bluuebunny/crossref_metadata_2025 huggingface dataset:
Visualizing the evolution of per capita carbon emissions of Chinese cities, 2001–2016
Authors: Xiong Weiting , Liu Zhicheng , Wang Shaojian , Li Yingcheng
Published: October 2019

As the world’s largest carbon emitter, China is under great pressure to cut down carbon emissions. Understanding the evolution of carbon emissions across Chinese cities is important for policymakers when allocating carbon emission quota among these cities. This paper draws upon the Open-source Data Inventory for Anthropogenic CO2 to calculate city-level per capita carbon emissions in China from 2001 to 2016. Overall, we find that per capita carbon emissions of Chinese cities have been generally on the rise during the 2001–2016 period. However, there has been on average a modest decline in per capita carbon emissions of cities in China’s Yangtze River Delta region and Pearl River Delta region from 2011 to 2016, after a remarkable increase during the 2001–2011 period. Besides, the average north-south gap has been enlarged, with northern cities having a relatively higher level of per capita carbon emissions.
Secondary Cleft Rhinoplasty in 1720 Patients: Are National Practices Consistent With Guidelines?
Authors: Chouairi Fouad , Torabi Sina J. , Gabrick Kyle S. , Persing John A. , Alperovich Michael
Published: October 2019

Objective:

To assess the timing, type, and associated adjunct procedures for secondary cleft rhinoplasty nationally.

Design:

Data were extracted from a national database of all secondary cleft rhinoplasty procedures (Current Procedural Terminology [CPT] codes 30460 and 30462). Frequency statistics were utilized to analyze demographics, comorbidities, surgical procedures, and timing. Chi-squared analysis and Fisher exact test were used for analysis.

Setting:

National Surgical Quality Improvement Program-Pediatric Database.

Participants:

A total of 1720 patients met inclusion criteria for secondary cleft rhinoplasty repair.

Interventions:

No relevant intervention.

Main Outcomes and Measures:

Age, demographics, comorbidities, and associated procedures.

Results:

Over 5 consecutive years, 1720 patients underwent secondary cleft lip rhinoplasty nationally. Mean patient age was 9.3 ± 5.3 years. Unilateral cleft rhinoplasty patients were older (9.0 years) than bilateral patients (7.8 years; P = .001). Rib grafting was performed in 6.3% of patients at a mean age of 10.6 years with a higher proportion of Asian and female patients. Auricular grafts were more commonly performed by otolaryngology than plastic surgery. The most common adjunct procedures included secondary cleft lip revision (33.1%) and tympanostomy tube placement (10.2%). When subdividing by type of cleft rhinoplasty, tip rhinoplasty was performed at a mean age of 7.3 years compared to rhinoplasty with osteotomies and a major septal component at 12.1 years ( P < .001).

Conclusions:

This study reveals that a large proportion of cleft rhinoplasties are performed in skeletally immature patients. Although patients undergoing rib grafting, nasal osteotomies, and a major septal component were older, these procedures are still performed in a large proportion of patients who are younger than expected.
Clinical Outcomes of Percutaneous Plantar Fasciotomy Using Microdebrider Coblation Wand
Authors: Colberg Ricardo E. , Ketchum Monte , Javer Avani , Drogosz Monika , Gomez Melissa , Fleisig Glenn S.
Published: October 2019

Background:

Plantar fasciitis is the most common cause of heel pain in adults. Multiple conservative treatment plans exist; however, some cases do not obtain significant clinical improvement with conservative treatment and require further intervention. This retrospective case study evaluated the success rate of percutaneous plantar fasciotomy and confounding comorbidities that negatively affect outcomes.

Methods:

A series of 41 patients treated with percutaneous plantar fasciotomy using the Topaz EZ microdebrider coblation wand were invited to participate in this retrospective follow-up study, and 88% ( N = 36) participated. A limited chart review was completed and the patients answered a survey with the visual analog scale (VAS) for pain and the Foot and Ankle Ability Measure (FAAM) questionnaire. Average outcomes were calculated and 45 variables were analyzed to determine if they were statistically significant confounders. Patients had symptoms for an average of 3 years before the procedure and were contacted for follow-up at an average of 14 months after the procedure.

Results:

The average VAS for pain score was 1.3 ± 1.8 and the average FAAM score was 92 ± 15. Eighty-nine percent of patients had a successful outcome, defined as FAAM greater than 75. In addition, patients at 18 months postprocedure reported complete or near-complete resolution of symptoms with an FAAM score greater than 97. Concurrent foot pathologies (eg, tarsal tunnel syndrome), oral steroid treatment prior to the procedure, and immobilization with a boot prior to the procedure were statistically significant negative confounders ( P < .05). Being an athlete was a positive confounder ( P = .02).

Conclusion:

Percutaneous plantar fasciotomy using a microdebrider coblation was an effective treatment for plantar fasciitis, particularly without concurrent foot pathology, with a low risk of complications.

Level of Evidence:

Level IV, retrospective case series.
Are Negative Parental Attributions Predicted by Situational Stress?: From a Theoretical Assumption Toward an Experimental Answer
Authors: Beckerman Marieke , van Berkel Sheila R. , Mesman Judi , Huffmeijer Rens , Alink Lenneke R. A.
Published: October 2019

In an experimental within-subjects research design, we studied the theoretical assumption that stress predicts negative parental attributions, which until now was mainly studied using cross-sectional study designs. During home visits to 105 families, mothers and fathers were subjected to two experimental conditions and two control conditions. In the experimental conditions, parents completed the Parental Attributions of Child behavior Task (PACT, a computerized attribution task) under two different stressful conditions (i.e., cognitive load and white noise); in the control conditions, the PACT was completed without additional stressors. Furthermore, parents completed questionnaires about existing risk factors (i.e., partner-related stress, parenting stress, and abuse risk). There were no main effects of induced stress on attributions for fathers and mothers, but we found that a combination of induced situational stress (cognitive load) and high risk resulted in the most negative parental attributions in mothers. The discussion focuses on intensity and origin of stressors, comparison between mother and father attributions, implications for interventions, and possible future research directions.
A patient’s decision aid for vascular access placement in the emergency department
Authors: Obadeyi Oluseyi , Baffoe Nana , Paxton James
Published: October 2019

Background:

Vascular access device placement is one of the most routinely performed procedures in the emergency department. Despite its high usage, most patients have limited knowledge about vascular access device placement. Patient decision aids have been utilized heavily in non-emergency department settings to provide basic clinical information regarding a patient’s medical care options. In this study, we investigated whether exposure to a patient decision aid on vascular access devices and patients’ experiences with vascular access devices would influence their vascular access device preference during an acute care episode.

Methods:

Patients in this institutional review board–approved study were enrolled prospectively in the emergency department at a busy level 1 trauma institution. A patient decision aid on vascular access device was constructed using criteria developed by the International Patient Decision Aid Standards. All participants were exposed to the patient decision aid and were asked to complete two questionnaires, and two tests.

Results:

Fifty subjects (50) were enrolled prospectively in the emergency department. The mean pretest score was 17.2% (95% confidence interval, 0.54–1.18), while the mean post-test score was 72.4% (95% confidence interval, 3.15–4.09). We found that patients who were exposed to the patient decision aid preferred landmark-based peripheral intravenous lines over ultrasound-guided peripheral intravenous lines in this data set.

Conclusion:

The result from this analysis indicated that most patients visiting the emergency department are not knowledgeable about their options related to vascular access device placement. The observed increase in the average correct responses on the post-test indicates that a patient decision aid can be an effective educational tool in the emergency department.
Pertuzumab and Trastuzumab Emtansine for Human Epidermal Growth Factor Receptor-2–Positive Metastatic Breast Cancer: Contemporary Population-Based Outcomes
Authors: Lupichuk Sasha , Cheung Winson Y , Stewart Douglas
Published: October 2019

Background:

Real-world outcomes for patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) treated with pertuzumab in combination with taxane chemotherapy plus trastuzumab (TaxTP) in the first line setting and trastuzumab emtansine (TE) in any line of treatment are lacking.

Methods:

Cohorts of patients treated with (1) TaxTP and (2) TE from January 1, 2013 through December 31, 2016 were retrospectively obtained from a population-based database. Cohorts were described according to age, hormone receptor (HR) status, prior systemic therapies, event-free survival (EFS) defined as time from start of treatment to start of next line of treatment or death, and overall survival (OS).

Results:

A total of 122 patients were treated with TaxTP and 104 with TE. In the TaxTP cohort, EFS was significantly longer in the trastuzumab-naïve group compared with the adjuvant trastuzumab group (median EFS = 27.0 vs 12.4 months; P = .002). In the TaxTP cohort, median OS was not reached. In the TE cohort, EFS was significantly longer in the pertuzumab-naïve group compared with pertuzumab-exposed group (median time to treatment failure [TTF] = 18.7 vs 5.5 months; P < .001). Overall survival was also significantly longer in the pertuzumab-naïve group compared with the pertuzumab-exposed group (median OS = 23.2 vs 14.1 months; P = .022). In multivariable analyses, adjuvant trastuzumab and prior pertuzumab exposure in the metastatic setting remained significant predictors of inferior EFS for patients treated with TaxTP and TE, respectively.

Conclusions:

New anti-HER2 therapies appear to be clinically relevant in the real-world.
A psychoanalytic probe into Academic Othering of the United States: Defenses of splitting and projection, consequences, and alternatives through emotion work
Authors: Ulus Eda
Published: October 2019

For this Special Paper Series of Organization, I work with a psychoanalytic perspective to scrutinize organizing processes as critical academics—specifically, unconscious dynamics of responding to US-based social crises. I contend that it is not feasible to organize effectively against the violent hate of right-wing populist movements sustained by Othering without commitment to confronting academics’ individual and collective Othering and defensive processes. These defenses include splitting and projecting onto convenient Others, which can serve performative gratifications. Through analysis of critical academic declarations in 2017, I analyze Academic Othering of the United States. Splitting the United States off as the ‘bad’ Other of the ‘good’ United Kingdom/European Union/non-United States undermines critical analysis and potential for solidarity and relational concern. Without probing these uncomfortable dynamics, we damage opportunities as elite, privileged academics to make a difference for global struggles, and collude in exclusion. Undertaking emotion work on our academic identities to move away from the defense of splitting, and toward nuance with Klein’s depressive position, will support listening to affected voices and extending—not merely performing—concern and care.
Exploring the role of language proficiency and cultural adaptation in travel risk perception: A study of Asian working holiday makers in Australia
Authors: Nagai Hayato , Tkaczynski Aaron , Benckendorff Pierre J
Published: October 2019

The perceived risk associated with international travel is frequently acknowledged as having a major influence on tourist behaviour. However, the influence of language proficiency and cultural adaptation on risk perception has not been well researched, especially in the context of tourists from non-English-speaking backgrounds. This study explored these influences and associations by focusing on Asian working holiday makers (WHMs) in Australia. It was found that English language proficiency and cultural adaptation were significant predictors of perceived risk. Asian WHMs who had difficulty adapting to the host culture perceived greater levels of risk. However, Asian WHMs with higher language proficiency tended to perceive greater travel risks. The findings have both theoretical and practical implications for the study of risk perceptions and the management of visitors with low language proficiency.
The cultural politics of commemoration: Media and remembrance of the Russian revolutions of 1917
Authors: Chatterje-Doody Precious N , Gillespie Marie
Published: October 2019

The year 2017 marked the centenary of the revolutions of February and October 1917 which led to the collapse of the Russian Empire. These events (and their accompanying mythologies) proved pivotal in creating a uniquely politicised approach to remembrances of revolution across and beyond the post-Soviet space. This special section uses the revolutions’ centenary as an entry point for reassessing the cultural politics of commemoration. In particular, it draws attention to the transformations in memory work brought about by an increasingly integrated global media environment, in which interactions between multiple cultural actors influence the formation of (and exclusion from) cultural memory. These diffuse memory-making processes influence contemporary political and social developments within and beyond the societies in question. The articles presented in this special section interrogate how Russian and international media represented the revolutions, both for their domestic and international audiences. Together, they address questions about what regime-sponsored narratives of the Russian revolutions of 1917 can tell us about contemporary neo-authoritarian politics of identity, history and memory; the cultural significance of real-time, interactive media events for ‘memory work’, and for the participatory re-creation of revolutionary ideas and passions; the ways in which TV audiences and social media users of different generations and political persuasions respond to and interact with representations of revolution; and the nature of the relationship between cultural politics, memory and newsmaking. In bringing into dialogue work from a variety of disciplines and with a range of methodological approaches, the articles in this special section interrogate the fundamentals of the relationship between culture, media and politics in today’s globalised real-time media ecology.
Indonesian Faculty Barriers in Providing Help to College Students in Distress
Authors: Putri Adelia Khrisna , Yahya Anna Nadia Febrina , Saputra Axel Rizqy
Published: October 2019

Colleges are experiencing a surge of students in distress, particularly those with suicidal and self-harm tendencies. Despite numerous researchers having explored this phenomenon, very little action has been taken to address this issue at the university level, indicating the existence of inhibitory factors that have not yet been explored. The purpose of this study is to explore barriers that inhibit Indonesian faculty members from providing help to distressed college students. As many as 173 academic faculty members from 72 universities across Indonesia participated in this exploratory study by completing an online self-reported survey. Free text responses were thematically analyzed to provide information about the challenges that faculty members face. The findings were categorized into three main themes: lack of mental health information, unclear professional boundaries, and lack of institutional support. Further implications of the study will be discussed.
Rs1982809 is a functional biomarker for the prognosis of severe post-traumatic sepsis and MODs
Authors: Gan Lebin , Hu Chen , Deng Zhihong , Lu Hongxiang , Sun Jiali , Peng Guoxuan , Jiang Jianxin , Zeng Ling , Deng Jin
Published: October 2019

BTLA is a useful biomarker to characterize the immune states of sepsis patients. We investigated the association between genetic variations of BTLA and morbidity of sepsis and MODS in severe traumatic patient. Three tag single nucleotide polymorphisms of BTLA were genotyped in 562 severe trauma patients. To further elucidate the mechanism, mRNA stability, BTLA 3ʹ-UTR activity, and its expression on T lymphocytes were measured. Only rs1982809 which located in 3ʹ-UTR of BTLA showed a significant clinical relevance with the incidence rate of sepsis and MOD scores. The sepsis incidence and MOD score of rs1982809 CC genotype carriers were higher than TT carriers. The percentage of circulating BTLA + CD4 + CD3 +  T lymphocytes was markedly lower in CC genotype carriers. Luciferase activity in plasmids containing C allele was lower than that of T allele. Thus, the differential expression of BTLA on T lymphocytes might be caused by the different 3ʹ-UTR activity induced by rs1982809 T/C. Therefore, rs1982809 is a useful clinical biomarker in the prognosis evaluating of sepsis and subsequent MODS. Moreover, it is also a functional single nucleotide polymorphism affecting the activity of BTLA 3ʹ-UTR and the expression of BTLA in peripheral blood T lymphocytes.

Impact statement

This work is useful in the field of genetic mechanism of severe post-traumatic complications, as it provides important evidence for the influence of BTLA gene polymorphism on sepsis and MODS susceptibility. The results are useful and of importance because rs1982809 is a useful clinical biomarker in the prognosis evaluating of sepsis and subsequent MODS. It is also a functional single nucleotide polymorphism affecting the activity of BTLA 3ʹ-UTR and the expression of BTLA in peripheral blood T lymphocytes.
Structure and development of single domain antibodies as modules for therapeutics and diagnostics
Authors: Hoey Robert J , Eom Hyeyoung , Horn James R
Published: October 2019

Since their discovery just over 25 years ago, the single variable domain from heavy-chain-only antibodies plays a role in an increasing number of antibody-based applications. Structural and biophysical studies have revealed that the small, ∼15 kDa, single variable domain found in camelids displays versatility in target recognition. Such insight has served as the foundation to develop and engineer VHH domains with enhanced properties capable of targeting a range of therapeutically relevant protein antigens or low-molecular weight haptens. Furthermore, the modular nature of VHH domains allows them to be introduced into constructs that are simply not possible with conventional antibodies. Here, we review the structural and biophysical properties of VHH domains, highlight recent VHH-based therapeutics and diagnostics, and provide insight into VHH engineering that may pave the way to next-generation single domain antibody applications.

Impact statement

The development of novel antibody formats, beyond conventional antibodies, opens new possibilities in medical therapies, diagnostics, and general life science applications requiring affinity reagents. The camelid VHH domain, from heavy-chain-only antibodies, has emerged as a jack-of-all-trades module for novel affinity reagents. Applications include targeted cancer therapies, novel antimicrobial agents, conformation specific reagents, and tailor-made molecular switch entities. The breadth of unique uses for the VHH will continue to grow, opening new opportunities to treat and understand disease.
Exploring aspects of the cognitive behavioural model of physical hoarding in relation to digital hoarding behaviours
Authors: Thorpe Susan , Bolster Alexander , Neave Nick
Published: October 2019

While the hoarding of physical objects has been extensively explored, there is little research relating to the hoarding of digital materials. The research that has been conducted suggests that digital hoarding (DH) behaviours appear to have some similarities with physical hoarding (PH) behaviours, and can be just as psychologically distressing. This study uses the framework of the cognitive behavioural model of PH to explore DH behaviours, including possible similarities regarding emotional attachment to digital possessions, and possible links with Obsessive Compulsive Disorder (OCD) and indecisiveness. For the study, 282 participants completed an online survey which measured levels of digital and physical hoarding, compulsive acquisition, OCD, indecisiveness and mood. Strong emotional attachments to particular types of digital possessions were evident: this was especially true for photographs and videos. Significant positive relationships were found between all the variables measured. However, a regression analysis revealed that only OCD and PH scores were significant predictors of DH. DH thus appears to share some of the features of PH. Implications, limitations and future research possibilities are discussed.
Evaluation of a Novel Wellness Assessment Device (Preventiometer): A Feasibility Pilot Study
Authors: Nanda Sanjeev , Mahapatra Saswati , Lindeen Stephanie A , Bernau Joleen L , Cutshall Susanne M , Schierwater Bernd , Chon Tony Y , Wahner-Roedler Dietlind L , Bauer Brent A
Published: October 2019

Background

Periodic wellness assessments can provide an estimate of a person’s relative risks for major diseases, but wellness visits are underused. Our suggestion is to use a comprehensive device during a single visit.

Objective

The goal of this pilot study was to evaluate the feasibility of a novel one-stop wellness device (Preventiometer; iPEx5 GmbH, Greifswald, Germany) for performing multiple tests and providing a comprehensive wellness assessment in a short period.

Methods

A Preventiometer was used to provide wellness assessments for 10 healthy volunteers who then answered a 25-question survey to rate their satisfaction with the testing and their overall impression.

Results

All volunteers agreed or strongly agreed with the following: The assessment reports were easy to understand, the Preventiometer met their satisfaction, the participants were comfortable during the assessment, and all measurements and testing were well coordinated. Participants liked the instant test result feature. Most (90%) agreed that the machine was useful for a quick health assessment for busy people, and 70% felt that it was time efficient.

Conclusion

In this feasibility pilot study, the Preventiometer performed multiple tasks and provided a comprehensive wellness assessment in a short period. Participants reported remarkably high satisfaction with the tests. A larger study is needed to prove that this is a pragmatic approach to help individuals improve their health.
Economic geography and the scaling of urban and regional income in India
Authors: Sahasranaman Anand , Bettencourt Luís MA
Published: October 2019

We undertake an exploration of the economic income (gross domestic product) of Indian districts and cities based on scaling analyses of the dependence of these quantities on associated population size. Scaling analysis provides a straightforward method for the identification of network effects in socioeconomic organization, which are the tell-tale signs of cities and urbanization. For districts, a sub-state regional administrative division in India comprising both urban and rural regions, we find almost linear scaling of gross domestic product with population, a result quite different from urban functional units in other national contexts. Using deviations from scaling, we explore the behaviour of these regional units to find strong distinct geographic patterns of economic behaviour. We characterize these patterns in detail and connect them to the literature on regional economic development for a diverse subcontinental nation such as India. Given the paucity of economic data for urban agglomerations in India, we use a set of assumptions to create a new dataset of gross domestic product based on districts, for large cities. This reveals superlinear scaling of income with city size, as expected from theory, while displaying similar underlying patterns of economic geography observed for district economic performance. This analysis of the economic performance of Indian cities is severely limited by the absence of higher-fidelity, direct city level economic data. We discuss the need for standardized and consistent estimates of the size and change in urban economies in India, and point to a number of proxies that can be explored to develop such indicators.
Removal of Normal Competition Increases Proliferation of Pre-Leukemic Cells in a Mouse Model of Pre-B Acute Lymphoblastic Leukemia.
Authors: Reid Gregor SD , Barrett David , Seif Alix Eden , Brown Valerie I. , Grupp Stephan A.
Published: October 2019

Abstract 1430

Poster Board I-453

B cell precursor (BCP) acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. While the peak age of onset for this disease is 4 years, abnormal cells that will eventually give rise to disease can be detected in blood taken from patients at birth. Interestingly, similar abnormal cell populations can also be detected in blood taken at birth from many children who do not go onto develop ALL. Understanding the factors that influence the survival and expansion or elimination of these abnormal pre-leukemic cells will shed light on the process of leukemogenesis and may suggest strategies for the prevention of BCP-ALL progression. We have used a mouse model of BCP-ALL to investigate the influence of normal immune cells on the pre-leukemic population. An abnormal BCP population arises in Eμ-RET (RFP) transgenic mice during fetal development, with overt leukemia developing between 3 and 9 months of age. We show that purified BCP from bone marrow of 4-week old pre-leukemic RFP mice undergo rapid expansion when adoptively transferred into immune-deficient mice, in many cases reaching white blood cell counts of >105 (with >90% showing the abnormal BCP phenotype). Secondary and tertiary transfer of expanded BCP into immune-deficient mice again produced a severe BCP lymphoproliferative disease. Such an expansion was not observed when purified BCP were transferred into wild-type mice or when unsorted pre-leukemic RFP bone marrow was transferred into immune-deficient mice. In addition, outgrowth of the abnormal cells was significantly curtailed if the purified RFP cells were mixed with a tenfold excess of wild-type bone marrow cells prior to adoptive transfer. This inhibition of BCP outgrowth was not achieved with Rag1-deficient bone marrow cells, suggesting that competition with normal adaptive immune cells for limited growth factors may impair the expansion of RFP pre-leukemic cells. Consistent with this hypothesis, blockade of the IL-7 receptor on pre-leukemic cells abrogated their expansion following adoptive transfer. As production of IL-7 is elevated in lymphopenic settings, we evaluated the impact of T cell-depletion on pre-leukemic cells in RFP mice. Pre-leukemic cell populations were significantly elevated in the spleen (31.3% +/- 15.4 vs 9% +/- 9, p<0.01) and blood (17% +/-19.2 vs 3% +/- 4.8, p<0.05) of T cell-depleted mice compared to controls. Taken together, these results suggest that competition for growth factors such as IL-7 may be a limiting step in the early expansion of pre-leukemic cell populations and may provide a mechanistic link between immune responses and pediatric ALL through the cytokine-mediated expansion of the pre-leukemic cell pool.

Disclosures

No relevant conflicts of interest to declare.
Purinergic Signaling Modulates Human Bone Marrow-Derived Mesenchymal Stem Cells Function.
Authors: Salvestrini Valentina , Ferrari Davide , Gulinelli Sara , Caione Luisa , Piacibello Wanda , Zini Roberta , Ciciarello Marilena , Manfredini Rossella , Lucchetti Giovanna , Ferrari Sergio , Virgilio Francesco Di , Lemoli Roberto M
Published: October 2019

Abstract 1441

Poster Board I-464

Nucleotides triphosphates are extracellular messengers binding to specific plasma membrane receptors (P2Rs) modulating a wide variety of biological responses in several cell types. In this study, we show that bone marrow-derived human mesenchymal stem cells (hMSCs) express several functional P2R subtypes at the molecular and protein level. hMSCs are very resistant to the cytotoxic effects of high concentrations of extracellular ATP, as demonstrated by the lack of morphological and mitochondrial changes or release of intracellular markers of cell death. Gene expression profiling revealed that hMSCs stimulated with ATP underwent a down-regulation of genes involved in cell proliferation, whereas those involved in cell migration were strongly up-regulated. Functional studies confirmed the inhibitory activity of ATP on proliferation of hMSCs and clonogenic stromal progenitors. Furthermore, ATP potentiated the chemotactic response of hMSCs to the chemokine CXCL12, and increased their spontaneous migration. In vivo, xenotransplant experiments demonstrated that the homing capacity of hMSCs to murine bone marrow was significantly increased by pre-treatment with ATP. Moreover ATP increased the production of the pro-inflammatory cytokines IL-2, IFN-gamma, and IL-12p70, while decreasing the anti-inflammatory cytokine IL-10. Thus, our data show that purinergic signaling modulates hMSCs functions and highlight a role for extracellular nucleotides in hMSCs biology.

Disclosures

Di Virgilio: F. Di Virgilio serves as a consultant for Cordex Pharma Inc. (USA) involved in the development of “P2 receptor-based drugs”. : Consultancy; F. Di Virgilio serves as a consultant for Affectis Pharmaceuticals AG (Germany), involved in the development of “P2 receptor-based drugs”. : Consultancy.
Stress Response Gadd45a Gene as Tumor Suppressor in MYC Expressing Myeloid Cells Is Cytokine Specific.
Authors: Mohamed-Hadley Alisha A , Liebermann Dan A. , Hoffman Barbara
Published: October 2019

Abstract 1481

Poster Board I-504

MYC, which regulates proliferation, apoptosis/survival and differentiation, is implicated in the etiology of a wide variety of hematologic malignancies. Multiple cooperating molecular pathways of cell survival and apoptosis determine if a cell lives or dies, and understanding how c-MYC interfaces with these pathways to influence the survival of cells is important to understand tumor initiation and progression, and response of tumors to different treatment regimens. Previously, this laboratory has shown that deregulated c-MYC blocks terminal myeloid differentiation and prematurely recruits both the Type I and Type II CD95/Fas apoptotic pathways, promoting an incompletely penetrant apoptotic response (Amanullah et al., Oncogene 19:2967-77, 2000; Amanullah et al., Oncogene 21;1600-10, 2002). Here we provide data to show that the response of myeloid cells to deregulated MYC expression depends on the status of the Gadd45 family of stress response genes. The gadd45 gene family plays pivotal roles as stress sensors that modulate signaling in response to physiological and environmental stressors, also modulating susceptibility of cells for transformation in vitro and tumor development in vivo. Gadd45 behaves as either tumor suppressor or oncogene depending upon the transforming oncogene and the cell type (Tront et al., Cancer Research 66:8448-54, 2006; Tront et al., manuscript in press). To elucidate the role Gadd45a plays in response to the proto-oncogene c-MYC in myeloid cells, bone marrow (BM) cells from wild type (WT) and Gadd45a null mice were retrovirally infected to constitutively express c-MYC. We showed that Gadd45a null BM expressing constitutive c-MYC exhibited less apoptosis than its WT counterpart in expansion media (IL-3, IL-6, SCF), demonstrating that Gadd45a is required for optimal MYC mediated apoptosis. In addition, enhancement of cell cycle progression was observed. Therefore, loss of gadd45a in conjunction with constitutive MYC expression results in enhanced proliferation. Furthermore, in GM-CSF treated cells the MYC–mediated block/delay in differentiation was more extensive in the Gadd45a null cells compared to similarly treated WT cells. Interestingly, the percent of apoptosis was higher in the Gadd54a null cells expressing constitutive MYC as compared to the WT counterpart. This observation was in contrast to the results seen in expansion media, suggesting that the role Gadd45a plays in the presence of deregulated MYC may be cytokine specific. Data will be presented to explain how gadd45 regulates both the apoptotic response, depending upon the specific cytokine, and differentiation of MYC-expressing myeloid cells. Furthermore, experiments to determine how loss of gadd45a influences MYC-mediated leukemia, including assessing the effect of manipulating the cytokine milieu, are currently underway.

Disclosures:

No relevant conflicts of interest to declare.
Antioxidant Defense to Hemolysis Is Organ-Specific and Reflects a Heterogeneity in Vascular Permeability in Sickle Cell Disease.
Authors: Ghosh Samit , Adisa Olufolake , Tan Fang , Ofori-Acquah Solomon F
Published: October 2019

Abstract 1537

Poster Board I-560

Sickle cell disease (SCD) is characterized by intravascular hemolysis generating cell-free hemoglobin at concentrations that exceed the scavenging capabilities of heme-binding plasma proteins. Heme is a major source of oxidative stress, which is widely known to increase vascular permeability and cause tissue edema. Barrier disruptive effects of oxidative stress can however be counterbalanced by adaptive antioxidant defenses. Hitherto, the identity of specific antioxidant enzymes and cognate mechanisms protecting individual organs from oxidative stress in SCD remains poorly defined. In this study, microarray analysis was performed using non-toxic concentrations of hemin to analyze mechanisms of antioxidant defense by the endothelium. Multiple candidate antioxidant enzymes were identified each differentially elevated in several major organs in anemic SCD mice compared to non-anemic heterozygote and hemizygote littermates. Remarkably, none of the antioxidants was elevated in the brain of sickle mice. Moreover, the antioxidant phenotype in the kidney, spleen and liver of sickle mice were predominantly acute while the sickle lung was characterized by a predominantly chronic antioxidant phenotype. This latter finding was confirmed in SCD patients with chronic lung disease. Antioxidant enzyme activity was significantly higher in the lungs of adult sickle mice aged 3-6 months than in younger mice aged 4-6 weeks (p=0.004). However, this enhanced antioxidant activity declined significantly in middle-age mice 11-13 months old (p=0.005). Vascular permeability assessed by extravsasation of Evans blue dye was normal in the brain of sickle mice of all ages in agreement with our data indicating absence of oxidative stress in this organ. On the contrary, vascular permeability in the lung, kidney and heart of adult sickle mice was abnormally high. This abnormality deteriorated significantly exclusively in the lung (p= 0.04) but not in the heart or kidney in middle-age mice. Increased lung permeability in middle-age sickle mice was confirmed by overt tissue edema determined by lung wet/dry weight ratios. Our study has shown for the first time that the antioxidant response to the systemic chronic hemolysis of SCD is organ-specific. Furthermore, we have identified decline of antioxidant reserve concomitant with tissue edema as potential age-dependant risk factors for fatal lung complications in SCD. Finally, our data provide a framework to develop targeted antioxidant therapies to preserve organ function in SCD.

Disclosures

No relevant conflicts of interest to declare.
Lipoprotein Cholesterol and Triglyceride in Children with Steady-State Sickle Cell Disease.
Authors: Seixas Magda Oliveira , Rocha Larissa , Carvalho Mauricio , Menezes Joelma , Lyra Isa , Nascimento Valma , Couto Ricardo , Atta Ajax , Reis Mitermayer Galvão , Goncalves Marilda Souza
Published: October 2019

Abstract 1547

Poster Board I-570

Introduction

Levels of high-density lipoprotein cholesterol have been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities. We hypothesized that lipoprotein cholesterol and triglycerides have important roles in sickle cell disease pathogenesis.

Patients and Methods

A prospective study of biochemical and hematological analyses of 152 steady-state children with sickle cell disease and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records. Data analyses were performed using Prism 5.01 (Graphpad Software, San Diego, CA), EPIinfo 6.04 (CDC, Atlanta, Georgia) and STATA SE 10 software (StataCorp, Texas, USA).

Results

There was a significant positive association of high-density lipoprotein cholesterol with hemoglobin (p<0.001), hematocrit (p<0.001) and total cholesterol (p<0.001) and a negative association with reticulocytes (p=0.046), leukocytes (p=0.015), monocytes (p=0.004) and platelets (p=0.005), bilirubins [total bilirubin (p<0.001), direct bilirubin (p<0.001) and indirect bilirubin (p<0.001], iron (p<0.001), aminotransferases [aspartate aminotransferase (p=0.004), alanine aminotransferase (p=0.035)], lactate dehydrogenase (p<0.001), urea (p=0.030), alpha 1-antitrypsin (p<0.001), very low-density lipoprotein cholesterol (p=0.003), triglycerides (p=0.005) and hemoglobin S (p=0.002). Low high-density lipoprotein cholesterol concentration was associated with cardiac abnormalities (p<0.025), pneumonia history (p=0.033) and blood transfusion use (p=0.025). Triglycerides (p=0.047), very low-density lipoprotein cholesterol (p=0.044), low-density lipoprotein cholesterol (p=0.033), total cholesterol (p=0.007), alpha 1-antitrypsin (p=0.040) and ferritin (p=0.008) levels were associated with cholelithiasis.

Conclusion

We hypothesize that some SCD patients can have a specific dyslipidemic subphenotype characterized by hypertriglyceridemia, high VLDL-C and low plasma LDL-C and HDL-C in association with other biomarkers, including those related to inflammation. This represents an important step toward a more reliable clinical prognosis. We suggest further studies and continued research into new mechanisms involving this complex network of markers in order to establish their role in SCD pathogenesis.

Disclosures

No relevant conflicts of interest to declare.
FLT3, NPM1 and MLL Mutations Help Risk Stratification in Pediatric Acute Myeloid Leukemia.
Authors: Shen Shuhong , Liu Yin , Tang JingYan , Gu Long-Jun
Published: October 2019

Abstract 1574

Poster Board I-600

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease which harbors various genetic alterations. Among theses genetic events, Mutations of FLT3, NPM1, MLL and other genes often predict prognosis, particularly in cases cytogenetic normal (CN-AML). Could these be criteria for risk stratification in Pediatric AML ?

Patients and Methods

155 cases of de novo AML were diagnosed routinely according to morphology, immunology, cytogenetics, and molecular biology examination on bone marrow (BM) aspirates between Jan. 2002 and Dec. 2008. All patients received chemotherapy according to the AML-XH-99 protocol, which consist of Daunorubicin, Cytosine arabinoside, Etoposide, Homoharringtonine. For acute promyelocytic leukemia, all-trans retinoic acid and Arsenic trioxide were also included. Meanwhile, total RNA of leukemic cells form all diagnostic BM samples were extracted, and then reverse transcribed. MLL partial tandem duplication (MLL/PTD) fusion transcripts were screened by real-time quantitative polymerase chain reaction. FLT3 internal tandem duplication (FLT3/ITD), FLT3 tyrosine kinase domain mutation (FLT3/TKD) and NPM1 mutation were examined by High resolution melting analysis.

Results

Of the 155 children with de novo AML, 121(78.1%) had received chemotherapy for more than one week with data available for analysis. Among them, 55(45.5%) was cytogenetically normal (CN-AML). In this total cohort of patients 49(27.09%) had FLT3/ITD (32.70% in CN-AML), 14 (9.03%) had FLT3/TKD (7.30% in CN-AML), 62 (40%) had NPM1 mutation (49% in CN-AML), and additional 8 (5.16%) had MLL/PTD (5.50% in CN-AML). In this cohort of patients 98 (63.22%) had at least one mutation. The clinical outcomes were listed in table 1. Generally, patients with FLT3 mutation (ITD or TKD mutation) usually have worse results after chemotherapy, as reported previously by other researchers. Meanwhile, NPM1 mutations usually predict better prognosis in our cohort of AML patients. MLL/PTD always predicts the worst outcome in AML as other MLL rearrangements in leukemia. Among CN-AML patients, 5-year EFS and OS were similar to whole cohort of patients according to those mutations. Cox regression analysis in a univariate model revealed that the presence of FLT3/ITD and NPM1 was significant prognostic factor of EFS, (P<0.05). We therefore proposed a molecular-risk classification of pediatric AML patients based on the data we got in this study. For the newly classified groups of low, medium and high risk groups, EFS rate was 62.03%±8.42%, 45.42%±4.52%, and 14.85%±2.99%, respectively, P=0.00. CRD for the 3 groups was 27.69±21.34 months, 22.62±19.64 months, 13.26±11.95 months, respectively, p=.022. Our results indicate that combinations of these couple of molecular events may be the useful tool for further classify AML in children.

Disclosures

No relevant conflicts of interest to declare.
Inhibition of STAT5 by IL-1β or the Inhibitor of Janus Kinases Stimulates Dormant Human Leukemia Stem Cells and Sensitizes Them to Anti-Leukemia Agents.
Authors: Ikezoe Takayuki , Jing Yang , Nishioka Chie , Kojima Shinsuke , Takeuchi Asako , Yokoyama Akihito
Published: October 2019

Abstract 1597

Poster Board I-623

Leukemia stem cells (LSCs) are in a quiescent state, which maybe contributes to their drug-resistant character. It is essential to eradicate LSCs to develop curative therapy for leukemia. To verify molecular mechanisms by which LSCs maintain a dormant state, we examined the activity of the major pro-survival signal pathways in LSCs (CD34+/CD38- compartment) and non-LSCs (CD34+/CD38+ compartment) counterparts from patients with acute myelogenous leukemia (AML, n=3) and acute lymphoblastic leukemia (ALL, n=1) by FACS. Interestingly, LSCs compartment expressed a greater amount of the phosphorylated forms of STAT5 (p-STAT5) than non-LSCs counterparts in all patients. Further studies found that levels of interleukin-1b (IL-1b) were significantly down-regulated in LSCs compared with non-LSCs (p<0.05) and normal hematopoietic stem cells (p<0.01), as measured by real-time RT-PCR. Importantly, exposure of LSCs to IL-1b (50 ng/ml) dephosphorylated STAT5 and decreased the population of cells in a dormant state, as assessed by cell cycle analysis. In addition, blockade of JAK2/STAT5 signaling by the specific JAK2 inhibitor AZ960 stimulated cell-cycling in LSCs in conjunction with down-regulation of cyclin-dependent kinase inhibitor p21waf1. As expected, IL-1b and AZ960 sensitized LSCs to cytarabine and the inhibitor of the FLT3 kinase, as assessed by clonogenic assay. Moreover, this study found that LSCs expressed a greater amount of anti-apoptotic protein Bcl-xL than non-LSCs counterparts. Exposure of LSCs to AZ960 potently induced apoptosis in parallel with down-regulation of Bcl-xL, as assessed by induction of the cleaved forms of PARP. Taken together, JAK2/STAT5 signaling may be a promising molecular target to eradicate LSCs in individuals with AML and ALL.

Disclosures

No relevant conflicts of interest to declare.
Baseline Serum Ferritin Predicts Rate of Infection in Patients with Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome.
Authors: Mattiuzzi Gloria , Amin Hesham M. , Kantarjian Hagop , Garcia-Manero Guillermo , Cortes Jorge
Published: October 2019

Abstract 1611

Poster Board I-637

Excess iron adversely affects the phagocytic, chemotactic and bactericidal activities of neutrophils and monocytes; inhibits the activity of natural killer cells and macrophages, and enhances the ability of microbes to grow in various host tissues. Iron overload has also been described to be an important risk factor for the development of mucormycosis. Serum ferritin is a surrogate marker of iron overload. Studies in recipients of bone marrow transplantation showed that elevated pre-transplant serum ferritin levels (as markers of iron overload) were associated with a high incidence of infection-related mortality.

Objective

1) To evaluate iron overload as a predictor of infection in patients with acute myelogenous leukemia (AML) or high risk myelodysplastic syndrome (HR-MDS) undergoing chemotherapy (CHEMO); 2) to compare baseline bone marrow iron stores (BMIS) versus baseline serum ferritin as predictor of infections.

Methods

Patients with AML or HR-MDS who underwent induction or first salvage CHEMO were included in this prospective observational study. BMIS was analyzed at baseline (prior CHEMO) in bone marrow aspirate smears by standard staining techniques. BMIS was evaluated using a light microscope and graded on a scale of 0 to 6, with a score of 1 to 3 considered normal. Serum ferritin levels were measured at baseline. Invasive fungal infections (IFI) were defined as probable or proven according to the EORTC-MSG criteria. Bacterial infections were defined by the presence of fever and positive culture from a sterile site. Ferritin values were considered normal if they fell in the range of 10ng/mL – 291ng/mL.

Results

112 patients were evaluated. Median age was 69 years (23-84 years) and 49% were female; 97% received induction CHEMO for AML. Forty–six patients developed at least one infectious episode from day 1 of chemotherapy until chemotherapy response was assessed (median days to response = 28). Nineteen patients developed bacterial infections, 9 patients developed fungal [2 candidiasis; 3 proven and 4 probable aspergillosis] and 18 patients had clinically but not microbiologically documented infections (cellulitis, pneumonia, neutropenic colitis). Baseline BMIS and serum ferritin were evaluable in 83 and 112 patients, respectively (Table 1).

Median baseline ferritin was significantly higher in patients who developed any infection compare to that of patients without infections (p = 0.018). In addition, patients who developed IFI had higher median baseline ferritin to those without IFI (p=0.039). There were no significant differences in the baseline BMIS between patients without infection and those who developed any infection (p= 0.94) or an IFI (p= 0.71).

Conclusions:

Disclosures

Mattiuzzi: Novartis: Research Funding.