bluuebunny/crossref_metadata_2025 huggingface dataset:
Accidental encounters: can accidents be adaptive?
Authors: Ferreira Giordano BS , Scheutz Matthias
Published: September 2018

Accidents happen in nature, from simple incidents like bumping into obstacles, to erroneously arriving at the wrong location, to mating with an unintended partner. Whether accidents are problematic for an animal depends on their context, frequency, and severity. In this article, we investigate the question of how accidents affect the task performance of agents in an agent-based simulation model for a wide class of tasks called “multi-agent territory exploration” tasks (MATE). In MATE tasks, agents have to visit particular locations of varying quality in partially observable environments within a fixed time window. As such, agents have to balance the quality of the location with how much energy they are willing to expend reaching it. Arriving at the wrong location by accident typically reduces task performance. We model agents based on two location selection strategies that are hypothesized to be widely used in nature: best-of-n and min-threshold. Our results show that the two strategies lead to different accident rates and thus overall different levels of performance based on the degree of competition among agents, as well as the quality, density, visibility, and distribution of target locations in the environment. We also show that in some cases, individual accidents can be advantageous for both the individual and the whole group.
A New Worldwide Measure of Happiness Explains National Differences in Suicide Rates and Cigarette Consumption
Authors: Minkov Michael , Schachner Michael , Sanchez Carlos , Morales Oswaldo
Published: September 2018

Studies of happiness or subjective well-being (SWB) employ a variety of conceptualizations and item formats. Some authorities prefer to focus on the cognitive or evaluative component of SWB in studies of national happiness, and consider the affective component a lesser priority. However, we show that the latter component has unique and important predictive properties. We measured the stable element of the affective component (being “usually happy and in a good mood”) in 44,096 respondents recruited probabilistically from 56 societies (nations and some ethnic groups), from all inhabited continents. Consistent with previous studies, we obtained the highest positive affect scores in the nations of northern Latin America and Africa, whereas the highest percentages of respondents “rarely in a good mood” were recorded in East Asia, Russia, Italy, and the Arab world. Our happiness measure is a significant negative predictor of national suicide rates and cigarette consumption, after controlling for other plausible predictors, including other SWB measures from the World Values Survey, Veenhoven’s World Database of Happiness, and climate and socioeconomic variables.
Cervical Cancer, Human Papillomavirus Infection, and Vaccine-Related Knowledge
Authors: Yuanyue Li , Baloch Zulqarnain , Shanshan Li , Yasmeen Nafeesa , Xiaomei Wu , Khan Jamal Muhammad , Xueshan Xia
Published: September 2018

Cervical cancer (CC) has a high incidence and mortality and is accompanied by lack of organized CC screening programs, lack of health-care facilities, and a lack of human papillomavirus (HPV) vaccination among female population in the world, particularly China. We recruited 487 females who visited the outpatient department of the First People’s Hospital of Yunnan Province from November 2015 to January 2016 to complete a standardized-designed questionnaire. We found that only 39.6% of the females knew about the role of HPVs in the development of cervical cancer. Moreover, none of the females knew that HPV could cause penile carcinomas, perianal carcinomas, and head and neck carcinomas. The majority of the participants acquired information about cervical cancer, HPV, and the HPV vaccine from medical workers. Only 15.6% of the recruited females had heard about the HPV vaccine. The overall HPV vaccine acceptance rate was higher (91.2%) if the vaccine was available free of cost. In this study, we found high acceptability of the HPV vaccine in Chinese women and high awareness about cervical cancer. However, very low levels of knowledge about HPVs and their role in cancer development among the recruited women is alarming. Therefore, it is very important to initiate educational programs to raise awareness and knowledge about cervical cancer, HPV, and the HPV vaccine in this region.
Breast Cancer Genetics: Relevance to Oncology Practice
Authors: Peters June
Published: September 2018

Our knowledge of genetic mechanisms involved in cancer initiation, promotion, and progression recently bas expanded. In order to benefit from this expansion and to apply genetic discoveries to current protocols for prevention, screening, diagnosis, treatment, prognosis, and monitoring for minimal residual disease, a working knowledge must be developed of the genetic principles, oncogenes, tumor suppressor genes, and genetic models of carcinogenesis. Genetic susceptibility testing for cancer soon will be introduced into oncology practice through established familial risk counseling programs, and the oncologist must be prepared to address the medical, ethical, legal, economic, psychological, and social issues that accompany this testing.
Comparison of Total Joint Replacement Rate Between Patients With Hemophilia A and Patients With Hemophilia B: A Population-Based and Retrospective Cohort Study
Authors: Lin Wen-Ya , Wang Jiaan-Der , Tsan Yu-Tse , Chan Wei-Cheng , Tong Kwok-Man , Chang Shin-Tsu , Cheng Yuan-Yang
Published: September 2018

Recurrent hemarthrosis in patients with hemophilia (PWH) results in chronic arthropathy requiring total joint replacement (TJR). This study aimed to compare the difference in TJR rate between patients with hemophilia A (HA) and hemophilia B (HB). A final total of 935 PWH (782 HA and 153 HB) without inhibitors were collected from the Taiwan’s National Health Insurance Research Database between 1997 and 2013. Demographics, clinical characteristics, and TJR rate were compared between the 2 groups. The annual use of clotting factor concentrate was not different between HA and HB groups ( P = .116). The rate of comorbidities except for 29 PWH having HIV who were all in the HA group was also not different between the 2 groups. A total of 99 (10.6%) PWH had undergone 142 TJR procedures during the study period. All of them had received on-demand therapy. No difference was found in the cumulative incidence of TJR between HA and HB ( P = .787). After adjusting for various confounders including age, pyogenic arthritis, and HIV infection, no increased risk of TJR was found in patients with HA versus Patients with HB (hazard ratio: 0.92, 95% confidence interval 0.54-1.58). This finding suggests that the rate of TJR between patients with HA and HB is not significantly different.
Songs of their lives: A narrative study of three older Korean immigrants in Los Angeles
Authors: Cho Eun
Published: September 2018

Conceptualized as a narrative inquiry, this study explored how music permeates the lives of older Korean immigrants in the United States. By closely examining three individuals’ lived experiences through the narratives they told, the study aimed to illuminate the complexity, depth, and uniqueness of meanings embedded in the musical lives of older immigrants. Narrative data revealed that while all interviewees had lived in the same time periods and went through many similar life events, each individual used different “colors and shapes” to “paint” their musical lives. Yet, some common themes also appeared from the narrative data: songs in the lives of the older immigrants portrayed their personhood, including who they are, where they come from, and what they like/dislike. Also, as a means of emotional communication, songs were intrinsically related to temporal moments at particular circumstances in the past, often paired with affective reactions. Finally, songs helped make sense of the socio-historical contexts in which the older immigrants have lived.
Fracture characterization of a cast aluminum alloy aiming machining simulation
Authors: Silva TEF , Gain S , Pinto D , de Jesus AMP , Xavier J , Reis A , Rosa PAR
Published: September 2018

Despite extensive research regarding metal cutting simulation, the current industrial practice very often relies on empirical data when it comes to tool design. In order accurately simulate the cutting process it is not only important to have robust numerical models that closely portray the phenomenon, but also to properly characterize the material taking into account the cutting conditions. The goal of this investigation focuses on the mechanical characterization of the cast aluminum alloy AlSi9Cu3 by conducting both compression and fracture tests. Due to its very good castability, machinability, and attractive mechanical properties, this alloy is widely used in casting industry for the manufacture of automotive components, among others. Besides the experimental characterization, a numerical methodology is proposed for the modeling of the cast alloy, making use of the Johnson–Cook constitutive material model, in Abaqus/CAE. The material model is calibrated based on compression tests at multiple conditions (quasi-static, incremental dynamic and high temperatures). The identified model is then validated by simulation of the ductile fracture tests of notched specimens. The obtained numerical results were consistent with the experimentally obtained, contributing to the validity of the presented characterization technique.
The Influence of Materialism and Self-Congruity on the Relationship of Human With Their Companion Dogs
Authors: Luna-Cortés Gonzalo
Published: September 2018

This research examines the relationship of materialism and self-congruity with behavioral problems of dogs and the owners’ intention to abandon them. This study focuses on owners of purebred dogs in Colombia (South America). Using the methodology of confirmatory factor analysis and structural equation modeling, the results show that more materialistic consumers own pets that, in their own opinions, present more behavioral problems. These problems influence owners’ intention to abandon their pets. In addition, materialism appears as a construct that directly influences the intention to abandon the dogs. However, the acquisition based on the congruence between the characteristics of the dog and the owners’ self-concept negatively influences the behavioral problems shown by their pets and, consequently, the intention of the owners to abandon the animals. A social marketing intervention is presented as a part of the conclusions, which focuses on these consumers’ motivations, in order to improve some aspects of the dogs’ welfare in Colombia.
Ideology, Party, and Opinion: Explaining Individual Legislator ACA
Implementation Votes in the States
Authors: Shor Boris
Published: September 2018

Why do state legislators vote the way they do? Which influence is
predominant: ideology, party, or public opinion? The implementation votes
surrounding the Affordable Care Act (ACA) provides a unique setting to
examine this question, as they make all three considerations highly salient.
State roll call votes on ACA implementation were sometimes polarized and
sometimes unexpectedly bipartisan. What accounts for the heterogeneity in
individual legislator behavior on bills implementing the ACA at the state
level? Using new data on legislator ideology and votes from 2011–2015, I
show evidence that legislator ideology was by far the most important
predictor of voting on implementation votes, far more so than legislator
party or public opinion. Moreover, I show the influence of ideology is
heterogeneous by issue area and bill.
Collagen Features of Dermatofibrosarcoma Protuberans Skin Base on Multiphoton Microscopy
Authors: Wu Shulian , Huang Yudian , Li Zhifang , Wu Huaqing , Li Hui
Published: September 2018

Dermatofibrosarcoma protuberans is a rare, low-grade skin fibroblastic tumor which tends to recur locally due to its high misdiagnosis. Dermatofibrosarcoma protuberans usually spreads through the intracutaneous and subcutaneous layers into the deep dermis layer in which the main component is collagen. Therefore, alterations in collagen shape and content are important for accurate diagnosis of dermatofibrosarcoma protuberans. In this study, multiphoton microscopy was employed to observe normal human skin and dermatofibrosarcoma protuberans skin. Then, a centerline based on an algorithm that skeletonizes a binary image of fibers was applied to analyze collagen shapes in 2 types of skin. Then, collagen content, including intensity and density, was quantitatively obtained to demonstrate differences between the 2 skin types. Results indicate that collagen shape and density can be considered as auxiliary diagnostic parameters to improve the accuracy of dermatofibrosarcoma protuberans diagnosis.
From Micro- to Nano-Multifunctional Theranostic Platform: Effective Ultrasound Imaging Is Not Just a Matter of Scale
Authors: Zullino Sara , Argenziano Monica , Stura Ilaria , Guiot Caterina , Cavalli Roberta
Published: September 2018

Ultrasound Contrast Agents (UCAs) consisting of gas-filled-coated Microbubbles (MBs) with diameters between 1 and 10 µm have been used for a number of decades in diagnostic imaging. In recent years, submicron contrast agents have proven to be a viable alternative to MBs for ultrasound (US)-based applications for their capability to extravasate and accumulate in the tumor tissue via the enhanced permeability and retention effect. After a short overview of the more recent approaches to ultrasound-mediated imaging and therapeutics at the nanoscale, phase-change contrast agents (PCCAs), which can be phase-transitioned into highly echogenic MBs by means of US, are here presented. The phenomenon of acoustic droplet vaporization (ADV) to produce bubbles is widely investigated for both imaging and therapeutic applications to develop promising theranostic platforms.
Clinically Historical and Prospective Associations Between Learning Disorders and Concussion in Young Adult Athletes
Authors: Pagani Linda S. , Ellemberg Dave , Moore Robert Davis
Published: September 2018

Background. Athletes with specific learning disorder (LD) tend to score lower on neuropsychological tests and are at increased risk of personal injury than their counterparts without such disorders. Using a retrospective historical and prospective design, we examined whether adult athletes with LD, the most prevalent of neurodevelopmental disorders, experience greater chances of past and future concussions than their counterparts without LD. We expected to find that young athletes with LD would show greater risk of past (historical) and future (prospective) cerebral concussions. Methods. Participants (95 men and 53 women aged 18 to 25 years) were recruited from university sports teams and followed during an entire season. Of these, 38 participants had a history of LD and 101 had a history of at least 1 concussion (72 males, 29 females) at the preseason baseline. One-third experienced a new concussion. Data analytic procedures include inferential cross-tabulations. Results. Athletes with LD were twice more likely to have a concussion history at baseline and to have a history of multiple concussions than athletes without LD; 95% CI = [0.86, 4.92] and [0.77, 3.40], respectively. Athletes with LD were twice more likely to incur a new concussion than those without LD; 95% CI = [0.86, 4.92]. Conclusions. Adult athletes with LD experience greater chances of previous and future concussions compared with counterparts without LD. Preventive practices regarding individuals with neurodevelopmental disorders may not only prevent the biopsychosocial consequences of brain trauma for the individual, but also represent a cost-effective public health measure.
Research on energy management strategy considering battery life for plug-in hybrid electric vehicle
Authors: Hu Jianjun , Hu Zhihua , Niu Xiyuan , Bai Qin
Published: September 2018

To improve the fuel efficiency and battery life-span of plug-in hybrid electric vehicle, the energy management strategy considering battery life decay is proposed. This strategy is optimized by genetic algorithm, aiming to reduce the fuel consumption and battery life decay of plug-in hybrid electric vehicle. Besides, to acquire better drive-cycle adaptability, driving patterns are recognized with probabilistic neural network. The standard driving cycles are divided into urban congestion cycle, highway cycle, and urban suburban cycle; the optimized energy management strategies in three representative driving cycles are established; meanwhile, a comprehensive test driving cycle is constructed to verify the proposed strategies. The results show that adopting the optimized control strategies, fuel consumption, and battery’s life decay drop by 1.9% and 3.2%, respectively. While using the drive-cycle recognition, the features of different driving cycles can be identified, and based on it, the vehicle can choose appropriate control strategy in different driving conditions. In the comprehensive test driving cycle, after recognizing driving cycles, fuel consumption and battery’s life decay drop by 8.6% and 0.3%, respectively.
Numerical and experimental investigation of Johnson–Cook material models for aluminum (Al 6061-T6) alloy using orthogonal machining approach
Authors: Akram Sohail , Jaffery Syed Husain Imran , Khan Mushtaq , Fahad Muhammad , Mubashar Aamir , Ali Liaqat
Published: September 2018

This research focuses on the study of the effects of processing conditions on the Johnson–Cook material model parameters for orthogonal machining of aluminum (Al 6061-T6) alloy. Two sets of parameters of Johnson–Cook material model describing material behavior of Al 6061-T6 were investigated by comparing cutting forces and chip morphology. A two-dimensional finite element model was developed and validated with the experimental results published literature. Cutting tests were conducted at low-, medium-, and high-speed cutting speeds. Chip formation and cutting forces were compared with the numerical model. A novel technique of cutting force measurement using power meter was also validated. It was found that the cutting forces decrease at higher cutting speeds as compared to the low and medium cutting speeds. The poor prediction of cutting forces by Johnson–Cook model at higher cutting speeds and feed rates showed the existence of a material behavior that does not exist at lower or medium cutting speeds. Two factors were considered responsible for the change in cutting forces at higher cutting speeds: change in coefficient of friction and thermal softening. The results obtained through numerical investigations after incorporated changes in coefficient of friction showed a good agreement with the experimental results.
A novel milling force model based on the influence of tool geometric parameters in end milling
Authors: Zhang Xianglei , Zhang Jing , Zhou Hongming , Ren Yan , Xu Mingming
Published: September 2018

A novel milling force model for cutting aviation aluminum alloy 7075 using carbide end mill is established in this article. A two-dimensional end-milling model is set up to investigate the influence of tool geometric parameters on milling force with the single-factor analysis. The relationship between milling forces and tool geometric parameters is obtained by nonlinear regression fitting method. Based on the existing empirical model of milling force, quadratic polynomial factor is taken into consideration to explore the influence of tool geometric parameters on milling force. Thus, a novel milling force model is built up which includes tool geometric parameters and milling parameters. The coefficients of the novel model are identified by the direct method and the loop method. The precisions of the coefficients obtained by the two methods are compared between prediction values and experiment values. After comparison, the model whose coefficients are obtained by loop method has higher prediction ability. End-milling experiments were carried out to verify the prediction accuracy of the novel milling force model. The result shows that the novel model of milling force has high accuracy in prediction. The method of building the milling force model proposed in this article can be applied to other types of milling cutter.
Role of polymorphonuclear neutrophils in the reperfused ischemic brain: insights from cell-type-specific immunodepletion and fluorescence microscopy studies
Authors: Hermann Dirk M. , Kleinschnitz Christoph , Gunzer Matthias
Published: September 2018

Polymorphonuclear neutrophil granulocytes (PMNs) are part of the early post-ischemic immune response that orchestrates the removal of infarcted brain tissue. PMNs contribute to secondary brain injury in experimental stroke models. In human patients, high PMN-to-lymphocyte ratios in peripheral blood are predictive of poor stroke outcome. Following earlier studies indicating that the cerebral microvasculature forms an efficient barrier that impedes PMN brain entry even under conditions of ischemia, more recent studies combining intravital two-photon microscopy and ex vivo immunohistochemistry unequivocally demonstrated the accumulation of PMNs in the ischemic brain parenchyma. In the meantime, transgenic mouse lines, such as mice expressing Cre-recombinase and the red fluorescent reporter protein tdTomato under the highly granulocyte-specific locus for the gene Ly6G (so-called Catchup mice), have become available that allow study of dynamic interactions of PMNs with brain parenchymal cells. These mice will further help us understand how PMNs promote brain injury and disturb brain remodeling and plasticity.
Occupational Health Hazards
Authors: Gitonga Lydia
Published: September 2018

Nurses from occupational health care settings around the world, interpreting the theme “Communication, Health Care, and the Community,” presented papers at the First International Conference on Occupational Health Nursing in Edinburgh, Scotland in October, 1986. In keeping with AAOHN's commitment to an international perspective, this is the fifth in a five part series of articles printed in the AAOHN Journal.
Diagnostic Criteria for Somatosensory Tinnitus: A Delphi Process and Face-to-Face Meeting to Establish Consensus
Authors: Michiels Sarah , Ganz Sanchez Tanit , Oron Yahav , Gilles Annick , Haider Haúla F. , Erlandsson Soly , Bechter Karl , Vielsmeier Veronika , Biesinger Eberhard , Nam Eui-Cheol , Oiticica Jeanne , de Medeiros Ítalo Roberto T. , Bezerra Rocha Carina , Langguth Berthold , Van de Heyning Paul , De Hertogh Willem , Hall Deborah A.
Published: September 2018

Since somatic or somatosensory tinnitus (ST) was first described as a subtype of subjective tinnitus, where altered somatosensory afference from the cervical spine or temporomandibular area causes or changes a patient’s tinnitus perception, several studies in humans and animals have provided a neurophysiological explanation for this type of tinnitus. Due to a lack of unambiguous clinical tests, many authors and clinicians use their own criteria for diagnosing ST. This resulted in large differences in prevalence figures in different studies and limits the comparison of clinical trials on ST treatment. This study aimed to reach an international consensus on diagnostic criteria for ST among experts, scientists and clinicians using a Delphi survey and face-to-face consensus meeting strategy. Following recommended procedures to gain expert consensus, a two-round Delphi survey was delivered online, followed by an in-person consensus meeting. Experts agreed upon a set of criteria that strongly suggest ST. These criteria comprise items on somatosensory modulation, specific tinnitus characteristics, and symptoms that can accompany the tinnitus. None of these criteria have to be present in every single patient with ST, but in case they are present, they strongly suggest the presence of ST. Because of the international nature of the survey, we expect these criteria to gain wide acceptance in the research field and to serve as a guideline for clinicians across all disciplines. Criteria developed in this consensus paper should now allow further investigation of the extent of somatosensory influence in individual tinnitus patients and tinnitus populations.
Legal liability in sepsis cases
Authors: Brown Julian M , Snell John M
Published: September 2018

The treatment of sepsis is a significant cause of clinical negligence. Determining causation is a key aspect to successful litigation. We have reviewed the use of medical evidence in establishing legal causation.
Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p
Authors: Barnes James I. , Divi Vasu , Begaye Adrian , Wong Russell , Coutre Steven , Owens Douglas K. , Goldhaber-Fiebert Jeremy D.
Published: September 2018

Key Points

At current prices, ibrutinib is not a cost-effective initial CLL therapy in older patients without 17p deletion. The cost of ibrutinib would need to be <$6800 per month to be cost-effective.
CD40L/IL-4–stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM
Authors: Lezina Larissa , Spriggs Ruth V. , Beck Daniel , Jones Carolyn , Dudek Kate M. , Bzura Aleksandra , Jones George D. D. , Packham Graham , Willis Anne E. , Wagner Simon D.
Published: September 2018

Key Points

CD40L/IL-4 responses mediate translational regulation of DNA damage repair genes, including ATM, and associate with baseline levels of ATM. Lower levels of baseline ATM, independent of 11q deletion, associate with reduced overall survival.
How ibrutinib, a B-cell malignancy drug, became an FDA-approved second-line therapy for steroid-resistant chronic GVHD
Authors: Jaglowski Samantha M. , Blazar Bruce R.
Published: September 2018

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for a number of hematologic conditions, both malignant and nonmalignant. However, its success can be limited by the development of acute and chronic graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) is the most common long-term complication following allo-SCT, and patients who develop this condition have significantly higher morbidity and mortality and significantly lower quality of life than patients who do not. Until recently, there were no US Food and Drug Administration (FDA)–approved therapies for cGVHD treatment. In this review article, we describe how ibrutinib was identified as potential cGVHD therapy based on preclinical cGVHD models and clinical studies in B-cell malignancies and elucidation of its mechanisms of action in cGVHD. Results from a phase 2 clinical trial that was designed based on National Institutes of Health Criteria for the grading and staging of cGVHD culminated in the FDA-approval of ibrutinib as second line therapy of steroid-refractory or steroid-resistant cGVHD. Results of ibrutinib studies in phase 3 randomized studies, for cGVHD prophylaxis and as first -line testing along with steroids will be especially important in selecting the preferred indications for ibrutinib in patients at risk for or who have developed cGVHD.
Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia
Authors: Ball Brian , Komrokji Rami S. , Adès Lionel , Sekeres Mikkael A. , DeZern Amy E. , Pleyer Lisa , Vey Norbert , Almeida Antonio , Germing Ulrich , Cluzeau Thomas , Platzbecker Uwe , Gore Steven D. , Fenaux Pierre , Prebet Thomas
Published: September 2018

Key Points

Induction led to response in 41% and 32%, survival of 10.8 and 6 months, and transplant in 40% and 42% of responders in MDS and AML. Treatment with high-dose cytarabine improved response rates in MDS and an anthracycline-containing regimen increased survival in AML.
Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma
Authors: Lee Jimmy , Zhang Liang Leo , Wu Wenjun , Guo Hui , Li Yan , Sukhanova Madina , Venkataraman Girish , Huang Shengjian , Zhang Hui , Alikhan Mir , Lu Pin , Guo Ailin , Galanina Natalie , Andrade Jorge , Wang Michael L. , Wang Y. Lynn
Published: September 2018

The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.
Development of a prognostically relevant cachexia index in primary myelofibrosis using serum albumin and cholesterol levels
Authors: Tefferi Ayalew , Nicolosi Maura , Penna Domenico , Mudireddy Mythri , Szuber Natasha , Lasho Terra L. , Hanson Curtis A. , Ketterling Rhett P. , Gangat Naseema , Pardanani Animesh D.
Published: September 2018

Key Points

Serum albumin and cholesterol levels predict survival in primary myelofibrosis, independent of each other and contemporary risk models. The cachexia index, determined by serum albumin and cholesterol levels, might further refine current prognostic models in myelofibrosis.
Early platelet count kinetics has prognostic value in lower-risk myelodysplastic syndromes
Authors: Itzykson Raphael , Crouch Simon , Travaglino Erica , Smith Alex , Symeonidis Argiris , Hellström-Lindberg Eva , Sanz Guillermo , Čermák Jaroslav , Stauder Reinhard , Elena Chiara , Germing Ulrich , Mittelman Moshe , Langemeijer Saskia , Mądry Krzysztof , Tatic Aurelia , Holm Mette Skov , Almeida Antonio Medina , Savic Aleksandar , Šimec Njetočka Gredelj , Luño Elisa , Culligan Dominic , Guerci-Bresler Agnes , Malcovati Luca , van Marrewijk Corine , Bowen David , de Witte Theo , Fenaux Pierre
Published: September 2018

Key Points

A drop in platelet count >25% relative to baseline at 6 months from diagnosis predicts inferior outcome in lower-risk MDS. Platelet drop combined with RBC-TD at 6 months provides an inexpensive and validated classifier of outcome in lower-risk MDS.
Induced pluripotent stem cell–based mapping of β-globin expression throughout human erythropoietic development
Authors: Vanuytsel Kim , Matte Taylor , Leung Amy , Naing Zaw Htut , Morrison Tasha , Chui David H. K. , Steinberg Martin H. , Murphy George J.
Published: September 2018

Key Points

iPSC-derived definitive erythroid cells display a globin expression profile corresponding to yolk sac erythromyeloid progenitors. iPSC-derived erythroblasts resemble their postnatal counterparts in terms of gene expression and essential biological processes.
Double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial)
Authors: Daak Ahmed A. , Dampier Carlton D. , Fuh Beng , Kanter Julie , Alvarez Ofelia A. , Black L. Vandy , McNaull Melissa A. , Callaghan Michael U. , George Alex , Neumayr Lynne , Hilliard Lee M. , Sancilio Fredrick , Rabinowicz Adrian L. , Heeney Matthew M.
Published: September 2018

Key Points

SC411 increases DHA in blood cell membranes and reduces home-managed SCD pain crisis and analgesic and opioid use at home to treat SCD pain. The rate of sickle cell crisis was 53% lower for the pooled active groups vs placebo.
Blood manufacturing methods affect red blood cell product characteristics and immunomodulatory activity
Authors: Almizraq Ruqayyah J. , Norris Philip J. , Inglis Heather , Menocha Somaang , Wirtz Mathijs R. , Juffermans Nicole , Pandey Suchitra , Spinella Philip C. , Acker Jason P. , Muszynski Jennifer A.
Published: September 2018

Transfusion of red cell concentrates (RCCs) is associated with increased risk of adverse outcomes that may be affected by different blood manufacturing methods and the presence of extracellular vesicles (EVs). We investigated the effect of different manufacturing methods on hemolysis, residual cells, cell-derived EVs, and immunomodulatory effects on monocyte activity. Thirty-two RCC units produced using whole blood filtration (WBF), red cell filtration (RCF), apheresis-derived (AD), and whole blood–derived (WBD) methods were examined (n = 8 per method). Residual platelet and white blood cells (WBCs) and the concentration, cell of origin, and characterization of EVs in RCC supernatants were assessed in fresh and stored supernatants. Immunomodulatory activity of RCC supernatants was assessed by quantifying monocyte cytokine production capacity in an in vitro transfusion model. RCF units yielded the lowest number of platelet and WBC-derived EVs, whereas the highest number of platelet EVs was in AD (day 5) and in WBD (day 42). The number of small EVs (<200 nm) was greater than large EVs (≥200 nm) in all tested supernatants, and the highest level of small EVs were in AD units. Immunomodulatory activity was mixed, with evidence of both inflammatory and immunosuppressive effects. Monocytes produced more inflammatory interleukin-8 after exposure to fresh WBF or expired WBD supernatants. Exposure to supernatants from AD and WBD RCC suppressed monocyte lipopolysaccharide-induced cytokine production. Manufacturing methods significantly affect RCC unit EV characteristics and are associated with an immunomodulatory effect of RCC supernatants, which may affect the quality and safety of RCCs.
Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, inhibits platelet aggregation and arterial thrombosis
Authors: Nayak Manasa K. , Dhanesha Nirav , Doddapattar Prakash , Rodriguez Omar , Sonkar Vijay K. , Dayal Sanjana , Chauhan Anil K.
Published: September 2018

Key Points

DCA, an inhibitor of PDKs, impedes glucose uptake and aerobic glycolysis in activated platelets. DCA inhibits agonist-induced human and mouse platelet aggregation and arterial thrombosis without altering hemostasis in mice.
Genomic analysis of transcriptional networks directing progression of cell states during MGE development
Authors: Sandberg Magnus , Taher Leila , Hu Jianxin , Black Brian L. , Nord Alex S. , Rubenstein John L. R.
Published: September 2018

Background

Homeodomain (HD) transcription factor (TF) NKX2–1 critical for the regional specification of the medial ganglionic eminence (MGE) as well as promoting the GABAergic and cholinergic neuron fates via the induction of TFs such as LHX6 and LHX8. NKX2–1 defines MGE regional identity in large part through transcriptional repression, while specification and maturation of GABAergic and cholinergic fates is mediated in part by transcriptional activation via TFs such as LHX6 and LHX8. Here we analyze the signaling and TF pathways, downstream of NKX2–1, required for GABAergic and cholinergic neuron fate maturation.

Methods

Differential ChIP-seq analysis was used to identify regulatory elements (REs) where chromatin state was sensitive to change in the Nkx2–1cKO MGE at embryonic day (E) 13.5. TF motifs in the REs were identified using RSAT. CRISPR-mediated genome editing was used to generate enhancer knockouts. Differential gene expression in these knockouts was analyzed through RT-qPCR and in situ hybridization. Functional analysis of motifs within hs623 was analyzed via site directed mutagenesis and reporter assays in primary MGE cultures.

Results

We identified 4782 activating REs (aREs) and 6391 repressing REs (rREs) in the Nkx2–1 conditional knockout (Nkx2–1cKO) MGE. aREs are associated with basic-Helix-Loop-Helix (bHLH) TFs. Deletion of hs623, an intragenic Tcf12 aRE, caused a reduction of Tcf12 expression in the sub-ventricular zone (SVZ) and mantle zone (MZ) of the MGE. Mutation of LHX, SOX and octamers, within hs623, caused a reduction of hs623 activity in MGE primary cultures.

Conclusions

Tcf12 expression in the SVZ of the MGE is mediated through aRE hs623. The activity of hs623 is dependent on LHX6, SOX and octamers. Thus, maintaining the expression of Tcf12 in the SVZ involves on TF pathways parallel and genetically downstream of NKX2–1.
Bacterial biofilm formation inside colonic crypts may accelerate colorectal carcinogenesis
Authors: Raskov Hans , Kragh Kasper Nørskov , Bjarnsholt Thomas , Alamili Mahdi , Gögenur Ismail
Published: September 2018

Background

Research in the field of relation between microbes and colorectal carcinogenesis has gained increasing interest in past years. Recently, link between microbial biofilm and carcinogenesis in colon was demonstrated by several authors indicating that biofilm not only is a key player in carcinogenesis, but also may contribute to the understanding of side‐specific colon cancer—right sided colon cancer versus left sided. In this article, we briefly highlight the major findings of the research of biofilm and carcinogenesis and demonstrate our findings of colonic cancer tissue and colonic polyp examined for biofilm.

Case presentation

Colonic cancer tissue from a patient with a right‐sided colon cancer, and an adenoma tubular polyp were examined for biofilm formation by flourescens in situ hybridization. In cancer tissue we found biofilm formation on the surface epithelium but surprisingly also deep into the crypts. No biofilms were found in tubular polyp tissue.

Conclusions

To our knowledge, this is the first‐time biofilm formation deep into colonic crypts are demonstrated in a patient with right‐sided colon cancer. This may indicate that bacterial biofilm may have a key role in carcinogenesis.
Guideline for the Management of Clostridium Difficile Infection in Children and Adolescents With Cancer and Pediatric Hematopoietic Stem-Cell Transplantation Recipients
Authors: Diorio Caroline , Robinson Paula D. , Ammann Roland A. , Castagnola Elio , Erickson Kelley , Esbenshade Adam , Fisher Brian T. , Haeusler Gabrielle M. , Kuczynski Susan , Lehrnbecher Thomas , Phillips Robert , Cabral Sandra , Dupuis L. Lee , Sung Lillian
Published: September 2018

Purpose

The aim of this work was to develop a clinical practice guideline for the prevention and treatment of Clostridium difficile infection (CDI) in children and adolescents with cancer and pediatric hematopoietic stem-cell transplantation (HSCT) patients.

Methods

An international multidisciplinary panel of experts in pediatric oncology and infectious diseases with patient advocate representation was convened. We performed systematic reviews of randomized controlled trials for the prevention or treatment of CDI in any population and considered the directness of the evidence to children with cancer and pediatric HSCT patients. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to generate recommendations.

Results

The panel made strong recommendations to administer either oral metronidazole or oral vancomycin for the initial treatment of nonsevere CDI and oral vancomycin for the initial treatment of severe CDI. Fidaxomicin may be considered in the setting of recurrent CDI. The panel suggested that probiotics not be routinely used for the prevention of CDI, and that monoclonal antibodies and probiotics not be routinely used for the treatment of CDI. A strong recommendation to not use fecal microbiota transplantation was made in this population. We identified key knowledge gaps and suggested directions for future research.

Conclusion

We present a guideline for the prevention and treatment of CDI in children and adolescents with cancer and pediatric HSCT patients. Future research should include randomized controlled trials that involve children with cancer and pediatric HSCT patients to improve the management of CDI in this population.
Rare Nash Equilibria and the Price of Anarchy in Large Static Games
Authors: Lacker Daniel , Ramanan Kavita
Published: September 2018

We study a static game played by a finite number of agents, in which agents are assigned independent and identically distributed random types and each agent minimizes its objective function by choosing from a set of admissible actions that depends on its type. The game is anonymous in the sense that the objective function of each agent depends on the actions of other agents only through the empirical distribution of their type-action pairs. We study the asymptotic behavior of Nash equilibria, as the number of agents tends to infinity, first by deriving laws of large numbers characterizing almost sure limit points of Nash equilibria in terms of so-called Cournot-Nash equilibria of an associated nonatomic game. Our main results are large deviation principles that characterize the probability of rare Nash equilibria and associated conditional limit theorems describing the behavior of equilibria conditioned on a rare event. The results cover situations when neither the finite-player game nor the associated nonatomic game has a unique equilibrium. In addition, we study the asymptotic behavior of the price of anarchy, complementing existing worst-case bounds with new probabilistic bounds in the context of congestion games, which are used to model traffic routing in networks.
A instrução explícita e seus efeitos na produção e na percepção dos fricativos anteriores do Português Brasileiro/L2 por hispanofalantes latino-americanos/L1
Authors: De Oliveira Rafael Alves
Published: September 2018

No português, as fricativas anteriores surdas e sonoras constituem-se como fonemas e ocupam posição de contraste (Camara Jr, 1977). No espanhol, enquanto as fricativas surdas constituem-se como fonemas, as sonoras só aparecem na língua como alofones posicionais ou por assimilação de vozeamento (Hualde, 2014). Este artigo tem como objetivo analisar as estratégias de pronúncia e investigar os efeitos da instrução fonética explícita na produção e na percepção dos fonemas fricativos anteriores sonoros por hispanofalantes latino-americanos aprendizes do português brasileiro. Os resultados, analisados com base nas teorias de percepção da fala em L2 (FLEGE, 1995; BEST, 1995; BEST; TYLER, 2007) e nas teorias dinamicistas sobre o desenvolvimento de L2 (LARSEN-FREEMAN, 1997; VERSPOOR, LOWIE, DE BOT, 2007), indicam, dentre outros aspectos, que a instrução explícita é uma ferramenta indispensável para o ensino da pronúncia em salas de Português como Língua Estrangeira.
FORMAÇÃO DOCENTE E ENSINO DE LÍNGUA PORTUGUESA EM TIMOR-LESTE: CONSIDERAÇÕES DE PROFESSORES BRASILEIROS
Authors: Guimarães Joice Eloi
Published: September 2018

Em 2002, após o processo de restauração da independência, a República Democrática de Timor-Leste elegeu como línguas oficiais e de instrução a língua portuguesa e a língua tétum. No processo de (re)introdução do português nas diversas esferas sociais do país atuaram, por meio do Programa de Qualificação Docente e Ensino de Língua Portuguesa em Timor-Leste (PQLP/CAPES), professores brasileiros de diferentes áreas do conhecimento. Desse conjunto de docentes, selecionamos, para participar deste trabalho, aqueles cuja prática em Timor era voltada ao ensino da língua portuguesa. Os dados coletados, por meio de instrumento de questionário, são enunciados escritos acerca da formação e da docência desses sujeitos. A metodologia utilizada para análise dos dados fundamenta-se nos estudos desenvolvidos por Bakhtin (2010; 2011). Pela teoria do dialogismo, elegemos como categorias de análise dos enunciados conceitos componentes do contexto extraverbal de sua produção: conceito de cronotopo – tempo (histórico) e espaço (social) – e de valoração, avaliação social do sujeito que enuncia em relação ao objeto sobre o qual ele enuncia. De forma geral, a análise realizada permite entrever a existência de lacunas na formação dos professores para atuação em Timor-Leste e, o reconhecimento, por parte desses sujeitos, da importância do uso da língua tétum e de aspectos da cultura timorense no ensino de português no país.
GÊNEROS COMO AÇÕES RECORRENTES: ANÁLISE DE MATERIAIS DIDÁTICOS DE PLE
Authors: WEISS DENISE BARROS , BESSA MARIANA CAMARGO , KREUTZFELD LUCIANA DAMASCENO
Published: September 2018

O objetivo deste artigo é analisar o modo como os gêneros textuais são explorados em dois conjuntos de materiais didáticos preparados para públicos específicos. O primeiro material analisado foi elaborado pela autora Denise Barros Weiss, professora da Universidade Federal de Juiz de Fora, e utilizado em um Curso de Português como Língua Estrangeira para alunos de nível intermediário. Já o segundo material analisado foi utilizado em um curso de português como língua estrangeira ocorrido no Instituto Federal de Educação, Ciência e Tecnologia do Sudeste de Minas Gerais (IF Sudeste) em 2016. Empregamos a definição de gêneros como ações sociais tipificadas e recorrentes, sustentada por autores como Miller (1984) e Bazerman (1994). A definição do conceito de texto sustentada por Bronckart (2012) e as noções de “propósito comunicativo" e "comunidade discursiva" elaboradas por Swales (1990) serviram de apoio à análise dos dados. Os conceitos teóricos empregados puderam iluminar o modo como analisamos os exemplos de atividades. Pretendemos, com este trabalho, demonstrar que, por meio da exploração dos usos de diversos gêneros textuais, os papéis sociais e as ações desempenhadas pelos falantes são enfatizados durante o ensino de uma língua estrangeira.
Concepções de letramento subjacentes em um material didático de Português Língua de Acolhimento (PLAc)
Authors: Soares Laura Fontana , Sirianni Gabrielle
Published: September 2018

Tendo em vista a necessidade de se aprimorar o ensino de Português Língua de Acolhimento (PLAc), neste trabalho analisamos os conceitos de leitura e de escrita subjacentes às tarefas e atividades da apostila Portas Abertas (REINOLDES; MANDALÁ; AMADO, 2017), pensando em como os alunos são preparados para o uso social da escrita e da leitura por meio deste material didático. Na metodologia de análise, definimos critérios que incidem sobre aspectos da apostila, como gêneros discursivos escolhidos e seu tratamento nas tarefas que guiam o trabalho com o texto, a partir das orientações trazidas em Bulla, Lemos e Schlatter (2012). Foi possível identificar, por meio do enfoque em uma das unidades didáticas, tarefas alinhadas ao modelo de letramento autônomo, bem como outras alinhadas ao modelo de letramento ideológico (KLEIMAN, 1995; STREET, 2003), resultados que sublinham os pontos positivos do material didático, além de indicarem aspectos a serem potencializados por meio de reformulações de atividades e criação de tarefas didáticas. A partir da leitura crítica deste material didático, ressaltamos a importância de apostilas de PLAc virem acompanhados por caderno do professor, com vistas a auxiliar o docente a conciliar os percalços que são encontrados nesse contexto, além de promover um ensino de língua com vistas à participação cidadã dos imigrantes deslocados forçados.