bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Hybrid Iron Regulation Network Combines Features from Pathogenic and Nonpathogenic Yeasts
Authors: Gerwien Franziska , Safyan Abu , Wisgott Stephanie , Hille Fabrice , Kaemmer Philipp , Linde Jörg , Brunke Sascha , Kasper Lydia , Hube Bernhard 
Published: October 2016

ABSTRACT

Iron is an essential micronutrient for both pathogens and their hosts, which restrict iron availability during infections in an effort to prevent microbial growth. Successful human pathogens like the yeast
Candida glabrata
have thus developed effective iron acquisition strategies. Their regulation has been investigated well for some pathogenic fungi and in the model organism
Saccharomyces cerevisiae
, which employs an evolutionarily derived system. Here, we show that
C. glabrata
uses a regulation network largely consisting of components of the
S. cerevisiae
regulon but also of elements of other pathogenic fungi. Specifically, similarly to baker’s yeast, Aft1 is the main positive regulator under iron starvation conditions, while Cth2 degrades mRNAs encoding iron-requiring enzymes. However, unlike the case with
S. cerevisiae
, a Sef1 ortholog is required for full growth under iron limitation conditions, making
C. glabrata
an evolutionary intermediate to
SEF1
-dependent fungal pathogens. Therefore,
C. glabrata
has evolved an iron homeostasis system which seems to be unique within the pathogenic fungi.

IMPORTANCE
The fungus
Candida glabrata
represents an evolutionarily close relative of the well-studied and benign baker’s yeast and model organism
Saccharomyces cerevisiae
. On the other hand,
C. glabrata
is an important opportunistic human pathogen causing both superficial and systemic infections. The ability to acquire trace metals, in particular, iron, and to tightly regulate this process during infection is considered an important virulence attribute of a variety of pathogens. Importantly,
S. cerevisiae
uses a highly derivative regulatory system distinct from those of other fungi. Until now, the regulatory mechanism of iron homeostasis in
C. glabrata
has been mostly unknown. Our study revealed a hybrid iron regulation network that is unique to
C. glabrata
and is placed at an evolutionary midpoint between those of
S. cerevisiae
and related fungal pathogens. We thereby show that, in the host, even a successful human pathogen can rely largely on a strategy normally found in nonpathogenic fungi from a terrestrial environment.
Volunteering and overseas placements in the NHS: a survey of current activity
Authors: Chatwin John , Ackers Louise 
Published: October 2016

ObjectiveThe study aimed to establish current levels of overseas volunteering and placement activity across all staff grades within the National Health Service (NHS) in the North West of England.DesignCross-sectional survey.InstrumentDescriptive statistics.Setting4 main regional hospitals in the North West of England, and additional NHS staff training events.ParticipantsConvenience sample of NHS staff (n=911).Results911 NHS staff took part in the survey. The medical and dental staff group returned the highest number of responses (32.1%). 42% of staff reported some form of overseas volunteering or placement experience. Most staff took an international placement as students (33.6% men; 40.6% women). Medium-term placements were undertaken by 46.7% of men, and 52.5% of women. Settlement stays (ie, over 1 year) were reported by 7.6% men, and 8.3% women). The majority of respondents engaged in international placement were from the age groups incorporating ‘below 25’ to ‘41–50’ (74%). Multiple placement experiences were uncommon: 2.5% of respondents reported three periods of overseas activity, and 1.5% reported four. All those with multiple placement experience came from the staff groups incorporating midwife/nurse/health visitor, and medical and dental.ConclusionsThis survey captured a snapshot of current levels of volunteering and overseas placement activity across NHS staff grades in the North West. Owing to relatively homogenous organisational structures, findings are likely to broadly represent the position across the organisation as a whole. Although some degree of overseas placement activity is undertaken by a relatively high proportion of NHS staff, such activity is currently heavily skewed towards higher clinical staff grades. Significant numbers of allied health professionals and equivalent non-clinical cadres also report overseas experience, and we anticipate that the numbers will continue to rise if current policy initiatives gain momentum.
Ethics knowledge of recent paediatric residency graduates: the role of residency ethics curricula
Authors: Kesselheim Jennifer C , Najita Julie , Morley Debra , Bair Elizabeth , Joffe Steven 
Published: October 2016

ObjectiveTo evaluate the relationship between recently trained paediatricians' ethics knowledge and exposure to a formal ethics or professionalism curriculum during residency.MethodsWe conducted a cross-sectional survey of recently trained paediatricians which included a validated 23-item instrument called the Test of Residents' Ethics Knowledge for Pediatrics. The sample included paediatricians who completed medical school in 2006–2008, whose primary specialty was paediatrics or a paediatric subspecialty, and who completed paediatric residency training in 2010–2011. This sample was stratified based on residency programme variables: presence of a formal curriculum in ethics or professionalism, programme size and American Board of Pediatrics certifying exam passage rate. Paediatricians were randomly selected from each stratum for survey participation.ResultsAmong the 370 responding paediatricians (55%), the mean knowledge score was 17.3 (SD 2.2) out of a possible 23. Presence of a formal curriculum in ethics and/or professionalism was not significantly associated with knowledge. Knowledge was lowest on items about parental requests for a child to undergo genetic testing (2 items, 44% and 85% incorrect), preserving patient confidentiality over email (55% incorrect), decision-making regarding life-sustaining technologies (61% incorrect), and decision-making principles such as assent and parental permission (2 items, 47% and 49% incorrect).ConclusionsThis study highlights several areas in which paediatricians' knowledge may be low and that are amenable to targeted educational interventions. These findings should prompt discussion and research among ethicists and educators about how ethics and professionalism curricula can more consistently influence paediatricians' knowledge.
Triple gauge couplings at future hadron and lepton colliders
Authors: Bian Ligong , Shu Jing , Zhang Yongchao 
Published: October 2016

The [Formula: see text] production is the primary channel to directly probe the triple gauge couplings (TGCs). We analyze the [Formula: see text] process at the proposed circular electron–positron collider (CEPC), and find that the anomalous TGCs and relevant dimension six operators can be probed up to the order of [Formula: see text]. We also estimate constraints at the 14 TeV (LHC), with both 300 fb[Formula: see text] and 3000 fb[Formula: see text] integrated luminosity from the leading lepton [Formula: see text] and azimuthal angle difference [Formula: see text] in the di-lepton channel. The constrain is somewhat weaker, up to the order of [Formula: see text]. The limits on the TGCs are complementary to those on the electroweak precision observables and Higgs couplings.
Independent coding of absolute duration and distance magnitudes in the prefrontal cortex
Authors: Marcos Encarni , Tsujimoto Satoshi , Genovesio Aldo 
Published: October 2016

The estimation of space and time can interfere with each other, and neuroimaging studies have shown overlapping activation in the parietal and prefrontal cortical areas. We used duration and distance discrimination tasks to determine whether space and time share resources in prefrontal cortex (PF) neurons. Monkeys were required to report which of two stimuli, a red circle or blue square, presented sequentially, were longer and farther, respectively, in the duration and distance tasks. In a previous study, we showed that relative duration and distance are coded by different populations of neurons and that the only common representation is related to goal coding. Here, we examined the coding of absolute duration and distance. Our results support a model of independent coding of absolute duration and distance metrics by demonstrating that not only relative magnitude but also absolute magnitude are independently coded in the PF. NEW & NOTEWORTHY Human behavioral studies have shown that spatial and duration judgments can interfere with each other. We investigated the neural representation of such magnitudes in the prefrontal cortex. We found that the two magnitudes are independently coded by prefrontal neurons. We suggest that the interference among magnitude judgments might depend on the goal rather than the perceptual resource sharing.
Effects of ion channel noise on neural circuits: an application to the respiratory pattern generator to investigate breathing variability
Authors: Yu Haitao , Dhingra Rishi R. , Dick Thomas E. , Galán Roberto F. 
Published: October 2016

Neural activity generally displays irregular firing patterns even in circuits with apparently regular outputs, such as motor pattern generators, in which the output frequency fluctuates randomly around a mean value. This “circuit noise” is inherited from the random firing of single neurons, which emerges from stochastic ion channel gating (channel noise), spontaneous neurotransmitter release, and its diffusion and binding to synaptic receptors. Here we demonstrate how to expand conductance-based network models that are originally deterministic to include realistic, physiological noise, focusing on stochastic ion channel gating. We illustrate this procedure with a well-established conductance-based model of the respiratory pattern generator, which allows us to investigate how channel noise affects neural dynamics at the circuit level and, in particular, to understand the relationship between the respiratory pattern and its breath-to-breath variability. We show that as the channel number increases, the duration of inspiration and expiration varies, and so does the coefficient of variation of the breath-to-breath interval, which attains a minimum when the mean duration of expiration slightly exceeds that of inspiration. For small channel numbers, the variability of the expiratory phase dominates over that of the inspiratory phase, and vice versa for large channel numbers. Among the four different cell types in the respiratory pattern generator, pacemaker cells exhibit the highest sensitivity to channel noise. The model shows that suppressing input from the pons leads to longer inspiratory phases, a reduction in breathing frequency, and larger breath-to-breath variability, whereas enhanced input from the raphe nucleus increases breathing frequency without changing its pattern.NEW & NOTEWORTHY A major source of noise in neuronal circuits is the “flickering” of ion currents passing through the neurons' membranes (channel noise), which cannot be suppressed experimentally. Computational simulations are therefore the best way to investigate the effects of this physiological noise by manipulating its level at will. We investigate the role of noise in the respiratory pattern generator and show that endogenous, breath-to-breath variability is tightly linked to the respiratory pattern.
The Biodistribution and Immune Suppressive Effects of Breast Cancer–Derived Exosomes
Authors: Wen Shu Wen , Sceneay Jaclyn , Lima Luize Goncalves , Wong Christina S.F. , Becker Melanie , Krumeich Sophie , Lobb Richard J. , Castillo Vanessa , Wong Ke Ni , Ellis Sarah , Parker Belinda S. , Möller Andreas 
Published: October 2016

Abstract
Small membranous secretions from tumor cells, termed exosomes, contribute significantly to intercellular communication and subsequent reprogramming of the tumor microenvironment. Here, we use optical imaging to determine that exogenously administered fluorescently labeled exosomes derived from highly metastatic murine breast cancer cells distributed predominantly to the lung of syngeneic mice, a frequent site of breast cancer metastasis. At the sites of accumulation, exosomes were taken up by CD45+ bone marrow–derived cells. Subsequent long-term conditioning of naïve mice with exosomes from highly metastatic breast cancer cells revealed the accumulation of myeloid-derived suppressor cells in the lung and liver. This favorable immune suppressive microenvironment was capable of promoting metastatic colonization in the lung and liver, an effect not observed from exosomes derived from nonmetastatic cells and liposome control vesicles. Furthermore, we determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs. Together, our findings provide novel insight into the tissue-specific outcomes of breast cancer–derived exosome accumulation and their contribution to immune suppression and promotion of metastases. Cancer Res; 76(23); 6816–27. ©2016 AACR.
A Hyaluronidase-Responsive Nanoparticle-Based Drug Delivery System for Targeting Colon Cancer Cells
Authors: Zhang Mingzhen , Xu Changlong , Wen Liuqing , Han Moon Kwon , Xiao Bo , Zhou Jun , Zhang Yuchen , Zhang Zhan , Viennois Emilie , Merlin Didier 
Published: October 2016

Abstract
The ability of nanoparticles to target tumors and to enable site-specific drug release provides a unique system for the delivery of effective therapy with reduced toxic side effects. In this study, we used mesoporous silica nanoparticles (MSN) to fabricate a targeted drug delivery system that is responsive to hyaluronidase (HAase). Following engraftment of desthiobiotin onto the surface of MSN, a streptavidin complex was generated, which was functionalized with biotin-modified hyaluronic acid (HA) to enable controlled drug release at cancer cells expressing HAase. Various technologies were used to confirm the successful fabrication of this MSN-based nanocarrier system for targeted drug delivery. In vitro analyses showed that the release of doxorubicin hydrochloride (Dox) was accelerated significantly in the presence of biotin or HAase and accelerated further in the presence of biotin and HAase. Uptake by cancer cells was mediated efficiently by CD44 receptor–mediated endocytosis and the MSN exhibited good biocompatibility in vitro and in vivo. MSN-HA/Dox nanoparticles induced apoptosis in cancer cells more efficiently than free doxorubicin and inhibited tumor growth with minimal systemic toxicity in vivo. Collectively, our findings offered a preclinical proof of concept for a novel targeted drug delivery carrier system for cancer therapy. Cancer Res; 76(24); 7208–18. ©2016 AACR.
Screening Men at Increased Risk for Prostate Cancer Diagnosis: Model Estimates of Benefits and Harms
Authors: Gulati Roman , Cheng Heather H. , Lange Paul H. , Nelson Peter S. , Etzioni Ruth 
Published: October 2016

Abstract
Background: Guidelines for PSA screening in subgroups with increased risk of prostate cancer diagnosis due to race or genotype are underdeveloped. Our goal was to investigate types of increased prostate cancer risk and implications for targeted screening.
Methods: We investigated computer simulation of subgroups with average and hypothetical increased risk(s) of onset of latent disease, progression, and/or cancer-specific death. For each subgroup, we predicted lifetime probabilities of overdiagnosis and life saved under more and less intensive PSA screening strategies. An application estimated risks of onset among BRCA1/2 mutation carriers in the Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls (IMPACT) study using maximum likelihood.
Results: Our simulations implied PSA screening can save more lives among subgroups with increased risk than with average risk, but more intensive screening did not always improve harm–benefit trade-offs. IMPACT data were consistent with increased risks of onset among BRCA1 and BRCA2 mutation carriers [HR = 1.05; 95% confidence interval (CI), 0.63–1.59 and HR = 1.81; 95% CI, 1.14–2.78, respectively]. Our analysis suggests screening BRCA2 mutation carriers earlier and more frequently than the average-risk population, but a lower PSA threshold for biopsy is unlikely to improve outcomes.
Conclusions: Effective screening in men with increased prostate cancer risk depends on the manner in which the risk is increased. More intensive screening is not always optimal.
Impact: Guidelines for screening men at increased prostate cancer risk should consider the mechanism inducing the increased risk. Although the benefit of screening may be greater in men with increased risks, more intensive screening is not always appropriate. Cancer Epidemiol Biomarkers Prev; 26(2); 222–7. ©2016 AACR.
Molecular Pathways: Maintaining MAPK Inhibitor Sensitivity by Targeting Nonmutational Tolerance
Authors: Smith Michael P. , Wellbrock Claudia 
Published: October 2016

Abstract
Targeting hyperactive MAPK signaling has proven to be an effective treatment for a variety of different cancers. Responses to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitors trametinib and cobimetinib are, however, transient, and complete remission is rarely observed; rather, outgrowth of resistant clones within progressed tumors appears inevitable. These resistant tumors display great heterogeneity, which poses a major challenge to any salvage therapy. Recent focus has, therefore, been on the early dynamics of inhibitor response during tumor regression. During this time, cells can persist in an adapted tolerant state, which results in a phase of nonmutational drug tolerance. In this article, we discuss how inhibition of the MAPK pathway leads to an adaptive rewiring that evolves from the relief of immediate negative feedback loops to short-term gene expression changes and adaptation of intracellular signaling. Tolerance can also be mediated by external signaling from the tumor microenvironment, which itself adapts upon treatment and the selection for cells with an innate drug-tolerant phenotype. In preclinical models, combination treatment with receptor tyrosine kinase (RTK) inhibitors (lapatinib and dasatinib), histone deacetylase (HDAC) inhibitors (vorinostat and entinostat), or drugs targeting cancer-specific mechanisms (nelfinavir in melanoma) can overcome this early tolerance. A better understanding of how nonmutational tolerance is created and supported may hold the key to better combinational strategies that maintain drug sensitivity. Clin Cancer Res; 22(24); 5966–70. ©2016 AACR.
Long-term Follow-up of Treatment with Ibrutinib and Rituximab in Patients with High-Risk Chronic Lymphocytic Leukemia
Authors: Jain Preetesh , Keating Michael J. , Wierda William G. , Sivina Mariela , Thompson Philip A. , Ferrajoli Alessandra , Estrov Zeev , Kantarjian Hagop , O'Brien Susan , Burger Jan A. 
Published: October 2016

Abstract
Background: Ibrutinib is an active therapy with an acceptable safety profile for patients with chronic lymphocytic leukemia (CLL), including high-risk patients with del17p or with TP53 mutations. Ibrutinib is broadly indicated for the treatment of patients with CLL and specifically including those with 17p deletion. The optimal use of ibrutinib in combination with other agents remains controversial.
Experimental Design: We report the long-term outcome [median follow-up of 47 months (range, 36–51 months)] of 40 patients with high-risk CLL, treated on the first ibrutinib combination trial with rituximab (IR). The majority of patients (36/40) were previously treated.
Results: Median age was 65 years, and 21 patients (52%) had 17p deletion. Median duration on treatment was 41 months (range, 2–51 months), and median number of treatment cycles was 42 (range, 2–49). Overall response rate was 95%, and 9 patients (23%) attained a complete remission. Twenty-one patients discontinued treatment, 10 due to disease progression, 9 for other causes, and 2 due to stem cell transplantation; the remaining 19 patients continue on ibrutinib. Median progression-free survival for all patients was 45 months, which was significantly shorter in the subgroup of patients with del17p (n = 21, 32.3 months, P = 0.02). Fourteen patients (35%) died, five from progressive disease, five from infections, and four from other causes. Median overall survival has not been reached.
Conclusions: IR combination therapy leads to durable remissions in high-risk CLL; the possible benefit from the addition of rituximab is currently explored in a randomized trial. Clin Cancer Res; 23(9); 2154–8. ©2016 AACR.
N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation
Authors: Wu Min , Huang Jinyan , Zhang Jianming , Benes Cyril , Jiao Bo , Ren Ruibao 
Published: October 2016

Abstract
RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block RAS oncogenic signaling by a distinct mechanism. Because the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS-specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS to the Golgi apparatus in a palmitoylation-dependent manner. The results indicate that NADA inhibits NRAS and KRAS4A plasma membrane translocation by targeting a novel molecular process. The new findings would help to develop novel targeted therapies for a broad range of human cancers. Mol Cancer Ther; 16(1); 57–67. ©2016 AACR.
Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations
Authors: Zhou Stanley , Treloar Aislinn E. , Lupien Mathieu 
Published: October 2016

Abstract
The emergence of whole-genome annotation approaches is paving the way for the comprehensive annotation of the human genome across diverse cell and tissue types exposed to various environmental conditions. This has already unmasked the positions of thousands of functional cis-regulatory elements integral to transcriptional regulation, such as enhancers, promoters, and anchors of chromatin interactions that populate the noncoding genome. Recent studies have shown that cis-regulatory elements are commonly the targets of genetic and epigenetic alterations associated with aberrant gene expression in cancer. Here, we review these findings to showcase the contribution of the noncoding genome and its alteration in the development and progression of cancer. We also highlight the opportunities to translate the biological characterization of genetic and epigenetic alterations in the noncoding cancer genome into novel approaches to treat or monitor disease.
Significance: The majority of genetic and epigenetic alterations accumulate in the noncoding genome throughout oncogenesis. Discriminating driver from passenger events is a challenge that holds great promise to improve our understanding of the etiology of different cancer types. Advancing our understanding of the noncoding cancer genome may thus identify new therapeutic opportunities and accelerate our capacity to find improved biomarkers to monitor various stages of cancer development. Cancer Discov; 6(11); 1215–29. ©2016 AACR.