bluuebunny/crossref_metadata_2025 huggingface dataset:
Analyses of infectious disease patterns and drivers largely lack insights from social epidemiology: contemporary patterns and future opportunities
Authors: Noppert Grace A , Kubale John T , Wilson Mark L
Published: November 2016

Background

Infectious disease epidemiologists have long recognised the importance of social variables as drivers of epidemics and disease risk, yet few apply analytic approaches from social epidemiology. We quantified and evaluated the extent to which recent infectious disease research is employing the perspectives and methods of social epidemiology by replicating the methodology used by Cohenet alin a 2007 study.

Methods

2 search strategies were used to identify and review articles published from 1 January 2005 to 31 December 2013. First, we performed a keyword search of ‘social epidemiology’ in the title/abstract/text of published studies identified in PubMed, PsychInfo and ISI Web of Science, and classified each study as pertaining to infectious, non-infectious or other outcomes. A second PubMed search identified articles that were cross-referenced under non-infectious or infectious, and search terms relating to social variables. The abstracts of all articles were read, classified and examined to identify patterns over time.

Results

Findings suggest that infectious disease research publications that explicitly or implicitly incorporate social epidemiological approaches have stagnated in recent years. While the number of publications that were explicitly self-classified as ‘social epidemiology’ has risen, the proportion that investigated infectious disease outcomes has declined. Furthermore, infectious diseases accounted for the smallest proportion of articles that were cross-referenced with Medical Subject Headings (MeSH) terms related to social factors, and most of these involved sexually transmitted diseases.

Conclusions

The current landscape of infectious disease epidemiology could benefit from new approaches to understanding how the social and biophysical environment sustains transmission and exacerbates disparities. The framework of social epidemiology provides infectious disease researchers with such a perspective and research opportunity.
Bleeding events and maintenance dose of prasugrel: BLESS pilot study
Authors: Carrabba Nazario , Parodi Guido , Marcucci Rossella , Valenti Renato , Gori Anna Maria , Migliorini Angela , Comito Vincenzo , Bellandi Benedetta , Abbate Rosanna , Gensini Gian Franco , Antoniucci David
Published: November 2016

Objective

To evaluate changes in residual platelet reactivity (RPR) over time, and bleeding and ischaemic events rate using 5 vs 10 mg maintenance dose (MD) regimens of prasugrel 1 month after acute coronary syndrome (ACS).

Background

The optimal level of RPR with prasugrel may change over time after an ACS.

Methods

After 60 mg loading dose of prasugrel (T0) followed by 10 mg/day for 1 month, patients were randomised to receive prasugrel 10 mg/day (n=95, group A) or 5 mg/day MD (n=98, group B) up to 1 year. RPR was assessed at T0, 37 (T1) and 180 days (T2). The primary end point was Bleeding Academic Research Consortium (BARC) bleeding events ≥2 between 1 and 12 months, and the secondary composite end point was cardiac death, myocardial infarction, stroke and definite/probable stent thrombosis.

Results

From T0 to T1, RPR significantly increased in both groups A and B and the increase was higher for group B (δ ADP 10 µmol: 13.8%±14.7% vs 23.5%±19.2%, p=0.001). At T2 a lower rate of high RPR patients were found in group A (2.6% vs13.3%; p=0.014). The BARC type ≥2 bleeding occurred in 12.6% of group A versus 4.1% of group B (OR 0.29, 95% CI 0.09 to 0.94) and secondary end point in 2.1% vs 1.0% (p=0.542), respectively, without stent thrombosis.

Conclusions

RPR increases shifting from 60 mg loading dose to 10 mg/day prasugrel MD with a further increase of RPR reducing prasugrel MD to 5 mg 1 month after ACS. Clinical value of these pharmacodynamic findings should be proved in larger clinical trials.

Trial registration number

NCT01790854.
Promoting effect of lactoferrin on barrier function and epithelial differentiation of human keratinocytes
Authors: Uchida Ryo , Aoki Reiji , Aoki-Yoshida Ayako , Tajima Atsushi , Takayama Yoshiharu
Published: November 2016

The purpose of this study was to elucidate the effects of bovine lactoferrin on keratinocyte differentiation and barrier function. Addition of bovine lactoferrin to differentiating HaCaT human keratinocytes led to increased transepithelial electrical resistance (TER), a marker of epithelial barrier function. This elevation was followed by upregulation of two differentiation markers, involucrin and filaggrin. The expression level of sterol regulatory element-binding protein-1 was also enhanced by bovine lactoferrin. The lactoferrin-induced upregulation of involucrin and filaggrin expression were confirmed in normal human epidermal keratinocytes (NHEK). Treatment with SB203580, a p38 mitogen-activated protein kinase (MAPK) α inhibitor, impaired the upregulation of involucrin and filaggrin expression in response to lactoferrin. The elevation of p38 MAPK phosphorylation was further enhanced by lactoferrin in the initial stage of differentiation of HaCaT keratinocytes. The findings suggest that bovine lactoferrin promotes epithelial differentiation by a p38-MAPK-dependent mechanism.
Flow and water temperature affect reproduction and recruitment of a Great Plains cyprinid
Authors: Haworth Matthew R. , Bestgen Kevin R.
Published: November 2016

Conservation of stream fishes requires an understanding of how their reproduction and recruitment are affected by environmental conditions. Flow regulation and habitat loss in North American Great Plains streams threaten many native fishes, including pelagic-broadcast spawning cyprinids. Pelagic-broadcast spawning by flathead chub (Platygobio gracilis), a species declining throughout much of its extensive range, began after temperatures exceeded 15 °C in Fountain Creek, Colorado (USA), despite different annual flows. Alternatively, streamflow patterns controlled recruitment of juveniles because high-magnitude summer flows (spikes) reduced abundance of larvae hatched just prior to or during such events. Juvenile recruitment was highest for larvae hatched just after summer flow spikes occurred or during stable base flow periods. Understanding environmental conditions suitable for reproduction as well as subsequent recruitment should inform conservation actions, especially in flow-altered streams, and improve prospects for persistence of imperiled Great Plains cyprinids, including flathead chub.
Fairness and Incentive Considerations in Energy Apportionment Policies
Authors: Vergara Ekhiotz Jon , Nadjm-Tehrani Simin , Asplund Mikael
Published: November 2016

The energy consumption of a system is determined by the system component usage patterns and interactions between the coexisting entities and resources. Energy accounting plays an essential role in revealing the contribution of each entity to the total consumption and for energy management. Unfortunately, energy accounting inherits the apportionment problem of accounting in general, which does not have a general single best solution. In this article, we leverage cooperative game theory, which is commonly used in cost allocation problems to study the energy apportionment problem, that is, the problem of prescribing the actual energy consumption of a system to the consuming entities (e.g., applications, processes, or users of the system).

We identify five relevant fairness properties for energy apportionment and present a detailed categorisation and analysis of eight previously proposed energy apportionment policies from different fields in computer and communication systems. In addition, we propose two novel energy apportionment policies based on cooperative game theory that provide strong fairness notion and a rich incentive structure. Our comparative analysis in terms of the identified five fairness properties as well as information requirement and computational complexity shows that there is a tradeoff between fairness and the other evaluation criteria. We provide guidelines to select an energy apportionment policy depending on the purpose of the apportionment and the characteristics of the system.
Reliability Analysis of SSDs Under Power Fault
Authors: Zheng Mai , Tucek Joseph , Qin Feng , Lillibridge Mark , Zhao Bill W. , Yang Elizabeth S.
Published: November 2016

Modern storage technology (solid-state disks (SSDs), NoSQL databases, commoditized RAID hardware, etc.) brings new reliability challenges to the already-complicated storage stack. Among other things, the behavior of these new components during power faults—which happen relatively frequently in data centers—is an important yet mostly ignored issue in this dependability-critical area. Understanding how new storage components behave under power fault is the first step towards designing new robust storage systems.

In this article, we propose a new methodology to expose reliability issues in block devices under power faults. Our framework includes specially designed hardware to inject power faults directly to devices, workloads to stress storage components, and techniques to detect various types of failures. Applying our testing framework, we test 17 commodity SSDs from six different vendors using more than three thousand fault injection cycles in total. Our experimental results reveal that 14 of the 17 tested SSD devices exhibit surprising failure behaviors under power faults, including bit corruption, shorn writes, unserializable writes, metadata corruption, and total device failure.
Theoretical Studies of the Stone-Wales Defect in C36 Fullerene Embedded inside Zigzag Carbon Nanotube
Authors: Grishakov Konstantin S. , Katin Konstantin P. , Maslov Mikhail M.
Published: November 2016

We apply density functional theory at PBE/6-311G(d) level as well as nonorthogonal tight-binding model to study the Stone-Wales transformation in C36 fullerene embedded inside the (14,0) zigzag carbon nanotube. We optimize geometries of two different isomers with the D2d and the D6h symmetries and the transition state dividing them. The mechanism of Stone-Wales transformation from D2d to D6h symmetry for the encapsulated C36 is calculated to be the same as for the isolated one. It is found that the outer carbon wall significantly stabilizes the D6h isomer. However, carbon nanotube reduces the activation barrier of Stone-Wales rearrangement by 0.4 eV compared with the corresponding value for the isolated C36.
Knowledge of Stroke Risk Factors among Stroke Survivors in Nigeria
Authors: Vincent-Onabajo Grace , Moses Taritei
Published: November 2016

Background. Knowledge of stroke risk factors is expected to reduce the incidence of stroke—whether first-ever or recurrent. This study examined knowledge of stroke risk factors and its determinants among stroke survivors.Methods. A cross-sectional survey of consenting stroke survivors at two physiotherapy facilities in Nigeria was carried out. Sociodemographic and clinical data were obtained and knowledge of stroke risk factors (defined as the ability to mention at least one correct risk factor) was assessed using open-ended questionnaire. Data were treated with descriptive statistics and logistic regression analysis.Results. Sixty-nine stroke survivors (male = 72.5%; mean ± SD age =49.7±10.6years) participated in the study. Thirty-four (49.4%) participants had knowledge of stroke risk factors. Only educational level was significantly associated with knowledge and participants with tertiary educational qualification were about 48 times (odds ratio = 48.5; CI = 7.6–309.8;P<0.0001) more likely to be knowledgeable than those with no education.Conclusion. Less than half of the participants had knowledge of stroke risk factors. Participants with tertiary education were significantly more knowledgeable than those with lower educational qualifications. Effective means of educating stroke survivors on stroke risk factors should be identified and adopted.
MediterrAsian Diet Products That Could Raise HDL-Cholesterol: A Systematic Review
Authors: Rondanelli Mariangela , Giacosa Attilio , Morazzoni Paolo , Guido Davide , Grassi Mario , Morandi Gabriella , Bologna Chiara , Riva Antonella , Allegrini Pietro , Perna Simone
Published: November 2016

Background. High HDL-cholesterol (HDL-C) values are negatively correlated with cardiovascular diseases. This review analyses the effect of the supplementation with various Mediterranean diet products (artichoke, bergamot, and olive oil) and Asian diet products (red yeast rice) on the HDL-C value in dyslipidemic subjects.Methods. A systematic review has been done involving all the English written studies published from the 1st of January 1958 to the 31st of March 2016.Results. The results of this systematic review indicate that the dietary supplementation with red yeast rice, bergamot, artichoke, and virgin olive oil has promising effects on the increase of HDL-C serum levels. The artichoke leaf extract and virgin olive oil appear to be particularly interesting, while bergamot extract needs further research and the effect of red yeast rice seems to be limited to patients with previous myocardial infarction.Conclusions. Various MediterrAsian diet products or natural extracts may represent a potential intervention treatment to raise HDL-C in dyslipidemic subjects.
Hypoxia-Inducible Factor-1α Expression in Indonesian Laryngeal Squamous Cell Carcinoma Patients
Authors: Surono Agus , Priyanto Priyanto , Indrasari Sagung Rai
Published: November 2016

Objectives. This research aimed to determine the association between hypoxia-inducible factor-1α (HIF-1α) expression and laryngeal squamous cell carcinoma clinical stage. Methods. We retrospectively analyzed paraffin-embedded tissue from 47 laryngeal squamous cell carcinoma (LSCC) patients from 2011 to 2014. HIF-1α expression was analyzed by immunohistochemistry using an anti-HIF-1α mouse monoclonal antibody. The association between HIF-1α expression and clinical stage was analyzed using the chi square test. Results. The glottis was the predominant site of laryngeal squamous cell carcinoma occurrence, and 43/47 (91.5%) patients presented at an advanced stage. Of the advanced stage patients, 27/43 stained positive for HIF-1α expression and 16/43 stained negative. Of the early stage patients, 2/4 stained positive for HIF-1α expression and 2/4 stained negative. Statistical analysis did not demonstrate significant association of HIF-1α expression. Conclusion. There was no statistically significant association between HIF-1α expression and the clinical stage or histological differentiation of LSCC.
Ectopic Fat Deposition on Insulin Sensitivity: Correlation of Hepatocellular Lipid Content andMValue
Authors: Hong Beverly S. , Li Ying , Lai Shuiqing , Liu Juan , Guan Hongyu , Ke Weijian , He Xiaoying , Li Yanbing
Published: November 2016

Purpose. This study aimed to explore the relationship among insulin sensitivity and ectopic fat depots in participants with different glucose status.Methods. Fifty-nine men and women were enrolled in this study: 29 with normal glucose tolerance (NGT), 17 with impaired glucose tolerance (IGT), and 13 with type 2 diabetes mellitus (T2DM). All participants underwent a hyperinsulinemic-euglycemic clamp to assess the insulin sensitivity index (Mvalue) and magnetic resonance imaging to measure the hepatocellular lipid content (HCL), skeletal muscle fat content including intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of tibialis anterior (ta), and soleus muscle (sol).Results. TheMvalue of NGT group was higher than those of IGT and T2DM groups (P=0.001). Participants with T2DM had the highest HCL and IMCL (ta) compared with those in NGT and IGT groups (P=0.001). TheMvalue had an inverse relationship with HCL (r=-0.789,P=0.001), IMCL (sol) (r=-0.427,P=0.002), and IMCL (ta) (r=-0.419,P=0.002). Stepwise linear regression analysis showed that HCL (standardizedβ=-0.416;P=0.001) had an independent relationship withMvalue.Conclusions. Hepatocellular lipid content deposition happens earlier than skeletal muscle fat deposition. HCL is an independent risk factor for insulin resistance and may be used to evaluate the risk of developing T2DM as a noninvasive marker of insulin sensitivity index.
Expression of CAF-Related Proteins Is Associated with Histologic Grade of Breast Phyllodes Tumor
Authors: Kim Hye Min , Lee Yu Kyung , Koo Ja Seung
Published: November 2016

Purpose. The purpose of this study was to investigate the expression of cancer-associated fibroblast- (CAF-) related proteins and the implications in breast phyllodes tumor (PT).Methods. Tissue microarrays of 194 PT cases (151 benign PT, 27 borderline PT, and 16 malignant PT) were constructed. We performed immunohistochemical staining for CAF-related proteins (podoplanin, prolyl 4-hydroxylase, FAPα, S100A4, PDGFRα/β, and NG2) and analyzed the results according to clinicopathologic parameters.Results. Expression of PDGFRαand PDGFRβin the stromal component increased with increasing histologic grade of PT (p=0.003andp=0.034, resp.). Among clinicopathologic parameters, only expression of FAPαin stroma was associated with distant metastasis (p=0.002). In univariate analysis, stromal expression of PDGFRαwas associated with shorter overall survival (p=0.002). In Cox multivariate analysis, stromal overgrowth and PDGFRαstromal positivity were associated with shorter overall survival (p=0.006andp=0.050, resp.). Furthermore, expression of PDGFRβin stroma was associated with shorter overall survival in patients with malignant PT (p=0.041).Conclusion. Stromal expression of PDGFRαand PDGFRβincreased with increasing histologic grade of PT. In addition, PDGFR stromal positivity was associated with shorter overall survival. These results suggest that CAFs are associated with breast PT progression.
Right Lung Agenesis with Tracheal Stenosis due to Complete Tracheal Rings and Postpneumonectomy Like Syndrome Treated with Tissue Expander Placement
Authors: Agrawal Yashwant , Patri Sandeep , Kalavakunta Jagadeesh K.
Published: November 2016

Congenital lung agenesis is an extremely rare condition with an estimated prevalence of 34 in 1,000,000 live births. It is often associated with other congenital malformations of the skeletal, cardiovascular, urogenital, and gastrointestinal systems. We discuss the case of a 5-month-old who presented with increasing stridor over 1 month. Imaging revealed right lung agenesis, complete dextromalposition of heart, and compression of distal trachea. An intrathoracic saline tissue expander was placed which marked improved distal tracheal stenosis. In patients who are symptomatic it becomes imperative to perform surgeries to increase survival as was the case in this patient.
On the Marginal Distribution of the Diagonal Blocks in a Blocked Wishart Random Matrix
Authors: Halvorsen Kjetil B. , Ayala Victor , Fierro Eduardo
Published: November 2016

Let A be a (m1+m2)×(m1+m2) blocked Wishart random matrix with diagonal blocks of orders m1×m1 and m2×m2. The goal of the paper is to find the exact marginal distribution of the two diagonal blocks of A. We find an expression for this marginal density involving the matrix-variate generalized hypergeometric function. We became interested in this problem because of an application in spatial interpolation of random fields of positive definite matrices, where this result will be used for parameter estimation, using composite likelihood methods.
A New Approach to the Study of Fixed Point Theorems withw-Distances viaR-Functions
Authors: Zarinfar Farzad , Khojasteh Farshid , Vaezpour Seyyed Mansour
Published: November 2016

We introduce some new generalization of fixed point theorems in complete metric spaces endowed withw-distances viaR-functions. Our results extend many of known fixed point theorems such as Reich type contraction, Geraghty contraction, Meir-Keeler contraction, andZ-contraction. In addition, the result and corollaries show that our approach has a constructive attitude and many known and unknown results can be constructed in such way.
Genomic Analysis of a Marine Bacterium: Bioinformatics for Comparison, Evaluation, and Interpretation of DNA Sequences
Authors: Rekadwad Bhagwan N. , Gonzalez Juan M. , Khobragade Chandrahasya N.
Published: November 2016

A total of five highly related strains of an unidentified marine bacterium were analyzed through their short genome sequences (AM260709–AM260713). Genome-to-Genome Distance (GGDC) showed high similarity to Pseudoalteromonas haloplanktis (X67024). The generated unique Quick Response (QR) codes indicated no identity to other microbial species or gene sequences. Chaos Game Representation (CGR) showed the number of bases concentrated in the area. Guanine residues were highest in number followed by cytosine. Frequency of Chaos Game Representation (FCGR) indicated that CC and GG blocks have higher frequency in the sequence from the evaluated marine bacterium strains. Maximum GC content for the marine bacterium strains ranged 53-54%. The use of QR codes, CGR, FCGR, and GC dataset helped in identifying and interpreting short genome sequences from specific isolates. A phylogenetic tree was constructed with the bootstrap test (1000 replicates) using MEGA6 software. Principal Component Analysis (PCA) was carried out using EMBL-EBI MUSCLE program. Thus, generated genomic data are of great assistance for hierarchical classification in Bacterial Systematics which combined with phenotypic features represents a basic procedure for a polyphasic approach on unambiguous bacterial isolate taxonomic classification.
Development of a Loop Mediated Isothermal Amplification for Diagnosis ofAscaris lumbricoidesin Fecal Samples
Authors: Shiraho Esther A. , Eric Agola L. , Mwangi Ibrahim N. , Maina Geoffrey M. , Kinuthia Joseph M. , Mutuku Martin W. , Mugambi Robert M. , Mwandi Jackson M. , Mkoji Gerald M.
Published: November 2016

Ascaris lumbricoidesis a nematode parasite that causes the common tropical infection ascariasis in humans. It is also considered among the neglected tropical diseases. Diagnosis relies mainly on microscopy-based methods which are laborious, are limited by low sensitivity, and require high expertise. We have developed a loop mediated isothermal amplification (LAMP) for diagnosis of ascariasis in fecal samples, based on the first internal transcribed (ITS-1) spacer region of the ribosomal DNA. We used Primer Explorer V4 software to design primers.Ascarisadult and ova were obtained from naturally infected school children, whose parents/guardians gave consent for their participation in the study. Genomic DNA was extracted using alkaline lysis method and amplified by LAMP at 63°C for 45 minutes. LAMP products were visualized by naked eyes after adding SYBR Green dye and also on agarose gel. LAMP successfully and reliably detectedAscarisDNA from a single egg and in fecal samples. The assay specifically detectedAscarisDNA without amplifying DNA from ova of other parasites which commonly coexist withA. lumbricoidesin feces. The developed LAMP assay has great potential for use in ascariasis diagnosis at the point of care and in low infection intensity situation that characterize control and elimination campaigns.
Revisiting the Practicality of Search on Encrypted Data: From the Security Broker’s Perspective
Authors: Han Peiyi , Liu Chuanyi , Fang Binxing , Wang Guofeng , Song Xiaobao , Wan Lei
Published: November 2016

The primary business challenge for the customers to use outsourced computation and storage is the loss of data control and security. So encryption will become a commodity in the near future. There is big diffusion with the above scenario: take advantage of current application’s full functionalities at the same time ensuring their sensitive data remains protected and under customers’ control. Prior works have achieved effective progress towards satisfying both sides. But there are still some technical challenges, such as supporting file or data-stream based applications and supporting full-text and advanced searches. In this paper, a novel security broker based encrypted data search scheme, called Enc-YUN, is proposed, which transparently builds a reverse index at the security broker when the data flow is transmitted to the cloud. And search firstly takes place on the index, in which the mapping structure corresponds to and retrieves the very encrypted data in the cloud on behalf of the client. With this scheme, updated-to-date full-text search techniques can be easily integrated to carry out the most advanced search functionalities, at the same time, maintaining the strongest levels of data protection from curious providers or third parties. Experimental results show that Enc-YUN is effective with broad categories of cloud applications, and the performance overhead induced is minor and acceptable according to user’s perceptual experience.
Pattern and Epidemiology of Poisoning in the East African Region: A Literature Review
Authors: Tagwireyi Dexter , Chingombe Patience , Khoza Star , Maredza Mandy
Published: November 2016

The establishment and strengthening of poisons centres was identified as a regional priority at the first African regional meeting on the Strategic Approach to International Chemicals Management (SAICM) in June 2006. At this meeting, the possibility of a subregional poisons centre, that is, a centre in one country serving multiple countries, was suggested. The WHO Headquarters following consultation with counterparts at the WHO Regional Office for Africa (AFRO) and the SAICM Africa Regional Focal Point successfully submitted a proposal to the SAICM Quick Start Programme (QSP) Trust Fund Committee for a feasibility study into a subregional poisons centre in the Eastern Africa subregion. However, before such a study could be conducted it was deemed necessary to carry out a literature review on the patterns and epidemiology of poisoning in this region so as to inform the feasibility study. The current paper presents the results of this literature review. The literature search was done in the months of June and July 2012 by two independent reviewers with no language or publication date restrictions using defined search terms on PUBMED. After screening, the eventual selection of articles for review and inclusion in this study was done by a third reviewer.
Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1β, IL8, CXCL5, and Mip-1α
Authors: Najjar Yana G. , Rayman Patricia , Jia Xuefei , Pavicic Paul G. , Rini Brian I. , Tannenbaum Charles , Ko Jennifer , Haywood Samuel , Cohen Peter , Hamilton Thomas , Diaz-Montero C. Marcela , Finke James
Published: November 2016

Purpose: Little is known about the association between myeloid-derived suppressor cell (MDSC) subsets and various chemokines in patients with renal cell carcinoma (RCC) or the factors that draw MDSC into tumor parenchyma.

Experimental Design: We analyzed polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1β, IL8, CXCL5, Mip-1α, MCP-1, and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCR2 and anti-PD1 and to elucidate the impact of IL1β blockade on MDSC.

Results: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, and I-MDSC correlate with IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2 and parenchymal PMN-MDSC correlated with IL8 and CXCL5, we assessed the response of CXCR2 blockade with or without anti-PD1. Combination therapy reduced tumor weight and enhanced CD4+ and CD8+ T-cell infiltration. In addition, anti-IL1β decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1β also delayed tumor growth.

Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMN-MDSC correlate with tumor grade, suggesting prognostic significance. Anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4+ and CD8+ T-cell infiltration in a Renca murine model, suggesting that CXCR2+ PMN-MDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition. Clin Cancer Res; 23(9); 2346–55. ©2016 AACR.
Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity
Authors: Kamel Walied A. , Sugihara Eiji , Nobusue Hiroyuki , Yamaguchi-Iwai Sayaka , Onishi Nobuyuki , Maki Kenta , Fukuchi Yumi , Matsuo Koichi , Muto Akihiro , Saya Hideyuki , Shimizu Takatsune
Published: November 2016

Osteosarcoma is the most common type of primary bone tumor, novel therapeutic agents for which are urgently needed. To identify such agents, we screened a panel of approved drugs with a mouse model of osteosarcoma. The screen identified simvastatin, which inhibited the proliferation and migration of osteosarcoma cells in vitro. Simvastatin also induced apoptosis in osteosarcoma cells in a manner dependent on inhibition of the mevalonate biosynthetic pathway. It also disrupted the function of the small GTPase RhoA and induced activation of AMP-activated protein kinase (AMPK) and p38 MAPK, with AMPK functioning upstream of p38 MAPK. Inhibitors of AMPK or p38 MAPK attenuated the induction of apoptosis by simvastatin, whereas metformin enhanced this effect of simvastatin by further activation of AMPK. Although treatment with simvastatin alone did not inhibit osteosarcoma tumor growth in vivo, its combination with a fat-free diet induced a significant antitumor effect that was enhanced further by metformin administration. Our findings suggest that simvastatin induces apoptosis in osteosarcoma cells via activation of AMPK and p38 MAPK, and that, in combination with other approaches, it holds therapeutic potential for osteosarcoma. Mol Cancer Ther; 16(1); 182–92. ©2016 AACR.
Dietary Weight Loss, Exercise, and Oxidative Stress in Postmenopausal Women: A Randomized Controlled Trial
Authors: Duggan Catherine , Tapsoba Jean de Dieu , Wang Ching-Yun , Campbell Kristin L. , Foster-Schubert Karen , Gross Myron D. , McTiernan Anne
Published: November 2016

Oxidative stress, a potential mechanism linking obesity and cancer, results from an imbalance between activation/inactivation of reactive oxygen species, byproducts of cellular metabolism. In a randomized controlled trial, we investigated effects of diet and/or exercise on biomarkers of oxidative stress. A total of 439 overweight/obese [body mass index (BMI) > 25 kg/m2] postmenopausal women, ages 50 of 75 years, were randomized to 12 months of (i) reduced-calorie weight loss diet (“diet”; n = 118); (ii) moderate-to-vigorous intensity aerobic exercise (“exercise”; n = 117); (iii) combined diet and exercise intervention (“diet + exercise”; n = 117); or (iv) control (n = 87). Outcomes were circulating markers of oxidative stress, including fluorescent oxidation products (FOP), F2-isoprostanes, and oxidized low-density lipoprotein (LDL). On average, participants were 57.9 years, with a BMI of 30.9 kg/m2. F2-isprostanes were significantly reduced in the diet (−22.7%, P = 0.0002) and diet + exercise (−23.5%, P < 0.0001) arms versus controls (−2.99%) and nonsignificantly reduced in the exercise arm (−14.5%, P = 0.01). Participants randomized to the diet and diet + exercise arms had significant increases in levels of FOP [control −5.81%; diet +14.77% (P = 0.0001); diet + exercise +17.45%, (P = 0.0001)]. In secondary analyses, increasing weight loss was statistically significantly associated with linear trends of greater reductions in oxidized LDL and in F2-isoprostanes and increases in FOP. Compared with controls, exercise participants whose maximal oxygen consumption increased had significant decreases in levels of F2-isoprostanes and in oxidized LDL and increases in FOP. Dietary weight loss, with or without exercise, significantly reduced some markers of oxidative stress in postmenopausal women. Cancer Prev Res; 9(11); 835–43. ©2016 AACR.
Abstract A014: CIITA dependent MHC class II IA expression in tumor cells triggers CD4 T cell protective and long lasting antitumor immunity
Authors: Eddine Farah Bou Nasser , Forlani Greta , Tosi Giovanna , Accolla Roberto S.
Published: November 2016

We previously demonstrated the generation of a CD4 T cell-specific long lasting anti-tumor immune response in the H-2d BALB/c mouse model by using tumor cells that have been genetically modified with CIITA to express MHC-II I-E and I-A molecules. We have now investigated the pertinence of this approach in the H-2b C57BL/6 mouse model despite the defect in their I-Eα gene and thus the lack of expression of I-E subset. To this purpose we injected in vivo the CIITA-driven I-A-only MHC-II-positive LLC (lewis Lung Carcinoma) and MC38 colon carcinoma in the C57BL/6 mice and their growth rate along with the recipient's immune response were analyzed. The CIITA-transfected, MHC-II-positive tumor cells were either completely rejected or showed a significant growth retardation compared to the MHC-II-negative parental tumor. The protected mice were re-injected with the parental tumors and a complete rejection was obtained proving that a specific long lasting immune response was triggered by the CIITA-transfected tumors. Furthermore, total splenocytes or purified CD4+, CD8+ T cells and B cells were transferred from the vaccinated recipients to naïve recipients that were co-injected with the parental tumor cells and the results showed that CD4+ TH cells were the main effectors of the immune response against the tumor cells. Interestingly, similar results were obtained in C57BL/6-DOG transgenic mice whose dendritic cells could be conditionally ablated after administration of Diphteria toxin. These results demonstrate the validity of triggering a specific, long-lasting anti-tumor immune response using CIITA-driven MHC class II positive tumor cells of different MHC haplotype as stimulators. Importantly, the results establish that expression of a single MHC-II restriction element, I-A, in tumor cells is sufficient to trigger CD4+ TH cell protective immune response, strongly suggesting that the relevant tumor-associated antigenic repertoire can be displayed without the need of the I-E restriction element. Finally, these results strongly suggest that CIITA-modified tumor cells can act as antigen presenting cells in vivo to prime naïve CD4+ TH cells against tumor antigens.

Citation Format: Farah Bou Nasser Eddine, Greta Forlani, Giovanna Tosi, Roberto S. Accolla. CIITA dependent MHC class II IA expression in tumor cells triggers CD4 T cell protective and long lasting antitumor immunity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A014.
Abstract A016: Multipotency of a CD40L-expressing recombinant vaccinia virus
Authors: Trella Emanuele
Published: November 2016

Vaccinia Virus (VV) is a viral vector used in pre-clinical and clinical studies of active cancer immunotherapeutic strategies. CD40 receptor is expressed on a broad range of immune cells. Furthermore, CD40 expression has been reported also in nearly all B-cell malignancies and solid tumors of different origins. Interestingly, CD40 ligation might result in different biological responses depending on the cell types and to the strength of CD40 ligand (CD40L; CD154)-mediated stimulation of CD40 receptor. Based on this background, we have generated a replication incompetent CD40 ligand-expressing recombinant vaccinia virus (rVV40L) and we have investigated its antitumor activity. Notably, rVV40L-infection resulted in an improvement of (i) the antigen presenting capacity of CD40+ nonprofessional CD14+ monocytes leading (ii) to the rapid expansion and differentiation of human naïve CD8+ T cells into central memory T cells (TCM) specific for tumor associated antigens (TAAs), (ii) the induction of apoptotic effects on CD40+ established tumor cell lines of different origin and (iii) the antitumor activity, TNF-mediated, of macrophages. Collectively, these data indicate that rVV40L can be considered a successful viral vector for cancer immunotherapy according to its multiple mechanisms of action.

Citation Format: Emanuele Trella. Multipotency of a CD40L-expressing recombinant vaccinia virus [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A016.
Abstract A044: Immunological effects of a novel RNA-based adjuvant in liver cancer patients
Authors: Circelli Luisa , Petrizzo Annacarmen , Tagliamonte Maria , Heidenreich Regina , Tornesello Maria Lina , Buonaguro Franco M. , Buonaguro Luigi
Published: November 2016

Evaluation of detailed biological effects of adjuvants on immune cells has been assessed in a limited number of studies performed only on samples derived from healthy individuals. No data are available on samples derived from cancer patients who may have a severe immune impairment. A novel RNA-based adjuvant (RNAdjuvant® developed by CureVac) is made of a synthetic single stranded RNA molecule combined with a polymeric carrier. It is known to interact with toll-like receptors (TLRs) 7. The effects of RNAdjuvant® on PBMCs of liver cancer patients was assessed in an ex vivo setting, using a multiparametric approach to analyze network dynamics of early human immune responses. PBMCs were obtained from 8 healthy volunteers and 17 HCC patients enrolled in the present study. After treatment in culture, the effects of RNAdjuvant® were assessed by evaluation of CD80, CD86 and HLA-DR expression, pattern of cytokine production as well as gene expression profile. Moreover, the downstream effect on CD4+ T cell phenotyping was evaluated. The TLR4 ligand LPS was used as comparison. Treatment with RNAdjuvant® showed comparable effects on PBMCs of both HCC and healthy subjects, as shown by all the evaluated parameters. CD80, CD86 and HLA-DR expression was found upregulated in circulating dendritic cells, which promoted a CD4+ T cell differentiation towards an effector phenotype. A mixed Th1/Th2 cytokine pattern was induced in PBMCs, although a more predominant production of TNFα and IFNγ was observed in HCC patients vs. healthy controls. The cytokine profile was further confirmed by gene transcriptional analysis, which showed up-regulation of several genes involved in innate and adaptive immune-related pathways.

Citation Format: Luisa Circelli, Annacarmen Petrizzo, Maria Tagliamonte, Regina Heidenreich, Maria Lina Tornesello, Franco M. Buonaguro, Luigi Buonaguro. Immunological effects of a novel RNA-based adjuvant in liver cancer patients [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A044.
Abstract A045: Inhibition of tumor growth by combination of metronomic chemotherapy and checkpoint inhibitor with a cancer vaccine
Authors: Tagliamonte Maria , Petrizzo Annacarmen , Mauriello Angela , Luciano Antonio , Rea Domenica , Barbieri Antonio , Arra Claudio , Maiolino Piera , Tornesello Maria Lina , Ciliberto Gennaro , Buonaguro Franco M. , Buonaguro Luigi
Published: November 2016

The efficacy of cancer immunotherapies can be significantly limited by the immune suppressive soluble factors and cell types characterizing the tumor microenvironment. Strategies combining anti-immune suppressive therapies and cancer vaccines need to be evaluated. In the present study, a novel combinatorial strategy was assessed in a mouse model using an aggressive therapeutic setting based on sub-cutaneous ectopic implantation of B16 melanoma cells. The anti-immune suppressive therapy included a novel mix of chemotherapy agents, administered in a metronomic fashion (MCT), and an anti-PD-1 checkpoint inhibitor (CI). The vaccine (VAC) was a multi-peptide cocktail, including melanoma-specific tumor-associated antigens. The newly designed strategy was shown to be safe, well tolerated and highly effective. Animals treated with MCT or CI showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such effect was significantly enhanced by the combination with the multi-peptide vaccine. In particular, the multi-pronged MCT+CI+VAC combination resulted in a remarkable inhibition of tumor growth in 5/6 animals. The anti-tumor effect was associated with a strong T cell immune response to vaccine peptides as well as significant intra-tumor T cell infiltration associated with reduction in Tregs. Overall, the results showed that the combination of anti-immune suppressive therapy and vaccine was able to strongly potentiate the anti-tumor effects. The described approach is highly promising to significantly enhance the anti-tumor effects induced by a therapeutic cancer vaccine.

Citation Format: Maria Tagliamonte, Annacarmen Petrizzo, Angela Mauriello, Antonio Luciano, Domenica Rea, Antonio Barbieri, Claudio Arra, Piera Maiolino, Maria Lina Tornesello, Gennaro Ciliberto, Franco M. Buonaguro, Luigi Buonaguro. Inhibition of tumor growth by combination of metronomic chemotherapy and checkpoint inhibitor with a cancer vaccine [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A045.
Abstract A065: Oscillatory genes in lymphocyte retention and egress
Authors: Chen Hsin , Schmidt Timothy , Xu Ying , Lu Erick , Cyster Jason G.
Published: November 2016

The adaptive immune system attacks cancer cells by initiating immune responses in lymphoid organs and egressing of activated effector cells into circulation to reach the tumor. Several G protein-coupled receptors have been reported to recruit lymphocytes to the lymphoid organ or to promote exit. However, how these signals crosstalk to ensure efficient lymphocyte recruitment and transit is not well understood. To further define how cell transit through the lymphoid tissue is controlled, we designed two parallel RNAseq to identify novel regulators for lymphocyte transit. We compared the transcriptome of naïve B cells from the blood and peripheral lymph node. Also, by utilizing photoconvertible proteins, we isolated naive B cells that newly enter the lymphoid organ and those that have been dwelling for several hours. We identified multiple genes whose transcript levels were correlated with lymphoid dwelling time. One of the genes, KLF11, encoding a transcription factor, is expressed more highly in the blood than in the lymph node, and the expression decreases with the dwelling time in the lymphoid organ. Analysis of the KLF11 knock-out mouse identified strong lymphocyte transit and developmental defects, but we found the strong phenotypes segregated independently of the KLF11 knock-out allele. The phenotypes were the result of a mutated DOCK2 allele in the commercial B6 background. We have now generated a KLF11 knock-out with wildtype DOCK2. The progress of characterizing the function of KLF11 in lymphocyte recruitment and egress will be reported.

Citation Format: Hsin Chen, Timothy Schmidt, Ying Xu, Erick Lu, Jason G. Cyster. Oscillatory genes in lymphocyte retention and egress [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A065.
Abstract A074: A Zap70-dependent negative feedback loop governs Lck activation by CD45
Authors: Courtney Adam H. , Kadlecek Theresa A. , Au-Yeung Byron , Weiss Arthur
Published: November 2016

The kinase Lck phosphorylates the T cell antigen receptor (TCR) complex when antigen is encountered and therefore its activity sets a critical threshold for T cell activation. Yet how Lck activity is regulated in resting or stimulated cells remains poorly understood. We have identified that a cryptic phosphosite within Lck, Y192, profoundly affects Lck activity when mutated. Notably, mutation of Y192 blocks critical TCR proximal signaling events including phosphorylation of the effector kinase Zap70 and subsequent calcium response. Accordingly, thymocyte development in retrogenic mice harboring a Y192 mutation is severely impaired. These mice are unable to produce mature T cells and accumulate double negative and double positive (CD4/CD8) thymocytes. We determined that these defects are caused by hyperphosphorylation of the canonical inhibitory phosphorylation site (Y505) within Lck's C-terminus. Lck's C-terminus is phosphorylated by the inhibitory kinase Csk and we have employed a regulatable reconstituted system to acutely inhibit Csk activity. Upon Csk inhibition, the phosphatase CD45 dephosphorylates Lck's C-terminus (Y505). Interestingly, mutation of Y192 disrupts CD45's ability to dephosphorylate Y505 and activate Lck. Because Y192 phosphorylation decreases in response to small molecule inhibition of Zap70, an Lck substrate, our findings support a mechanism of negative feedback. We predict that tonic or basal signaling events that occur in the absence of TCR ligand use negative feedback, including Y192 phosphorylation, to tune Lck activity. Because modulation of Lck activity impacts TCR sensitivity, feedback mechanisms are likely critical to establishing a threshold for T cell activation.

Citation Format: Adam H. Courtney, Theresa A. Kadlecek, Byron Au-Yeung, Arthur Weiss. A Zap70-dependent negative feedback loop governs Lck activation by CD45 [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A074.