bluuebunny/crossref_metadata_2025 huggingface dataset:
Linking Moral Identity With Moral Emotions: A Meta-Analysis
Authors: Lefebvre Jean Paul , Krettenauer Tobias
Published: October 2019

This meta-analysis examined the relationship between moral identity and moral emotions drawing on 57 independent studies. Moral identity was significantly associated with moral emotions, r = .32, p < .01, 95% confidence interval [CI: .27, .36]. Effect sizes were moderated by the type of moral emotion. Studies reporting other-regarding emotions (sympathy, empathy, and compassion) had the largest effect sizes ( r = .41), while negative other-evaluative emotions (moral anger, contempt, and disgust) had the smallest ( r = .16). Self-evaluative and other-evaluative positive emotions had intermediate effect sizes ( r values between .29 and .32). The type of emotion measure also was a significant moderator, with trait measures of emotion ( r = .38) correlating more strongly with moral identity than state measures ( r = .24). Effect sizes did not differ for the type of moral identity measure being used, publication status, or cultural origin of the study sample. The results of this meta-analysis demonstrate a robust empirical connection between moral identity and moral emotions, which confirms the multifaceted role of moral identity in moral functioning.
CoMM: A Collaborative Mixed Model That Integrates GWAS and eQTL Data Sets to Investigate the Genetic Architecture of Complex Traits
Authors: Yeung Kar-Fu , Yang Yi , Yang Can , Liu Jin
Published: October 2019

Genome-wide association study (GWAS) analyses have identified thousands of associations between genetic variants and complex traits. However, it is still a challenge to uncover the mechanisms underlying the association. With the growing availability of transcriptome data sets, it has become possible to perform statistical analyses targeted at identifying influential genes whose expression levels correlate with the phenotype. Methods such as PrediXcan and transcriptome-wide association study (TWAS) use the transcriptome data set to fit a predictive model for gene expression, with genetic variants as covariates. The gene expression levels for the GWAS data set are then ‘imputed’ using the prediction model, and the imputed expression levels are tested for their association with the phenotype. These methods fail to account for the uncertainty in the GWAS imputation step, and we propose a collaborative mixed model (CoMM) that addresses this limitation by jointly modelling the multiple analysis steps. We illustrate CoMM’s ability to identify relevant genes in the Northern Finland Birth Cohort 1966 data set and extend the model to handle the more widely available GWAS summary statistics.
‘Walking on ice’: The future of parole in a risk-obsessed society
Authors: Barry Monica
Published: October 2019

The aim of risk assessment and management in criminal justice is increasingly about minimizing opportunities to create harm to the public rather than maximizing opportunities to create change in offenders. This seems to be particularly the case in respect of parole, where the balance of public protection with rehabilitation has become increasingly unstable in prioritizing the former. This article examines parole decision making and management within the UK from the perspectives of both high risk offenders on licence and parole professionals. It discusses two key drivers to burgeoning recall rates: the stringency of licence conditions and the propensity of professionals to recall in the name of risk elimination rather than risk reduction. The article concludes that the effectiveness of parole is in question, not least in enabling re-entry and reintegration of high risk prisoners. In particular, the future sustainability of parole itself is deemed to be under threat.
Revolution from the margins: Commemorating 1917 and RT’s scandalising of the established order
Authors: Hutchings Stephen
Published: October 2019

In this article, I explore what RT’s unusually open-ended project commemorating the centenary of the Russian Revolution - #1917Live – tells us about its tendentious, mainstream output. I adopt an epistemological framework locating meaning in the marginal and different rather than the normative and recurrent, treating this ‘un-RT like’ project’s components as multi-layered cultural texts to be interpreted rather than sociological data to be counted and coded. I read them through a hermeneutically inflected version of mediatisation theory. This theory’s central precept posits a fusion of media practices with those of politics and everyday life. An under-researched corollary of that precept is a short-circuiting of the ‘subject’ and ‘object’ of media representations. As well as influencing #1917Live’s emphasis on broadcaster-audience co-production, the short-circuiting effect foregrounds the modality of those representations – their truth claims and the subjectivities attached to the realities they depict. In analysing this effect, I highlight (1) #1917Live’s chronotopic intertwining of past and present; (2) its ‘event-ness’: the sense that it constitutes a news story in its own right and (3) the ludic elements modalising its commemorative narratives by according them a distinctive ironic voice which re-establishes distance between ‘subject’ and ‘object’. Linked to a late Soviet cultural phenomenon known as ‘ stiob’, such features render #1917Live reflexive, carnivalesque and deeply dialogic, realigning it with RT’s disruptive mainstream output and constituting a new kind of ‘media event’. They indicate that RT’s scandalous, ‘pariah’ reputation is internalised within a fragmented institutional identity key to the entire ‘information war’ dynamic.
Regime legitimation, not nation-building: Media commemoration of the 1917 revolutions in Russia’s neo-authoritarian state
Authors: Chatterje-Doody Precious N , Tolz Vera
Published: October 2019

Scholars predicted that official Russian commemorations of the centenary of the 1917 revolutions would prioritise ‘reconciliation and accord’ between pro- and anti-communists. Such a frame might help construct a new post-Soviet Russian identity. Yet, in 2017, state-affiliated political and media actors gave accounts that contrasted with their previous narratives and with each other. Domestic state-aligned media were unprecedentedly negative about the revolutions’ events and enduring legacies, while Russia’s international broadcaster, Russia Today, emphasised the revolutions’ positive international legacies. We explain this paradox by arguing that regimes of commemoration are directly related to political systems: in neo-authoritarian regimes such as contemporary Russia, history is not used primarily for nation-building, but to build legitimacy for the ruling regime. Referencing similar practices in other neo-authoritarian regimes, we show how state-affiliated actors selectively co-opt interpretations of historical events that circulate in the global media ecology, to ‘arrest’ the ‘memory of the multitude’. Simultaneously, they reinforce core messages that legitimise the existing government.
Evaluating the factors that influence cloud technology adoption—comparative case analysis of health and non-health sectors: A systematic review
Authors: Sadoughi Farahnaz , Ali Omar , Erfannia Leila
Published: October 2019

Cloud technology has brought great benefits to the health industry, including enabling improvement in the quality of services. The objective of this review study is to investigate the reported factors affecting the adoption of cloud in the health sector by comparing studies in the health and non-health sectors. This article is a systematized review of studies conducted in 2018. From 541 articles, 47 final articles were selected and classified into two categories: health and non-health studies; conclusions were drawn from the two sectors by comparing their effective factors. Based on the results of this review, the factors were categorized as technological, organizational, environmental, and individual. The results of this review study could be a beneficial guide to the health empirical research on cloud adoption. Individual domains have not been examined in health sector studies. Since the process of adoption of new technologies in organizations is time-consuming, due to the lack of managerial knowledge about the efficient factors, recognition of these factors by decision-makers while planning for cloud adoption becomes of great importance. The findings of this review study aim to help health decision-makers by increasing their awareness of the cloud and of the factors that impact decisions at both the organizational and individual levels.
The social life of screenshots: the power of visibility in teen friendship groups
Authors: Jaynes Victoria
Published: October 2019

Taking a screenshot, an exact duplication of the content on the screen of a device, is a taken-for-granted practice. Through an analysis of ethnographic data, this article considers the everyday use of screenshots among teenagers. I examine the taking, possession, and circulation of screenshots among teens to ask: What is screenshot? What function do they have? and How are screenshots significant beyond teens? The article draws attention to the ‘social life’ that screenshots have beyond their duplicative function. Screenshots were framed by teens as an everyday aspect of digital communication that are integral to negotiating hierarchies of friendship, power, and for establishing peer trust. This article takes screenshots seriously in their own right, drawing on existing insights from feminist media studies to demonstrate how the visibility afforded by screenshots is gendered in practice. This article explores screenshots as powerful communicative tools and as a socio-cultural phenomenon worthy of further interrogation.
Patterns of media coverage repeated in online abuse on high-profile criminal cases
Authors: Are Carolina
Published: October 2019

What relationship do the mainstream media have with online abuse on high-profile criminal cases? This article hopes to make a start at answering this question by examining tweets containing the #McCann hashtag, utilised by a highly engaged community of users to comment on all matters related to the disappearance of British child Madeleine McCann. On #McCann, the child’s parents and other players are often singled out as the perpetrators of her disappearance and other crimes, in a blend of harassment, defamation and insults with conspiracy theories, disinformation and a strong anti-establishment vein typical of the posttruth era. Through an experimental digital ethnography blending elements of content and discourse analysis, this research has observed the #McCann conversation and analysed 500 tweets with the hashtag, observing that some of the most offensive theories posted by users on Twitter reprised themes seen in the mainstream media at the time of the disappearance, which resulted in defamation lawsuits by the McCanns and in complaints about unethical reporting at the Leveson Inquiry. This raises questions about the mainstream media’s responsibility and duty of care towards people they report on in the digital age, and showcases a symbiotic yet diffident relationship between anti-establishment online users and traditional news media.
#RelationshipGoals? Suicide Squad and Fandom’s Love of “Problematic” Men
Authors: Salter Anastasia
Published: October 2019

In the DC Comics Universe, Harley Quinn and the Joker have been an iconic and problematic canonical couple, represented as everything from enviable “mad” lovers to abusive relationship cautionary tale. The couple made cinematic headlines in 2016 with the release of Suicide Squad. In this case study of the “mad love” canon/fanon ship (as embodied in recent works of fanfiction, shipper manifestos posted and shared through social media, and Tumblr discourse), I examine the progressive rhetoric and feminist elevation of Harley Quinn as a shield for the underlying toxicity of the Joker. Fandom’s discourse of “problematic faves” is important as it provides space for fans to love a text even while admitting its representational problems; however, in the case of Harley and the Joker, this discourse risks becoming an excuse for not subverting the toxic tropes of the idolized, abusive, yet still lovable, villain and his obsessive fangirl following.
The fragility of Finnish parliamentary democracy at the moment when Prussianism fell
Authors: Ihalainen Pasi
Published: October 2019

The Finnish case is in many ways illustrative of the complexities of democratisation after World War I. Finland found itself at the nexus of a Swedish constitutional tradition, legalism and ideological controversies adopted from Imperial Germany, the radicalised Russian Revolution, and Western parliamentary democracy. After having been a model for reformers demanding women’s suffrage, for instance, the country found itself in autumn 1918 going in the opposite direction to almost all other European countries. This article analyses the fragility of Finnish parliamentary democracy then, contrasting it with longer-term trends supportive of democratisation. ‘Democracy’ had been the goal for most Finnish political parties since the adoption of universal suffrage in 1906, but the meaning of the concept remained contested and became increasingly so after the Russian Revolution in disputes concerning parliamentary sovereignty, the declaration of independence, a civil war, monarchical reaction, and the search for a republican compromise. For as long as Germany was expected to win the war, democracy in Finland remained fragile, challenged from within first by the revolutionary far-left and then by the reactionary right. The victory of ‘Western democracies’ forced both the left and the right to rethink their opposition to ‘Western’ parliamentary democracy and to adapt to a constitutional compromise. The ideological contestability of democracy remained but confrontations were confined by extremism’s loss of credibility, the growing influence of centrist groups, and a shared determination to avoid another civil war.
The prognostic value of B7H1 and B7H4 expression in pancreatic cancer: A meta-analysis
Authors: Qi Zi-juan , Yu Dan , Chen Chun-hong , Jiang Hong , Li Ran , Kang Yong-ming
Published: October 2019

Objective:

The clinical implications of B7H1 and B7H4 in pancreatic cancer have been described however, the prognostic significance of these genes in pancreatic cancer patients remains inconclusive. The aim of the present study was to evaluate the prognostic role of B7H1 and B7H4 in pancreatic cancer patients.

Methods:

Electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched for relevant articles published before May 2019. Meta-analyses were performed by pooling the hazard ratios (HRs) between overall survival or cancer-specific survival and high or low expression of B7H1/B7H4 in pancreatic cancer patients. Subgroup and sensitivity analyses were performed, and sources of variabilities were explored by performing meta-regression.

Results:

Sixteen studies (1434 patients’ data) were included. Compared with low expression, high expression of B7H1 was associated with significantly poor overall survival (HR 1.92 (95% confidence interval (CI) 1.35, 2.74); P<0.001) and cancer-specific survival (HR 2.46 (95% CI 1.55, 3.90); P<0.001). High expression of B7H4 also predicted poor overall survival (HR 2.38 (95% CI 1.89, 3.00); P<0.001). In subgroup analyses, a significant association between B7H1 and overall survival was observed for trials conducted in China (HR 2.08 (95% CI 1.29, 3.34)) but not in Japan (HR 1.98 (95% CI 1.33, 2.96)); or in studies with <50% patients having high expression (HR 2.02 (95% CI 1.40, 2.91)) but not in studies with >50% patients with high expression (HR 1.40 (95% CI 0.87, 2.26)).

Conclusion:

The current study suggests that high B7H1 and B7H4 expression is associated with a poor prognosis in pancreatic cancer patients.
Modeling Ketogenesis for Use in Pediatric Diabetes Simulation
Authors: Pinnaro Catherina , Christensen Gary E. , Curtis Vanessa
Published: October 2019

Background:

Simulation is being increasingly integrated into medical education. Diabetes simulation is well-received by trainees and has demonstrated improved clinical results, including reduced adult inpatient hyperglycemia. However, no pediatric-specific diabetes simulation programs exist for use in medical education. None of the existing diabetes models incorporate ketones as an input or an output, which is essential for use in teaching pediatric diabetes management.

Methods:

We created a pediatric diabetes simulation incorporating both blood sugar and urine ketones as output. Ketone output is implemented as a state variable but is obfuscated to simulate hospital experience. Blood sugar output is similar to other models and incorporates the current blood sugar, insulin on board (IOB) and carbohydrates on board (COB), and insulin and carbohydrate sensitivities. The program calculates all IOB and COB every 15 minutes based on user input and provides written summary feedback at the end of the simulation about inaccurate dosing and timing.

Results:

The simulation realistically incorporated both blood glucose and urine ketones in clinically valid and actionable formats. After completing this simulation, 16/17 pediatric residents indicated that they wanted more simulated diabetes cases integrated into their curriculum.

Conclusion:

Implementing simulation into pediatric diabetes education was feasible and well-received. More work is needed to further study the role of simulation in pediatric diabetes education when used adjunctively or in lieu of lectures when time or resources are limited.
Inhibitory Effects and Kinetic-Docking Studies of Xanthohumol From Humulus lupulus Cones Against Carbonic Anhydrase, Acetylcholinesterase, and Butyrylcholinesterase
Authors: Aydin Tuba , Senturk Murat , Kazaz Cavit , Cakir Ahmet
Published: October 2019

Xanthohumol is an essential prenyl flavonoid of Humulus lupulus L. cones, and the taste of beer is due to this compound. Lately, xanthohumol has earned significant interest due to its potential anticancer, antigenotoxic, and adipogenesis effects. In this paper, the inhibitory effects of xanthohumol on human carbonic anhydrase isozymes (hCAI and hCAII), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) were studied. Also, molecular docking studies were used to investigate ligand interaction diagrams of xanthohumol at the binding cavities of hCAI and II. Xanthohumol was isolated from hop cones by silica gel column chromatography. Carbonic anhydrase enzyme activities were determined spectrophotometrically. In addition, molecular modeling approaches were used for the hCAI and hCAII isoenzymes. Ellman’s method was used for the inhibitor activities of AChE and BChE. The K I values of xanthohumol were detected as 0.085 µM for hCAI, 0.049 µM for hCAII, 95.5 nM for AChE, and 124.9 nM for BChE. In conclusion, xanthohumol can pleiotropically exert health promoting effects. It has antiglaucoma, anticonvulsant, antiepileptic, and anticancer activities due to its potent inhibitory effects on hCAI and hCAII. These findings may open new avenues for the design and development of novel hCAI, hCAII, AChE, and BChE inhibitors compared with sulfonamide/sulfamate.
Reinforcement of Brands Inspired by Faith with the Paradox of Cultural Divergence in Indian FMCG Market
Authors: Gnanakumar P. Baba
Published: October 2019

Self-esteem values, with the new art of living, in the minds of Indians, lead to establish faith among the spiritual organization. Later on, the spiritual organization branded their names and market the products in their branded name. These brands, which are inspired by faith and created by Indian spiritual gurus have even disrupted the fast-moving consumer goods (FMCG) market by being customer-centric instead of being geared by lucrative returns. It is in this context this research is motivated: to find the cultural divergence factors that lead to change the consumption pattern of FMCG and how Indian spiritual gurus are segmenting the market. The research concludes that cultural divergence variables such as power distance, collectivism, uncertainty avoidance and long-term orientation influence the brands that are inspired by faith. Spiritual gurus in India are using sociocultural marketing activities such as social endorsement and cause-related marketing strategies for segmenting the markets.
An Examination of the Effects of Employee Words in Organizational Crisis: Public Forgiveness and Behavioral Intentions
Authors: Lee Yeunjae
Published: October 2019

This study examines how employees’ messages about a corporate crisis affect external publics’ attitudes and behaviors toward an organization. Specifically, the study investigates whether the valence (positive vs. negative) and communication channels (face-to-face vs. social media) of employees’ messages interact with each other. The results of an online experiment indicate that negative messages concerning an organizational crisis significantly affect publics’ perception of message credibility, behavioral forgiveness, and message retransmission intentions when the messages were delivered during face-to-face communication, while negative messages on social media do not significantly affect publics’ attitudes and behaviors. Positive messages had almost equal impacts on the outcomes, regardless of the communication channels through which the message was shared. Theoretical and practical implications for corporate and business communication are discussed.
Understanding the eHRM Promise and Adoption Imperatives
Authors: Iyer Suryanarayan
Published: October 2019

Organisations invest in Electronic Human Resource management (eHRM) by buying into its potential of strategically transforming the Human Resource (HR) function. However, the posited performance gains are often obstructed by users and organisations alike in adopting the systems towards realisation of stated outcomes. The article aims to provide an understanding of the promise of eHRM in terms of the posited goals and outcomes of eHRM. Through a qualitative study with Chief Human Resources Officers of 15 large organisations, the article also highlights the key factors influencing adoption of eHRM in organisations.
Transcriptional Control of Memory T Cell Differentiation
Authors: Goldrath Ananda
Published: October 2019

Tissue-resident memory CD8+ T cells (TRM) are optimally positioned at common sites of pathogen exposure, where they elicit rapid and robust antiviral immune responses. However, the molecular signals controlling tissue residency and homeostasis of TRM remain unclear. Exploiting a dual-screening platform integrating computational and RNAi in vivo screening approaches, we have identified transcriptional regulators of TRM differentiation. This strategy revealed numerous transcription factors with indispensable roles in TRM differentiation and homeostasis. Further, we show that tumor infiltrating lymphocytes (TIL) share a core TRM transcriptional signature, and that these factors control TIL residency. These results provide novel insight into the biology of T cell residency, which could be leveraged to enhance vaccine efficacy or adoptive therapy treatments against cancer.

Disclosures

No relevant conflicts of interest to declare.
Kruppel-Like Factors in Thrombosis and Hemostasis
Authors: Jain Mukesh
Published: October 2019

Armed with the appreciation that the blood and vascular system share common origins and cooperate to ensure fundamental processes (e.g. blood flow/fluidity, oxygen/nutrient delivery, immunity) essential for organismal survival, we posited that shared molecular pathways may be operative in coordinating the function of both systems. Over the past 2 decades, studies from our group and others have identified a family of transcription factors termed Kruppel-like factors (KLFs) as essential for development, differentiation, and function of cellular constituents of both the hematopoietic and vascular systems. In this presentation, discussion will focus on the role KLFs in control of endothelium and myeloid cell biology in physiology and disease. Specifically, cellular and in vivo evidence will be discussed implicating KLFs as master regulators of all cardinal endothelial functions (permeability, vasoreactivity, blood fluidity, and inflammation). Further, studies demonstrating KLF-control of myeloid cell development, subset specification, and pro-inflammatory activation will be reviewed with particular emphasis on results of efforts altering myeloid KLFs in the context of acute (e.g. bacterial infection, sepsis) and chronic (e.g. atherosclerosis, arterial/venous thrombosis) inflammatory processes. Correlative studies in human subjects will be presented. And finally, insights into how targeting KLFs can be exploited for therapeutic gain will be discussed.

Disclosures

No relevant conflicts of interest to declare.
Geographic Trends in Clinical Trials in Lymphoma, 1997-2017
Authors: Oren Ohad
Published: October 2019

Background

In order to fulfil their medical and academic mission, clinical trials have to be available to the very populations they are intended to serve. A broad and homogenous geographic distribution is thus paramount to ensure patient fairness as well as to allow optimal generalizability of trial results to real-world populations. We aimed to investigate trends in the geographic distribution of clinical trials in lymphoma performed over the past 2 decades.

Methods

We systematically searched the Clinicaltrials.gov registry for phase 3 and 4 clinical trials in lymphoma conducted between 01/01/1997 and 12/31/2017. We divided the time period into two intervals and analysed the geographic distribution of trials during these time periods. The Gini coefficient, a statistical measure of inequality ranging from 0 (equal distribution) to 1 (most unequal distribution), was calculated for each period.

Results

We found 633 clinical trials in lymphoma conducted between 1997 and 2017 globally. 284 and 349 trials were performed in the 1997-2007 and 2008-2017 time periods, respectively. 127 (50%) and 138 (39.5%) of the trials were done in the US. Hodgkin Lymphoma accounted for 55 (19.3%) and 42 (12.0%) studies in the two time periods. CA, TX, IL and NY were consistently in the upper one-fifth of trial-abundant states (each accounting for 3.5-4.5% of all trials). AK, WY, MT and RI were consistently in the lower one-fifth of trial-abundant states (each accounting for 0.13-0.84% of trials). The trial participation of NY and AK mildly increased during the time period while that of TX and RI decreased. In each of the time periods, the 12 most trial-intense states accounted for 41.5% of all investigations. The 12 least trial-intense states were responsible for 8.8% of all the trials. The extent of geographic inequality increased over the years with the Gini coefficient rising from 0.246 to 0.3 between the first and second study period. The geographical pattern of state-specific trial intensity was strongly mitigated after adjusting for each state's population size.

Conclusions

The geographic distribution of clinical trials in lymphoma in the U.S is not uniform. Our data suggests that the trend of geographic mal-distribution is worsening, a phenomenon that may lead to deleterious public health outcomes. As patients' enrolment continues to be linked to geographic factors, patients' ability to enter clinical trials may be limited and the representation of real-world participants may be skewed (towards particular zip codes, socio-economical status and education levels, etc), consequently affecting the yield and generalizability of clinical trials. Innovative solutions must be devised to minimise any barriers to trial participation for suitable patients.

Disclosures

No relevant conflicts of interest to declare.
Investigation-Based Drug Value Framework in Hodgkin Lymphoma
Authors: Oren Ohad
Published: October 2019

Background

Currently available drug value frameworks integrate data about a medication's benefits and risks. However, the strength of the research data supporting the use of one medication versus another is highly variable. The greater the number and quality of well-conducted trials underlying a certain intervention, the stronger its potential favorable contribution to public health. Drug value should therefore also be a function of the magnitude of clinical evidence gleaned from high-quality clinical trials.

Methods

We propose an investigation-driven value framework that determines the merit of a drug based on the overall available evidence, including the rigour of relevant trials. The NCCN Hodgkin Lymphoma guidelines were reviewed and data collected about commonly used regimens for Classic HL. Value scores were determined for each drug combination.

Results

A model was designed incorporating information about the number of RCTs conducted, the total number of participants enrolled, and the generalizability to real-world populations, in addition to the drug's efficacy, significant toxicity and cost (Figure 1). Practice-changing trials supporting each of the currently-endorsed regimens were collected from the HL NCCN guidelines (ABVD, 4; Stanford V 4; Esc BEACOPP 2). The average number of participants per trial was higher for ABVD (1,126) and Esc BEACOPP (1,890) than for Stanford V (267). The generalizability score for the three compounds was 0.5 (ABVD), 0.25 (Stanford V) and -1 (Esc BEACOPP). The mean 5-year overall survival rate was higher in the case of ABVD (96.2%) and Esc BEACOPP (96.1%) compared with Stanford V (92.0%). The toxicity score was 1.24 (ABVD), 3 (Stanford V) and 2.5 (Esc BEACOPP). Using a multi-factorial value scoring system, ABVD, Esc BEACOPP and Stanford V obtained 11.5, 9.5 and 8.5 points, respectively. A scoring system that focused on traditional factors alone (efficacy, toxicity, cost) yielded different scores (ABVD, 7.7; Stanford V 6.7; Esc BEACOPP, 6.5).

Conclusion

The robustness of clinical trials investigating anti-cancer regimens deserves special consideration when defining drug value. Three high-quality trial characteristics help stratify common regimens in HL into higher/lower value strata using a simple, easy to use algorithm.

Disclosures

No relevant conflicts of interest to declare.
Allogeneic Stem Cell Transplantation after Exposure to Checkpoint Inhibitors: Graft Versus Host Disease and Non-Relapse Mortality in Pooled Analysis
Authors: Dada Reyad , Binyam Usman
Published: October 2019

Objectives: Relapsed cHL patients after autologous stem cell transplantation with treatment sensitive disease are usually potential candidates for curative allogeneic stem cell transplantation (HCT). However, there are some concerns around performing such procedure after treatment with checkpoint inhibitors.

Methods: We collected published data of patients undergoing allogeneic (HCT) after treatment with checkpoint inhibitors. Abstracts of recent conferences (2015-2017) (ASCO, ASH, EBMT) were also included. Results (cohort 1) were compared with safety of recent studies with allogeneic HCT in cHL (2015-2018) without prior exposure to checkpoint inhibitors (cohort2). Only studies reporting on outcome of ≥3 patients were considered. Two reviewers studied the publications independently and matched extracted data. In case of author/group duplication, the publications were jointly rescanned by the reviewers and unified decision was taken whether the reported cohorts are the same. In case of confirmed duplication, the most recent report or the one with more detailed information was chosen. End points were rates for grade 3-4 acute GVHD, chronic GVHD and Non-relapse mortality (NRM).

Results: Total of 259 records with 1100 patients were screened. Mean number of checkpoint inhibitors cycles received prior to allogeneic HCT was nine (range 1-38). Grade 3-4 acute GVHD in cohort 1 was 28% (95% CI, 20-37%) in comparison with 8% (95% CI, 6-10%) in historical cohort. Chronic GVHD was observed in 26% (95% CI, 19-36%) versus 29% (95%, CI 26-31%) respectively. In cohort 1, NRM rate was 15% (95% CI, 9-23%) which remained relatively stable after 6 months of allogeneic HCT versus 19% in cohort 2. Only 6.6% deaths were attributed to GVHD while the remaining 7.4% deaths were due to other complications of allogeneic HCT. Other relevant results will be presented at the 60th Annual Meeting of the American Society for Hematology in December 2018.

Conclusions: This is the largest pooled analysis of its kind published so far. Our results suggest that allogeneic stem cell transplantation after checkpoint inhibitors is feasible and not associated with higher mortality. However, careful consideration should be given for prevention, early detection and effective treatment of GVHD in these cases.

Disclosures

No relevant conflicts of interest to declare.
Early Diagnosis of an Infant with Gaucher's Disease Type 3. Case Report
Authors: Bello Adriana C. , Cortez Rossana
Published: October 2019

Background

Gaucher's disease is a rare autosomal recessive disorder that results from the deficiency of the enzyme glucocerebrosidase, causing deposition of glucocerebroside in cells of the macrophage-monocyte system.

Type 3 disease has varied presentations, with neurologic involvement, in addition to progressive hepato-splenomegaly, anemia, thrombocytopenia and skeletal manifestations.

Case Report

2 month old infant girl, was noted to have abdominal enlargement, and was taken to the local rural provider. She was referred to a pediatrician. From there, she was transferred to our institution, after a red blood cell transfusion.

Past history is noteworthy for early passage of a first degree cousin, at the age of 3 months, with hepatosplenomegaly and transfusion requirements.

Parents deny consanguinity. However, they live in a very rural, closed population. A detailed pedigree chart was not obtained.

Physical exam revealed an infant in regular overall conditions, grade IV hepatosplenomegaly. Pale, fussy, hyporexic, with mild breathing difficulty, from enlarged abdomen. She had oculomotor apraxia, at the horizontal gaze. Rest of neurological examination was uneventful.

Dry blood sample was obtained and sent to a specialized laboratory (Greenwood Genetic Center, USA). Bone marrow biopsy showed almost total replacement of normal hematopoiesis, with Gaucher cells.

Beta glucosidase activity was low. GBA gene sequencing, at chromosome 1q21-22, revealed homozygous pL483p mutation, on exon 11. She was 5 months old, when diagnosis of Gaucher's disease type 3, was genetically confirmed.

Imiglucerase was initiated, biweekly, at 60 unit/kg. Dose was increased, on a monthly basis, up to 120 unit/kg. Ambroxol was also started, as a chaperone therapy 15mg/kg/d, as per recent literature (Narita et al, Ann Clin Transl Neurol 2016 Feb 2;3(3):200-15), providing increased glucocerebrosidase activity, in the cerebrospinal fluid, with improvement of neurologic symptoms.

Blood counts, including platelets, normalized shortly after starting enzyme replacement therapy. Neurologic milestones, growth and constitutional features, are adequate for age.

Hepatosplenomegaly has decreased with ongoing therapy, and we expect it will continue to ultimately improve, with treatment. She is now 14 months old.

Conclusion

Gaucher's disease is a rare condition that should be considered in an infant with hepato-splenomegaly and low blood counts, and or bleeding manifestations. Gold standard for diagnosis should be sought by the enzyme measurement, and molecular confirmation.

Enzyme replacement therapy is the therapy of choice, in these patients.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
A Heterozygous Mutation of G-Protein-Coupled Receptor 25 in a Family with Inherited Thrombocytopenia and Thrombosis
Authors: Yamanouchi Jun , Ikeda Yuichi , Hato Takaaki , Yasukawa Masaki , Takenaka Katsuto
Published: October 2019

Background

Inherited thrombocytopenia is associated with bleeding tendency and no association with thrombotic tendency has been reported. We found a Japanese family with autosomal dominant form of thrombocytopenia associated with arterial and venous thrombosis.

Aims

To identify a causative gene for hereditary thrombocytopenia with thrombosis.

Methods

A propositus was a 42-year-old Japanese woman with thrombocytopenia and deep vein thrombosis (DVT). She had normal activities of antithrombin, protein C, and protein S, and negative results for lupus anticoagulant and anti-cardiolipin antibodies. She has suffered from thrombocytopenia (20 - 50 x 109/L) for at least 20 years. Six members among her family pedigree had thrombocytopenia, and also suffered from thrombosis including mesenteric artery thrombosis, young-onset myocardial infarction, femoral artery thrombosis, repeated cerebral infarction, DVT, and pulmonary embolism. Importantly, the family members with these thrombotic disorders had exclusively thrombocytopenia. Whole exome sequencing was performed with venous blood from the 6 affected and 6 non-affected family members to identify a causative gene for thrombocytopenia.

Results

We identified a heterozygous change (c.764G>T:p.G255V) in GPR25 gene, an uncharacterized G protein-coupled receptor. The mutation was completely linked with thrombocytopenia. The mutated residue was located at the transmembrane domain of GPR25. We generated anti-GPR25 monoclonal antibodies and confirmed that GPR25 was expressed on the platelet surface. The patient's platelets showed the same level of PAC1 (a monoclonal antibody recognizing the active conformation of integrin αIIbβ3) binding and P-selectin expression as platelets from healthy subjects. However, ADP-induced aggregation of patient's washed platelets was enhanced as compared with normal washed platelets. Moreover, the patient's platelets had an increase in thrombin + collagen-induced and A23187-induced Annexin V binding compared with platelets from healthy subjects.

Conclusion

We identified a novel gene mutation responsible for inherited thrombocytopenia and thrombosis that may induce platelet hyper-reactivity.

Disclosures

No relevant conflicts of interest to declare.
Outpatient Autotransplants for Persons with Multiple Sclerosis
Authors: Gomez-Cruz Gisela B. , Gale Robert Peter , Olivares Gazca Juan Carlos , Leon-Peña Andres , Gomez-Almaguer David , Gomez De Leon Andres , Gonzalez-Lopez Elias Eugenio , Ruiz-Argüelles Alejandro , Soto-Vega Elena , Muñoz-Perez Maria Jose , Ruiz-Delgado Guillermo J. , Ruiz-Argüelles Guillermo J.
Published: October 2019

Background. High-dose cyclophosphamide and a haematopoietic cell autotransplant is an effective therapy of multiple sclerosis (MS). This is often done in an inpatient setting using frozen blood cells either blood or bone marrow cells.

Objective. Determine if this procedure can be safely and effectively simplified.

Methods. We developed an autotransplant protocol actionable in an outpatient setting using refrigerated blood cells collected after giving cyclophosphamide, 50 mg/kg/d x 2 d and filgrastim, 10 μg/kg/d. A 2nd identical dose of cyclophosphamide was given 9 d later followed by infusion of blood cells stored at 4º C for 1-4 d. Subjects received rituximab after bone marrow recovery, 100 mg, every 2 mo for 1 y or rituximab, 1 g in 1 dose based on the subject's residence country (Figure 1). The co-primary outcomes were rate of bone marrow recovery and therapy-related mortality (TRM). Secondary outcomes included MS relapse-free survival (MS-RFS) and survival. Cumulative dose of cyclophosphamide was 200 mg/Kg

Results. We treated 426 consecutive subjects. Median age was 47 y (range, 21-68 y). 145 (34%) were male. 84 (20%) had primary progressive MS, 173 (41%), relapsing remitting MS and 169 (39%), secondary progressive MS. Median blood cell storage time was 1 d (range, 1-4 d). Median intervals to granulocytes >0.5 x10E+9/L was 8 d (range, 2-12) and to platelets >20 x10E+/L, 8 days (range, 1-12). 412 subjects (96%) were treated as outpatients. Median follow-up is 6 mo (range, 3-30 mo). There was 1 death from TRM. In 304 subjects (71%) with data from neurologic evaluations ≥3 posttransplant median MS RFS is 27 mo (95% confidence interval [CI], 24, 30 mo). Estimated 1 y MS RFS is 85% (80, 90%) with no significant difference between the 3 MS variants. Median survival will exceed 30 mo. An unusual aspect of our study was giving two 2-d blocks of cyclophosphamide 8 days apart rather than 4 d continuously done for 3 reasons: (1) use of cyclophosphamide to mobilize blood cells for the autograft; (2) facilitate using a refrigerated rather than frozen autograft; and (3) decrease toxicity. Our finding of rapid bone marrow recovery using refrigerated grafts is like our experience in persons with plasma cell myeloma and lymphomas receiving high-dose therapy and an autotransplant.

Conclusion. The strategy we developed was actionable in an outpatient setting with rapid recovery of granulocytes and platelets and only 1 early death. Estimated MS-RFS and survival were good. MS variant type did not correlate with MS-RFS or survival.

Disclosures

Gomez-Almaguer: AbbVie: Consultancy; Novartis: Consultancy.
Race, Socioeconomic Status, and Time to Transplantation in Multiple Myeloma
Authors: Pan Darren , Coltoff Alexander , Ozbek Umut , Lin Jung-Yi , Afshar Solmaz , Steinberg Amir
Published: October 2019

Race, Socioeconomic Status, and Time to Transplantation in Multiple Myeloma

Background: Multiple myeloma is the most common hematologic malignancy in blacks. Previous studies have found that black patients undergo autologous stem cell transplant (ASCT) less frequently than their white counterparts, though the reasons for this have not been fully elucidated. To identify whether racial differences in timing of referrals to transplant centers and transplantation may play a role in this observed disparity, we analyzed data from transplants undergone at The Mount Sinai Hospital between 2011 and 2016.

Methods: We retrospectively analyzed 416 black and white patients who received their first autologous stem cell transplant for multiple myeloma at The Mount Sinai Hospital between 2011 and 2016. We compared the time from initial diagnosis to stem cell harvest and the time from harvest to transplant between the two groups while controlling for age, socioeconomic status, and functional status.

Results: In total, 264 white patients and 152 black patients were identified as receiving their first transplant between 2011 and 2016. Data regarding each patient's demographic, date of diagnosis, date of harvest and transplant, and functional status were available. Age, socioeconomic status (as assessed through census data of median income of the patients' zip code), and functional status were considered possible confounders. Linear regression analysis was used to assess differences in transplant timing between races while controlling for these factors. We found that between racial groups, neither the time from diagnosis to harvest (528 days vs. 406 days respectively, p=.95) nor the time from harvest to transplant (113 days vs. 150 days respectively, p=.31) was significantly different. Age and socioeconomic status also did not significantly affect either time point, although patients with higher socioeconomic status had a decreased time from diagnosis to harvest which approached significance (p=0.07) regardless of their race. Finally, better functional status was associated with a shorter time from diagnosis to harvest (p=0.003).

Conclusion: Based on these findings, race and socioeconomic status did not significantly affect expediency of referral to and completion of transplantation following initial disease diagnosis. Further studies are needed to clarify the factors contributing to observed differences in ASCT utilization between blacks and whites.

Disclosures

No relevant conflicts of interest to declare.
Preclinical Evaluation of MAX-40279, a FLT3/FGFR Dual Kinase Inhibitor for Treatment of Acute Myeloid Leukemia
Authors: Wang Yuguang , Bao Hanying , Zhang Nong , Wang Feilan , He Yunsong , Wu Tianzhi
Published: October 2019

Background: In newly diagnosed AML patients, the prevalence is about 30% for FLT3-ITD. FLT3-ITD is associated with disease progression, increased risk of relapse and shorter overall survival. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research.

FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations which indicated that inhibition of both FLT3 and FGFR is highly desirable for the development of the next generation of FLT3 inhibitors. We discovered MAX-40279, a dual inhibitor of FLT3 and FGFR for the potential AML treatment.

Methods: MAX-40279 has been tested in the enzyme assays, cellular assays, signal transduction assays and xenograft assays to evaluate their FLT3 and FGFR inhibitory activity; At the enzyme level, FLT3-wt, FLT3-ITD and FLT3-D835Y were compared, and the FGFR subtypes FGFR1, FGFR2 and FGFR3 were profiled. MAX-40279 was dosed orally to SD rats and the drug AUC was calculated and the comparison was made in plasma and bone marrow. KG-1 xenograft model known to have FGFR1-FGFR1 QP fusion and the MV4-11 xenograft known to have FLT3 aberrant were developed to compare the in vivo efficacy as measured by tumor growth inhibition of MAX-40279.

Results: We report here the preclinical evaluation of MAX-40279, a potent, selective, and bioavailable FLT3/FGFR dual kinase inhibitor. MAX-40279 inhibited AML xenograft tumor growth by 58% to 106% without significant body weight loss. MAX-40279 has much higher drug concentration in bone marrow than in plasma. In addition, MAX-40279 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the urrent FLT3 inhibitors (e.g., AC220 and sorafenib).

Conclusion: MAX-40279 demonstrated superior FGFR inhibitory activity and higher bone marrow drug concentration while maintaining similar activity against FLT3-ITD. All of these results supported that MAX-40279 is the next generation FLT3-mutant inhibitor with great potential to overcome the drug resistance via FGF pathway in bone marrow. Now it is in the phase 1 clinical trial in Australia. In this presentation, we will describe the full preclinical profile of Max-40279 and some of the phase 1 clinical data.

Disclosures

No relevant conflicts of interest to declare.