bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a Computerized Reminder on Splinting of Pediatric Upper Limb Fractures in the Emergency Department
Authors: Mills Erin , Craig Simon , Oakley Ed
Published: October 2016

Objective

The primary objective was to assess if a computerized pop-up reminder increased splint application before X-ray in pediatric emergency department patients with deformed upper limb fractures. The secondary objective was to evaluate whether this same reminder improved pharmaceutical analgesia provision in this population.

Methodology

This was a prospective study of 518 pediatric emergency department patients with upper limb fractures after the implementation of a computerized pop-up reminder to give analgesia and apply a splint. The records of those with fractures requiring manipulation were identified and reviewed for data on demographics, clinical characteristics, splint application, and analgesic use. These data were compared with that in a previous retrospective study of 1407 patients in the same population before implementation of the computerized reminder.

Results

There were 86 patients with upper limb fractures requiring manipulation identified during the study period. After the computerized intervention, splint application rates improved from 22% to 49% (P = <0.001). There was no significant change to analgesia provision in the first hour after presentation.

Conclusions

A computerized reminder at the point of X-ray ordering significantly improved splint application rates for children with deformed upper limb fractures, though it did not affect pharmaceutical analgesia provision. The computerized pop-up is cheap to implement, easy to use, and potentially transferrable to other institutions and for other uses.
Role of monkeys in the sylvatic cycle of chikungunya virus in Senegal
Authors: Althouse Benjamin M. , Guerbois Mathilde , Cummings Derek A. T. , Diop Ousmane M. , Faye Ousmane , Faye Abdourahmane , Diallo Diawo , Sadio Bakary Djilocalisse , Sow Abdourahmane , Faye Oumar , Sall Amadou A. , Diallo Mawlouth , Benefit Brenda , Simons Evan , Watts Douglas M. , Weaver Scott C. , Hanley Kathryn A.
Published: October 2016

Athropod-borne viruses (arboviruses) pose the greatest risk of spillover into humans of any class of pathogens. Such spillover may occur as a one-step jump from areservoirhost species into humans or as a two-step jump from the reservoir to a differentamplificationhost species and thence to humans. Despite the widespread havoc wreaked by emerging arboviruses, little is known about their transmission dynamics in reservoir and amplification hosts. Here we used serosurveillance and mathematical modeling to elucidate the role of monkeys in the sylvatic, enzootic cycle of chikungunya virus (CHIKV). Over three years, 219 African green monkeys, 78 patas monkeys, and 440 Guinea baboons were captured in the region surrounding Kedougou, Senegal. The age of each animal was determined by anthropometry and dentition, and exposure to CHIKV was determined by detection of neutralizing antibodies. We estimate age-specific CHIKV seroprevalence, force of infection (FoI), and basic reproductive number (R0) in each species. Among the different species, CHIKV Fol ranged from 0.13 to 1.12 (95% CI, 0.81–2.28) andR0ranged from 1.5 (95% CI, 1.3–1.9) to 6.6 (95% CI, 5.1–10.4). CHIKV infection of infant monkeys was detected even when the virus was not detected in a concurrent survey of primatophilic mosquitoes and when population seropositivity, and therefore immunity, was too high for monkeys themselves to support continuous CHIKV transmission. We therefore conclude that monkeys in this region serve primarily as amplification rather than reservoir hosts of CHIKV. Additional efforts are needed to identify other vertebrate hosts capable of supporting continuous circulation.
Rate of rise in diastolic blood pressure influences vascular sympathetic response to mental stress
Authors: El Sayed Khadigeh , Macefield Vaughan G. , Hissen Sarah L. , Joyner Michael J. , Taylor Chloe E.
Published: October 2016

Key points

Research indicates that individuals may experience a rise (positive responders) or fall (negative responders) in muscle sympathetic nerve activity (MSNA) during mental stress.

In this study, we examined the early blood pressure responses (including the peak, time of peak and rate of rise in blood pressure) to mental stress in positive and negative responders.

Negative MSNA responders to mental stress exhibit a more rapid rise in diastolic pressure at the onset of the stressor, suggesting a baroreflex‐mediated suppression of MSNA. In positive responders there is a more sluggish rise in blood pressure during mental stress, which appears to be MSNA‐driven.

This study suggests that whether MSNA has a role in the pressor response is dependent upon the reactivity of blood pressure early in the task.

Research indicates that individuals may experience a rise (positive responders) or fall (negative responders) in muscle sympathetic nerve activity (MSNA) during mental stress. The aim was to examine the early blood pressure response to stress in positive and negative responders and thus its influence on the direction of change in MSNA. Blood pressure and MSNA were recorded continuously in 21 healthy young males during 2 min mental stressors (mental arithmetic, Stroop test) and physical stressors (cold pressor, handgrip exercise, post‐exercise ischaemia). Participants were classified as negative or positive responders according to the direction of the mean change in MSNA during the stressor tasks. The peak changes, time of peak and rate of changes in blood pressure were compared between groups. During mental arithmetic negative responders experienced a significantly greater rate of rise in diastolic blood pressure in the first minute of the task (1.3 ± 0.5 mmHg s−1) compared with positive responders (0.4 ± 0.1 mmHg s−1; P = 0.03). Similar results were found for the Stroop test. Physical tasks elicited robust parallel increases in blood pressure and MSNA across participants. It is concluded that negative MSNA responders to mental stress exhibit a more rapid rise in diastolic pressure at the onset of the stressor, suggesting a baroreflex‐mediated suppression of MSNA. In positive responders there is a more sluggish rise in blood pressure during mental stress, which appears to be MSNA‐driven. This study suggests that whether MSNA has a role in the pressor response is dependent upon the reactivity of blood pressure early in the task.
Continuous Monitoring of Metal Working Fluid Quality in Machining Processes
Authors: Glasse Benjamin , Fritsching Udo
Published: October 2016

Metal working fluid (MWF) emulsions are utilized as coolants and lubricants in machining processes like turning or drilling. During their operation life time cycle, MWFs change their properties due to impacting stresses which may influence the machining and tool performance. A frequent refreshing or renewal of MWFs in machining process is thus necessary. This investigation discusses measurement techniques of MWF emulsions to be used for MWF quality assessment and process monitoring. By means of optical spectroscopic measurement techniques (turbidimetry and laser diffraction), the evaluation of the temporal change of the wavelength exponent and the MWF emulsion droplet size is related to the MWF stability. The in-process monitoring of the MWFs in machining during several weeks of operation is shown. Thus, it will be demonstrated that optical spectroscopic measurement techniques may be applied to determine stability change of the emulsion system.
Quantitative Comparison of Pocket Geometry and Pocket Decomposition to Obtain Improved Spiral Tool Path: A Novel Approach
Authors: Patel Divyangkumar D. , Lalwani Devdas I.
Published: October 2016

In the 2.5D pocket machining, the pocket geometry (shape of the pocket) significantly affects the efficiency of spiral tool path in terms of tool path length, cutting time, surface roughness, cutting forces, etc. Hence, the pocket geometry is an important factor that needs to be considered. However, quantitative methods to compare different pocket geometries are scarcely available. In this paper, we have introduced a novel approach for quantitative comparison of different pocket geometries using a dimensionless number, “DN.” The concept and formula of DN are developed, and DN is calculated for various pocket geometries. A concept of percentage utilization of tool (PUT) is also introduced and is considered as a measure and an indicator for a good tool path. The guidelines for comparing pocket geometries based on DN and PUT are reported. The results show that DN can be used to predict the quality of tool path prior to tool path generation. Further, an algorithm to decompose pocket geometry into subgeometries is developed that improves the efficiency of spiral tool path for bottleneck pockets (or multiple-connected pocket). This algorithm uses another dimensionless number “HARIN” (HARI is the acronym of “helps in appropriate rive-lines identification” and suffix “N” stands for number) to compare parent pocket geometry with subgeometries. The results indicate that decomposing pocket geometry with the new algorithm improves HARIN and removes the effect of bottlenecks. Furthermore, the algorithm for decomposition is extended for pockets that are bounded by free-form curves.
Ga+ focused ion beam lithography as a viable alternative for multiple fin field effect transistor prototyping
Authors: Leonhardt Alessandra , Puydinger dos Santos Marcos Vinicius , Diniz José Alexandre , Manera Leandro Tiago , Lima Lucas Petersen Barbosa
Published: October 2016

A novel method for fast and flexible fin field effect transistor (FinFET) prototyping using a Ga+ focused ion beam is presented. The fin width and height control is explored, aiming for the successful fabrication of prototypes. This method results in fins with negligible Ga incorporation, when compared to traditional focused ion beam milling techniques. Our method for multiple fin FinFET prototyping enables advanced device fabrication and great flexibility regarding both the number of fins and fin width. Working FinFET prototypes have been fabricated using the proposed fin definition method, and the electrical characterization is discussed.
Regulating the rate of mRNA degradation
Authors: Mushegian Alexandra A.
Published: October 2016

Histone acetyltransferases and deacetylases control mRNA stability.
Papers of note in
Science Translational Medicine
Authors: Ferrarelli Leslie K.
Published: October 2016

This week’s articles highlight a lipokine that limits atherosclerosis, biomaterials for bone regeneration, and a cytokine associated with malaria pathogenesis.
Retreatment of a choroidal vein of Galen malformation with embolization 42 years after open surgical treatment in the neonatal period
Authors: Elijovich Lucas , Choudhri Asim F , Arthur Adam S , Klimo Paul , Boop Frederick A , Berenstein Alejandro
Published: October 2016

In 1976 an infant boy initially presented with a choroidal vein of Galen malformation (cVOGM). Craniotomy and clipping of the anterior cerebral artery and posterior choroidal arteries was performed, which was reported in the literature 40 years ago. The patient remained asymptomatic until age 42 when he re-presented with an isolated intraventricular hemorrhage. Angiography demonstrated cVOGM with venous sinus occlusive disease leading to venous hypertension and subsequent intraventricular hemorrhage. The angiogram also demonstrated a ‘pseudo-nidus’ composed of multiple arterial-to-arterial anastomoses that had developed as a result of the original surgical treatment. We embolized a portion of the lesion to reduce the venous hypertension. The patient has been asymptomatic for more than 2 years. To our knowledge, this is the first reported case of a symptomatic neonatal VOGM treated with open surgery that required embolization as an adult for a delayed hemorrhagic presentation.
Reducing the occurrence of errors in a laboratory's specimen receiving and processing department
Authors: Al Saleem Nouf , Al-Surimi Khaled
Published: October 2016

Frequent, preventable medical errors can have an adverse effect on patient safety and quality as well as leading to wasted resources. In the laboratory, errors can occur at any stage of sample processing; pre-analytical, analytical, and post analytical stages. However evidence shows most of the laboratory errors occur during the pre-analytical stage. The receipt and processing of specimens is one of the main steps in the pre-analytical stage. Errors in this stage could be due to mislabeling, incorrect test entry and entering the wrong location, among other reasons. Most of these errors are preventable. At the Riyadh Regional Laboratory of the Ministry of Health, we found that there was an average of 2.31 errors per 1000 processed samples; these errors had occurred during the pre-analytical stage. These samples were returned back from other laboratory departments, such as Chemistry, Hematology and Microbiology, to the receiving and processing department. We decided to carry out an improvement project where we applied a systematic approach to identify and analyse the root causes of the problem using quality tools such as a process flowchart and a fish-bone diagram. The Model for Improvement was used and several PDSA (Plan, Do, Study, Act) cycles were run to test interventions which aimed to prevent laboratory processing errors and mistakes. The project results showed a 25% reduction in errors during the pre-analytical stage.
The relationship between pay day and violent death in Guatemala: a time series analysis
Authors: Ramírez Dorian E , Branas Charles C , Richmond Therese S , Bream Kent , Xie Dawei , Velásquez-Tohom Magda , Wiebe Douglas J
Published: October 2016

Objective

To assess if violent deaths were associated with pay days in Guatemala.

Design

Interrupted time series analysis.

Setting

Guatemalan national autopsy databases.

Participants

Daily violence-related autopsy data for 22 418 decedents from 2009 to 2012. Data were provided by the Guatemalan National Institute of Forensic Sciences. Multiple pay-day lags and other important days such as holidays were tested.

Outcome measures

Absolute and relative estimates of excess violent deaths on pay days and holidays.

Results

The occurrence of violent deaths was not associated with pay days. However, a significant association was observed for national holidays, and this association was more pronounced when national holidays and pay days occurred simultaneously. This effect was observed mainly in males, who constituted the vast majority of violent deaths in Guatemala. An estimated 112 (coefficient=3.12; 95% CI 2.15 to 4.08; p<0.01) more male violent deaths occurred on holidays than were expected. An estimated 121 (coefficient=4.64; 95% CI 3.41 to 5.88; p<0.01) more male violent deaths than expected occurred on holidays that coincided with the first 2 days following a pay day.

Conclusions

Men in Guatemala experience violent deaths at an elevated rate when pay days coincide with national holidays. Efforts to be better prepared for violence during national holidays and to prevent violent deaths by rescheduling pay days when these days co-occur with national holidays should be considered.
Cancer care in Romania: challenges and pitfalls of children's and adolescents' multifaceted involvement
Authors: Badarau Domnita O , De Clercq Eva , Wangmo Tenzin , Dragomir Monica , Miron Ingrid , Kühne Thomas , Elger Bernice S
Published: October 2016

Communication about diagnosis and medical treatment for children suffering from life-threatening illnesses is complex. It is a primary step in involving underage patients and families in care and lays the foundation for obtaining parental permission and patient assent for treatment. In practice child participation in care is often difficult to obtain due to patients' different and sometimes fluctuating preferences, but also parents' protective strategies. Physicians may be susceptible to parental wishes to limit information and feel uncomfortable discussing issues related to uncertainty of cure with patients. A qualitative study in Romanian paediatric oncology units was conducted to explore children's involvement from the perspectives of parents and oncologists. Interviews with participants discussed 18 patient cases. Data were transcribed and thematic analysis was used to interpret and mine patients' involvement during treatment. Different facets of patient participation were identified: restricting, widening and enhancing involvement. A fourth category, unintentional involvement, occurred for all patients due to children's observations during long-term hospitalisations and access to Internet. Uncertainty overarched parental attitudes regarding the extent to which children should be included. Physicians usually complied with parental wishes to limit involvement, but together with parents involved patients at least in a practical way. Adults' protective attitude may backfire, as adolescents' online searches often expose patients to worse-case scenarios. Further research should acknowledge the hazards of restricted diagnosis disclosure and develop clinician tools to support families in communicating with patients. This should be paralleled by physician efforts to elicit patients' needs regarding participation.
FINANCIAL DEVELOPMENT AND CARBON EMISSIONS IN CHINESE PROVINCES: A SPATIAL PANEL DATA ANALYSIS
Authors: XIONG LING , QI SHAOZHOU
Published: October 2016

Using the panel data of 30 provinces in China between 1997 and 2011, we employed the extended STIRPAT model and spatial panel econometrics methods to investigate the relationship between financial development and carbon emissions and test the influence of financial development as well as other factors on provincial carbon emissions per capita among Chinese provinces. The estimation results show that: (i) spatial spillover effects play a role in provincial carbon emissions in China; and (ii) the sum of technical effect and structure effect of financial development surpass its’ sum of direct effect and wealth effect in China, which suggests that financial development reduces carbon emissions per capita. China should pay more attention to the integration of green finance policy and environmental regulation, and establish appropriate mechanisms to strengthen inter-provincial interaction and coordinated development.
Free Vibration Analysis of Cable Structures Using Isogeometric Approach
Authors: Thai Son , Kim Nam-Il , Lee Jaehong
Published: October 2016

This paper presents a free vibration analysis of cable structures based on the isogeometric approach. The nonuniform rational B-splines (NURBS) basis functions are employed to represent both the exact geometry of cable and displacement fields. In order to enrich the basis functions, the [Formula: see text]-, [Formula: see text]- and [Formula: see text]-refinement strategies are implemented. Therefore, these refinement schemes increase the accuracy of solution fields. For determining the static configuration of slack cables as a reference configuration, the well-known penalty method is used. Three numerical examples for slack and taut cable structures are presented in which different refinement schemes are utilized to obtain the converged results. The accuracy and reliability of the present numerical method are verified by comparing the natural frequencies with the results given by other researchers.
A Comparative Investigation on the Performance of Different Micro Mixers: Toward Cerebral Microvascular Analysis
Authors: Abdi Mohsen , Pishbin Esmail , Karimi Alireza , Navidbakhsh Mahdi
Published: October 2016

In this study, a novel fluidic concept was presented to resemble the cerebral microvascular in four types to assess its complexity by using centrifugal platform. The setup consisted of a microstructured disk with a round mixing chamber rotating on a macroscopic drive unit. The left and right internal carotid arteries (L.ICA and R.ICA) and basilar artery (BA) are two isolated vascular system supplying circle of Willis (CoW). The left and right middle cerebral arteries (L.MCA and R.MCA), left and right anterior cerebral arteries (L.ACA and R.ACA), and finally left and right posterior cerebral arteries (L.PCA and R.PCA) constitute efferent arteries of CoW. In this study, cerebral microvascular was investigated by microfluidics approach. The results revealed that a more complex mixing chamber provides normal pixel percentage distribution with respect to the other ones. The outcomes of this study may have implications not only for perception of the intracranial vascular hemodynamic in healthy circumstance, but also for diagnosing the diseases in the blood circulatory system of the human body.
A mean value of the representation function for the sum of two primes in arithmetic progressions
Authors: Suzuki Yuta
Published: October 2016

In this paper, assuming a variant of the Generalized Riemann Hypothesis, which does not exclude the existence of real zeros, we prove an asymptotic formula for the mean value of the representation function for the sum of two primes in arithmetic progressions. This is an improvement of the result of F. Rüppel in 2009, and a generalization of the result of A. Languasco and A. Zaccagnini concerning the ordinary Goldbach problem in 2012.
Semileptonic Decays ofB(Bs)to Light Tensor Mesons
Authors: Khosravi Reza , Sadeghi S.
Published: October 2016

The semileptonicBs(B)→K2⁎(a2,f2)lν,l=τ,μ, transitions are investigated in the frame work of the three-point QCD sum rules. Considering the quark condensate contributions, the relevant form factors of these transitions are estimated. The branching ratios of these channel modes are also calculated at different values of the continuum thresholds of the tensor mesons and compared with the obtained data for other approaches.
Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration
Authors: Bruun Susanne W. , Josefsen Knud , Tanassi Julia T. , Marek Aleš , Pedersen Martin H. F. , Sidenius Ulrik , Haupt-Jorgensen Martin , Antvorskov Julie C. , Larsen Jesper , Heegaard Niels H. , Buschard Karsten
Published: October 2016

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.
Cox‐2 Inhibition Protects against Hypoxia/Reoxygenation‐Induced Cardiomyocyte Apoptosis via Akt‐Dependent Enhancement of iNOS Expression
Authors: Pang Lei , Cai Yin , Tang Eva Hoi Ching , Yan Dan , Kosuru Ramoji , Li Haobo , Irwin Michael G. , Ma Haichun , Xia Zhengyuan
Published: October 2016

The present study explored the potential causal link between ischemia‐driven cyclooxygenase‐2 (COX‐2) expression and enhanced apoptosis during myocardial ischemia/reperfusion (I/R) by using H9C2 cardiomyocytes and primary rat cardiomyocytes subjected to hypoxia/reoxygenation (H/R). The results showed that H/R resulted in higher COX‐2 expression than that of controls, which was prevented by pretreatment with Helenalin (NFκB specific inhibitor). Furthermore, pretreatment with NS398 (COX‐2 specific inhibitor) significantly attenuated H/R‐induced cell injury [lower lactate dehydrogenase (LDH) leakage and enhanced cell viability] and apoptosis (higher Bcl2 expression and lower level of cleaved caspases‐3 and TUNEL‐positive cells) in cardiomyocytes. The amelioration of posthypoxic apoptotic cell death was paralleled by significant attenuation of H/R‐induced increases in proinflammatory cytokines [interleukin 6 (IL6) and tumor necrosis factor (TNFα)] and reactive oxygen species (ROS) production and by higher protein expression of phosphorylated Akt and inducible nitric oxide synthase (iNOS) and enhanced nitric oxide production. Moreover, the application of LY294002 (Akt‐specific inhibitor) or 1400W (iNOS‐selective inhibitor) cancelled the cellular protective effects of NS398. Findings from the current study suggest that activation of NFκB during cardiomyocyte H/R induces the expression of COX‐2 and that higher COX‐2 expression during H/R exacerbates cardiomyocyte H/R injury via mechanisms that involve cross talks among inflammation, ROS, and Akt/iNOS/NO signaling.
Infinite Queue Management via Cascade Control for Industrial Routers in Smart Grid IP Networks
Authors: Kim Ku-Hwan , To Hoang-Linh , Hwang Won-Joo , Lee Jung-Tae
Published: October 2016

Smart grid applications experience an extremely wide range of communication delay. Data flows of those applications are normally aggregated at industrial network routers in substations, form infinite (long) queues termed bufferbloat issue, and might damage the operation of transmission control protocol. The default queue management scheme, DropTail, in such routers just drops packets if queue is full while the others in literature are mostly based on one-loop feedback control where an optimal point of performance between queue length and drop rate is limited. In this paper, we study the problem of managing a long queue of industrial router at substation under heterogeneous smart grid networks. Specifically, we propose an enqueue-dequeue dropping cascade control using a two-loop design method to control both window size and queue length. Moreover, our proposal can be easily implemented into router firmware with provided discrete expressions. Finally, our simulation results are presented to validate the possible benefits that can be gained from cascade control and compare the existing queue management methods as well.
Fractal Reflectarray Antennas: State of Art and New Opportunities
Authors: Costanzo S. , Venneri F. , Di Massa G. , Borgia A. , Costanzo A. , Raffo A.
Published: October 2016

Fractal geometries are appealing in all applications where miniaturization capabilities are required, ranging from antennas to frequency selective surfaces (FSS) design. Recently, some fractal patches configurations, giving low losses, reduced size, and quite good phase ranges, have been proposed for the design of reflectarray unit cells. This paper reviews existing fractal-based reflectarrays, highlighting their benefits and limitations. Furthermore, a comprehensive analysis of an innovative reflectarray unit cell, using a fractal-shaped fixed-size patch, is presented. The miniaturization capabilities of the Minkowski fractal shape are fully exploited to obtain a compact cell offering quite good phase agility, by leaving unchanged the patch size and acting only on the fractal scaling factor. Experimental validations are fully discussed on a realized 10 GHz0.3λ×0.3λcell. This is subsequently adopted to synthesize various reflectarray prototypes offering single or multiple-beam capabilities over a quite large angular region (up to 50 degrees). Finally, experimental validations on a realized15×15elements prototype are presented to demonstrate the wide angle beam-pointing capabilities as well as a quite large bandwidth of about 6%.
EpCAM Inhibition Sensitizes Chemoresistant Leukemia to Immune Surveillance
Authors: Zheng Xiaohu , Fan Xiaolei , Fu Binqing , Zheng Meijuan , Zhang Aimei , Zhong Kai , Yan Jialai , Sun Rui , Tian Zhigang , Wei Haiming
Published: October 2016

The lack of effective tumor-associated antigens restricts the development of targeted therapies against myeloid leukemia. In this study, we compared gene expression patterns of acute myeloid leukemia (AML) and normal bone marrow samples and found that epithelial cell adhesion molecule (EpCAM) is frequently overexpressed in patients with AML, with EpCAM+ leukemic cells exhibiting enhanced chemoresistance and oncogenesis. The chemotherapeutic resistance of EpCAM-positive leukemic cells is a consequence of increased WNT5B signaling. Furthermore, we generated EpCAM antibodies that enabled phagocytosis or cytotoxicity of AML cells by macrophage or natural killer cells, respectively. Finally, EpCAM antibody treatment depleted AML in subcutaneous, disseminated, and intramedullary engrafted mice. In summary, EpCAM exhibits promise as a novel target for the treatment of leukemia. Cancer Res; 77(2); 482–93. ©2016 AACR.
TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer
Authors: Mercogliano María F. , De Martino Mara , Venturutti Leandro , Rivas Martín A. , Proietti Cecilia J. , Inurrigarro Gloria , Frahm Isabel , Allemand Daniel H. , Deza Ernesto Gil , Ares Sandra , Gercovich Felipe G. , Guzmán Pablo , Roa Juan C. , Elizalde Patricia V. , Schillaci Roxana
Published: October 2016

Purpose: Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it.

Experimental Design: Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab.

Results: TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008).

Conclusions: We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636–48. ©2016 AACR.
Fecal Bacteria Act as Novel Biomarkers for Noninvasive Diagnosis of Colorectal Cancer
Authors: Liang Qiaoyi , Chiu Jonathan , Chen Yingxuan , Huang Yanqin , Higashimori Akira , Fang Jingyuan , Brim Hassan , Ashktorab Hassan , Ng Siew Chien , Ng Simon Siu Man , Zheng Shu , Chan Francis Ka Leung , Sung Joseph Jao Yiu , Yu Jun
Published: October 2016

Purpose: Gut microbiota have been implicated in the development of colorectal cancer. We evaluated the utility of fecal bacterial marker candidates identified by our metagenome sequencing analysis for colorectal cancer diagnosis.

Experimental Design: Subjects (total 439; 203 colorectal cancer and 236 healthy subjects) from two independent Asian cohorts were included. Probe-based duplex quantitative PCR (qPCR) assays were established for the quantification of bacterial marker candidates.

Results: Candidates identified by metagenome sequencing, including Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), and one undefined species (labeled as m7), were examined in fecal samples of 203 colorectal cancer patients and 236 healthy controls by duplex-qPCR. Strong positive correlations were demonstrated between the quantification of each candidate by our qPCR assays and metagenomics approach (r = 0.801–0.934, all P < 0.0001). Fn was significantly more abundant in colorectal cancer than controls (P < 0.0001), with AUROC of 0.868 (P < 0.0001). At the best cut-off value maximizing sum of sensitivity and specificity, Fn discriminated colorectal cancer from controls with a sensitivity of 77.7%, and specificity of 79.5% in cohort I. A simple linear combination of four bacteria (Fn + Ch + m7-Bc) showed an improved diagnostic ability compared with Fn alone (AUROC = 0.886, P < 0.0001) in cohort I. These findings were further confirmed in an independent cohort II. In particular, improved diagnostic performances of Fn alone (sensitivity 92.8%, specificity 79.8%) and four bacteria (sensitivity 92.8%, specificity 81.5%) were achieved in combination with fecal immunochemical testing for the detection of colorectal cancer.

Conclusions: Stool-based colorectal cancer–associated bacteria can serve as novel noninvasive diagnostic biomarkers for colorectal cancer. Clin Cancer Res; 23(8); 2061–70. ©2016 AACR.
Plerixafor Improves Primary Tumor Response and Reduces Metastases in Cervical Cancer Treated with Radio-Chemotherapy
Authors: Chaudary Naz , Pintilie Melania , Jelveh Salomeh , Lindsay Patricia , Hill Richard P. , Milosevic Michael
Published: October 2016

Purpose: There is an important need to improve the effectiveness of radio-chemotherapy (RTCT) for cervical cancer. The CXCL12/CXCR4 pathway can influence RT response by recruiting normal myeloid cells to the tumor microenvironment that in turn can exert radioprotective effects, and may promote metastases. The objective of this study was to explore the efficacy and toxicity of combining RTCT with CXCL12/CXCR4 inhibition in cervical cancer.

Experimental Design: CXCR4 expression was measured in 115 patients with cervical cancer. Two primary orthotopic cervical cancer xenografts (OCICx) with different levels of CXCR4 expression were treated with RT (30 Gy: 15 daily fractions) and weekly cisplatin (4 mg/kg), with or without the CXCR4 inhibitor Plerixafor (5 mg/kg/day). The endpoints were tumor growth delay and lymph node metastases. Acute intestinal toxicity was assessed using a crypt cell assay.

Results: There was a fivefold variation in CXCR4 mRNA expression in the patient samples, and good correlation between the expression in patients and in the xenografts. The combination of RTCT and Plerixafor produced substantial tumor growth delay and reduced lymph node metastases compared with RTCT alone in both of the xenograft models. There was a trend toward reduced acute intestinal toxicity with the addition of Plerixafor to RTCT. There were no changes in normal organ morphology to suggest increased late toxicity.

Conclusions: This study demonstrates that the addition of Plerixafor to standard RTCT improves primary tumor response and reduces metastases in cervical cancer with no increase in toxicity. This combination warrants further investigation in phase I/II clinical trials. Clin Cancer Res; 23(5); 1242–9. ©2016 AACR.
Evaluation of the Obesity Genes FTO and MC4R for Contribution to the Risk of Large Artery Atherosclerotic Stroke in a Chinese Population
Authors: Song Zhi , Qiu Lingling , Hu Zhongyang , Liu Jia , Liu Ding , Hou Deren
Published: October 2016

Background: Obesity is a well-established risk factor for large artery atherosclerotic (LAA) stroke. The aim of the study was to explore whether obesity genes, such as MC4R and FTO, contribute to LAA stroke risk in the Chinese Han population. Methods: 322 LAA stroke patients and 473 controls were recruited. Gene polymorphism of MC4R (rs17782313) and FTO (rs8050136 and rs9939609) were genotyped. Results: No differences were observed in genotype frequencies of variants of FTO (rs8050136 and rs9939609) or MC4R (rs17782313) between LAA stroke patients and control subjects. However, rs17782313 of the MC4R gene was associated with LAA stroke susceptibility in smokers (rs17782313: p = 0.020, OR (95% CI) = 1.55 (1.07-2.23)) in the stratified analysis. Furthermore, multifactor dimensionality reduction analysis revealed that the combination of MC4R variant (rs17782313), hypertension and smoking habit was significantly associated with increased risk of LAA stroke (p < 0.0001, OR (95% CI) = 6.57 (4.79-9.01)). Conclusion: Our study indicated that the synergistic effects of MC4R variants, hypertension, and smoking habit contribute significantly to the risk of LAA stroke in the Chinese Han population. The finding revealed that obesity gene MC4R contribute to the risk of LAA stroke via a synergistic mechanism, which will provide new insight into the genetic architecture of LAA stroke.
Bilateral Endoscopic Lung Volume Reduction in Patients with Severe Emphysema
Authors: Trudzinski Franziska C. , Lepper Philipp M. , Leppert Daniela , Langer Frank , Lensch Christian , Flaig Monika , Bals Robert , Wilkens Heinrike , Minko Peter , Fähndrich Sebastian
Published: October 2016

Reducing hyperinflated areas in chronic obstructive pulmonary disease, either surgically or endoscopically, leads to improvement of functional parameters. It is unclear if bilateral treatment with endobronchial valves (EBV) aiming at total lobar occlusion is beneficial. The aim of this study was to assess the results after staged bilateral endoscopic treatment with EBV. This is a retrospective analysis of patients with severe airflow obstruction, who were treated bilaterally with EBV in two stages, aiming at subsequent atelectasis. Pre- and postintervention lung function parameters, the 6-minute walk test (6-MWT), complications, and follow-up were recorded. Sixteen patients were treated bilaterally in two stages. There was an overall improvement in lung function from baseline to second-treatment follow-up with an increase in FEV1 (23.57-29.21% of predicted) and a decrease in residual volume (299.21-240.10% of predicted) and total lung capacity (140.78-128.71% of predicted). The 6-MWT improved up to 54 m. After each procedure, 9 of 16 patients (56.25%) developed an atelectasis of the target lobe. Overall, pneumothorax occurred in 8 of 32 procedures (25%). No patient died. Patients benefitted from the first EBV treatment. The second treatment did not lead to marked improvements compared to the first treatment. Bilateral lung volume reduction with valves is possible; however, the current results seem not to justify bilateral valve treatment as a routine approach.
Arousal From Sleep and Sympathetic Excitation During Wakefulness
Authors: Taylor Keri S. , Murai Hisayoshi , Millar Philip J. , Haruki Nobuhiko , Kimmerly Derek S. , Morris Beverley L. , Tomlinson George , Bradley T. Douglas , Floras John S.
Published: October 2016

Obstructive apnea during sleep elevates the set point for efferent sympathetic outflow during wakefulness. Such resetting is attributed to hypoxia-induced upregulation of peripheral chemoreceptor and brain stem sympathetic function. Whether recurrent arousal from sleep also influences daytime muscle sympathetic nerve activity is unknown. We therefore tested, in a cohort of 48 primarily nonsleepy, middle-aged, male (30) and female (18) volunteers (age: 59±1 years, mean±SE), the hypothesis that the frequency of arousals from sleep (arousal index) would relate to daytime muscle sympathetic burst incidence, independently of the frequency of apnea or its severity. Polysomnography identified 24 as having either no or mild obstructive sleep apnea (apnea–hypopnea index <15 events/h) and 24 with moderate-to-severe obstructive sleep apnea (apnea–hypopnea index >15 events/h). Burst incidence correlated significantly with arousal index (
r
=0.53;
P
<0.001), minimum oxygen saturation (
r
=−0.43;
P
=0.002), apnea–hypopnea index (
r
=0.41;
P
=0.004), age (
r
=0.36;
P
=0.013), and body mass index (
r
=0.33;
P
=0.022) but not with oxygen desaturation index (
r
=0.28;
P
=0.056). Arousal index was the single strongest predictor of muscle sympathetic nerve activity burst incidence, present in all best subsets regression models. The model with the highest adjusted
R
2
(0.456) incorporated arousal index, minimum oxygen saturation, age, body mass index, and oxygen desaturation index but not apnea–hypopnea index. An apnea- and hypoxia-independent effect of sleep fragmentation on sympathetic discharge during wakefulness could contribute to intersubject variability, age-related increases in muscle sympathetic nerve activity, associations between sleep deprivation and insulin resistance or insomnia and future cardiovascular events, and residual adrenergic risk with persistence of hypertension should therapy eliminate obstructive apneas but not arousals.
Introducing Elitist Black-Box Models: When Does Elitist Behavior Weaken the Performance of Evolutionary Algorithms?
Authors: Doerr Carola , Lengler Johannes
Published: October 2016

Black-box complexity theory provides lower bounds for the runtime of black-box optimizers like evolutionary algorithms and other search heuristics and serves as an inspiration for the design of new genetic algorithms. Several black-box models covering different classes of algorithms exist, each highlighting a different aspect of the algorithms under considerations. In this work we add to the existing black-box notions a new elitist black-box model, in which algorithms are required to base all decisions solely on (the relative performance of) a fixed number of the best search points sampled so far. Our elitist model thus combines features of the ranking-based and the memory-restricted black-box models with an enforced usage of truncation selection. We provide several examples for which the elitist black-box complexity is exponentially larger than that of the respective complexities in all previous black-box models, thus showing that the elitist black-box complexity can be much closer to the runtime of typical evolutionary algorithms. We also introduce the concept of p-Monte Carlo black-box complexity, which measures the time it takes to optimize a problem with failure probability at most p. Even for small  p, the p-Monte Carlo black-box complexity of a function class [Formula: see text] can be smaller by an exponential factor than its typically regarded Las Vegas complexity (which measures the expected time it takes to optimize [Formula: see text]).
The Fragmentary Corpus of Theagenes
Authors: Focanti Lorenzo
Published: October 2016

In this article the various problems related to the fragmentarycorpusof Theagenes (FGrHist774) are tackled. The author first proposes an analysis of theAntiquities of Macedonia(Μακεδονικὰ πάτρια), delving into its connections with local Greek historiography. Then he produces evidence to confirm Theagenes’ authorship of theHistory of Caria(Καρικά) quoted by Stephanus of Byzantium (cf.FGrHist774 F 16). In addition he reaffirms the identification of the historian with the obscure Theogenes, author of a workOn Aegina(Περὶ Αἰγίνης: cf.FGrHist300). He finally suggests a new chronology for Theagenes, and dates his works to the late third centurybc, linking the topics addressed in thecorpusto the reign of Philip V of Macedonia.
Ibycus and Diomedes
Authors: Rodríguez-Noriega Guillén Lucía , Uría Javier
Published: October 2016

The fourth-century Latin grammarian Diomedes reports the otherwise unparalleled doctrine that the Latin onomastic system is derived from that of the Greeks. To sustain this view, he mentions the various names of some Greek heroes, some of which seem to be drawn from the lyric poet Ibycus of Rhegium. This poet is also mentioned when the grammarian needs to provide examples of some rare patronymics. These two references to Ibycus in Diomedes are extensively dealt with in this paper, in which we try to disentangle the arguments and intentions behind this strange doctrine, as well as the role Ibycus plays in it. The alleged possibility that Ibycus is not the archaic poet, but rather a later grammarian, is discussed and rejected. Possible sources for the doctrine are proposed.
Gorgias’ Lehrmethode
Authors: Schollmeyer Jonas
Published: October 2016

At the end of the Sophistici Elenchi, Aristotle claims that Gorgias gave his pupils ready-made speeches to learn by heart rather than teaching them a τέχνη. Gorgias’ Helen is often considered to have been a speech used by pupils as a model for the composition of their own speeches. However, there is little extant research into the question as to whether there are speeches still preserved that were composed with the aid of such models. In this paper I will argue that the Helen served as a model for the author of De flatibus. The stylistic similarities between both writings are well known. In addition, De flatibus imitates the composition and argumentation of the Helen. At multiple points, the mechanisms of λόγος as they are described by Gorgias are applied to medical problems. These and other connections between the two texts offer a unique perspective on the ways in which Gorgias’ method of instruction could function and be successful. It is likely that physicians were among Gorgias’ regular students.
Innovation and Artistry in Phaedrus’ Morals
Authors: Lefkowitz Jeremy B.
Published: October 2016

In his creative and original deployment of the ‘morals’ attached to his fables, Phaedrus boldly asserts his independence from the prosaic fable tradition and embeds his work within the framework of a broadly fictionalized poetic career. Whilepro- andepimythiain Phaedrus have attracted scholarly attention as aides in calculating his chronology or deciphering his perspective on life in Rome, Phaedrian ‘morals’ do more than express a particular historical or socio-political outlook. Indeed, in his morals Phaedrus repeatedly challenges the idea that fables carry any universal or even coherent meaning, and in so doing he transforms the traditional framing devices into sites for the development of his complex poetic persona.
All or Nothing: Reading Franco Moretti Reading
Authors: Lesjak Carolyn
Published: October 2016

Published in tandem in 2013, Franco Moretti’s two most recent books continue his on-going project to develop radical new methods of literary history and to propose new formulations and frameworks for understanding the relationship between form and history and form and ideology. Bringing together the series of essays through which he developed his concept of distant reading, his collection of the same name argues for a ‘falsifiable criticism’ grounded in the data now available through digital technologies and for the concept of a ‘world literature’ that it is the task of comparatists to theorise. His book on the bourgeois – characterised by Moretti as a project of an entirely different nature – finds in the minutiae of language the construction of a bourgeois culture in which the figure of the bourgeois himself ultimately disappears. Contra Moretti, the review contends that these books are deeply interrelated and that the limits of Moretti’s method are to be found specifically in the issues of scale raised by reading these two works in dialectical relationship to each other. In particular, while Moretti importantly forces us to confront in world literature what Fredric Jameson refers to as the ‘scandal of multiplicity’, his method is unable, in the end, to account for a reading of the world in literature in which both the empirical fact of a dead history and the allegorical possibility of another history already in the making can be found.