bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary Markers of Tubular Injury in Early Diabetic Nephropathy
Authors: Fiseha Temesgen , Tamir Zemenu
Published: May 2016

Diabetic nephropathy (DN) is a common and serious complication of diabetes associated with adverse outcomes of renal failure, cardiovascular disease, and premature mortality. Early and accurate identification of DN is therefore of critical importance to improve patient outcomes. Albuminuria, a marker of glomerular involvement in early renal damage, cannot always detect early DN. Thus, more sensitive and specific markers in addition to albuminuria are needed to predict the early onset and progression of DN. Tubular injury, as shown by the detection of tubular injury markers in the urine, is a critical component of the early course of DN. These urinary tubular markers may increase in diabetic patients, even before diagnosis of microalbuminuria representing early markers of normoalbuminuric DN. In this review we summarized some new and important urinary markers of tubular injury, such as neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), N-acetyl-beta-glucosaminidase (NAG), alpha-1 microglobulin (A1M), beta 2-microglobulin (B2-M), and retinol binding protein (RBP) associated with early DN.
Spectrum Sensing Based on Nonparametric Autocorrelation in Wireless Communication Systems under Alpha Stable Noise
Authors: Chen Riqing , Wang Jun , Lin Ruiquan , Zhao Xiangning
Published: May 2016

Cognitive radio is regarded as a core technology to support wireless information systems. Spectrum sensing is one of the key steps to achieve cognitive radio technology. To address this problem in the presence of Alpha stable noise in wireless communication systems, we propose a nonparametric autocorrelation method, which takes advantages of the characteristics of signal autocorrelation and noise nonstationarity. The autocorrelated signal is distinguished from Alpha stable noise. As a result, the proposed method is immune from noise uncertainty. Simulation results show the validity of the proposed method under Alpha stable noise, for example, impulsive noise in wireless information systems.
Immediate Nonfunctional Loading of Two Single-Maxillary Postextractive Implants: 6-Year Postloading Results of Two Case Reports
Authors: Ariano Vincenzo , Mancini Manuele , Cardi Andrea , Condò Roberta , Cerroni Loredana , Pasquantonio Guido
Published: May 2016

Objectives. The aim of the study was to evaluate and compare crestal bone loss of single-maxillary immediate postextractive implants and immediate nonfunctional loading (INFL) during 72 months of follow-up.Material and Methods. Two single titanium implants (Certain Prevail, Biomet 3I, USA) were placed in two patients using INFL technique. Implant stability and crestal bone level were measured on periapical radiographs at 1, 3, and 6 months after surgery.Results. All osseointegrated implants were clinically successful after 6 years of functional loading.Conclusion. Within the limit of the present case report, the paper supports the concept that INFL of single dental implant can be a successful treatment procedure.
Roles and Mechanisms of Obstructive Sleep Apnea‐Hypopnea Syndrome and Chronic Intermittent Hypoxia in Atherosclerosis: Evidence and Prospective
Authors: Ma Linqin , Zhang Jingchun , Liu Yue
Published: May 2016

The morbidity and mortality of obstructive sleep apnea‐hypopnea syndrome (OSAHS) are regarded as consequences of its adverse effects on the cardiovascular system. Chronic intermittent hypoxia (CIH) induced by OSAHS can result in vascular endothelial injury, thus promoting development of atherosclerosis (AS). Studies have shown that CIH is an independent risk factor for the occurrence and development of AS, but the underlying mechanism remains unclear. Here, we review clinical and fundamental studies reported during the last 10 years on the occurrence and development of AS mediated by CIH, focusing on inflammation, oxidative stress, insulin resistance, cell apoptosis, vascular endothelial injury, platelet activation, and neuroendocrine disorders. This review will offer current evidence and perspective to researchers for the development of effective intervention strategies for OSAHS‐related cardiocerebrovascular diseases.
Eighth-Order Compact Finite Difference Scheme for 1D Heat Conduction Equation
Authors: Yosaf Asma , Rehman Shafiq Ur , Ahmad Fayyaz , Ullah Malik Zaka , Alshomrani Ali Saleh
Published: May 2016

The purpose of this paper is to develop a high-order compact finite difference method for solving one-dimensional (1D) heat conduction equation with Dirichlet and Neumann boundary conditions, respectively. A parameter is used for the direct implementation of Dirichlet and Neumann boundary conditions. The introduced parameter adjusts the position of the neighboring nodes very next to the boundary. In the case of Dirichlet boundary condition, we developed eighth-order compact finite difference method for the entire domain and fourth-order accurate proposal is presented for the Neumann boundary conditions. In the case of Dirichlet boundary conditions, the introduced parameter behaves like a free parameter and could take any value from its defined domain but for the Neumann boundary condition we obtained a particular value of the parameter. In both proposed compact finite difference methods, the order of accuracy is the same for all nodes. The time discretization is performed by using Crank-Nicholson finite difference method. The unconditional convergence of the proposed methods is presented. Finally, a set of 1D heat conduction equations is solved to show the validity and accuracy of our proposed methods.
Defining the Best Nasal Tip Projection among Iranian Women
Authors: Mohebbi Alireza , Jahandideh Hesam , Faham Zhaleh , Jafari Morteza
Published: May 2016

Rhinoplasty is one of the most complicated aesthetic surgeries. One important factor in nasal profile analysis before surgery is the NTP (Nasal Tip Projection). There has been controversy over defining the best tip projection and due to cultural differences there is a need to find the best formulation for Iranian noses. We selected 50 randomized patients. Lateral nasal views were captured from all of the patients. In order to equalize the photos, all tip rotations changed first to 105. We selected four methods for measuring NTP (Goode, Crumley 1, Crumley 2, and Powell and Humphreys). Based on these methods NTP was shown in four pictures. A questionnaire was designed for rating the pictures. Questionnaires were filled in by 3 different groups: rhinoplasty surgeons, general people, and artists. A total of 73 questionnaires were filled in. The analysis and comparison were done. Crumley 2 is the best NTP measurement method from the surgeons’ and artists’ view. Goode is the method preferred by general people. Powell & Humphreys method seems to be the worst method from all 3 groups’ view. It seems that general people prefer smaller noses, because projection in Goode method is almost less than Crumley 2.
A Benign Cardiac Growth but Not So Indolent
Authors: Wani Adil S. , Reddy Sahadev T. , Harinath Lakshmi , Biederman Robert W. W.
Published: May 2016

Cardiac lipomatous hypertrophy is a rare benign condition that usually involves the interatrial septum. Due to its benign nature it rarely requires intervention. Its presence outside the interatrial septum is reported infrequently. We present a case of lipomatous hypertrophy in the intraventricular septum that was complicated by a severe, symptomatic, and disabling dynamic left ventricular outflow tract obstruction. The symptoms significantly improved following the excision of the mass. In our case transthoracic echocardiogram was used to visualize the mass and measure the severity of the obstruction; Cardiac Magnetic Resonance Imaging was used to characterize the mass and histopathology confirmed the diagnosis.
Cutaneous Squamous Cell Carcinoma with Invasion through Ear Cartilage
Authors: Boisen Julie , Malone C. Helen , Kelly Brent , Wagner Richard F.
Published: May 2016

Cutaneous squamous cell carcinoma of the ear represents a high-risk tumor location with an increased risk of metastasis and local tissue invasion. However, it is uncommon for these cancers to invade through nearby cartilage. Cartilage invasion is facilitated by matrix metalloproteases, specifically collagenase 3. We present the unusual case of a 76-year-old man with an auricular squamous cell carcinoma that exhibited full-thickness perforation of the scapha cartilage. Permanent sections through the eroded cartilage confirmed tumor invasion extending to the posterior ear skin.
Delay in the Detrended Fluctuation Analysis Crossover Point as a Risk Factor for Type 2 Diabetes Mellitus
Authors: Varela Manuel , Vigil Luis , Rodriguez Carmen , Vargas Borja , García-Carretero Rafael
Published: May 2016

Detrended Fluctuation Analysis (DFA) measures the complexity of a glucose time series obtained by means of a Continuous Glucose Monitoring System (CGMS) and has proven to be a sensitive marker of glucoregulatory dysfunction. Furthermore, some authors have observed a crossover point in the DFA, signalling a change of dynamics, arguably dependent on the beta-insular function. We investigate whether the characteristics of this crossover point have any influence on the risk of developing type 2 diabetes mellitus (T2DM). To this end we recruited 206 patients at increased risk of T2DM (because of obesity, essential hypertension, or a first-degree relative with T2DM). A CGMS time series was obtained, from which the DFA and the crossover point were calculated. Patients were then followed up every 6 months for a mean of 17.5 months, controlling for the appearance of T2DM diagnostic criteria. The time to crossover point was a significant predictor risk of developing T2DM, even after adjusting for other variables. The angle of the crossover was not predictive by itself but became significantly protective when the model also considered the crossover point. In summary, both a delay and a blunting of the crossover point predict the development of T2DM.
Elevated Expression of Human Papillomavirus-16/18 E6 Oncoprotein Associates with Persistence of Viral Infection: A 3-Year Prospective Study in China
Authors: Yu Lu-Lu , Kang Le-Ni , Zhao Fang-Hui , Lei Xiao-Qin , Qin Yu , Wu Ze-Ni , Wang Hong , Chen Wen , Qiao You-Lin
Published: May 2016

Background: An association between high-risk human papillomavirus (HR-HPV) oncoprotein expression and viral persistence has been suggested by the outcome of etiology studies, but there are no epidemiologic studies evaluating that link.

Methods: We performed a 3-year prospective study in which 2,498 Chinese women ages 25 to 65 years were screened by six screening tests, including the OncoE6 Cervical Test (Arbor Vita Corporation) in 2011 (baseline). Six-hundred and ninety women who were positive for any of the tests and a random sample of 164 women with all negative results received colposcopy, and cervical specimens for the cobas 4800 HPV test (“cobas,” Roche Molecular Systems) were collected before colposcopy; of this group, 737 cervical specimens were collected to perform cobas and OncoE6 Cervical Test in 2014 (follow-up). Twenty-four cases of HPV16/18 E6 positives and 204 selected controls at baseline, 13 cases of HPV16/18 E6 positive and another 204 selected controls at follow-up were analyzed separately using unconditional logistical regression models to estimate ORs and 95% confidence intervals (CI).

Results: Compared with women who were HPV16 E6 oncoprotein negative at baseline, women in the E6-positive group had a much higher risk of HPV persistence (adjusted OR, 54.64; 95% CI, 7.19–415.09) at 3-year follow-up; a statistically strong association was also found between HPV16/18 HPV persistence and E6 oncoprotein expression detected at follow-up (adjusted OR, 360.57; 95% CI, 28.30–4,593.55).

Conclusions: A single detection of HPV16/18 E6 oncoprotein expression was strongly associated with viral persistence.

Impact: HPV16/18 E6 oncoprotein constitutes a marker for risk of HPV persistence. Cancer Epidemiol Biomarkers Prev; 25(7); 1167–74. ©2016 AACR.
A Tissue Systems Pathology Assay for High-Risk Barrett's Esophagus
Authors: Critchley-Thorne Rebecca J. , Duits Lucas C. , Prichard Jeffrey W. , Davison Jon M. , Jobe Blair A. , Campbell Bruce B. , Zhang Yi , Repa Kathleen A. , Reese Lia M. , Li Jinhong , Diehl David L. , Jhala Nirag C. , Ginsberg Gregory , DeMarshall Maureen , Foxwell Tyler , Zaidi Ali H. , Lansing Taylor D. , Rustgi Anil K. , Bergman Jacques J.G.H.M. , Falk Gary W.
Published: May 2016

Background: Better methods are needed to predict risk of progression for Barrett's esophagus. We aimed to determine whether a tissue systems pathology approach could predict progression in patients with nondysplastic Barrett's esophagus, indefinite for dysplasia, or low-grade dysplasia.

Methods: We performed a nested case–control study to develop and validate a test that predicts progression of Barrett's esophagus to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), based upon quantification of epithelial and stromal variables in baseline biopsies. Data were collected from Barrett's esophagus patients at four institutions. Patients who progressed to HGD or EAC in ≥1 year (n = 79) were matched with patients who did not progress (n = 287). Biopsies were assigned randomly to training or validation sets. Immunofluorescence analyses were performed for 14 biomarkers and quantitative biomarker and morphometric features were analyzed. Prognostic features were selected in the training set and combined into classifiers. The top-performing classifier was assessed in the validation set.

Results: A 3-tier, 15-feature classifier was selected in the training set and tested in the validation set. The classifier stratified patients into low-, intermediate-, and high-risk classes [HR, 9.42; 95% confidence interval, 4.6–19.24 (high-risk vs. low-risk); P < 0.0001]. It also provided independent prognostic information that outperformed predictions based on pathology analysis, segment length, age, sex, or p53 overexpression.

Conclusion: We developed a tissue systems pathology test that better predicts risk of progression in Barrett's esophagus than clinicopathologic variables.

Impact: The test has the potential to improve upon histologic analysis as an objective method to risk stratify Barrett's esophagus patients. Cancer Epidemiol Biomarkers Prev; 25(6); 958–68. ©2016 AACR.
Clinicopathologic Features of Colorectal Carcinoma in HIV-Positive Patients
Authors: Sigel Carlie , Cavalcanti Marcela S. , Daniel Tanisha , Vakiani Efsevia , Shia Jinru , Sigel Keith
Published: May 2016

Background: Emerging evidence suggests differences in colorectal cancer in HIV-infected patients (HIV+) compared with HIV− patients. Microsatellite instability (MSI), occurring in a subset of colorectal cancer, is present at a higher rate in certain cancers in HIV+ patients. Colorectal cancer with MSI share some characteristics with those reported for HIV+ colorectal cancer. On this premise, we studied clinical and pathologic features of HIV+ colorectal cancer and evaluated for MSI using matched HIV− colorectal cancer controls.

Methods: Two nested, matched cohorts were identified from a hospital-based cohort of colorectal cancer patients. HIV+ colorectal cancers were identified and random control patients were matched for selected characteristics. Mismatch repair protein (MMR) IHC was performed as the detection method for MSI. Variables were compared between cases and controls using fixed-effects logit modeling to account for matching.

Results: We included 184 colorectal cancer samples (38 HIV+, 146 HIV− control). Median patient age at colorectal cancer onset was 55. When compared with HIV− colorectal cancer, HIV+ patients were more likely to have smoked (P = 0.001), have right-sided colorectal cancer (37% vs. 14%; P = 0.003), and tumor-infiltrating lymphocytes (TIL) above 50/10 high-power fields (21% vs. 7%). There was no difference in MMR protein expression (P = 0.6). HIV+ colorectal cancer patients had reduced overall survival (P = 0.02) but no difference in progression-free survival.

Conclusions: HIV+ patients developed colorectal cancer at a lower median age than population estimates, had a higher frequency of right-sided disease, and increased TILs, suggesting potential biologic differences compared with uninfected patients.

Impact: Clinicopathologic differences in colorectal cancer of HIV+ persons may have implications for tumor pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(7); 1098–104. ©2016 AACR.
Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia
Authors: Ojha Juhi , Codd Veryan , Nelson Christopher P. , Samani Nilesh J. , Smirnov Ivan V. , Madsen Nils R. , Hansen Helen M. , de Smith Adam J. , Bracci Paige M. , Wiencke John K. , Wrensch Margaret R. , Wiemels Joseph L. , Walsh Kyle M.
Published: May 2016

Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Shorter mean telomere length in leukemic cells has been associated with more aggressive disease. Germline polymorphisms in telomere maintenance genes affect telomere length and may contribute to CLL susceptibility.

Methods: We collected genome-wide data from two groups of patients with CLL (N = 273) and two control populations (N = 5,725). In ancestry-adjusted case–control comparisons, we analyzed eight SNPs in genes definitively associated with inter-individual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208, and RTEL1.

Results: Three of the eight LTL-associated SNPs were associated with CLL risk at P < 0.05, including those near: TERC [OR, 1.46; 95% confidence interval (CI), 1.15–1.86; P = 1.8 × 10−3], TERT (OR = 1.23; 95% CI, 1.02–1.48; P = 0.030), and OBFC1 (OR, 1.36; 95% CI, 1.08–1.71; P = 9.6 × 10−3). Using a weighted linear combination of the eight LTL-associated SNPs, we observed that CLL patients were predisposed to longer LTL than controls in both case–control sets (P = 9.4 × 10−4 and 0.032, respectively). CLL risk increased monotonically with increasing quintiles of the weighted linear combination.

Conclusions: Genetic variants in TERC, TERT, and OBFC1 are associated with both longer LTL and increased CLL risk. Because the human CST complex competes with shelterin for telomeric DNA, future work should explore the role of OBFC1 and other CST complex genes in leukemogenesis.

Impact: A genetic predisposition to longer telomere length is associated with an increased risk of CLL, suggesting that the role of telomere length in CLL etiology may be distinct from its role in disease progression. Cancer Epidemiol Biomarkers Prev; 25(7); 1043–9. ©2016 AACR.
PIWI-Interacting RNAs in Gliomagenesis: Evidence from Post-GWAS and Functional Analyses
Authors: Jacobs Daniel I. , Qin Qin , Lerro Michael C. , Fu Alan , Dubrow Robert , Claus Elizabeth B. , DeWan Andrew T. , Wang Guilin , Lin Haifan , Zhu Yong
Published: May 2016

Background: PIWI-interacting RNAs (piRNAs), the largest class of noncoding RNAs in mammals, cooperate with PIWI proteins to safeguard the genome from insertional mutations during germline development. Although a growing number of studies have linked the PIWI–piRNA pathway to carcinogenesis, the role of piRNAs in glioma has not been explored.

Methods: Utilizing directly measured and imputed genotypes from the GliomaScan genome-wide association study (1,840 cases and 2,401 controls), genetic variants in 1,428 piRNAs were analyzed for association with glioma risk. In vitro assays were performed to interrogate the functional impact of a top identified piRNA and its variant allele.

Results: Variants in five piRNAs were considered to be associations of interest and four of these showed narrow clusters of enhanced association signals surrounding the index variant. Functional analyses of one of these piRNAs, piR-598, revealed that transfection of the wild-type piRNA impacted expression of genes involved in cell death/survival and reduced glioma cell viability and colony formation. However, upon delivery of piR-598 containing the variant allele at rs147061479 [OR, 1.80; 95% confidence interval (CI), 1.33–2.46; P = 1.69 × 10−4], cell proliferation was sharply increased.

Conclusions: The genetic association analysis identifies several piRNAs associated with glioma risk, and follow-up functional analyses suggest that variant rs147061479 in piR-598 increases glioma risk by abolishing the tumor-suppressive function of piR-598, instead conferring growth-promoting properties.

Impact: This transdisciplinary study demonstrates a role of piRNAs in gliomagenesis by evidence from both post-GWAS and in vitro functional analyses and supports expanded investigation into the link between the PIWI–piRNA pathway and cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1073–80. ©2016 AACR.
Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab
Authors: Sade-Feldman Moshe , Kanterman Julia , Klieger Yair , Ish-Shalom Eliran , Olga Mizrahi , Saragovi Amijai , Shtainberg Hani , Lotem Michal , Baniyash Michal
Published: May 2016

Purpose: High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33+CD11b+HLA-DR− MDSCs could be used as immune system monitoring biomarkers to predict response and survival of patients with stage IV melanoma treated with anti-CTLA4 (ipilimumab) therapy.

Experimental Design: Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33+CD11b+HLA-DR− MDSC percentage, NO−, and hROS levels by flow cytometry. We determined whether MDSC levels and suppressive features detected before anti-CTLA4 therapy correlate with the patients' response and overall survival (OS).

Results: Patients with melanoma had significantly higher levels of circulating CD33+CD11b+HLA-DR− MDSCs with suppressive phenotype when compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status. No predictive impact was observed for lactate dehydrogenase (LDH). Kaplan–Meier and log-rank tests performed on the 56 patients showed that the presence of more than 55.5% of circulating CD33+CD11b+ out of the HLA-DR− cells, were associated with significant short OS (P < 0.003), a median of 6.5 months, in comparison with the group showing lower MDSC frequencies, with a median survival of 15.6 months.

Conclusions: Our study suggests the use of CD33+CD11b+HLA-DR− cells as a predictive and prognostic biomarker in patients with stage IV melanoma treated with anti-CTLA4 therapy. This monitoring system may aid in the development of combinatorial modalities, targeting the suppressive environment in conjunction with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res; 22(23); 5661–72. ©2016 AACR.
In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype
Authors: Bossi Daniela , Cicalese Angelo , Dellino Gaetano I. , Luzi Lucilla , Riva Laura , D'Alesio Carolina , Diaferia Giuseppe R. , Carugo Alessandro , Cavallaro Elena , Piccioni Rossana , Barberis Massimo , Mazzarol Giovanni , Testori Alessandro , Punzi Simona , Pallavicini Isabella , Tosti Giulio , Giacó Luciano , Melloni Giorgio , Heffernan Timothy P. , Natoli Gioacchino , Draetta Giulio F. , Minucci Saverio , Pelicci PierGiuseppe , Lanfrancone Luisa
Published: May 2016

The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (∼50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identified genes, the Histone–lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways.

Significance: Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specific signaling pathways are activated in tumors. Cancer Discov; 6(6); 650–63. ©2016 AACR.

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High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial
Authors: Pearson Alex , Smyth Elizabeth , Babina Irina S. , Herrera-Abreu Maria Teresa , Tarazona Noelia , Peckitt Clare , Kilgour Elaine , Smith Neil R. , Geh Catherine , Rooney Claire , Cutts Ros , Campbell James , Ning Jian , Fenwick Kerry , Swain Amanda , Brown Gina , Chua Sue , Thomas Anne , Johnston Stephen R.D. , Ajaz Mazhar , Sumpter Katherine , Gillbanks Angela , Watkins David , Chau Ian , Popat Sanjay , Cunningham David , Turner Nicholas C.
Published: May 2016

FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.

Significance: Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838–51. ©2016 AACR.

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Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression
Authors: Kaneda Megan M. , Cappello Paola , Nguyen Abraham V. , Ralainirina Natacha , Hardamon Chanae R. , Foubert Philippe , Schmid Michael C. , Sun Ping , Mose Evangeline , Bouvet Michael , Lowy Andrew M. , Valasek Mark A. , Sasik Roman , Novelli Francesco , Hirsch Emilio , Varner Judith A.
Published: May 2016

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a low 5-year survival rate, yet new immunotherapeutic modalities may offer hope for this and other intractable cancers. Here, we report that inhibitory targeting of PI3Kγ, a key macrophage lipid kinase, stimulates antitumor immune responses, leading to improved survival and responsiveness to standard-of-care chemotherapy in animal models of PDAC. PI3Kγ selectively drives immunosuppressive transcriptional programming in macrophages that inhibits adaptive immune responses and promotes tumor cell invasion and desmoplasia in PDAC. Blockade of PI3Kγ in PDAC-bearing mice reprograms tumor-associated macrophages to stimulate CD8+ T-cell–mediated tumor suppression and to inhibit tumor cell invasion, metastasis, and desmoplasia. These data indicate the central role that macrophage PI3Kγ plays in PDAC progression and demonstrate that pharmacologic inhibition of PI3Kγ represents a new therapeutic modality for this devastating tumor type.

Significance: We report here that PI3Kγ regulates macrophage transcriptional programming, leading to T-cell suppression, desmoplasia, and metastasis in pancreas adenocarcinoma. Genetic or pharmacologic inhibition of PI3Kγ restores antitumor immune responses and improves responsiveness to standard-of-care chemotherapy. PI3Kγ represents a new therapeutic immune target for pancreas cancer. Cancer Discov; 6(8); 870–85. ©2016 AACR.

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Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma
Authors: Kamiya Takahiro , Chang Yu-Hsiang , Campana Dario
Published: May 2016

Viral infection of the liver is a major risk factor for hepatocellular carcinoma (HCC). Natural killer (NK) cells recognize virally infected and oncogenically transformed cells, suggesting a therapeutic role for NK-cell infusions in HCC. Using the K562-mb15-41BBL cell line as a stimulus, we obtained large numbers of activated NK cells from the peripheral blood of healthy donors. Expanded NK cells exerted remarkably high cytotoxicity against HCC cell lines, which was generally much higher than that of unstimulated or IL2-activated NK cells. In immunodeficient NOD/scid IL2RGnull mice engrafted with Hep3B, treatment with expanded NK cells markedly reduced tumor growth and improved overall survival. HCC cells exposed for 48 hours to 5 μmol/L of sorafenib, a kinase inhibitor currently used for HCC treatment, remained highly sensitive to expanded NK cells. HCC cell reductions of 39.2% to 53.8% caused by sorafenib in three cell lines further increased to 80.5% to 87.6% after 4 hours of culture with NK cells at a 1:1 effector-to-target ratio. NK-cell cytotoxicity persisted even in the presence of sorafenib. We found that NKG2D, an NK-cell–activating receptor, was an important mediator of anti-HCC activity. We therefore enhanced its signaling capacity with a chimeric NKG2D-CD3ζ-DAP10 receptor. This considerably increased the anti-HCC cytotoxicity of expanded NK cells in vitro and in immunodeficient mice. The NK expansion and activation method applied in this study has been adapted to clinical-grade conditions. Hence, these results warrant clinical testing of expanded NK-cell infusions in patients with HCC, possibly after genetic modification with NKG2D-CD3ζ-DAP10. Cancer Immunol Res; 4(7); 574–81. ©2016 AACR.
Prolonged Benefit from Ipilimumab Correlates with Improved Outcomes from Subsequent Pembrolizumab
Authors: Shreders Amanda , Joseph Richard , Peng Chengwei , Ye Fei , Zhao Shilin , Puzanov Igor , Sosman Jeffrey A. , Johnson Douglas B.
Published: May 2016

Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti–programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti–PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02–1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569–73. ©2016 AACR.
Brain in Congenital Heart Disease Across the Lifespan
Authors: Marelli Ariane , Miller Steven P. , Marino Bradley Scott , Jefferson Angela L. , Newburger Jane W.
Published: May 2016

The number of patients surviving with congenital heart disease (CHD) has soared over the last 3 decades. Adults constitute the fastest-growing segment of the CHD population, now outnumbering children. Research to date on the heart-brain intersection in this population has been focused largely on neurodevelopmental outcomes in childhood and adolescence. Mutations in genes that are highly expressed in heart and brain may cause cerebral dysgenesis. Together with altered cerebral perfusion in utero, these factors are associated with abnormalities of brain structure and brain immaturity in a significant portion of neonates with critical CHD even before they undergo cardiac surgery. In infancy and childhood, the brain may be affected by risk factors related to heart disease itself or to its interventional treatments. As children with CHD become adults, they increasingly develop heart failure, atrial fibrillation, hypertension, diabetes mellitus, and coronary disease. These acquired cardiovascular comorbidities can be expected to have effects similar to those in the general population on cerebral blood flow, brain volumes, and dementia. In both children and adults, cardiovascular disease may have adverse effects on achievement, executive function, memory, language, social interactions, and quality of life. Against the backdrop of shifting demographics, risk factors for brain injury in the CHD population are cumulative and synergistic. As neurodevelopmental sequelae in children with CHD evolve to cognitive decline or dementia during adulthood, a growing population of CHD can be expected to require support services. We highlight evidence gaps and future research directions.
The taxonomy of Speodromia platyarthrodes (Stebbing, 1905) (Crustacea: Brachyura), an unusual dromiid crab endemic to South Africa
Authors: NG PETER K. L.
Published: May 2016

The poorly known dromiid crab Speodromia platyarthrodes (Stebbing, 1905), endemic to South Africa, is redescribed and figured. Speodromia is unique among dromiids in possessing a large cavity on the anterior part of the sub-branchial region, which is believed to be associated with respiration. The systematics of the genus is discussed and is confirmed to be a member of Dromiinae De Haan, 1833, s. str.
The Role of Surface Drag in Tornadogenesis within an Idealized Supercell Simulation
Authors: Roberts Brett , Xue Ming , Schenkman Alexander D. , Dawson Daniel T.
Published: May 2016

To investigate the effect of surface drag on tornadogenesis, a pair of idealized simulations is conducted with 50-m horizontal grid spacing. In the first experiment (full-wind drag case), surface drag is applied to the full wind; in the second experiment (environmental drag case), drag is applied only to the background environmental wind, with storm-induced perturbations unaffected. The simulations are initialized using a thermal bubble within a horizontally homogeneous background environment that has reached a balance between the pressure gradient, Coriolis, and frictional forces. The environmental sounding is derived from a prior simulation of the 3 May 1999 Oklahoma tornado outbreak but modified to account for near-ground frictional effects. In the full-wind drag experiment, a tornado develops around 25 min into the simulation and persists for more than 10 min; in the environmental-only drag experiment, no tornado occurs. Three distinct mechanisms are identified by which surface drag influences tornadogenesis. The first mechanism is the creation by drag of near-ground vertical wind shear (and associated horizontal vorticity) in the background environment. The second mechanism is generation of near-ground crosswise horizontal vorticity by drag on the storm scale as air accelerates into the low-level mesocyclone; this vorticity is subsequently exchanged into the streamwise direction and eventually tilted into the vertical. The third mechanism is frictional enhancement of horizontal convergence, which strengthens the low-level updraft and stretching of vertical vorticity. The second and third mechanisms are found to work together to produce a tornado, while baroclinic vorticity plays a negligible role.
Buy Local? Organizational Identity in the Localism Movement
Authors: Ciuchta Michael P. , O’Toole Jay
Published: May 2016

Localism is a social movement often associated with “buy local” food initiatives or the prevention of big-box retail expansion. At its core, however, localism is also about fostering local independence by encouraging businesses to opt for local alternatives when making purchasing decisions. In this article, we develop and test hypotheses that organizations with stronger community-oriented identities are more likely to source locally and that this relationship is moderated by the importance of the focal firm’s purchasing decisions. Results support the strong influence of identity but the conditional effect is unconfirmed.
The Ethnographic Method in CSR Research: The Role and Importance of Methodological Fit
Authors: Bass A. Erin , Milosevic Ivana
Published: May 2016

Corporate social responsibility (CSR) research has burgeoned in the past several decades. Despite significant advances, our review of the literature reveals a problematic gap: We know little about how culture, practices, and interactions shape CSR. On further investigation, we discover that limited research utilizes ethnography to understand CSR, which may provide some explanation for this gap. Thus, the purpose of this article is to illustrate the utility of ethnography for advancing business and society research via a multistage framework that demonstrates how three different types of ethnography may be applied to the exploration of CSR. We specifically focus on the alignment between stages in the research process, or methodological fit, as a key criterion of high-quality research. In doing so, we provide researchers embracing different worldviews a tool they may utilize to conduct and evaluate ethnographies in business and society research.
How does war become a legitimate undertaking? Re-engaging the post-structuralist foundation of securitization theory
Authors: Wilhelmsen Julie
Published: May 2016

How does war become a legitimate undertaking? This article challenges the interpretation of securitization as a narrow, linear and intentional event by re-engaging the post-structuralist roots of Copenhagen School securitization theory. To uncover the social process that makes war acceptable, the framework presented in this article is informed by securitization theory but foregrounds the web of meaning and representation between a myriad of actors in society to unearth the contents – and changes – in how war is articulated and carried out with public consent. This matters not only for the question of how war becomes a legitimate undertaking, but also for the very practices through which the war is fought: the emergency measures that are enabled in a discourse of existential threat. The article re-visits the Second Chechen War to illustrate how war is made logical and legitimate to leaders and their publics.
Roles of Social Movement Organizations for Securing Workers’ Safety in Korea
Authors: Park Ji-Eun , Kim Myoung-Hee
Published: May 2016

Many restaurants in Korea maintain quick-delivery service programs to satisfy customers. This service allows delivery workers limited time to deliver, which frequently put them in danger. Most of the workers are young, work part-time, and are rarely organized into trade unions. In this article, through a case study of the social movement to abolish the 30-minute delivery guarantee program of pizza companies in Korea, we argue that social movements involving social movement organizations (SMOs) and individual citizens could serve as a means to rectify this problem. We show how the SMOs developed and expanded the movement using a framing perspective and how the general public became involved through social media. Data was collected via online searching. Interview scripts from key players of SMOs and unofficial documents they provided were also reviewed. Three SMOs primarily led the movement, successfully forming a frame that emphasized social responsibility. SMOs also utilized social media to link their standing frame with unmobilized citizens and to expand the movement. We identified contributing factors and limitations of the movement and drew lessons that could be applied to other sectors where workers are in vulnerable positions.
Characterization and modeling of the effective electrical conductivity of a carbon nanotube/polymer composite containing chain-structured ferromagnetic particles
Authors: Jang Sung-Hwan , Yin Huiming
Published: May 2016

The effective electrical conductivity of multi-walled carbon nanotube/polydimethylsiloxane composites with chain-structured ferromagnetic particles has been investigated by experiments and micromechanics-based modeling. A multi-scale modeling approach is used to consider different size of fillers of multi-walled carbon nanotubes and particles as well as their distribution in the matrix. At nanoscale, for multi-walled carbon nanotube/polydimethylsiloxane composite, eight-chain model and influence of waviness of multi-walled carbon nanotube are considered to render an effective electrical conductivity. At microscale, ferromagnetic particles are aligned in the matrix made of the multi-walled carbon nanotube/polydimethylsiloxane composite, and an analytical model is established based on representative volume element. The influence of inter-particle distance is evaluated. The proposed analytic results agree well with the experimental results. The present model can be a useful tool for design and analysis of these composites for sensing applications considering their percolation threshold and overall electrical conductivity.
Bulk modulus evolution of thermoset resins during crosslinking: Is a direct and accurate measurement possible?
Authors: Péron Mael , Sobotka Vincent , Boyard Nicolas , Le Corre Steven
Published: May 2016

The determination of the mechanical properties of thermoset resin and their evolution during transformation still represents a scientific issue in the composite materials community. A homemade apparatus named PvTα has recently been adapted to the measurement of neat resin bulk modulus evolution during cure and has been presented in a previous study. Several assumptions were used to directly obtain this value but they cannot be checked in situ. A multi-physic modelling of the system is proposed for this purpose in this paper. It accounts for the thermal, chemical and mechanical behaviours of the different components of the apparatus as well as their interactions during an experiment. This model is thoroughly validated thanks to several comparisons with experimental results. This study shows that the early assumptions are not verified during the whole cure in the case of RTM6 resin. It leads to 40% error in the bulk modulus estimation, thus making impossible a direct measurement of the resin bulk modulus using the simple protocol proposed by Nawab et al. A new procedure, which is based on the developed model, is proposed to improve the analysis accuracy.
The “Deviant Good Mother”
Authors: Couvrette Amélie , Brochu Serge , Plourde Chantal
Published: May 2016

When drug-using and lawbreaking women are mothers, their competence as mothers is often questioned because good mothers are not supposed to do such things. Consequently, they are often labeled as unfit mothers. This qualitative study seeks to examine the experience of motherhood in substance-using and lawbreaking mothers. Interviews with 38 substance-using women who had broken the law were conducted. Women in our study embrace two models of motherhood: one is an idealized view of motherhood as worthwhile, gratifying, and true to social expectations, and the other a model of the “deviant good mother,” which conforms more closely to their deviant lifestyle. Both of these models influence the way that these mothers perceive their substance use, their criminal behavior, and the possibility of being a good mother. The “deviant good mother” model also allowed them to build (or rebuild) a positive and fulfilling maternal identity.
Relative Difference and Burglary Location
Authors: Chamberlain Alyssa W. , Boggess Lyndsay N.
Published: May 2016

Objectives:

Neighborhood characteristics predict burglary targets, but target attractiveness may be colored by the conditions in which a potential offender resides. We test whether relative differences in concentrated disadvantage, racial/ethnic composition, and ethnic heterogeneity influence where burglars offend, controlling for distance. From a relative deprivation perspective, economically advantaged areas make more attractive targets to burglars residing in disadvantage neighborhoods, but a social disorganization perspective predicts areas lower in social cohesion are most attractive, which may be neighborhoods with greater disadvantage.

Methods:

Drawing upon a unique sample of cleared burglaries in the City of Tampa, Florida from 2000 to 2012, we utilize discrete choice modeling to predict burglar offense destination.

Results:

Offenders target neighborhoods that are geographically proximate or ecologically similar to their own. When accounting for relative differences, burglars from all neighborhood types are more likely to target highly disadvantaged or heterogeneous neighborhoods.

Conclusions:

Burglars generally select targets that are similar to their residence. However, when suspects do discriminate, there is evidence that they target neighborhoods that are worse off relative to their own on characteristics such as residential instability, disadvantage, racial composition, and racial/ethnic diversity. These neighborhoods are associated with lower social control and lower risk of detection.
Structural Power and the Politics of Bank Capital Regulation in the United Kingdom
Authors: Bell Stephen , Hindmoor Andrew
Published: May 2016

This article describes and explains a significant tightening in bank capital regulation in the United Kingdom since the 2008 financial crisis. The banks fiercely resisted the new capital regulations but in a novel theoretical contribution we argue that the structural power of business was reduced due to the changing ideas of state leaders, by changing institutional arrangements within the state and by wider open politicisation of banking reform.