bluuebunny/crossref_metadata_2025 huggingface dataset:
A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome
Authors: Tomas Cara , Newton Julia , Watson Stuart
Published: October 2013

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.
Rainbow: An Operating System for Software-Hardware Multitasking on Dynamically Partially Reconfigurable FPGAs
Authors: Jozwik Krzysztof , Honda Shinya , Edahiro Masato , Tomiyama Hiroyuki , Takada Hiroaki
Published: October 2013

Dynamic Partial Reconfiguration technology coupled with an Operating System for Reconfigurable Systems (OS4RS) allows for implementation of a hardware task concept, that is, an active computing object which can contend for reconfigurable computing resources and request OS services in a way software task does in a conventional OS. In this work, we show a complete model and implementation of a lightweight OS4RS supporting preemptable and clock-scalable hardware tasks. We also propose a novel, lightweight scheduling mechanism allowing for timely and priority-based reservation of reconfigurable resources, which aims at usage of preemption only at the time it brings benefits to the performance of a system. The architecture of the scheduler and the way it schedules allocations of the hardware tasks result in shorter latency of system calls, thereby reducing the overall OS overhead. Finally, we present a novel model and implementation of a channel-based intertask communication and synchronization suitable for software-hardware multitasking with preemptable and clock-scalable hardware tasks. It allows for optimizations of the communication on per task basis and utilizes point-to-point message passing rather than shared-memory communication, whenever it is possible. Extensive overhead tests of the OS4RS services as well as application speedup tests show efficiency of our approach.
Thrombogenic Catheter-Associated Superior Vena Cava Syndrome
Authors: Shaikh Imran , Berg Kenneth , Kman Nicholas
Published: October 2013

Superior vena cava syndrome has historically been associated with malignancy. With the increasing use of indwelling central lines, catheters, and pacemakers in the past decade, there have been an increasing number of cases associated with thrombosis rather than by direct external compression. Patients presenting to the ED with an acute process of SVC syndrome need to be assessed in a timely fashion. Computed tomography angiography (CTA) or magnetic resonance angiogram (MRA) are superb modalities for diagnosis and can quickly be used in the ED. Treatment is oriented towards the underlying cause of the syndrome. In cases of thrombogenic catheter-associated SVC syndrome, anticoagulation is the mainstay of treatment. We present a case report and discussion of a 56-year-old male with a history of metastatic colorectal cancer and an indwelling central venous port with acute signs and symptoms of superior vena cava syndrome.
Phytoestrogenα-Zearalanol Attenuates Homocysteine-Induced Apoptosis in Human Umbilical Vein Endothelial Cells
Authors: Liu Teng , Hou Dan-dan , Zhao Qian , Liu Wei , Zhen Pan-pan , Xu Jian-ping , Wang Ke , Huang Hai-xia , Li Xiao , Zhang Hui , Xu Hai-bo , Wang Wen
Published: October 2013

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. The enhanced nitrative stress plays an important role in homocysteine-induced endothelial dysfunction. Previous studies have showed that phytoestrogenα-zearalanol alleviated endothelial injury in ovariectomized hyperhomocysteinemic rats; however, the underlying mechanism remains to be clarified. This study was to investigate the effects ofα-zearalanol on homocysteine-induced endothelial apoptosisin vitroand explore the possible role of nitrative stress in these effects. Results showed that homocysteine (500 μmol/L, 24 h) induced the apoptosis of human umbilical vein endothelial cells (HUVECs) obviously, and this effect was significantly attenuated by pretreatment withα-zearalanol (10−8~10−6 mol/L). Moreover,α-zearalanol downregulated proapoptotic protein Bax, upregulated antiapoptotic proteins Bcl-2 and Bcl-XL, and decreased the expression and activity of caspase-9. These findings demonstrated thatα-zearalanol could effectively alleviate homocysteine-induced endothelial apoptosis, and this antiapoptosis effect might be related to the inhibition of the intrinsic pathway. Western blot indicated an enhanced 3-nitrotyrosine expression in HUVECs when challenged with homocysteine, which was attenuated by pretreatment withα-zearalanol. This result implied that inhibition of nitrative stress might play a role in the protective effect ofα-zearalanol on endothelial cells. Such discovery may shed a novel light on the antiatherogenic activities ofα-zearalanol in hyperhomocysteinemia.
Effects of Temperature on the Microstructure and Magnetic Property of Cr‐Doped ZnO DMS Prepared by Hydrothermal Route Assisted by Pulsed Magnetic Fields
Authors: Wang Shiwei , Zhong Min , Liu Cong , Li Ying , Zhu Mingyuan , Jin Hongming , Hu Yemin
Published: October 2013

In the present work, Cr‐doped ZnO diluted magnetic semiconductor was synthesized by hydrothermal method under pulsed magnetic fields. The samples were characterized by XRD, SEM, VSM, Raman, and XPS techniques. Results demonstrated that Zn ions in the ZnO crystal lattice were partially displaced by Chromium (III) ions. All samples show room temperature ferromagnetism which was enhanced by pulsed magnetic fields. The mechanism of ferromagnetism of Cr‐doped ZnO particles was discussed.
Circulating CD4+CD28null T Cells May Increase the Risk of an Atherosclerotic Vascular Event Shortly after Kidney Transplantation
Authors: Betjes Michiel G. H. , Weimar Willem , Litjens Nicolle H. R.
Published: October 2013

Proinflammatory CD4+T cells without the costimulatory molecule CD28 (CD4+CD28null T cells) are expanded in patients with end-stage renal disease (ESRD) and associated with atherosclerotic vascular events (AVE). In a prospective study, the number of circulating CD4+CD28null T cells was established in 295 ESRD patients prior to receiving a kidney allograft. Within the first year after transplantation, an AVE occurred in 20 patients. Univariate analysis showed that besides a history of cardiovascular disease (CVDpos, HR 8.1, ), age (HR 1.04, ), dyslipidaemia (HR 8.8, ), and the % of CD4+CD28null T cells (HR 1.04 per % increase, 95% CI 1.00–1.09, ) were significantly associated with the occurrence of a posttransplantation AVE. In a multivariate analysis, only CVDpos remained a significant risk factor with a significant and positive interaction between the terms CVDpos and the % of CD4+CD28null T cells (HR 1.05, 95% CI 1.03–1.11, ). Within the CVDpos group, the incidence of an AVE was 13% in the lowest tertile compared to 25% in the highest tertile of % of CD4+CD28null T cells. In conclusion, the presence of circulating CD4+CD28null T cells is associated with an increased risk for a cardiovascular event shortly after kidney transplantation.
Micropapillary Pattern at the Invasive Front and Its Association with Unresectable Colorectal Carcinomas
Authors: Akimoto Naohiko , Fujimori Takahiro , Mitomi Hiroyuki , Ichikawa Kazuhito , Tomita Shigeki , Tatsuguchi Atsushi , Fujimori Shunji , Naito Zenya , Sakamoto Choitsu
Published: October 2013

Unresectable colorectal carcinomas (CRCs) as considered incurable even if the primary tumors and the metastatic ones can undergo resection are correlated with poor prognosis. We evaluated the association between micropapillary pattern at the invasive front and unresectable CRCs. Thirty-four out of 264 (12.9%) CRC patients with stages III and IV were unresectable cases. The patients with unresectable CRCs had significantly worse survival than those with resectable CRCs (). Micropapillary pattern was evident in 12 (4.5%) out of 264 cases. This pattern was observed in 6 of 34 (17.6%) unresectable CRCs and in 6 of 230 (2.6%) resectable cases (). Unresectable CRCs revealed more frequently deeper invasion (odds ratio (OR), 1.175; 95% confidence interval (CI), 1.113–1.241), lymph node metastasis (OR, 2.356; 95% CI, 1.132–4.905), and presence of micropapillary pattern at the invasive front (OR, 8.000; 95% CI, 2.415–26.504) as compared to resectable cases. By multivariable logistic regression analysis, only micropapillary pattern was shown to be an independent predictor of unresectable CRCs (OR, 9.451; 95% CI, 2.468–36.196; ). In conclusion, micropapillary pattern at the invasive front is associated with unresectable CRCs, and detection of it could help identify unresectable CRC cases.
Association between Obesity, Serum Lipids, and Colorectal Polyps in Old Chinese People
Authors: Yang Wen , Chang Yan , Huang Haiyan , Wang Yuzhu , Yu Xiaohong
Published: October 2013

Background. Colorectal cancer mostly arises from the polyps of colon. The aim of our study was to examine the association of body mass index (BMI) and serum lipids with the colorectal polyps in old Chinese people.Methods. The risk of developing colorectal polyps was studied in 244 subjects (212 men and 32 women, 74.63 ± 11.63 years old) who underwent colonoscopy for the first time from January 2008 to July 2012 at the Navy General Hospital, Beijing, China. According to the results of colonoscopy, all the subjects were divided into 112 normal control, 38 right colorectal polyps, 53 left colorectal polyps, and 41 both right and left colorectal polyps groups. The total plasma cholesterol, plasma triglyceride, plasma creatinine concentration, blood urinary nitrogen, and fasting glucose were determined using a multichannel analyzer.Results. There were significant differences among normal control, right colorectal polyps, left colorectal polyps, and both right and left polyps groups, which were the BMI, total cholesterol, triglycerides, creatinine, and urinary nitrogen. In binary logistic regression analysis, there were two risk factors associated with the occurrence of colorectal polyps, which included BMI and systolic blood pressure.Conclusions. Colorectal polyps were significantly associated with increased BMI, total cholesterol, and triglycerides levels.
In VitroToxicity Evaluation of Engineered Cadmium-Coated Silica Nanoparticles on Human Pulmonary Cells
Authors: De Simone Uliana , Manzo Luigi , Profumo Antonella , Coccini Teresa
Published: October 2013

Cytotoxicity of cadmium-containing silica nanoparticles Cd-SiO2NPs (0.05–100 µg/mL) versus SiO2NPs and CdCl2was evaluated by anin vitrotest battery in A549 by assessing (i) mitochondrial function, (ii) membrane integrity/cell morphology, (iii) cell growth/proliferation, (iv) apoptotic pathway, (v) oxidative stress, after short- (24–48 h) and long-term (10 days) exposure. Both Cd-SiO2NPs and CdCl2produced dose-dependent cytotoxic effects: (i)MTT-assay: similar cytotoxicity pattern was observed at both 24 and 48 h, with a more Cd-SiO2NPs pronounced effect than CdCl2. Cd-SiO2NPs induced mortality (about 50%) at 1 μg/mL, CdCl2at 25 μg/mL; (ii)calcein-AM/PI staining: decrease in cell viability, noticeable at 25 μg/mL, enhanced markedly at 50 and 100 μg/mL, after 24 h. Cd-SiO2NPs induced higher mortality than CdCl2(25% versus 4%, resp., at 25 μg/mL) with further exacerbation after 48h; (iii)clonogenic assay: exposure for longer period (10 days) compromised the A549 proliferative capacity at very low dose (0.05 μg/mL); (iv) a progressive activation ofcaspase-3 immunolabellingwas detected already at 1 μg/mL; (v) GSH intracellular level was modified by all compounds. In summary,in vitrodata demonstrated that both Cd-SiO2NPs and CdCl2affected all investigated endpoints, more markedly after Cd-SiO2NPs, while SiO2NPs influenced GSH only.
Spontaneous Renal Pelvis Rupture: Unexpected Complication of Urolithiasis Expected to Passage with Observation Therapy
Authors: Tas Tuncay , Cakıroglu Basri , Aksoy Süleyman Hilmi
Published: October 2013

Seventy percent of ureteral stones are located at distal ureter. Effective and safe passage of distal ureter stones is mediated by observation or medical expulsive treatment. Most of stones located at distal ureter pass spontaneously under observation; however, some are complicated with urinary tract infection, hydronephrosis, and renal function disturbances. Spontaneous perforation of the upper ureter is a rare condition that poses diagnostic and therapeutic problems. This case is reported, because the patient developed an unexpected spontaneous renal pelvis rupture (SRPR), while she was under observation and expected to pass her right ureteral stone spontaneously through hydration and analgesic treatment.
Receptors and Lethal Effect ofBacillus thuringiensisInsecticidal Crystal Proteins to theAnticarsia gemmatalis(Lepidoptera, Noctuidae)
Authors: Fiuza Lidia Mariana , Knaak Neiva , da Silva Rogério Fernando Pires , Henriques João Antônio Pêgas
Published: October 2013

Bioassays with insecticidal crystal proteins (ICPs) fromBacillus thuringiensishave demonstrated that Cry1Aa, Cry1Ac, and Cry1Ba are the most active toxins on larvae of theAnticarsia gemmatalis. The toxins Cry1Da and Cry1Ea are less toxic, and toxins Cry2Aa are not active. Binding of these ICPs to midgut sections of theA. gemmatalislarvae was studied using streptavidin-mediated detection. The observed staining patterns showed that Cry1Aa and Cry1Ac bound to the brush border throughout the whole length of the midgut. However, the binding sites of Cry1Ba were not evenly distributed in the midgut microvilli. Thein vivoassays against larvae of 2nd instarA. gemmatalisconfirmed the results from thein vitrobinding studies. These binding data correspond well with the bioassay results, demonstrating a correlation between receptors binding and toxicity of the tested ICPs in this insect.
Parameter Estimation for Type III Discrete Weibull Distribution: A Comparative Study
Authors: Barbiero Alessandro
Published: September 2013

The type III discrete Weibull distribution can be used in reliability analysis for modeling failure data such as the number of shocks, cycles, or runs a component or a structure can overcome before failing. This paper describes three methods for estimating its parameters: two customary techniques and a technique particularly suitable for discrete distributions, which, in contrast to the two other techniques, provides analytical estimates, whose derivation is detailed here. The techniques’ peculiarities and practical limits are outlined. A Monte Carlo simulation study has been performed to assess the statistical performance of these methods for different parameter combinations and sample sizes and then give some indication for their mindful use. Two applications of real data are provided with the aim of showing how the type III discrete Weibull distribution can fit real data, even better than other popular discrete models, and how the inferential procedures work. A software implementation of the model is also provided.
Relationship between Repeated Sprint Ability and Aerobic Capacity in Professional Soccer Players
Authors: Jones Rhys M. , Cook Christian C. , Kilduff Liam P. , Milanović Zoran , James Nic , Sporiš Goran , Fiorentini Bruno , Fiorentini Fredi , Turner Anthony , Vučković Goran
Published: October 2013

Aim. The aim of the present study was to investigate the relationship between maximal aerobic capacity (VO2 max) and repeated sprint ability (RSA) in a group of professional soccer players. Methods. Forty‐one professional soccer players (age 23 ± 4 yrs, height 180.0 ± 5.3 cm, weight 79.6 ± 5.3 kg) were required to perform tests to assess RSA and VO2 max on two separate days with at least 48 hr rest between testing sessions. Each player performed a treadmill test to determine their VO2 max and a test for RSA involving the players completing 6 × 40 m sprints (turn after 20 m) with 20 s active recovery between each sprint. Results. There was a significant negative correlation between body mass normalised VO2 max and mean sprint time (RSAmean) (r = −0.655; P < 0.01) and total sprint time (RSAtotal) (r = −0.591, P < 0.01). Conclusion. Results of the current study indicate that VO2 max is one important factor aiding soccer players in the recovery from repeated sprint type activities.
Application of the New Jersey Department of Environmental Protection Water Budget Manual to Finderne Farms Wetland Mitigation and Assessment of Project Performance
Authors: Messaros Roy C.
Published: October 2013

The U.S. Army Corps of Engineers, NY District’s wetland mitigation proposal for Finderne Farms in Bridgewater, NJ, was approved in August 2005 by the state regulatory agency. The design goal was to provide mitigation for wetlands impacted by the Green Brook Flood Control project at a ratio of 2 : 1. As part of the design process in 2001, the available historical hydrologic data was evaluated. At that time, the NJ Department of Environmental Protection (NJDEP) Water Budget Manual was not available as a tool for accessing an acceptable design hydroperiod. Construction of the Finderne mitigation site was completed in July 2006. A six-year postconstruction monitoring program has determined that certain areas at the site have not achieved the established wetland success criteria. In 2012, there was a 28% survival of planted woody vegetation and a 74% cover of invasive species within Creation Area 1, a palustrine forested wetland. With the advent of the Water Budget Manual, a reevaluation of the historical hydrologic data was performed. Based on this analysis, the hydroperiod and soil moisture conditions are not representative of sustainable wetlands. Adaptive management measures are currently being developed and evaluated to improve the hydrology, hydric soil conditions, and survival of target vegetation at the Finderne site.
Arzanol, a Potent mPGES‐1 Inhibitor: Novel Anti‐Inflammatory Agent
Authors: Kothavade Pankaj S. , Nagmoti Dnyaneshwar M. , Bulani Vipin D. , Juvekar Archana R.
Published: October 2013

Arzanol is a novel phloroglucinol α‐pyrone, isolated from a Mediterranean plant Helichrysum italicum (Roth) Don ssp. microphyllum which belongs to the family Asteraceae. Arzanol has been reported to possess a variety of pharmacological activities. However, anti‐inflammatory, anti‐HIV, and antioxidant activities have been studied in some detail. Arzanol has been reported to inhibit inflammatory transcription factor NFκB activation, HIV replication in T cells, releases of IL‐1β, IL‐6, IL‐8, and TNF‐α, and biosynthesis of PGE2 by potentially inhibiting mPGES‐1 enzyme. Diversity of mechanisms of actions of arzanol may be useful in treatment of disease involving these inflammatory mediators such as autoimmune diseases and cancer. This review presents comprehensive information on the chemistry, structure‐activity relationship, and pharmacological activities of arzanol. In addition this review discusses recent developments and the scope for future research in these aspects.
From Doctor to Nurse Triage in the Danish Out-of-Hours Primary Care Service: Simulated Effects on Costs
Authors: Moth Grete , Huibers Linda , Vedsted Peter
Published: October 2013

Introduction. General practitioners (GP) answer calls to the Danish out-of-hours primary care service (OOH) in Denmark, and this is a subject of discussions about quality and cost-effectiveness. The aim of this study was to estimate changes in fee costs if nurses substituted the GPs. Methods. We applied experiences from The Netherlands on nurse performance in the OOH triage concerning the number of calls per hour. Using the 2011 number of calls in one region, we examined three hypothetical scenarios with nurse triage and calculated the differences in fee costs. Results. A new organisation with 97 employed nurses would be needed. Fewer telephone consultations may result in an increase of face-to-face contacts, resulting in an increase of 23.6% in costs fees. Under optimal circumstances (e.g., a lower demand for OOH services, a high telephone termination rate, and unchanged GP fees) the costs could be reduced by 26.2% though excluding administrative costs of a new organisation. Conclusion. Substituting GPs with nurses in OOH primary care may increase the cost in fees compared to a model with only GPs. Further research is needed involving more influencing factors, such as costs due to nurse training and running the organisation.
PI3K Pathway Activation Provides a Novel Therapeutic Target for Pediatric Ependymoma and Is an Independent Marker of Progression-Free Survival
Authors: Rogers Hazel A. , Mayne Cerys , Chapman Rebecca J. , Kilday John-Paul , Coyle Beth , Grundy Richard G.
Published: September 2013

Purpose: Currently, there are few effective adjuvant therapies for pediatric ependymoma outside confocal radiation, and prognosis remains poor. The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in cancer. PI3Ks transduce signals from growth factors and cytokines, resulting in the phosphorylation and activation of AKT, which in turn induces changes in cell growth, proliferation, and apoptosis.

Experimental Design: PI3K pathway status was analyzed in ependymoma using gene expression data and immunohistochemical analysis of phosphorylated AKT (P-AKT). The effect of the PI3K pathway on cell proliferation was investigated by immunohistochemical analysis of cyclin D1 and Ki67, plus in vitro functional analysis. To identify a potential mechanism of PI3K pathway activation, PTEN protein expression and the mutation status of PI3K catalytic subunit α-isoform gene (PIK3CA) was investigated.

Results: Genes in the pathway displayed significantly higher expression in supratentorial than in posterior fossa and spinal ependymomas. P-AKT protein expression, indicating pathway activation, was seen in 72% of tumors (n = 169) and P-AKT expression was found to be an independent marker of a poorer progression-free survival. A significant association between PI3K pathway activation and cell proliferation was identified, suggesting that pathway activation was influencing this process. PTEN protein loss was not associated with P-AKT staining and no mutations were identified in PIK3CA.

Conclusions: Our results suggest that the PI3K pathway could act as a biomarker, not only identifying patients with a worse prognosis but also those that could be treated with therapies targeted against the pathway, a strategy potentially effective in a high percentage of ependymoma patients. Clin Cancer Res; 19(23); 6450–60. ©2013 AACR.
A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem–like Cells in S/G2/M Phases
Authors: Yano Shuya , Tazawa Hiroshi , Hashimoto Yuuri , Shirakawa Yasuhiro , Kuroda Shinji , Nishizaki Masahiko , Kishimoto Hiroyuki , Uno Futoshi , Nagasaka Takeshi , Urata Yasuo , Kagawa Shunsuke , Hoffman Robert M. , Fujiwara Toshiyoshi
Published: October 2013

Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem–like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem–like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem–like cells.

Experimental Design: We established CD133+ cancer stem–like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem–like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem–like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI).

Results: CD133+ gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133+ cancer stem–like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G0–G1 to S/G2/M phases and subsequent cell death in quiescent CD133+ cancer stem–like cells by mobilizing cell-cycle–related proteins. FUCCI enabled visualization of quiescent CD133+ cancer stem–like cells and proliferating CD133− non–cancer stem–like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133+ cancer stem–like cells maintained stemness by remaining in G0–G1 phase. We showed that OBP-301 mobilized quiescent cancer stem–like cells in tumor spheres and xenografts into S/G2/M phases where they lost viability and cancer stem–like cell properties and became chemosensitive.

Conclusion: Oncolytic adenoviral infection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem–like cells. Clin Cancer Res; 19(23); 6495–505. ©2013 AACR.
A Drug Repositioning Approach Identifies Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors
Authors: Jahchan Nadine S. , Dudley Joel T. , Mazur Pawel K. , Flores Natasha , Yang Dian , Palmerton Alec , Zmoos Anne-Flore , Vaka Dedeepya , Tran Kim Q.T. , Zhou Margaret , Krasinska Karolina , Riess Jonathan W. , Neal Joel W. , Khatri Purvesh , Park Kwon S. , Butte Atul J. , Sage Julien
Published: September 2013

Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein–coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.

Significance: Our work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells. Cancer Discov; 3(12); 1364–77. ©2013 AACR.

See related commentary by Wang and Byers, p. 1333

This article is highlighted in the In This Issue feature, p. 1317
Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
Authors: Akbay Esra A. , Koyama Shohei , Carretero Julian , Altabef Abigail , Tchaicha Jeremy H. , Christensen Camilla L. , Mikse Oliver R. , Cherniack Andrew D. , Beauchamp Ellen M. , Pugh Trevor J. , Wilkerson Matthew D. , Fecci Peter E. , Butaney Mohit , Reibel Jacob B. , Soucheray Margaret , Cohoon Travis J. , Janne Pasi A. , Meyerson Matthew , Hayes D. Neil , Shapiro Geoffrey I. , Shimamura Takeshi , Sholl Lynette M. , Rodig Scott J. , Freeman Gordon J. , Hammerman Peter S. , Dranoff Glenn , Wong Kwok-Kin
Published: September 2013

The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non–small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.

Significance: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non–cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape. Cancer Discov; 3(12); 1355–63. ©2013 AACR.

See related commentary by Rech and Vonderheide, p. 1330

This article is highlighted in the In This Issue feature, p. 1317
Genetic Influence of COMT and BDNF Gene Polymorphisms on Resilience in Healthy College Students
Authors: Kang Jee In , Kim Se Joo , Song Yun Young , Namkoong Kee , An Suk Kyoon
Published: October 2013

Purpose: Resilience refers to the individual positive capacity to cope with stress and to restore homeostasis, which may be mediated by adaptive neurobiological changes in the brain. We investigated the genetic influence of the catechol-O-methyltransferase (COMT) Val158Met and the brain-derived neurotrophic factor (BDNF) Val66Met for individual differences in resilience in healthy Korean college students. Methods: A sample of 321 healthy college volunteers (167 males, 154 females) was assessed by genotyping and with the 25-item Connor-Davidson Resilience Scale. Two-way analysis of covariance was used to test the association between participants' COMT and BDNF functional polymorphisms and their resilience. Results: A significant main effect of the COMT polymorphism on resilience and a gene-gene interaction effect between the COMT and BDNF on resilience were observed for males. Male subjects with the COMT Met-present genotype had a significantly higher resilience than those with the Val/Val genotype. Among males with the COMT Val/Val genotype, subjects with the homozygous Val allele of the BDNF tended to have lower resilience than the BDNF Met carriers, while among males with the COMT Met-present genotype, those with the homozygous Val allele of the BDNF tended to have higher resilience than BDNF Met carriers. No main or interaction effects of the COMT and BDNF on resilience were observed for females. Conclusion: These findings suggest the effects of COMT Val158Met polymorphism on resilience could be modulated by BDNF Val66Met polymorphism in males.
Antenatal Betamethasone Associates with Transient Immunodepression in Very Low Birth Weight Infants
Authors: Palojärvi Anniina , Andersson Sture , Turpeinen Ursula , Janér Cecilia , Petäjä Jari
Published: October 2013

Background: Antenatal betamethasone (BM) treatment for mothers at risk for premature delivery is effective in reducing neonatal morbidity. Immunodepression, defined as monocyte human leukocyte antigen (HLA)-DR expression <60%, is common in patients in intensive care. In very low birth weight (VLBW) infants, immunodepression correlates with gestational age and may predispose to infections. Objectives: To evaluate whether timing of antenatal BM associates with immunodepression in VLBW infants. Methods: We determined monocyte HLA-DR expression by flow cytometry and measured 13 cytokines, cortisol, and BM in plasma from 56 VLBW infants. We calculated total glucocorticoid index as the sum of BM and cortisol at the ratio 33.3:1. Results: HLA-DR expression both in cord (R2 = 0.175, p = 0.033, n = 26) and on day 1 (R2 = 0.125, p = 0.011, n = 51) showed an association with timing of BM. A short interval from BM to birth induced more pronounced and prolonged immunodepression, with lower HLA-DR% on postnatal day 7. On day 3, 25 infants (45%) met the criteria of immunodepression. HLA-DR expression correlated negatively with total glucocorticoid index (cord: R2 = -0.573, p = 0.003, n = 13; day 1: R2 = -0.213, p = 0.008, n = 32). Elapsed time from maternal BM correlated positively with concentrations of cytokines IL-6 and IL-10 on day 1. Conclusions: In VLBW infants, antenatal BM associated with transient immunodepression in a time-dependent manner. Suppression of both anti- and proinflammatory cytokines occurred. These effects may lead to an increased risk for later infections.
Pregnancy-Associated Plasma Protein-A as a Marker of Culprit Lesion Instability in Unstable Angina Patients: An Intravascular Ultrasound Study
Authors: Wu Xiao-fan , Liu Xiao-hui , Dong Jian-zeng , Wang Lu-ya , Yang Ya , Nie Shao-ping , Zhang Yin , Ma Chang-sheng
Published: October 2013

Background: We evaluated the relationship between pregnancy-associated plasma protein-A (PAPP-A) and coronary plaque instability as assessed by intravascular ultrasound (IVUS). Methods: We performed greyscale IVUS analysis in culprit lesions of 93 patients with unstable angina (UA) and 72 with stable angina (SA). A sandwich enzyme-linked immunosorbent assay technique was used to assay circulating PAPP-A. Results: Patients with UA had higher PAPP-A levels than those with SA 10.8 mIU/l [interquartile range (IQR) 8.3-14.4] vs. 5.4 (IQR 2.9-9.8) mIU/l, p < 0.001]. Lesions in patients with higher PAPP-A levels were associated with larger plaque burden than lesions in patients with lower PAPP-A levels. IVUS attenuated plaque, positive remodeling and plaque rupture. Thrombus and angiographic Ambrose type-II eccentric lesions or multiple irregularities were more common in patients with higher PAPP-A levels than in those with lower PAPP-A levels. They were also more common in patients with UA and higher PAPP-A levels than in patients with (1) SA and higher PAPP-A levels, (2) UA and lower PAPP-A levels or (3) SA and lower PAPP-A levels. Conclusions: Higher PAPP-A levels were associated with coronary plaque instability in vivo and unstable symptoms in patients with coronary artery disease.
Relationship between Visual Acuity and Spectral Domain Optical Coherence Tomography Retinal Parameters in Neovascular Age-Related Macular Degeneration
Authors: Ristau Tina , Keane Pearse A. , Walsh Alexander C. , Engin Alicia , Mokwa Nils , Kirchhof Bernd , Sadda SriniVas R. , Liakopoulos Sandra
Published: October 2013

Purpose: Relationship between spectral domain optical coherence tomography (SD-OCT) and visual acuity (VA) in neovascular age-related macular degeneration (NVAMD). Procedures: VA and SD-OCTs of 64 treatment-naive eyes with NVAMD were retrospectively collected at baseline and 1 year (n = 30). Retinal and subretinal spaces were manually analyzed. Volume and thickness measurements were correlated with VA. Results: At baseline, lower VA correlated with increased volume of subretinal hyperreflective material (R = 0.4, p < 0.001) and with decreased volume of the photoreceptor layer (PRL, R = -0.4, p < 0.01). At 1 year, lower VA correlated with decreased volume of the retina (R = -0.7, p < 0.001), outer nuclear layer (R = -0.6, p < 0.05) and PRL (R = -0.7, p < 0.001). Decrease in VA after 1 year correlated with a decrease in PRL (R = 0.4, p < 0.05). Conclusions: Quantitative analysis of SD-OCT revealed correlations between VA and retinal and subretinal morphological changes in NVAMD. Message: Atrophy of the outer retina is an important correlate for lower VA in NVAMD.
Study of Corneal Copper Deposits in Wilson's Disease by in vivo Confocal Microscopy
Authors: Ceresara Gaia , Fogagnolo Paolo , Zuin Massimo , Zatelli Stefania , Bovet Jerôme , Rossetti Luca
Published: October 2013

Purpose: To study corneal copper deposits in Wilson's disease (WD) patients by traditional biomicroscopy and in vivo laser scanning confocal microscopy (LSCM). Methods: Twenty WD patients and 20 matched controls underwent an ophthalmic examination in one eye randomly chosen, including slit lamp biomicroscopy with Goldmann's three-mirror contact lens examination and LSCM, in order to evaluate copper deposits in the peripheral cornea. Results: No control subjects had corneal changes at both traditional biomicroscopy and LSCM. Only 25% of WD patients had detectable slit lamp changes, compared with 75% with LSCM examination. All cases detected by slit lamp were detected by LSCM. A significant correlation (p < 0.01) was found between deposit intensity at LSCM and daily urinary copper excretion. Conclusion: LSCM could detect copper deposition in WD corneas in more patients than traditional examination; it may therefore provide important information in cases of suspected WD diagnosis.
The Validity of Predicting Prognosis by the Lymph Node Ratio in Node-Positive Colon Cancer
Authors: Sugimoto Kiichi , Sakamoto Kazuhiro , Tomiki Yuichi , Goto Michitoshi , Kojima Yutaka , Komiyama Hiromitsu
Published: October 2013

Background/Aims: Because the TNM system disregards the number of lymph nodes dissected and inter-individual differences exist in the number of regional lymph nodes, the lymph node ratio (LNR), which is estimated by dividing the number of metastatic lymph nodes by the number of dissected lymph nodes, has been proposed as a prognostic factor in recent years. The purpose of the present study is to examine the validity of predicting prognosis using the LNR in node-positive colon cancer. Methods: Three hundred and eleven patients with lymph node metastases who underwent curative surgery for colon cancer at our department between 1992 and 2005 were enrolled. Univariate and multivariate analyses were performed to evaluate the relationship between clinicopathological factors and prognosis. Results: Among the patients with ≥12 dissected lymph nodes, differentiation, invasion depth and TNM N category were found to be significant independent prognostic factors. On the other hand, among the patients with ≤11 dissected lymph nodes, differentiation and the LNR were found to be significant independent prognostic factors. Conclusion: Among the patients with ≤11 dissected lymph nodes, LNR was a significant independent prognostic factor.
Inaccuracy of Estimated Resting Oxygen Uptake in the Clinical Setting
Authors: Narang Nikhil , Thibodeau Jennifer T. , Levine Benjamin D. , Gore M. Odette , Ayers Colby R. , Lange Richard A. , Cigarroa Joaquin E. , Turer Aslan T. , de Lemos James A. , McGuire Darren K.
Published: September 2013

Background—

The Fick principle (cardiac output = oxygen uptake (

V
˙

O
2
)/systemic arterio-venous oxygen difference) is used to determine cardiac output in numerous clinical situations. However, estimated rather than measured

V
˙

O
2
is commonly used because of complexities of the measurement, though the accuracy of estimation remains uncertain in contemporary clinical practice.

Methods and Results—

From 1996 to 2005, resting

V
˙

O
2
was measured via the Douglas bag technique in adult patients undergoing right heart catheterization. Resting

V
˙

O
2
was estimated by each of 3 published formulae. Agreement between measured and estimated

V
˙

O
2
was assessed overall, and across strata of body mass index, sex, and age. The study included 535 patients, with mean age 55 yrs, mean body mass index 28.4 kg/m
2
; 53% women; 64% non-white. Mean (±standard deviation) measured

V
˙

O
2
was 241 ± 57 ml/min. Measured

V
˙

O
2
differed significantly from values derived from all 3 formulae, with median (interquartile range) absolute differences of 28.4 (13.1, 50.2) ml/min, 37.7 (19.4, 63.3) ml/min, and 31.7 (14.4, 54.5) ml/min, for the formulae of Dehmer, LaFarge, and Bergstra, respectively (
P
<0.0001 for each). The measured and estimated values differed by >25% in 17% to 25% of patients depending on the formula used. Median absolute differences were greater in severely obese patients (body mass index > 40 kg/m
2
), but were not affected by sex or age.

Conclusions—

Estimates of resting

V
˙

O
2
derived from conventional formulae are inaccurate, especially in severely obese individuals. When accurate hemodynamic assessment is important for clinical decision-making,

V
˙

O
2
should be directly measured.
Repetitive Myocardial Ischemia Promotes Coronary Growth in the Adult Mammalian Heart
Authors: Lavine Kory J. , Kovacs Attila , Weinheimer Carla , Mann Douglas L.
Published: October 2013

Background

Coronary artery disease and ischemic cardiomyopathy represent the leading cause of heart failure and continue to grow at exponential rates. Despite widespread availability of coronary bypass surgery and percutaneous coronary intervention, subsequent ischemic events and progression to heart failure continue to be common occurrences. Previous studies have shown that a subgroup of patients develop collateral blood vessels that serve to connect patent and occluded arteries and restore perfusion to ischemic territories. The presence of coronary collaterals has been correlated with improved clinical outcomes; however, the molecular mechanisms governing this process remain largely unknown.

Methods and Results

To date, no mouse models of coronary arterial growth have been described. Using a closed‐chest model of myocardial ischemia, we have demonstrated that brief episodes of repetitive ischemia are sufficient to promote the growth of both large coronary arteries and the microvasculature. Induction of large coronary artery and microvascular growth resulted in improvements in myocardial perfusion after prolonged ischemia and protected from subsequent myocardial infarction. We further show that repetitive ischemia did not lead to increased expression of classic proangiogenic factors but instead resulted in activation of the innate immune system and recruitment of macrophages to growing blood vessels.

Conclusions

These studies describe a novel model of coronary angiogenesis and implicate the cardiac macrophage as a potential mediator of ischemia‐driven coronary growth.
Zorotypus in Peninsular Malaysia (Zoraptera: Zorotypidae),
with the description of three new species
Authors: MASHIMO YUTA , YOSHIZAWA KAZUNORI , ENGEL MICHAEL S. , GHANI IDRIS ABD. , DALLAI ROMANO , BEUTEL ROLF G. , MACHIDA RYUICHIRO
Published: October 2013

Three new species of the uncommonly encountered insect order Zoraptera are described and figured from Peninsular Malaysia—Zorotypus magnicaudelli sp. n., Zorotypus cervicornis sp. n., and Zorotypus impolitus sp. n. Another species from the region, identified as Zorotypus caudelli Karny, 1927, was also collected and is reevaluated herein based on new material. A brief discussion of characters used in zorapteran systematics is provided, and a key to the species of Peninsular Malaysia provided. This is the first report for the order Zoraptera from Peninsular Malaysia.
Response of North Atlantic Ocean Circulation to Atmospheric Weather Regimes
Authors: Barrier Nicolas , Cassou Christophe , Deshayes Julie , Treguier Anne-Marie
Published: October 2013

A new framework is proposed for investigating the atmospheric forcing of North Atlantic Ocean circulation. Instead of using classical modes of variability, such as the North Atlantic Oscillation (NAO) or the east Atlantic pattern, the weather regimes paradigm was used. Using this framework helped avoid problems associated with the assumptions of orthogonality and symmetry that are particular to modal analysis and known to be unsuitable for the NAO. Using ocean-only historical and sensitivity experiments, the impacts of the four winter weather regimes on horizontal and overturning circulations were investigated. The results suggest that the Atlantic Ridge (AR), negative NAO (NAO−), and positive NAO (NAO+) regimes induce a fast (monthly-to-interannual time scales) adjustment of the gyres via topographic Sverdrup dynamics and of the meridional overturning circulation via anomalous Ekman transport. The wind anomalies associated with the Scandinavian blocking regime (SBL) are ineffective in driving a fast wind-driven oceanic adjustment. The response of both gyre and overturning circulations to persistent regime conditions was also estimated. AR causes a strong, wind-driven reduction in the strengths of the subtropical and subpolar gyres, while NAO+ causes a strengthening of the subtropical gyre via wind stress curl anomalies and of the subpolar gyre via heat flux anomalies. NAO− induces a southward shift of the gyres through the southward displacement of the wind stress curl. The SBL is found to impact the subpolar gyre only via anomalous heat fluxes. The overturning circulation is shown to spin up following persistent SBL and NAO+ and to spin down following persistent AR and NAO− conditions. These responses are driven by changes in deep water formation in the Labrador Sea.
Characterizing the viscoelastic behaviour of poly(lactide-co-glycolide acid)–hydroxyapatite foams
Authors: Leung Linus H , Naguib Hani E
Published: September 2013

The viscoelasticity of poly(lactide-co-glycolid acid) 75/25 and hydroxyapatite composite open-pore foams were examined in this study. The foams were fabricated using the gas foaming/salt leaching process, and two specific experiments were performed. The first was to test the viscoelastic dependency of the foams on the load frequency, and the second was to measure the creep of the foams under a static load. The experiments showed that the viscoelasticity of the foams did not vary with the addition nano-hydroxyapatite particles, but the environment of testing significantly affected these properties. These results can be used to better understand the behaviour of the scaffolds when in the physiological environment.
Lignin-based rigid polyurethane foams with improved biodegradation
Authors: Cateto Carolina A , Barreiro Maria F , Ottati Carolina , Lopretti Mary , Rodrigues Alírio E , Belgacem Mohamed N
Published: September 2013

Rigid polyurethane (RPU) foams have been synthesized using lignin-based polyols obtained by oxypropylation of four distinct lignins (Alcell, Indulin AT, Curan 27-11P, and Sarkanda). Polyol formulations with two lignin/propylene oxide/catalyst content (L/PO/C) ratios were chosen (30/70/2 and 20/80/5). RPU foams have been prepared with a polyol component that incorporates the lignin-based one at contents ranging from 25 to 100%. A 100% commercial polyol-based (Lupranol® 3323) RPU foam was also prepared and used as the reference. RPU foams were characterized in terms of density, compressive modulus, and conductivity. Cell morphology and size estimation were accessed by scanning electron microscopy. Moreover, biodegradation of the Alcell- and Indulin AT-based foams was evaluated using respirometry tests in liquid and solid media. The Alcell- and Indulin AT-based polyols together with the 20/80/5 Curan 27-11P-based one led to RPU foams with properties quite similar to those of the reference homolog. Biodegradation seems to be, particularly, favored if using Indulin AT-based polyols mixed with Lupranol® 3323.
Principals Responding to Constant Pressure
Authors: Wells Caryn M.
Published: September 2013

This conceptual article presents a review of the research concerning the stress level of principals over the past three decades, with emphasis on the occupational stress that principals encounter because of heightened accountability and expectations for student achievement. Mindfulness meditation, as a stress management intervention, provides the theoretical background for this article; the scientific evidence concerning benefits of mindfulness meditations are reviewed. Finally, the author presents suggestions for the prevention and reduction of stress for principals.