bluuebunny/crossref_metadata_2025 huggingface dataset:
What factors are important for deprescribing in Australian long-term care facilities? Perspectives of residents and health professionals
Authors: Turner Justin P , Edwards Susan , Stanners Melinda , Shakib Sepehr , Bell J Simon
Published: March 2016

Objectives

Polypharmacy and multimorbidity are common in long-term care facilities (LTCFs). Reducing polypharmacy may reduce adverse events and maintain quality of life. Deprescribing refers to reducing medications after consideration of therapeutic goals, benefits and risks, and medical ethics. The objective was to use nominal group technique (NGT) to generate then rank factors that general medical practitioners (GPs), nurses, pharmacists and residents or their representatives perceive are most important when deciding whether or not to deprescribe medications.

Design

Qualitative research using NGT.

Setting

Participants were invited if they worked with, or resided in LTCFs across metropolitan and regional South Australia.

Participants

11 residents/representatives, 19 GPs, 12 nurses and 14 pharmacists participated across six separate groups.

Methods

Individual groups of GPs, nurses, pharmacists and residents/representatives were convened. Using NGT each group ranked factors perceived to be most important when deciding whether or not to deprescribe. Then, using NGT, the prioritised factors from individual groups were discussed and prioritised by a multidisciplinary metropolitan and regional group comprised of resident representatives, GPs, nurses and pharmacists.

Results

No two groups had the same priorities. GPs ranked ‘evidence for deprescribing’ and ‘communication with family/resident’ as most important factors. Nurses ranked ‘GP receptivity to deprescribing’ and ‘nurses ability to advocate for residents’ as most important. Pharmacists ranked ‘clinical appropriateness of therapy’ and ‘identifying residents’ goals of care’ as most important. Residents ranked ‘wellbeing of the resident’ and ‘continuity of nursing staff’ as most important. The multidisciplinary groups ranked ‘adequacy of medical and medication history’ and ‘identifying residents’ goals of care’ as most important.

Conclusions

While each group prioritised different factors, common and contrasting factors emerged. Future deprescribing interventions need to consider the similarities and differences within the range of factors prioritised by residents and health professionals.
Health service utilisation for anogenital warts in Ontario, Canada prior to the human papillomavirus (HPV) vaccine programme introduction: a retrospective longitudinal population-based study
Authors: Guerra Fiona M , Rosella Laura C , Dunn Sheila , Wilson Sarah E , Chen Cynthia , Deeks Shelley L
Published: March 2016

Objective

Trends in occurrence of anogenital warts (AGWs) can provide early evidence of human papillomavirus (HPV) vaccination programme impact on preventing HPV infection and HPV-induced lesions. The objective of this study was to provide a baseline of AGW epidemiology in Ontario prior to the introduction of the publicly-funded school-based HPV vaccination programme in September 2007.

Setting and participants

As a retrospective longitudinal population-based study, we used health administrative data as a proxy to estimate incident AGWs and total health service utilisation (HSU) for AGWs for all Ontario residents 15 years and older with valid health cards between 1 April 2003 and 31 March 2007.

Outcome measures

The outcome of interest was AGW healthcare utilisation identified using the International Classification of Diseases, 10th revision (ICD-10) diagnostic code for AGWs, as well as an algorithm for identifying AGW physician office visits in a database with a unique system of diagnostic and procedural codes. An AGW case was considered incident if preceded by 12 months without HSU for AGWs. Time trends by age group and sex were analysed.

Results

Between fiscal years 2003 and 2006, we identified 123 247 health service visits for AGWs by 51 436 Ontario residents 15 years and older. Incident AGWs peaked in females and males in the 21–23 year age group, at 3.74 per 1000 and 2.81 per 1000, respectively. HSU for AGWs peaked in females and males within the 21–23 year age group, at 9.34 per 1000 and 7.22 per 1000, respectively.

Conclusions

To the best of our knowledge, this is the first population-based study of AGW incidence and HSU in Ontario. The sex and age distribution of individuals with incident and prevalent AGWs in Ontario was similar to that of other provinces before HPV vaccine programme implementation in Canada.
Past speculations of the future: a review of the methods used for forecasting emerging health technologies
Authors: Doos Lucy , Packer Claire , Ward Derek , Simpson Sue , Stevens Andrew
Published: March 2016

Objectives

Forecasting can support rational decision-making around the introduction and use of emerging health technologies and prevent investment in technologies that have limited long-term potential. However, forecasting methods need to be credible. We performed a systematic search to identify the methods used in forecasting studies to predict future health technologies within a 3–20-year timeframe. Identification and retrospective assessment of such methods potentially offer a route to more reliable prediction.

Design

Systematic search of the literature to identify studies reported on methods of forecasting in healthcare.

Participants

People are not needed in this study.

Data sources

The authors searched MEDLINE, EMBASE, PsychINFO and grey literature sources, and included articles published in English that reported their methods and a list of identified technologies.

Main outcome measure

Studies reporting methods used to predict future health technologies within a 3–20-year timeframe with an identified list of individual healthcare technologies. Commercially sponsored reviews, long-term futurology studies (with over 20-year timeframes) and speculative editorials were excluded.

Results

15 studies met our inclusion criteria. Our results showed that the majority of studies (13/15) consulted experts either alone or in combination with other methods such as literature searching. Only 2 studies used more complex forecasting tools such as scenario building.

Conclusions

The methodological fundamentals of formal 3–20-year prediction are consistent but vary in details. Further research needs to be conducted to ascertain if the predictions made were accurate and whether accuracy varies by the methods used or by the types of technologies identified.
Development and validation of a simple lupus severity index using ACR criteria for classification of SLE
Authors: Bello Ghalib A , Brown Michael A , Kelly Jennifer A , Thanou Aikaterini , James Judith A , Montgomery Courtney G
Published: March 2016

Objective

To develop a simple systemic lupus erythematosus (SLE) severity index that requires knowledge of only American College of Rheumatology (ACR) criteria and subcriteria.

Methods

This study used demographic, mortality and medical records data of 1915 patients with lupus from the Lupus Family Registry and Repository. The data were randomly split (2:1 ratio) into independent training and validation sets. A logistic regression with ridge penalty was used to model the probability of being prescribed major immunosuppressive drugs—a surrogate indicator of lupus severity. ACR criteria and subcriteria were used as predictor variables in this model, and the resulting regression coefficient estimates obtained from the training data were used as item weightings to construct the severity index.

Results

The resulting index was tested on the independent validation dataset and was found to have high predictive accuracy for immunosuppressive use and early mortality. The index was also found to be strongly correlated with a previously existing severity score for lupus. In addition, demographic factors known to influence lupus severity (eg, age of onset, gender and ethnicity) all showed robust associations with our severity index that were consistent with observed clinical trends.

Conclusions

This new index can be easily computed using ACR criteria, which may be among the most readily available data elements from patient medical records. This tool may be useful in lupus research, especially large dataset analyses to stratify patients by disease severity, an important prognostic indicator in SLE.
Current management practices and interventions prioritised as part of a nationwide mastitis control plan
Authors: Down P. M. , Bradley A. J. , Breen J. E. , Hudson C. D. , Green M. J.
Published: March 2016

The objectives of this study were to report performance and management data taken from a sample of UK dairy farms that have participated in the Agriculture and Horticulture Development Board Dairy Mastitis Control Plan (DMCP) and to identify important mastitis prevention practices that are not currently widely implemented. A total of 234 UK dairy herds were included in the study from which farm management and udder health data were collected. Herds were grouped according to their mastitis epidemiology and could be classed as (i) environmental dry period (EDP) (i.e. environmental pathogen with majority of infections being acquired during the dry period), (ii) environmental lactation (EL), (iii) contagious dry period (CDP) or (iv) contagious lactation (CL). The results of this study showed that many mastitis‐related management practices that are generally considered to be important were not widely performed. A better understanding of those practices not widely adopted by UK dairy farmers at present may aid practitioners in identifying and overcoming potential barriers to improved mastitis control.
Particle accelerator development: Selected examples
Authors: Wei Jie
Published: March 2016

About 30 years ago, I was among several students mentored by Professor Yang at Stony Brook to enter the field of particle accelerator physics. Since then, I have been fortunate to work on several major accelerator projects in USA and in China, guided and at times directly supported by Professor Yang. The field of accelerator physics is flourishing worldwide both providing indispensable tools for fundamental physics research and covering an increasingly wide spectrum of applications beneficial to our society.
The fate of Schwarzschild–de Sitter black holes in f(R) gravity
Authors: Addazi Andrea , Capozziello Salvatore
Published: March 2016

The semiclassical effects of anti-evaporating black holes can be discussed in the framework of f(R) gravity. In particular, the Bousso–Hawking–Nojiri–Odinstov anti-evaporation instability of degenerate Schwarzschild–de Sitter black holes (the so-called Nariai spacetime) leads to a dynamical increasing of black hole horizon in f(R) gravity. This phenomenon causes the following transition: emitting marginally trapped surfaces (TS) become space-like surfaces before the effective Bekenstein–Hawking emission time. As a consequence, Bousso–Hawking thermal radiation cannot be emitted in an anti-evaporating Nariai black hole. Possible implications in cosmology and black hole physics are also discussed.
Structure-dielectric property relationship in Nb-doped Ca4La2Ti5O17 ceramics
Authors: Muhammad Raz , Iqbal Yaseen
Published: March 2016

A number of compounds in the [Formula: see text] (x = 0–2) series were prepared through a mixed oxide solid-state sintering route. These compounds crystallized into orthorhombic (Pbnm) structure. The relative permittivity [Formula: see text] and temperature coefficient of resonance frequency [Formula: see text] depended on the polarizability of constituent cations while the quality factor [Formula: see text] was affected by ordering of cations. These compounds exhibited promising [Formula: see text] (74–90) and [Formula: see text] (10[Formula: see text]208–14[Formula: see text]116 GHz); however, the observed high [Formula: see text] (157–542 ppm/[Formula: see text]C) requires further investigations to tune it through zero.
Security Estimation in Wireless Sensor Network Simulator
Authors: Díaz Álvaro , González-Bayon Javier , Sánchez Pablo
Published: March 2016

Sensor nodes are low-power and low-cost devices with the requirement of a long autonomous lifetime. Therefore, the nodes have to use the available power carefully and avoid expensive computations or radio transmissions. In addition, as some wireless sensor networks (WSNs) process sensitive data, selecting a security protocol is vital. Cryptographic methods used in WSNs should fulfill the constraints of sensor nodes and should be evaluated for their security and power consumption. WSN engineers use several metrics to obtain estimations prior to network deployment. These metrics are usually related to power and execution time estimation. However, security is a feature that cannot be estimated and it is either “active” or “inactive”, with no possibility of introducing intermediate security levels. This lack of flexibility is a disadvantage in real deployments where different operation modes with different security and power specifications are often needed. This paper proposes including a new security estimation metric in a previously proposed framework for WSN simulation and embedded software (SW) performance analysis. This metric is called Security Estimation Metric (SEM) and it provides information about the security encryption used in WSN transmissions. Results show that the metric improves flexibility, granularity and execution time compared to other cryptographic tests.
Analysis and Modeling of Imperfections in Multi-Bit Per Stage Pipelined ADCs
Authors: Rahmani Najmeh , Farshidi Ebrahim , Fatemi-Behbahani Esmaeil
Published: March 2016

In this paper, an approach to estimate signal to noise ratio (SNR) and effective number of bits (ENOB) in nonideal multi-bit stages of pipelined analog to digital converters (ADCs) is presented. The most significant error sources in multistage ADCs are the capacitor mismatch and the finite and imprecise gain of amplifier. Output voltage of each stage in pipelined ADC is modeled by an ideal and a nonideal output, where nonideal output is the error due to circuit imperfections in each stage. Using an appropriate model, the SNR and ENOB due to circuit nonidealities and in terms of standard deviation of random errors are calculated. Simulation results show the accuracy of the analytical proposed approach in estimation of SNR and ENOB in multi-bit per stage pipelined converters.
Effects of porphyrin deformation on the 13C and1H NMR chemical shifts in high-spin five- and six-coordinate manganese(III) porphyrin complexes
Authors: Ikezaki Akira , Nakamura Mikio
Published: March 2016

As an extension of our study to reveal the effect of porphyrin deformation on the [Formula: see text]C and1H NMR chemical shifts, both five- and six-coordinate high-spin (S [Formula: see text] 2) Mn(III) complexes such as Mn(Por)Cl and [Mn(Por)(CD3OD)2]Cl have been prepared, where Por is a porphyrin dianion such as TPP, OMTPP, and T[Formula: see text]PrP. Molecular structures of five-coordinate Mn(OMTPP)Cl and Mn(TiPrP)Cl have been determined by the X-ray crystallographic analysis. As expected, Mn(OMTPP)Cl and Mn(TiPrP)Cl have exhibited a highly saddled and highly ruffled porphyrin core, respectively. The [Formula: see text]C NMR spectra have revealed that these complexes generally exhibit the [Formula: see text]-pyrrole signals at the downfield positions and [Formula: see text]-pyrrole an. meso signals at the upfield positions. The results suggest that the spin polarization of Mn(III)–NPσ bonds, which occurs in all the high-spin Mn(III) complexes, is the major factor to determine the chemical shifts of the porphyrin carbon signals (Cheng, R.-J.; Chang, S.-H.; Hung, K.-C. Inorg. Chem. 2007; 46: 1948–1950). Although th. meso and [Formula: see text]-pyrrole signals are observed at the upfield and downfield positions, respectively, these signals are widely dispersed depending on the deformation mode of the porphyrin ring. The results have been explained in terms of the strong spin polarization of the Mn–NPbond together with the specific metal-porphyrin orbital interactions such as: (i) the a2u-dz2 interaction in five-coordinate complexes, (ii) the a2u-dxyinteraction in ruffled complexes, and (iii) the a2u-dx2-y2 interaction in saddled complexes.
Targeting of the epidermal growth factor receptor with mesoporphyrin IX-peptide conjugates
Authors: Fontenot Krystal R. , Ongarora Benson G. , LeBlanc Logan E. , Zhou Zehua , Jois Seetharama D. , Vicente M. Graça H.
Published: March 2016

The synthesis and in vitro evaluation of four mesoporphyrin IX-peptide conjugates designed to target EGFR, over-expressed in colorectal and other cancers, are reported. Two peptides with known affinity for EGFR, LARLLT (1) and GYHWYGYTPQNVI (2), were conjugated to mesoporphyrin IX (MPIX, 3) via one or both the propionic side chains, directly (4, 5) or with a triethylene glycol spacer (7, 8). The conjugates were characterized using NMR, MS, CD, SPR, UV-vis and fluorescence spectroscopies. Energy minimization and molecular dynamics suggest different conformations for the conjugates. SPR studies show that conjugate 4, bearing two LARLLT with no PEG spacers, has the greatest affinity for binding to EGFR, followed by conjugate 7with two PEG and two LARLLT sequences. Molecular modeling and docking studies suggest that both conjugates 4 and 7 can bind to monomer and dimer EGFR in open and closed conformations. The cytotoxicity and cellular targeting ability of the conjugates were investigated in human HEp2 cells over-expressing EGFR. All conjugates showed low dark- and photo-toxicities. The cellular uptake was highest for conjugates 4 and 8 and lowest for 7 bearing two LARLLT linked via PEG groups, likely due to decreased hydrophobicity. Among the conjugates investigated, 4 is the most efficient EGFR-targeting agent, and therefore the most promising for the detection of cancers that over-express EGFR.
Indirect and direct damage to genomic DNA induced by 5,10,15-tris(1-methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin upon photodynamic action
Authors: Bartolomeu Maria , Coimbra Šónia , Cunha Ângela , Neves Maria G.P.M.S. , Cavaleiro José A.S. , Faustino Maria A.F. , Almeida Adelaide
Published: March 2016

Photodynamic inactivation has been proposed as an efficient antimicrobial treatment for localized infections. Even though it is generally accepted that the cell wall and membrane components are the main targets of the photodynamic process, the importance of the nucleic acids as photodynamic targets is not yet fully understood. In this study, we investigated the photodamage of the genomic nucleic acids of the Gram negative bacterium Escherichia coli, using 5,10,15-tris(1-methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin tri-iodide (Tri-Py[Formula: see text]-Me-PF) as photosensitizing agent. We tested, for the first time, the indirect photodamage effects on genomic DNA extracted from photosensitized bacteria and compared it with the direct effects on genomic DNA extracted from non-photosensitized cells, treated in otherwise similar experimental conditions. The results suggest that DNA does not seem to be a major target of photodynamic inactivation, once direct exposure to photosensitization does not damage DNA and does not significantly alter DNA concentration. The decrease in DNA concentration observed during the indirect exposure to photosensitization is directly related with the reduction of the concentration of bacterial cells. However, RNA synthesis was severely affected, once an indirect effect on proteins involved in the transcription process may cause a marked decrease in the RNA pool.
Influence of alkyl substituents in corrphycene on geometry, electronic structure, hydrogen bonding, and tautomerization
Authors: Gorski Alexandr , Leśniewska Barbara , Orzanowska Grażyna , Waluk Jacek
Published: March 2016

Geometry, electronic and vibrational structure, and relative energies of different tautomeric forms have been calculated for free base corrphycene and its five tetra-, octa-, and dodeca-alkyl-substituted derivatives, of which only one has been synthesized so far. The results demonstrate that the lowest energy structure always corresponds to the transtautomeric form. Comparison with the experimental IR and X-ray data available for 2,3,6,7,11,12,17,18-octaethylcorrphycene shows, in contrast to previous suggestions, that th. transspecies is dominant both in solution and crystalline phase. Based on structural, spectral, and computational data, rates of double hydrogen transfer can be predicted. Tautomerization is expected to occur in a nanosecond or subnanosecond range. The rate should strongly decrease upon substituting parent corrphycene with alkyl groups at the pyrrolic [Formula: see text] positions, whereas the opposite effect is expected for mesosubstitution. Depending on the position of substituent, planar or nonplanar geometries of the corrphycene chromophore are predicted. The nonplanarity leads to a substantial increase of the intensity of the low energy electronic transitions (Q-bands).
General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice
Authors: Phillipson-Weiner Lindsey , Mirek Emily T. , Wang Yongping , McAuliffe W. Geoffrey , Wek Ronald C. , Anthony Tracy G.
Published: March 2016

Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (Δ Gcn2) mice. Mean pancreas weights in Δ Gcn2 mice treated with asparaginase for 8 days were increased ( P < 0.05) above all other groups. Histological examination revealed acinar cell swelling and altered staining of zymogen granules in Δ Gcn2, but not WT, mice. Oil Red O staining and measurement of pancreas triglycerides excluded lipid accumulation as a contributor to acini appearance. Instead, transmission electron microscopy revealed dilatation of the endoplasmic reticulum (ER) and accumulation of autophagic vacuoles in the pancreas of Δ Gcn2 mice treated with asparaginase. Consistent with the idea that loss of GCN2 in a pancreas exposed to asparaginase induced ER stress, phosphorylation of protein kinase R-like ER kinase (PERK) and its substrate eIF2 was increased in the pancreas of asparaginase-treated Δ Gcn2 mice. In addition, mRNA expression of PERK target genes, activating transcription factors 4, 3, and 6 ( Atf4, Atf3, and Atf6), fibroblast growth factor 21 ( Fgf21), heat shock 70-kDa protein 5 ( Hspa5), and spliced Xbp1 ( sXbp1), as well as pancreas mass, was elevated in the pancreas of asparaginase-treated Δ Gcn2 mice. Furthermore, genetic markers of oxidative stress [sirtuin ( Sirt1)], inflammation [tumor necrosis factor-α ( Tnfα)], and pancreatic injury [pancreatitis-associated protein ( Pap)] were elevated in asparaginase-treated Δ Gcn2, but not WT, mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas to a maladaptive ER stress response and autophagy during asparaginase treatment and represent a genetic basis for development of asparaginase-associated pancreatitis.
Intermittent severe hypoxia induces plasticity within serotonergic and catecholaminergic neurons in the neonatal rat ventrolateral medulla
Authors: Givan Scott A. , Cummings Kevin J.
Published: March 2016

5-HT neurons contribute to autoresuscitation and survival during intermittent severe hypoxia (IsH). In adults, catecholaminergic neurons in the ventrolateral medulla (VLM) contribute to the autonomic response to hypoxia. We hypothesized that 1) catecholaminergic neurons in the neonatal VLM are activated following IsH, 2) this activation is compromised following an acute loss of brain stem 5-HT, and 3) IsH induces cellular and/or transcriptomic plasticity within catecholaminergic and serotonergic neurons that are within or project to the VLM, respectively. To test these hypotheses, we treated rat pups with 6-fluorotryptophan, a tryptophan hydroxylase (TPH) inhibitor, and then exposed treated and vehicle controls to IsH or air. Along with immunohistochemistry to detect tyrosine hydroxylase (TH)- or Fos-positive neurons, we used RNA sequencing to resolve the effects of IsH and 5-HT deficiency on the expression of serotonergic and catecholaminergic system genes in the VLM. 5-HT deficiency compromised autoresuscitation and survival. IsH significantly increased the number of identifiable TH-positive VLM neurons, an effect enhanced by 5-HT deficiency ( P = 0.003). Contrary to our hypothesis, 5-HT-deficient pups had significantly more Fos-positive neurons following IsH ( P = 0.008) and more activated TH-positive neurons following IsH or air ( P = 0.04). In both groups the expression of the 5-HT transporter and TPH2 was increased following IsH. In 5-HT-deficient pups, the expression of the inhibitory 5-HT1Areceptor was decreased following IsH, while the expression of DOPA decarboxylase was increased. These data show that the serotonergic and catecholaminergic systems in the VLM of the neonatal rat are dynamically upregulated by IsH, potentially adapting cardiorespiratory responses to severe hypoxia.
Vitamin D3 intake modulates diaphragm but not peripheral muscle force in young mice
Authors: Ray Andrew D. , Personius Kirkwood E. , Williamson David L. , Dungan Cory M. , Dhillon Samjot S. , Hershberger Pamela A.
Published: March 2016

Recent data support an important role for vitamin D in respiratory health. We tested the hypothesis that dietary vitamin D3 (VD3) intake modulates diaphragm (DIA) strength. Four-week-old female A/J mice ( n = 10/group) were randomized to receive diets containing 100 IU VD3/kg (low), 1,000 IU VD3/kg (reference), or 10,000 IU VD3/kg (pharmacologic). After 6 wk of dietary intervention, plasma 25-hydroxyvitamin D3 (25D3) levels, DIA and extensor digitorum longus (EDL) in vitro contractile properties, and fiber cross-sectional area (CSA) were measured. Myosin heavy chain (MHC) composition and Akt/Foxo3A growth signaling were studied in the DIA and tibialis anterior. Mice fed the low, reference, and pharmacologic diets had average 25D3 levels of 7, 21, and 59 ng/ml, respectively. Maximal DIA force, twitch force, and fiber CSA were reduced 26%, 28%, and 10% ( P < 0.01), respectively, in mice receiving the low-VD3 diet compared with the reference and pharmacologic diets. EDL force parameters were unaltered by diet. Effects of VD3 intake on DIA force were not observed in mice that began dietary intervention at 12 wk of age. VD3 intake did not alter the MHC composition of the DIA, indicating that decreases in force and CSA in young mice were not due to a switch in fiber type. Paradoxically, low VD3 intake was associated with activation of anabolic signaling in muscle (hyperphosphorylation of Akt and Foxo3A and decreased expression of autophagy marker LC3). These studies identify a potential role of dietary VD3 in regulating DIA development and insulin sensitivity.
Mutant p53 Promotes Epithelial Ovarian Cancer by Regulating Tumor Differentiation, Metastasis, and Responsiveness to Steroid Hormones
Authors: Ren Yi A. , Mullany Lisa K. , Liu Zhilin , Herron Alan J. , Wong Kwong-Kwok , Richards JoAnne S.
Published: March 2016

Mutations in the tumor protein p53 (TP53) are the most frequently occurring genetic events in high-grade ovarian cancers, especially the prevalence of the Trp53R172H-mutant allele. In this study, we investigated the impact of the Trp53R172H-mutant allele on epithelial ovarian cancer (EOC) in vivo. We used the Pten/KrasG12D–mutant mouse strain that develops serous EOC with 100% penetrance to introduce the mutant Trp53R172H allele (homolog for human Trp53R172H). We demonstrate that the Trp53R172H mutation promoted EOC but had differential effects on disease features and progression depending on the presence or absence of the wild-type (WT) TP53 allele. Heterozygous WT/Trp53R172H alleles facilitated invasion into the ovarian stroma, accelerated intraperitoneal metastasis, and reduced TP53 transactivation activity but retained responsiveness to nutlin-3a, an activator of WT TP53. Moreover, high levels of estrogen receptor α in these tumors enhanced the growth of both primary and metastatic tumors in response to estradiol. Ovarian tumors homozygous for Trp53R172H mutation were undifferentiated and highly metastatic, exhibited minimal TP53 transactivation activity, and expressed genes with potential regulatory functions in EOC development. Notably, heterozygous WT/Trp53R172H mice also presented mucinous cystadenocarcinomas at 12 weeks of age, recapitulating human mucinous ovarian tumors, which also exhibit heterozygous TP53 mutations (∼50%–60%) and KRAS mutations. Therefore, we present the first mouse model of mucinous tumor formation from ovarian cells and supporting evidence that mutant TP53 is a key regulator of EOC progression, differentiation, and responsiveness to steroid hormones. Cancer Res; 76(8); 2206–18. ©2016 AACR.
STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation
Authors: Lemos Henrique , Mohamed Eslam , Huang Lei , Ou Rong , Pacholczyk Gabriela , Arbab Ali S. , Munn David , Mellor Andrew L.
Published: March 2016

Cytosolic DNA sensing is an important process during the innate immune response that activates the stimulator of interferon genes (STING) adaptor and induces IFN-I. STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists, and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). Although STING also induced IDO in tumor-draining lymph nodes (TDLN) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8+ T-cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL10 production in the TME. Depletion of CD8+ T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8+ T-cell effector functions during tumorigenesis. In contrast with native LLC tumors, STING signaling neither promoted growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity and how IDO inhibition can overcome this state by attenuating tumor tolerance. Furthermore, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials. Cancer Res; 76(8); 2076–81. ©2016 AACR.
GSK-3 Inhibition Sensitizes Acute Myeloid Leukemia Cells to 1,25D-Mediated Differentiation
Authors: Gupta Kalpana , Stefan Tammy , Ignatz-Hoover James , Moreton Stephen , Parizher Gary , Saunthararajah Yogen , Wald David N.
Published: March 2016

1,25-dihydroxyvitamin D3 (1,25D), the biologically active form of vitamin D, is widely considered a promising therapy for acute myeloid leukemia (AML) based on its ability to drive differentiation of leukemic cells. However, clinical trials have been disappointing in part to dose-limiting hypercalcemia. Here we show how inhibiting glycogen synthase kinase 3 (GSK3) can improve the differentiation response of AML cells to 1,25D-mediated differentiation. GSK3 inhibition in AML cells enhanced the differentiating effects of low concentrations of 1,25D. In addition, GSK3 inhibition augmented the ability of 1,25D to induce irreversible growth inhibition and slow the progression of AML in mouse models. Mechanistic studies revealed that GSK3 inhibition led to the hyperphosphorylation of the vitamin D receptor (VDR), enabling an interaction between VDR and the coactivator, SRC-3 (NCOA3), thereby increasing transcriptional activity. We also found that activation of JNK-mediated pathways in response to GSK3 inhibition contributed to the potentiation of 1,25D-induced differentiation. Taken together, our findings offer a preclinical rationale to explore the repositioning of GSK3 inhibitors to enhance differentiation-based therapy for AML treatment. Cancer Res; 76(9); 2743–53. ©2016 AACR.
Integrated Whole Genome and Transcriptome Analysis Identified a Therapeutic Minor Histocompatibility Antigen in a Splice Variant of ITGB2
Authors: Pont Margot J. , van der Lee Dyantha I. , van der Meijden Edith D. , van Bergen Cornelis A.M. , Kester Michel G.D. , Honders Maria W. , Vermaat Martijn , Eefting Matthias , Marijt Erik W.A. , Kielbasa Szymon M. , Hoen Peter A.C. 't , Falkenburg J.H. Frederik , Griffioen Marieke
Published: March 2016

Purpose: In HLA-matched allogeneic hematopoietic stem cell transplantation (alloSCT), donor T cells recognizing minor histocompatibility antigens (MiHAs) can mediate desired antitumor immunity as well as undesired side effects. MiHAs with hematopoiesis-restricted expression are relevant targets to augment antitumor immunity after alloSCT without side effects. To identify therapeutic MiHAs, we analyzed the in vivo immune response in a patient with strong antitumor immunity after alloSCT.

Experimental Design: T-cell clones recognizing patient, but not donor, hematopoietic cells were selected for MiHA discovery by whole genome association scanning. RNA-sequence data from the GEUVADIS project were analyzed to investigate alternative transcripts, and expression patterns were determined by microarray analysis and qPCR. T-cell reactivity was measured by cytokine release and cytotoxicity.

Results: T-cell clones were isolated for two HLA-B*15:01–restricted MiHA. LB-GLE1-1V is encoded by a nonsynonymous SNP in exon 6 of GLE1. For the other MiHAs, an associating SNP in intron 3 of ITGB2 was found, but no SNP disparity was present in the normal gene transcript between patient and donor. RNA-sequence analysis identified an alternative ITGB2 transcript containing part of intron 3. qPCR demonstrated that this transcript is restricted to hematopoietic cells and SNP-positive individuals. In silico translation revealed LB-ITGB2-1 as HLA-B*15:01–binding peptide, which was validated as hematopoietic MiHA by T-cell experiments.

Conclusions: Whole genome and transcriptome analysis identified LB-ITGB2-1 as MiHAs encoded by an alternative transcript. Our data support the therapeutic relevance of LB-ITGB2-1 and illustrate the value of RNA-sequence analysis for discovery of immune targets encoded by alternative transcripts. Clin Cancer Res; 22(16); 4185–96. ©2016 AACR.
Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance
Authors: Malorni Luca , Giuliano Mario , Migliaccio Ilenia , Wang Tao , Creighton Chad J. , Lupien Mathieu , Fu Xiaoyong , Hilsenbeck Susan G. , Healy Nuala , De Angelis Carmine , Mazumdar Abhijit , Trivedi Meghana V. , Massarweh Suleiman , Gutierrez Carolina , De Placido Sabino , Jeselsohn Rinath , Brown Myles , Brown Powel H. , Osborne C. Kent , Schiff Rachel
Published: March 2016

The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo. AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.

Implications: AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470–81. ©2016 AACR.
Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti–PD-1 Therapy
Authors: Greenplate Allison R. , Johnson Douglas B. , Roussel Mikael , Savona Michael R. , Sosman Jeffrey A. , Puzanov Igor , Ferrell P. Brent , Irish Jonathan M.
Published: March 2016

Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti–PD-1 agent. Myeloid blasts comprised <1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474–80. ©2016 AACR.
The Time to Clearance of Peripheral Blood Blasts Predicts Complete Remission and Survival in Chinese Adults with Acute Myeloid Leukemia
Authors: Li Xiaoyang , Zhu Hongming , Zhang Yunxiang , Zhao Weili , Mi Jianqing , Hu Jiong , Li Junmin
Published: March 2016

The value of clearance of peripheral blood blasts (PBB) as a predictor of outcomes in acute myeloid leukemia (AML) is controversial. To investigate the prognostic significance of the time to clearance of PBB after induction in Chinese patients with AML, a retrospective analysis of 146 patients with newly diagnosed AML at Shanghai Ruijin Hospital was performed. Patients were categorized into early blast clearance (EBC; ≤5 days) and delayed blast clearance (DBC; >5 days) groups based on a receiver operating characteristic analysis. Complete remission (CR) after induction chemotherapy was related to the time to clearance of PBB (p < 0.001). Relapse-free survival (RFS; p = 0.003) and overall survival (p < 0.001) were longer in the EBC group. Multivariate analysis demonstrated that the time to clearance of PBB and cytogenetic risk independently predicted CR and RFS. Early clearance of PBB after induction chemotherapy can be a significant predictor of survival outcomes in AML patients.
Staphylococcus aureus Induces Shedding of IL-1RII in Monocytes and Neutrophils
Authors: Giai Constanza , Gonzalez Cintia D. , Sabbione Florencia , Garofalo Ailin , Ojeda Diego , Sordelli Daniel O. , Trevani Analía S. , Gómez Marisa I.
Published: March 2016

Interleukin 1 (IL-1) β is a critical cytokine that orchestrates host defenses against Staphylococcus aureus and is crucial for the eradication of bacteria. The production and action of IL-1β are regulated by multiple control pathways. Among them, IL-1RII (the type II IL-1 receptor) acts as a decoy receptor and has been shown to regulate the biological effects of IL-1β. High levels of soluble IL-1RII are present in septic patients; however, the stimuli that regulate the expression and release of IL-1RII in pathological conditions are incompletely elucidated. In the present study, we demonstrated the ability of S. aureus and protein A to induce IL-1RII shedding in myeloid cells. The positive modulation of IL-1RII expression and cleavage was associated with the failure to detect IL-1β in response to S. aureus both in vitro and in vivo, suggesting that the soluble form of the receptor could be masking the availability of IL-1β. The absence of detectable IL-1β was associated with low levels of inflammatory cytokines and chemokines known to be regulated by IL-1β and with increased bacterial persistence. Modulation of decoy receptors during systemic S. aureus infection is proposed as a new strategy used by this bacterium to evade the immune response.
Comparison of the Visual Capabilities of an Amphibious and an Aquatic Goby That Inhabit Tidal Mudflats
Authors: Takiyama Tomo , Hamasaki Sawako , Yoshida Masayuki
Published: March 2016

The mudskipper Periophthalmus modestus and the yellowfin goby Acanthogobius flavimanus are gobiid teleosts that both inhabit the intertidal mudflats in estuaries. While P. modestus has an amphibious lifestyle and forages on the exposed mudflat during low tide, the aquatic A. flavimanus can be found at the same mudflat at high tide. This study primarily aimed to elucidate the differential adaptations of these organisms to their respective habitats by comparing visual capacities and motor control in orienting behavior during prey capture. Analyses of retinal ganglion cell topography demonstrated that both species possess an area in the dorsotemporal region of the retina, indicating high acuity in the lower frontal visual field. Additionally, P. modestus has a minor area in the nasal portion of the retina near the optic disc. The horizontally extended specialized area in P. modestus possibly reflects the need for optimized horizontal sight on the exposed mudflat. Behavioral experiments to determine postural and eye direction control when orienting toward the object of interest revealed that these species direct their visual axes to the target situated below eye level just before a rapid approach toward it. A characteristic feature of the orienting behavior of P. modestus was that they aimed at the target by using the specialized retinal area by rotating the eye and lifting the head before jumping to attack the target located above eye level. This behavior could be an adaptation to a terrestrial feeding habitat in which buoyancy is irrelevant. This study provides insights into the adaptive mechanisms of gobiid species and the evolutionary changes enabling them to forage on land.
Effects of Metabolic Programming on Juvenile Play Behavior and Gene Expression in the Prefrontal Cortex of Rats
Authors: Hehar Harleen , Ma Irene , Mychasiuk Richelle
Published: March 2016

Early developmental processes, such as metabolic programming, can provide cues to an organism, which allow it to make modifications that are predicted to be beneficial for survival. Similarly, social play has a multifaceted role in promoting survival and fitness of animals. Play is a complex behavior that is greatly influenced by motivational and reward circuits, as well as the energy reserves and metabolism of an organism. This study examined the association between metabolic programming and juvenile play behavior in an effort to further elucidate insight into the consequences that early adaptions have on developmental trajectories. The study also examined changes in expression of four genes (Drd2, IGF1, Opa1, and OxyR) in the prefrontal cortex known to play significant roles in reward, bioenergetics, and social-emotional functioning. Using four distinct variations in developmental programming (high-fat diet, caloric restriction, exercise, or high-fat diet combined with exercise), we found that dietary programming (high-fat diet vs. caloric restriction) had the greatest impact on play behavior and gene expression. However, exercise also induced changes in both measures. This study demonstrates that metabolic programming can alter neural circuits and bioenergetics involved in play behavior, thus providing new insights into mechanisms that allow programming to influence the evolutionary success of an organism.
Age, Gender, Comorbidity, and the MDS-UPDRS: Results from a Population-Based Study
Authors: Keezer Mark R. , Wolfson Christina , Postuma Ronald B.
Published: March 2016

Background: Understanding sources of variation in International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores is essential for planning clinical trials in Parkinson's disease and interpreting studies of mild parkinsonian signs. Methods: We describe the characteristics of the MDS-UPDRS in a population-based sample of individuals without parkinsonism. Multiple linear regression and Spearman's rank correlation coefficients were used to examine potential associations. Results: Among 194 consecutive individuals without parkinsonism, the mean total MDS-UPDRS score was 12.5 (SD 9.8). Sixty-nine percent (134/193) had motor examination (Part III) scores of 2 or more, 16% (30/194) had scores of 10 or more. Female sex, arthritis or spondylosis, diabetes mellitus, and essential tremor were found to be associated with statistically significant increases in MDS-UPDRS Part III scores. For every 10-year increase in age, the Part III score was greater on average by 2.2 (1.5-2.8). Conclusions: Elevated MDS-UPDRS scores are common in the general population. The overall burden of motor signs of parkinsonism is especially high in older age groups, in women, and in those with particular comorbidities. Whether this represents evidence of a subclinical neurodegenerative process or the effect of comorbid conditions requires further examination.
Short Stature in Isodicentric Y Chromosome and Three Copies of the SHOX Gene: Clinical Report and Review of Literature
Authors: Valetto Angelo , Bertini Veronica , Michelucci Angela , Toschi Benedetta , Dati Eleonora , Baroncelli Giampietro I. , Bertelloni Silvano
Published: March 2016

Short stature homeobox gene (SHOX) mutations and pseudoautosomal region 1 (PAR1) deletions encompassing SHOX are known causes of Léri-Weill dyschondrosteosis and isolated short stature, while 3 copies of SHOX in cases with triple sex chromosome constitution are responsible for tall stature. Duplications involving SHOX have been rarely reported, and they were found in individuals with short, normal and tall stature. An adopted boy with short stature, isodicentric Y chromosome and 3 copies of SHOX is described. Normal growth hormone (GH) secretion and insulin-like growth factor 1 (IGF1) increase during an IGF1 generation test were found, ruling out impaired GH-IGF1 axis. No other organic or psychiatric causes of impaired growth were found. GH treatment improved linear growth, as reported in children with SHOX haploinsufficiency. This new report and the review of literature support that SHOX duplication may cause short stature, especially in those children with duplications of the 5′SHOX regulatory elements. Chromosome analysis and detailed molecular characterization of the duplicated region should be warranted in individuals with SHOX duplications in order to investigate the presence of occult chromosome imbalance. Additional reports and follow-up till adult height are needed to give conclusions on long-term efficacy and safety of GH treatment in short children with SHOX duplication.