of PLG-rSAG1/2 MPs capable of sustaining triphasic release of rSAG1/2 protein induces long-lasting triphasic immunity against T. gondii in mice. Our data indicate the feasibility of PLG-rSAG1/2 MPs to be developed as a single-dose vaccine against T. gondii for potential use in domestic animals.
Party Size and Portfolio Payoffs: The Proportional Allocation of Ministerial Posts in Coalition Governments

Over 30 years ago, Eric Browne and Mark Franklin demonstrated that parties in a coalition tend to receive portfolio payoffs in almost perfect proportionality to their seat share. Even though this result has been confirmed in several studies, few researchers have asked what the underlying mechanism is that explains why parties receive a proportional payoff. The aim of this paper is to investigate the causal mechanism linking party size and portfolio payoffs. To fulfil this aim, a small-n analysis is performed. By analysing the predictions from a statistical analysis of all post-war coalition governments in 14 Western European countries, two predicted cases are selected, the coalitions that formed after the 1976 Swedish election and the 1994 German election. In these case studies two hypotheses are evaluated: that the proportional distribution of ministerial posts is the result of a social norm, and that parties obtain payoffs according to their bargaining strength. The results give no support to the social norm hypothesis. Instead, it is suggested that proportionality serves as a bargaining convention for the actors involved, thus rendering proportional payoffs more likely.
Unleashing the immune response against childhood solid cancers

Tumor immunotherapy has come to the fore fuelled by impressive clinical responses to checkpoint inhibitor antibodies in a range of adult malignancies and by the success of chimeric antigen receptor T cells targeting adult and pediatric B‐cell malignancies. Clearly, if appropriately fine‐tuned, the immune system has the capability to seek out and destroy cancer. Studies in pediatric solid cancers so far have not shown the therapeutic potential checkpoint inhibitors described in adult cancers and this may reflect fewer tumor‐associated antigens or different immune evasion mechanisms. One potential approach to overcome these limitations will be to combine interventions to undermine immune evasion mechanisms with engineered T‐cell adoptive transfer.
Exploring Web Partition in DHT-Based Distributed Web Crawling

The basic requirements of the distributed Web crawling systems are: short download time, low communication overhead and balanced load which largely depends on the systems' Web partition strategies. In this paper, we propose a DHT-based distributed Web crawling system and several DHT-based Web partition methods. First, a new system model based on a DHT method called the Content Addressable Network (CAN) is proposed. Second, based on this model, a network-distance-based Web partition is implemented to reduce the crawler-crawlee network distance in a fully distributed manner. Third, by utilizing the locality on the link space, we propose the concept of link-based Web partition to reduce the communication overhead of the system. This method not only reduces the number of inter-links to be exchanged among the crawlers but also reduces the cost of routing on the DHT overlay. In order to combine the benefits of the above two Web partition methods, we then propose 2 distributed multi-objective Web partition methods. Finally, all the methods we propose in this paper are compared with existing system models in the simulated experiments under different datasets and different system scales. In most cases, the new methods show their superiority.
Empirical Matching Functions: Searchers, Vacancies, and (Un-)Biased Elasticities

This paper shows that conventional empirical estimates of matching functions are systematically biased, because unobservable and endogenous search behaviour, such as on-the-job search by workers or the use of different search channels by firms, is neglected. I propose an approach for recovering unbiased elasticities under different scenarios of competition for workers and jobs without the need for constructing proxies for unobserved stocks of searchers and vacancies. Using German administrative data, I estimate the biases affecting conventional studies and derive bias-corrected estimates of the matching elasticities under different scenarios.
A comparison of spirometric measurements in allergen bronchial challenge testing

We compared the usefulness of several spirometric measurements in detecting asthmatic reactions after allergen bronchial challenge in fourteen asthmatic children. All of the children had a history suggesting mite‐induced asthma and eleven had a 3 mm or larger diameter weal on prick testing with Dermatophagoides farinae extract. On bronchial challenge testing with dilutions of this extract twelve children had an early asthmatic reaction and nine had a late asthmatic reaction. In decreasing order of sensitivity for detecting the early asthmatic reaction the tests ranked as follows: FEV1, FEF50%, FEF25‐75%, PEFR and FVC. For the late asthmatic reaction the order was FEF50% FEV1, FEF25‐75%, PEFR and FVC. No single test identified all the early or all the late reactions but the FEV1, a test useful for indicating large airways obstruction, when combined with the FEF25‐75%, a test influenced by small airways obstruction, detected all early and late asthmatic reactions. The FEF50%, was a sensitive test but was the only one to become falsely positive. It became falsely positive in four patients. Although the FEV1, was the most useful single test the results suggest that it is, by itself, an inadequate indicator of the asthmatic reaction and that it should be used with the FEF25‐75%, to ensure the detection of all asthmatic reactions induced by allergen bronchial challenge testing.
Endogenous Deposit Dollarization

This paper explores sources of deposit dollarization unrelated to standard moral hazard arguments.We argue that the equal treatment of peso and dollar claims on a bank in the event of default can induce banks to attract dollar deposits above the socially desirable level. The distortion arises because dollar depositors are the only source of default risk in the model, but they share the burden of the default with peso depositors as interest rates cannot be set contingent to the (unobserved) level of deposit dollarization. The incentive to dollarize is reinforced by common banking system safety nets such as deposit and bank insurance. Our findings suggest that regulators in bi-currency economies should depart from the currency-blind benchmark and instead distinguish across currencies in a way that prevents undesirable currency mismatches, even in the absence of moral hazard related to the relaxation of market discipline.
The Nuclear Envelope Protein Emerin Binds Directly to Histone Deacetylase 3 (HDAC3) and Activates HDAC3 Activity*

Background: Emerin regulates the expression of a large number of genes. Results: Emerin binds HDAC3, mediates its nuclear envelope localization, and activates HDAC3 activity. Conclusion: Decreased HDAC3 activity may contribute to changes in genomic organization seen in emerin-null cells. Significance: These studies uncovered a putative mechanism for initiating and maintaining repressed genes at the nuclear periphery. Organization of the genome is critical for maintaining cell-specific gene expression, ensuring proper cell function. It is well established that the nuclear lamina preferentially associates with repressed chromatin. However, the molecular mechanisms underlying repressive chromatin formation and maintenance at the nuclear lamina remain poorly understood. Here we show that emerin binds directly to HDAC3, the catalytic subunit of the nuclear co-repressor (NCoR) complex, and recruits HDAC3 to the nuclear periphery. Emerin binding stimulated the catalytic activity of HDAC3, and emerin-null cells exhibit increased H4K5 acetylation, which is the preferred target of the NCoR complex. Emerin-null cells exhibit an epigenetic signature similar to that seen in HDAC3-null cells. Emerin-null cells also had significantly less HDAC3 at the nuclear lamina. Collectively, these data support a model whereby emerin facilitates repressive chromatin formation at the nuclear periphery by increasing the catalytic activity of HDAC3.
The Sendai virus nucleocapsid exists in at least four different helical states

Sendai virus nucleocapsids have been observed by electron microscopy to coexist in three different helical pitch conformations, 5.3, 6.8, and 37.5 nm. The 5.3- and 6.8-nm conformations are present both in uranyl acetate negatively stained preparations and in tantalum-tungsten metal-shadowed preparations, whereas the 37.5-nm conformation, which has not been previously reported, is present only in the shadowed preparations. The 5.3-nm pitch conformation appears to be a mixture of two discrete structural states, with a small difference in the twist of the structure between the two. We have used image reconstruction techniques on an averaged data set from eight negatively stained nucleocapsids to produce a three-dimensional reconstruction at 2.4-nm resolution of the structure in one of the 5.3-nm pitch states. There are 13.07 nucleocapsid protein (NP) subunits in each turn of the helix in this state. The helical repeat is 79.5 nm, containing 196 subunits in 15 turns of the left-handed 5.3-nm helix. The arrangement of subunits produces a 5.0-nm-diameter hollow core which forms an internal helical groove. The RNA accounts for about 3% of the mass of the nucleocapsid, and so its location is not conspicuous in the reconstruction. Because of the RNA remains associated with the NP subunits during mRNA transcription and genome replication, structural transitions in the nucleocapsid may determine the accessibility of the genome to polymerases. Alternatively, the large hollow core and internal helical groove we have reconstructed may allow access to the RNA even in the tightly coiled 5.3-nm pitch conformation.
Spillover effects and dynamic correlations between spot and forward tanker freight markets

Monitoring and analysing information transmission across different shipping markets is an important tool for participants to predict shipping freight rates, design portfolio investments and manage freight rate risks. The purpose of this article is to investigate spillover effects and dynamic correlations between shipping spot and derivatives markets (tanker forward freight agreement, FFA) under the multivariate generalized autoregressive conditional heteroscedasticity framework. Empirical results show that spillovers in returns are unilateral from one-month FFA to spot markets, while they are bilateral between one-month and two-month FFA markets. However, insignificant mean spillovers between spot and two-month FFA markets are found. Volatility spillover effects among one-month FFA, two-month FFA and spot freight markets are bilateral. By analysing the correlation between different markets, highly persistent and significantly volatile correlations are found. Moreover, time-varying correlations between one-month and two-month FFA markets are much higher than those of between spot and each FFA market. Results from this article will be helpful to improve participants’ predictions of return, volatility and correlation, which are significant for determining hedge strategies. In addition, the management of freight rate risk and portfolio investment can also benefit from the empirical results obtained in this article.
The contribution of genetics to milk composition: evidence from Spain

This article focuses on the role that genetic progress may play in improving milk quality. Despite important genetic advances in dairy production, the absence of genetic records in farm management databases has precluded empirical production models from explicitly accounting for differences in genetics across herds. The influence of genetics on milk composition is analyzed by splitting milk production into protein, fat, and other components. The article explores some modeling issues associated with the specification of the effect of genetics in this multi-output technology framework. In particular, genetic indexes are considered as allocable inputs and the remaining inputs as nonallocable. Our results show that genetics have a significant impact on milk composition. In particular, we find that farmers’ income increases by 6.6% when genetic indexes are augmented by one sample standard deviation.
Autonomous spatial orientation in patients with mild to moderate Alzheimer's disease by using mobile assistive devices: a pilot study.

BACKGROUND/OBJECTIVE Spatial orientation declines early in patients with Alzheimer's disease (AD) and is a major cause for institutionalization of patients. METHODS Use of either an aerial map or an assistive device to get from start to goal zone, both located on the campus of the hospital (distance between start and goal zone 300 m to 500 m). Use of the assistive device was trained for 15 minutes prior to the task. RESULTS We assessed 14 patients with mild to moderate AD (DSM-IV and NINCDS-ADRDA criteria; 9 female patients, 5 male patients; age 71.9 ± 7.4 years; MMSE 21.7 ± 2.9 (mean ± SD), range 16-26). Each patient had to find the way for three different routes with different start and goal zones. None of the patients found their way to the goal zone for any of the routes when using an aerial map in which the way was highlighted. With use of the assistive device, patients found their way from start to goal zones autonomously for 20 of 42 routes (3 routes each for 14 patients). For 22 of 42 routes intermediate re-assurance was necessary, but herewith routes were completed. CONCLUSION This study lays ground for the use of mobile technical devices in patients with mild to moderate AD. Mobile assistive devices may enable patients with mild to moderate AD to maintain autonomous spatial orientation in unfamiliar environments. Improvement of the familiarization of patients with the device and further sophistication of assistive cues is likely to further improve autonomous use of navigational devices in patients with mild to moderate AD.
Performance Impact of User Grouping on Fractional Power Loading in the OFDMA Downlink

In the OFDMA-based downlink of wireless communication networks, in order to counteract the strong influence of multi-cell interference on the cell edge users, the so-called fractional power loading strategy was proposed. The key idea is to divide the whole frequency band into two parts, one part has lower transmission power, the other has higher transmission power and is orthogonal in the neighboring cells. With such power allocation, a natural thinking is to schedule the cell edge users onto the high power band, and to schedule the cell center users onto the other. Such strategy leads to the partitioning of users into the cell center/edge user groups. This paper proposes a way to do dynamic user grouping, and compares the cell performance for elastic traffic, with and without the user grouping. Extensive system level simulations with multi-channel proportional fair scheduler are conducted to reveal the effect of user grouping on the scheduler performance and QoS fulfillment.
University challenge: sharing some experiences of engaging with industry

Purpose – This paper aims to share the experiences of one team working in management education for hospitality practitioners in a UK context, a setting in which the primacy of employers – as the key stakeholder in education provision – has been articulated for three decades.Design/methodology/approach – The paper undertakes a literature review exploring practitioner education and the stakeholders in the UK settings, and presents a study of the approach taken at one university.Findings – Despite being the dominant factor in this mono‐stakeholder approach in training policy provision and delivery employers continue to complain of skill shortage and difficulties when recruiting for skilled hospitality jobs. At heart, the problem rests with the assumption that skill needs are the same for all employers and that all employers know what skills they need and will need in the future. The paper also provides insights into one team's experiences of working exclusively with commercial clients.Research limitations/im.
A Debt-owing Democracy: The Political Impact of Housing Market Recession at the British General Election of 1992

The 1992 British general election took place in the context of a severe housing recession which hit hardest in those regions from which the government usually drew much of its electoral support. The slump notwithstanding, however, the government went on to win its fourth successive election victory. The paper investigates the impact of the housing recession on the geography of the vote at the 1992 general election. Party fortunes were linked to local housing market conditions, and the failure of the housing market was a factor in reducing support for the government. Negative equity is identified as a particularly important problem in this regard.
Developing a brand structure pyramid model for travel-related online social networks

Purpose – The aim of this paper is to develop a comprehensive model that combines brand awareness, brand image, brand emotional attachment, brand evaluation and also shows how these constructs affect e-loyalty through the use of travel-related online social network (OSN) websites. Design/methodology/approach – Based on an in-depth literature review, a conceptual e-loyalty model was developed. Empirical data were collected through a web-based questionnaire from 236 respondents. A structural equation modeling was utilized to test the e-loyalty model. Findings – Results indicate that brand awareness positively affects brand image. Brand awareness directly and indirectly influences brand emotional attachment and brand evaluations. The total effects of brand awareness and brand image suggest that higher awareness level and positive image encourage OSN users to be more loyal. In return, this increases the probability that OSN members will repurchase through the OSN websites that they are emotionally connected w.