bluuebunny/crossref_metadata_2025_split huggingface dataset:
Side-effects of checkpoint inhibitor-based combination therapy
Authors: Kourie Hampig R. , Klastersky Jean A. 
Published: April 2016

Purpose of review
After the dramatic and often long-standing response rates of checkpoint inhibitors as single agents, the new era for checkpoint inhibitors is combined therapy (either with other checkpoint inhibitors, chemotherapies, targeted therapies or immunotherapies) that is aiming to do even better. Although one can speculate that these combinations will result in improved results, high cost and potential toxicity are limiting factors for their use. In this review, we plan to report on the different side-effects of the checkpoint inhibitor-based combination therapies and to discuss the future perspectives of these new modalities.

Recent findings
Many checkpoint inhibitor-based combinations are associated with high response rates (>50%) in melanomas and nonsmall cell lung cancers (NSCLCs). As a result, the combination of nivolumab and ipilimumab for metastatic melanoma was recently approved by the Food and Drug Administration; however, 30% of the patients had to discontinue this combination because of high toxicity. In NSCLC, the combination of chemotherapy and anti-programmed cell death protein 1 or anti-programmed cell death protein ligand 1 agents is leading to high response rate (exceeding 65%) but with more than 40% of the patients presenting grade 3/4 toxicities. Despite the discouraging results with the combination of ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) with vemurafenib (anti-proto-oncogene protein B-raf-targeted therapy) due to hepatotoxicity, more recent trials are showing less frequent and severe toxicities with other combinations of checkpoint inhibitors and targeted therapies.

Summary
Despite the high toxicity rates observed with some checkpoint inhibitor-based combination therapies, these combinations will likely become the new paradigm for the management of various malignancies, namely, melanomas, renal cell carcinomas and NSCLC, provided that their side-effects can be effectively managed.
Dipeptidyl peptidase-4 inhibitor use is not associated with elevated risk of severe joint pain in patients with type 2 diabetes: a population-based cohort study
Authors: Hou Wen-Hsuan , Chang Kai-Cheng , Li Chung-Yi , Ou Huang-Tz 
Published: April 2016

Abstract
This is the first large longitudinal cohort study to investigate the putative association of severe joint pain (SJP) with dipeptidyl peptidase-4 inhibitor (DPP4i) use in patients with type 2 diabetes. The propensity score-matched population-based cohort study was performed between 2009 and 2013 in a group of type 2 diabetes patients with stable metformin use. In total, 4743 patients with type 2 diabetes used a DPP4i as the second-line antidiabetic drug (ie, DPP4i users), and the same number of matched non-DPP4i users was selected. The 2 study groups were followed up until SJP diagnosis (International Classification of Diseases, Ninth Reversion, Clinical Modification code 719.4), health insurance policy termination, or the end of 2013. The incidence rate of SJP was estimated under the Poisson assumption. Multiple Cox proportional hazard model was used to estimate the covariate-adjusted hazard ratio and 95% CI of SJP in association with DPP4i use. Over a maximum follow-up of 5 years, 679 DPP4i users and 767 non-DPP4i users were newly diagnosed with SJP, representing incidence rates of 47.20 and 50.66 per 1000 person-years, respectively. Cox proportional hazard model indicated that DPP4i use slightly but nonsignificantly reduced the risk of SJP (adjusted hazard ratio: 0.92 [95% CI: 0.83-1.02]). Such null results were also observed among all age and sex stratifications and in a sensitivity analysis using all nonspecific arthropathies as the study endpoint. This study provides no support for the putative risk of SJP related to DPP4i use in type 2 diabetes patients during a maximum follow-up of 5 years.
Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders
Authors: Chiang Mark Y. , Radojcic Vedran , Maillard Ivan 
Published: April 2016

Purpose of review
This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses the therapeutic potential of Notch inhibition.

Recent findings

NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B-cell malignancies truncate the C-terminal proline (P), glutamic acid (E), serine (S), threonine (T)-rich (PEST) domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein–protein interactions at Notch-dependent superenhancers that underlie oncogenic Notch functions.

Summary
Notch signaling is a recurrent oncogenic pathway in multiple T- and B-cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.
Allergan Style 410 Implants for Breast Reconstruction: A Prospective Study in Efficacy, Safety, and Symmetry
Authors: Unger Jacob G. , Carreras Jennel M. , Nagarkar Purushottam , Jeong Haneol S. , Carpenter William 
Published: April 2016

Background:
Implant-based breast reconstruction is performed with both saline and silicone. In 2001, a study was conducted in which a novel implant made of highly cohesive silicone gel in anatomical shape was used. It differs from others because it holds its anatomical shape and forces tissue to conform to the implant.

Methods:
Two hundred twelve consecutive patients who underwent reconstruction with Allergan 410 cohesive gel anatomical implants were enrolled prospectively over a 12-year period. Complications and satisfaction rates were recorded.

Results:
Average age of the patients was 48.5 years and average body mass index was 24.1 kg/m2. Bilateral reconstruction was performed in 83 percent of patients. Long-term follow-up was achieved in all patients and averaged 3.3 years (range, 0.5 to 10.2 years). The overall complication rate was 19.8 percent; most were minor complications, such as rippling (9.4 percent) and asymmetry (4.2 percent). Major complications included infection (2.4 percent), malposition (1.4 percent), capsular contracture (0.9 percent), seroma (0.5 percent), extrusion (0.5 percent), and implant rupture (0.5 percent). The rate of implant-related reoperation, excluding cancer recurrence, was 9.0 percent, consisting of implant replacement (5.7 percent), implant removal (1.9 percent), and implant repositioning (1.4 percent). Patient satisfaction averaged 4.83 (range, 2 to 5) on a five-point scale. Surgeon satisfaction averaged 4.9 (range, 2 to 5).

Conclusions:
Allergan 410 cohesive gel anatomical implants have a favorable risk profile in reconstruction, with excellent patient and surgeon satisfaction. This novel implant allows for a paradigm shift in implant-based breast reconstruction. Surgeons can now use an implant to help shape the final contour of the breast mound rather than rely on mastectomy flaps and suture techniques to create aesthetic contours needed to create an attractive breast reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, IV.
Subcortical source and modulation of the narrowband gamma oscillation in mouse visual cortex
Authors: Saleem Aman B , Lien Anthony D , Krumin Michael , Haider Bilal , Rosón Miroslav Román , Ayaz Asli , Reinhold Kimberly , Busse Laura , Carandini Matteo , Harris Kenneth D 
Published: April 2016

SummaryPrimary visual cortex (V1) exhibits two types of gamma rhythm: broadband activity in the 30–90 Hz range, and a narrowband oscillation seen in mice at frequencies close to 60 Hz. We investigated the sources of the narrowband gamma oscillation, the factors modulating its strength, and its relationship to broadband gamma activity. Narrowband and broadband gamma power were uncorrelated. Increasing visual contrast had opposite effects on the two rhythms: it increased broadband activity, but suppressed the narrowband oscillation. The narrowband oscillation was strongest in layer 4, and was mediated primarily by excitatory currents entrained by the synchronous, rhythmic firing of neurons in the lateral geniculate nucleus (LGN). The power and peak frequency of the narrowband gamma oscillation increased with light intensity. Silencing the cortex optogenetically did not affect narrowband oscillation in either LGN firing or cortical excitatory currents, suggesting that this oscillation reflects unidirectional flow of signals from thalamus to cortex.Highlights•Local field potential in mouse primary visual cortex exhibits a pronounced narrowband gamma oscillation close to 60 Hz.•Narrowband gamma is highest in the thalamorecipient layer 4•Narrowband gamma increases with light intensity and arousal state, and is suppressed by visual contrast.•Lateral geniculate nucleus neurons fire synchronously at the narrowband gamma frequency, independent of V1 activity.
Urbanization drives parallel adaptive clines in plant populations
Authors: Thompson Ken A. , Renaudin Marie , Johnson Marc T.J. 
Published: April 2016

AbstractUrban areas are a new and increasingly dominant feature of terrestrial landscapes that dramatically alter environments. It is unclear whether wild populations can adapt to the unique challenges presented by urbanization. To address this problem, we sampled the frequency of a Mendelian-inherited trait—cyanogenesis—in white clover (Trifolium repensL.) plants along urbanization gradients in four large cities. Cyanogenesis protects plants from herbivores, but also reduces freezing tolerance. Plants evolved reduced cyanogenesis with increasing proximity to the urban center in three of the four cities. In an experiment, we demonstrate that gradients in herbivore pressure do not cause these clines. Instead, urban areas experience relatively cold minimum winter ground temperatures because of reduced snow cover within cities, which selects against cyanogenesis. Together, our study demonstrates that wild populations exhibit parallel adaptive evolution in response to urbanization, which likely facilitates the persistence of these plants and promotes pollinator abundance and diversity.
A qualitative model of the rod photoreceptor in natural context
Authors: Dubuc Timothée T. , Roesch Etienne B. 
Published: April 2016

AbstractGiven the intricacies of the retinal neural circuit, which bears a striking resemblance to that of the brain, it is proposed that retinal function goes beyond mere spatiotemporal prefiltering. We hypothesise that aspects related to motion detection and discrimination, anticipation and adaptation to environmental and contextual conditions, which have traditionally been ascribed to the brain, may be supported by neurons in the retina. Such early computations may be dependent on compensative and adaptive mechanisms that stem from qualities intrinsic to the retinal neural circuit and its interaction with the environment (neural transduction time, connectivity patterns, regularities in the input signal, temporal dynamics and light variations).With a view to investigating the contribution of the photoreceptor population to the processing performed by the retina in natural scotopic conditions, we present a continuous model of the rod photoreceptor. Our model permits the reproduction and exploration of a set of qualitative features displayed in vitro, such as excitation-dependent activation level and time-to-membrane current integration. We captured qualitative aspects of key features selected for their presumed importance in early visual function. Further, we subjected our model to extensive parameter sensitivity analyses, aiming to provide a visual representation of their contribution to the observed qualitative behavior.Author SummaryPrimate rod photoreceptor cells constitute the very first processing step in retinal function. This layer influences most of the visual field and presents itself as a tightly packed photosensitive array. Yet, no computational formulation of this neuron is suited for large-scale, time continuous modeling. With a view to studying retinal function in natural contexts, we describe a qualitative, continuous model of the rod. We subject this model to parameter analyses against selected behavioral features. We aim to provide a model that can integrate in further experiments, as well as in large scale network simulation.
Shhand ZRS enhancer co-localisation is specific to the zone of polarizing activity
Authors: Williamson Iain , Lettice Laura A. , Hill Robert E. , Bickmore Wendy A. 
Published: April 2016

AbstractLimb-specificShhexpression is regulated by the (~1 Mb distant) ZRS enhancer. In the mouse, limb bud restricted spatiotemporal expression ofShhoccurs from ~E10-E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation ofShhin expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies ofShh/ZRS co-localisation only in theShhexpressing regions of the limb bud. However,Shh-ZRS spatial distances were consistently shorter than intervening distances to a neural enhancer in all tissues and developmental stages analysed. 5C identified a topologically associating domain (TAD) over theShh/ZRS genomic region and enriched interactions betweenShhand ZRS throughout E11.5 embryos.Shh/ZRS co-localisation, therefore, correlates with the spatiotemporal domain of limb bud-specificShhexpression, but closeShh/ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigateShhexpression.
Boards attributes that increase firm risk – evidence from the UK
Authors: Mathew Sudha , Ibrahim Salma , Archbold Stuart 
Published: April 2016

PurposeThe purpose of this paper is to identify the board attributes that significantly increase firm risk. The study aims to find whether board size, percentage of non-executive directors, women on the board, a powerful chief executive officer, equity ownership amongst executive board directors and institutional investor ownership are associated with firm risk. This is the first study that examines which board attributes increase firm risk using a UK-based sample.Design/methodology/approachThis empirical study collected secondary data from Bloomberg and Morningstar databases. The data sample is an unbalanced panel of 260 companies’ secondary data on FTSE 350 index in the UK, from 2005 to 2010. The data were statistically analysed using STATA.FindingsThe study establishes the board attributes that were significantly related to firm risk. The results show that a board which can increase firm risk is one that is small in size, has high equity ownership amongst executive board directors and has high institutional investor ownership.Research limitations/implicationsThe governance culture and regulatory system in the UK is different from other countries. As the data are a UK-based sample, the results can lack generalisability.Practical implicationsThe results are useful for investors who invest in large firms, to have the knowledge about the board attributes that can increase firm risk. Regulators can also use the results to strengthen regulatory guidelines.Originality/valueThis study fills the gap in knowledge in UK governance literature on the board attributes that can increase firm risk.
TDAS: a touch dynamics based multi-factor authentication solution for mobile devices
Authors: Teh Pin Shen , Zhang Ning , Teoh Andrew Beng Jin , Chen Ke 
Published: April 2016

Purpose
The use of mobile devices in handling our daily activities that involve the storage or access of sensitive data (e.g. on-line banking, paperless prescription services, etc.) is becoming very common. These mobile electronic services typically use a knowledge-based authentication method to authenticate a user (claimed identity). However, this authentication method is vulnerable to several security attacks. To counter the attacks and to make the authentication process more secure, this paper aims to investigate the use of touch dynamics biometrics in conjunction with a personal identification number (PIN)-based authentication method, and demonstrate its benefits in terms of strengthening the security of authentication services for mobile devices.

Design/methodology/approach
The investigation has made use of three light-weighted matching functions and a comprehensive reference data set collected from 150 subjects.

Findings
The investigative results show that, with this multi-factor authentication approach, even when the PIN is exposed, as much as nine out of ten impersonation attempts can be successfully identified. It has also been discovered that the accuracy performance can be increased by combining different feature data types and by increasing the input string length.

Originality/value
The novel contributions of this paper are twofold. Firstly, it describes how a comprehensive experiment is set up to collect touch dynamics biometrics data, and the set of collected data is being made publically available, which may facilitate further research in the problem domain. Secondly, the paper demonstrates how the data set may be used to strengthen the protection of resources that are accessible via mobile devices.
Midstream social marketing intervention to influence retailers’ compliance with the minimum legal drinking age law
Authors: Kamin Tanja , Kokole Daša 
Published: April 2016

Purpose
Alcohol availability is strongly related to excessive alcohol consumption. This study aims to examine social marketing’s response to concerns about retailers’ noncompliance with the minimum legal drinking age (MLDA) law by proposing and evaluating a social marketing intervention directed at sellers in off-premise stores.

Design/methodology/approach
The study is based on a non-randomized quasi-experimental design, focusing on an evaluation of the implementation of the “18 rules!” intervention in four cities in Slovenia. Two waves of underage purchase attempts were conducted pre- and post-intervention in 24 off-premise businesses, following a mystery shopping protocol.

Findings
The initial rate of retailers’ noncompliance with the MLDA law in off-premise establishments was high. After the social marketing intervention, an increase with compliance with the law was observed; the proportion of cashiers selling alcohol to minors after the intervention decreased from 96 to 67 per cent. Qualitative insight suggests an existence of retailers’ dilemma in complying with the MLDA.

Research limitations/implications
A social marketing approach could contribute to a better understanding of the social working of the MLDA law.

Practical implications
A social marketing approach could complement the usual enforcement strategies and contribute to a better understanding of the social working of the MLDA law, and encourage deliberate retailers’ compliance with it while developing valuable exchanges among people and stakeholders.

Originality/value
The paper conceptualizes retailers’ dilemma in complying with the minimal legal drinking age law and offers social marketing response to it. Results of the study show that also solely non-coercive measures have the potential in increasing retailers’ compliance with regulations.
Leaf traits of African woody savanna species across climate and soil fertility gradients: evidence for conservative versus acquisitive resource‐use strategies
Authors: Wigley Benjamin J. , Slingsby Jasper A. , Díaz Sandra , Bond William J. , Fritz Hervé , Coetsee Corli 
Published: April 2016

SummaryEstablishing trade‐offs among traits and the degree to which they covary along environmental gradients has become a key focal point in the effort to develop community ecology into a predictive science. While there is evidence for these relationships across global data sets, they are often too broad in scale and do not consider the particularities of local to regional species pools. This decreases their usefulness for developing predictive models at scales relevant for conservation and management.We tested for trade‐offs between traits and relationships with environmental gradients in trees and shrubs sampled across southern African savannas and explored evidence for acquisitive versus conservative resource‐use strategies using a phylogenetically explicit approach.We found a distinct trade‐off between two major poles of specialization indicative of acquisitive (high leaf nitrogen concentration, leaf phosphorus concentration, leaf N:P, specific leaf area and average leaf area) and conservative resource‐use strategies (high leaf carbon to nitrogen ratios (C:N), tensile strength and leaf dry matter content). Although we found that trait variance and species occurrence were constrained by phylogeny, phylogenetically informed analyses did not contradict non‐phylogenetic analyses, strengthening relationships in most cases.The high intrasite trait variability and weak relationships with soils and climate may in part be explained by the high levels of deciduousness and disturbance (i.e. fire and herbivory) inherent in African savannas.Synthesis. The relationships between traits and between traits and environmental gradients were far weaker than, and often contradictory to, broad‐scale studies that compare these relationships across biomes and growth forms, cautioning against making generalizations about relationships at specific sites based on broad‐scale analyses.