bluuebunny/crossref_metadata_2025 huggingface dataset:
Grouting Design of Rich Water Tunnels and the Calculation of Distance between Annular Blind Pipes
Authors: Fu Helin , An Pengtao , Li Kai , Cheng Guowen , Li Jie , Yu Xiaohui
Published: November 2020

The rich water tunnel often uses “water blocking and drainage limiting” waterproofing and drainage systems. On the one hand, the drainage system is set behind the lining to reduce the water pressure. On the other hand, the stratum grouting is used to control the discharge flow of groundwater. In the drainage system, it is important to determine the distance between the annular blind pipes, but there is no clear calculation formula, which leads to the designer often relying on experience. First, the groundwater drainage system is constructed. Based on Darcy’s law and the law of conservation of mass, the formula for calculating the seepage discharge and the seepage pressure with the parameters of annular blind pipe spacing is derived. At the same time, the design parameters of the grouting circle are optimised, and then the formula of annular blind pipe spacing is derived according to the design value of the antiwater pressure of the secondary lining structure and the allowable seepage discharge of the tunnel. Finally, based on the case study of the Hongtu extra‐long tunnel under construction, it is verified by field monitoring data. The results show that (1) grouting reinforcement is an important means to reduce water seepage, and tunnel water seepage can be adjusted by changing the thickness and permeability coefficient of the grouting reinforcement circle, in which the thickness of the reinforcement circle should not be too large, and the permeability coefficient should not be less than 1/80 of the surrounding rock permeability coefficient; (2) according to the derived formula, the water pressure of the secondary lining structure decreases in a parabolic manner from the middle of the two rows of annular blind pipes to the place where the annular blind pipes are set; (3) the allowable water seepage of the tunnel and the design value of the water pressure resistance of the lining structure should be considered when determining the distance between annular blind pipes; and (4) based on the derived formula, the distance between the annular blind pipes in the test section of the Hongtu extra‐long tunnel is determined to be 8 m.
Clearing the Haze: What Do We Still Need to Learn about Electronic Nicotine Delivery Systems?
Authors: Fucito Lisa M. , Malinosky Hannah , Baldassarri Stephen R. , Herbst Roy S.
Published: November 2020

Electronic nicotine delivery systems (ENDS; i.e., electronic cigarettes, e-cigarettes, vaping devices, vape pens) were introduced to the U.S. market in 2007 as a potential harm reduction alternative for people who smoked combustible cigarettes. Since that time, ENDS popularity grew very quickly, particularly among individuals who smoke cigarettes. However, young people and never smokers also started using ENDS, cohorts for whom these products were not intended. There are now a broad range of devices and e-liquid constituents. ENDS devices vary considerably in their design and generation of potentially toxic chemicals, with higher power devices likely much more hazardous than lower power devices. This landscape may further change after September 9, 2020, when all ENDS manufacturers are required to submit a premarket tobacco product application to the FDA to obtain authorization for marketing. Research has not kept pace with this rapidly changing technology and important questions remain regarding the relative benefits versus risks of ENDS. In light of these challenges, we propose key ENDS research priorities to address these gaps.
Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism
Authors: Heida Judith E. , Minović Isidor , van Faassen Martijn , Kema Ido P. , Boertien Wendy E. , Bakker Stephan J.L. , van Beek André P. , Gansevoort Ron T.
Published: November 2020

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production. Methods: Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured. Results: At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 μmol/24 h, p = 0.007, and 0.29 vs. 0.53 μmol/24 h, p < 0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p < 0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 μmol/24 h, p < 0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed. Conclusions: Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment.
Sintomas osteomioarticulares em bombeiros militares do Distrito Federal
Authors: Oliveira Eva Pereira de , Lima Alexandra Lopes de , Leal Josevan Cerqueira , Matheus João Paulo Chieregato , Garcia Patrícia Azevedo , Martins Wagner Rodrigues , Macedo Osmair Gomes de
Published: November 2020

Objetivo: Verificar a prevalência de sintomas osteomioarticulares em bombeiros militares do Distrito Federal. Metódo: Trata-se de um estudo transversal, realizado com bombeiros militares de idades entre 18 e 55 anos. Foi utilizado o Questionário Nórdico de Sintomas Osteomusculares e os participantes relataram a ocorrência dos sintomas nos 12 meses e nos sete dias precedentes à entrevista, bem como os afastamentos das atividades no último ano. Os dados foram tabulados no programa Microsoft Excel 2016 e foi feita a estatística descritiva. Resultados: Dos 178 bombeiros participantes, 89% eram do sexo masculino, com idade média de 39 anos e média do índice de massa corporal de 25,93. As regiões de maior prevalência foram a região lombar (20,90%), seguida dos joelhos (14,24%) e da região dorsal (12,26%) nos últimos 12 meses e a região lombar (20,35%), seguida dos joelhos (16,48%) e dos ombros (11,97%) nos últimos sete dias. Conclusão: Verificou-se maior prevalência de sintomas osteomioarticulares na região lombar, joelhos e região dorsal para alterações crônicas, e maior prevalência de sintomas na região lombar, joelhos e ombros para alterações agudas. Os bombeiros apontaram como causas a realização de força, fadiga e/ou cansaço, posturas mantidas por um longo período de tempo, movimentos bruscos e movimentos repetitivos.
Cidade encruzilhada
Authors: Alexêvitch Yuri
Published: November 2020

Ensaio fotográfico "Cidade Encruzilhada"
Judicial Recognition of Outlawed Bigamous Marriage in Ethiopian Federal Supreme Court Cassation: Legal Gap-Filling or Judicial Lawmaking?
Authors: Chewaka Jetu Edosa
Published: November 2020

Bigamous marriage has been outlawed under the Family and Criminal Codes of Ethiopia despite its wide practice in Ethiopia. This article examines the legality of judicial recognition of the effects of bigamous marriage by the Federal Supreme Court Cassation and its implications for the regulation of marriage. The article reviews the substance of the current family laws in light of selected decisions of Federal Supreme Court Cassation on bigamous marriage by juxtaposing principles of legal interpretation. The article argues that the recognition of outlawed bigamous marriage by the Federal Supreme Court Cassation, even for relief purposes, amounts to an act of judicial law-making. The Court’s reasoning based on the gap-filling role of the judiciary under the guise of the necessity to address problems of bigamous marriage as a ‘social reality’ deviates from the purpose of the current rules under the family law that were deliberately designed to regulate monogamous marriage.
Targeted Killings: Assessing the Legal Contours for Protection of Africans with Albinism
Authors: Nkrumah Bright
Published: November 2020

As the world mourns and condemns the brutal death of George Floyd by police brutality, one cannot ignore, but reflect on similar atrocities committed against hundreds of Africans by virtue of their skin pigmentation. These victims are Africans with albinism (AwA). Widespread discrimination and targeted attacks against these individuals occur against the backdrop of an erroneous mythology that the body parts of AwA have magic powers which could enhance electoral victory, guarantee bumper harvest, cure medical complications and bring riches. Indeed, many states have attempted to avert further abuse by arresting and prosecuting perpetrators. Yet, violations abound. By June 2020, more than 200 Africans with albinism have been killed in 30 African countries, and a disproportionate percentage has been subjected to abduction, rape and violent attacks. These atrocities question the effectiveness of existing (inter)national human rights mechanisms in safeguarding vulnerable populations from their attackers. Coincidentally, the day June 13 is significant as it marks the 5th Anniversary of the International Albinism Awareness Day (IAAD). While reminding us to combat different forms of discrimination faced by AwA, the day also starkly entreats us to survey the level of legal safeguard afforded this vulnerable community in the region. In a bid to forestall further attacks, the paper argues that while it may be vital for the international community to adopt an overarching binding legal instrument speaking to the protection of AwA, African countries should use the IAAD to reinforce information dissemination and awareness campaigns to destigmatize albinism in local communities.
1. Listening as an Innu-French Contact Zone in the Jesuit Relations
Authors: Bloechl Olivia
Published: November 2020

Acoustemologies—or ways of listening and knowing the world through sound—are culturally specific; they have had a role in histories of colonial interaction and integration within sense-based ‘contact zones’. This chapter illustrates the role of contact and acoustemologies with a case drawn from the history of missionization in Nitassinan (Innu territory in eastern Quebec/Labrador), as documented in the Jesuit Relations (1632–1673). Especially in the earliest field reports, the priests' minute documentation of song, sound, and listening outlines distinct Innu and French Jesuit acoustemologies, whose differences clearly mattered for all sides. Focusing on these listening ‘bodies in contact’ (Ballantyne and Burton, 2005) offers a unique perspective on the close, improvisatory engagement of Indigenous and European people in a period of enormous regional upheaval. It also directs our attention to the larger stakes that are attached to sonic micro-interactions in world history.
3. Performance in the Periphery: Colonial Encounters and Entertainments
Authors: Akhimie Patricia
Published: November 2020

When early modern English travellers relate their exchanges with the people they have met in far-flung places, they frequently include descriptions of music both familiar and strange, performed by foreign visitors and Indigenous peoples alike. The presence of music, however, and its seemingly transparent meanings enables perilous miscommunications. Failures of musical interpretation or sudden alterations of meaning in musical exchanges proliferate in reports of English and European encounters in the New World. This chapter argues that the English carried with them an epistemology of musical meaning that was predicated on the ways that music functioned in European entertainments, particularly those associated with English country estates.
6. Little Black Giovanni’s Dream: Black Authorship and the ‘Turks, and Dwarves, the Bad Christians’ of the Medici Court
Authors: Wilbourne Emily
Published: November 2020

This chapter provides a close reading and English translation of the one surviving poem by the enslaved, black, possibly castrated chamber singer, Giovanni Buonaccorsi, who was active at the Medici court from at least 1651 until his death in 1674. I argue that the poem was written by Buonaccorsi, that performances were sung, and that in the text Buonaccorsi makes an important claim to community among the ‘Turks, and Dwarves, the bad Christians’ who lived in the court. Several individuals mocked in the poem are matched up with historical persons who were present at the Medici court in the early 1650s.
8. ‘La stiava dolente in suono di canto’: War, Slavery, and Difference in a Medici Court Entertainment
Authors: Cusick Suzanne G.
Published: November 2020

On 24 February 1607, a central Italian court invited select guests to celebrate the final night of carnival at one of their palaces. Part of the entertainment was a sung and danced spectacle characterized by ‘una musica stupenda’, the success of which launched Francesca Caccini’s theatrical career and her reputation as a pioneer in the history of opera. Like most court entertainments, this one had political overtones. Situating the entertainment in relationship to the court's attitudes toward Muslim power in the eastern Mediterranean, and the court's innovations in the Mediterranean slave trade, this paper explores the ways that the entertainment's sonic design both activated and enabled the disavowal of ethnoreligious biases. The chapter concludes by meditating briefly on implications for the historiographies of aurality, women's musical culture, and opera.
9. ‘Now Despised, a Servant, Abandoned’: Wounded Italy, the Moresca, and the Performance of Alterity
Authors: Treadwell Nina
Published: November 2020

During Carnival at the court of Urbino in 1513, two intermedii (interludes) were staged across the course of two unrelated comedies, both highlighting the personification of a ransacked Italy. This chapter explores the presentation of violated Italy in the broader context of the Italian Wars (1494–1559) and specifically in relation to the Urbinate audience, whose own city had been sacked some ten years previously. Drawing on tropes familiar to the audience, including those associated with popular laments, this chapter demonstrates how performances were designed to elicit an intense, bodily identification. Italy’s first performance was wracked by her inability to speak, while her second, envoiced performance engaged with themes of sexual violence and betrayal. The performance concluded with a moresca demonstrating military expertise, seemingly to eviscerate the memory of Italia’s suffering, yet the efficacy of the moresca, as antidote to Italy’s (and the Italian peninsula’s) alterity, was questionable.
A 3-month Journey: The Case of a 29-year Old Woman With Metastatic Renal Cell Carcinoma
Authors: Kubi Boateng , Johnston Fabian M.
Published: November 2020

Early goal-oriented conversations at the end of life can help alleviate suffering and anxiety for surgical patients with cancer and their loved ones. This is especially important in the young adult population in whom there are limited patient-reported perspectives about their experiences at the end of life. We report the illustrative case of a 29-year-old woman who underwent palliative surgery for widely metastatic renal cell carcinoma. Her postoperative course was complicated by a proximal anastomotic stricture, bilateral pulmonary emboli, and delayed gastric emptying, ultimately leading to a functional decline in health and quality of life. Several wide-ranging palliative care needs arose during our patient’s surgery, discharge, and subsequent readmissions. In addition to our patient’s case, we discuss 3 fundamental surgical palliative care principles, and broad considerations for end-of-life management of young adults with advanced malignancies.
Neonates with Asymptomatic Central Venous Catheter-Related Thrombosis - a Systematic Review
Authors: Allahyani Bader , Alanazi Abdullah , Feder Joshua , Simpson Ewurabena
Published: November 2020

Background:

Central venous catheters (CVCs) are the most frequent cause of thrombosis in acutely unwell neonates. The natural history CVC-RT remains unclear. The current guideline for symptomatic CVC-related thrombus suggests that anticoagulation likely leads to minimizing complications while the recommendation for pediatric patients with asymptomatic deep vein thrombosis (DVT) is equivocal.

Objective:

This systematic review was undertaken to summarize evidence from the pediatric literature on the prevalence of asymptomatic CVC-RT in the neonate and whether anticoagulation therapy (ACT) improves the outcomes of asymptomatic CVC-RT in the neonate.

Methods:

We searched CENTRAL, MEDLINE, Embase, CINAHL, the Web of Science, and clinical trial databases. We considered data from retrospective and prospective cohort studies, case series, and randomized controlled studies evaluating the prevalence and outcomes of CVC-RT following the use or non-use of ACT. Data were analyzed using Fisher exact and Chi-square statistics.

Results:

In total 762 articles were identified and screened, of which 16 articles included (1 RCT, 4 prospective studies and 8 retrospective cohort studies, and 3 case reports) that met inclusion criteria and contained extracted case data; these studies reported on a total of 1909 neonates with CVC have been screened for thrombosis. All studies were considered at moderate or high risk of bias. Tau2 and I2 suggested a high degree of heterogeneity. Ultimately, 309 cases were identified with the prevalence of asymptomatic CVC-RT was 16%. Notably, only 6.5% of neonates with symptomatic CVC-RT had undergone ultrasound (US) screening. The majority of the cases were premature neonates. 45% of the neonate had Umbilical Vein Catcher (UVC). 114 (41%) of the cases received ACT, of which none complicated with major bleeding. Overall there was no difference following the use or nonuse of ACT in patency of the asymptomatic CVC-RT, recurrence, and thrombosis related mortality. The frequency of each outcome according to therapy is shown in Table1.

CONCLOSION:

This systematic review has provided additional evidence supporting the favorable outcome of asymptomatic CVC-RT in the neonate regardless of the use of ACT. Further well-designed, prospective, multi-center clinical trials are needed to establish evidence-based treatment recommendations for neonates with asymptomatic CVC-RT.

Figure

Disclosures

No relevant conflicts of interest to declare.
The Current Practice of Management of Asymptomatic Central Venous Catheters Associated Venous Thromboembolism in Children: A Result of Saudi Arabian Pediatric Hematology/Oncology Society Survey
Authors: Allahyani Bader , Ali Abdullah , Feder Joshua , Alshahrani Mohammad , Alsultan Abdulrahman , Alzahrani Azzah
Published: November 2020

Introduction:Central venous catheters (CVCs) are the main cause of venous thromboembolism (VTE) in critically ill children. The optimal first-line treatment for children with asymptomatic CVC-related VTE is unknown. Due to a paucity of clinical trials, clinical practice guidelines can offer only weak recommendations for the management of asymptomatic CVC- related VTE. This case-based survey was designed to assess current trends in local management strategies for pediatric patients with an asymptomatic CVC- related thrombosis. The survey focused on the use of the thrombophilia testing, management approach, duration of anticoagulation, and the use of secondary prophylaxis. We hypothesize that there will be significant variation in these four management areas, in large part due to the aforementioned paucity of available data.

Method:After Institutional Review Board approval, REDCap® questions were sent to members of the Saudi Arabian Pediatric Hematology/Oncology Society (SAPHOS) clinical forum/email database. We used a hypothetical case to assess management strategies for asymptomatic CVC-related VTE and secondary prophylaxis.

Result:Seventy-one (30%) physicians responded to the survey. The majority of the respondents (83.3%) did not use thrombophilia testing. 95% treated with anticoagulation, of which 20% treated only if clot propagation was identified on follow-up and 3.3% treated only if a thrombophilia was identified. In contrast, the survey respondents varied widely in the duration of anticoagulation (19% for 6 weeks, 41.4% for 12 weeks, 29.3% until CVC removal). Secondary prophylaxis was used by 20% of the respondents, whereas 21.4% did so, only if there was a previously identified thrombophilia.

Conclusion:Asymptomatic CVC-related VTE is a common clinical entity with limited data guiding management. In Saudi Arabia there remains considerable variability in clinical management; particularly, in the duration of treatment and use of secondary prophylaxis. These findings will help identify crucial knowledge gaps in the management of asymptomatic CVC-related VTE and facilitate clinical trials that will help establish evidence-based treatment guidelines.

Disclosures

No relevant conflicts of interest to declare.
NSD2 Regulates Pro-Metastatic Gene PTP4A3 through Chromatin Remodeling in Multiple Myeloma
Authors: Chong Phyllis SY , Chooi Jing Yuan , Lim Julia , Chng Wee-Joo
Published: November 2020

Nuclear receptor-binding SET domain 2 (NSD2) is the primary oncogenic driver and represent a good druggable target due to its universal overexpression in t(4;14) MM. However, given the challenges in the development of small molecule inhibitors against NSD2, we took on a discovery approach to characterize NSD2 interactome as an alternative strategy to target NSD2. We employed SILAC-based mass-spectrometry coupled with gene ontology analysis to uncover the spectrum of NSD2-interacting proteins which are relevant in t(4;14) MM. Validation using in silico protein-protein interaction analysis and immunoprecipitation confirmed that SMARCA2, a bromodomain-containing chromatin remodeler, interacts with NSD2 independent of the SWI/SNF complex. SMARCA2 is primarily expressed in t(4;14) cell lines, and functional assays indicated that dual inhibition of SMARCA2 and NSD2 impairs growth of t(4;14)+ cells. Next, we performed RNA sequencing which led to the identification of PTP4A3 as a downstream target of NSD2 that is co-regulated by SMARCA2. Mechanistically, SMARCA2 is required for the recruitment of NSD2 to PTP4A3 promoter, leading to a transcriptionally permissive state for expression. Importantly, upregulation of PTP4A3 is sufficient for the activation of MYC, which is crucial for t(4;14) myelomagenesis. PFI-3, which belongs to the class of bromodomain and extra-terminal motif protein inhibitors (BETi), displaced SMARCA2 and NSD2 occupancy from PTP4A3 promoter, and selectively inhibited t(4;14) myeloma cell viability. Interestingly, PFI-3 treatment did not perturb the levels of NSD2 nor SMARCA2, rather, the targeting effect is achieved through their occupancy on oncogenes. Finally, high expression of NSD2 and SMARCA2 were predictive of poor survival outcome in a large cohort of myeloma patients. Collectively, we demonstrated a proof-of-concept of how histone modifying enzyme and chromatin remodeling complex cooperatively caused an altered epigenetic state in myelomagenesis through the regulation of an important myeloma gene. Our study proposed that the pharmacological inhibition of SMARCA2 may represent a novel strategy to target t(4;14) myeloma cells using BETi and also explore as combinational therapy with anti-myeloma agents that are currently in the clinics.

Disclosures

No relevant conflicts of interest to declare.
Leukemia Stem Cells Demonstrate Increased DNA Damage Repair and Chemoresistance in Acute Myeloid Leukemia
Authors: Egan Grace , Thomas Geethu Emily , Patel Parasvi , Hurren Rose , MacLean Neil , Hakem Razq , Schimmer Aaron D
Published: November 2020

While most patients with AML achieve remission with standard induction chemotherapy, the majority ultimately relapse. Relapsed AML is due, at least in part, to the persistence of chemoresistant leukemia stem cells (LSCs). The mechanisms of chemoresistance in LSCs are not fully understood. Here, we explored DNA damage repair in LSCs.

8227 cells are low passage primary AML cells that maintain a hierarchical organization with functionally defined stem cells in the CD34+CD38- fraction. We FACS sorted 8227 cells into stem and bulk fractions and measured expression of DNA repair genes. LSCs were primed for DNA repair with increased expression of genes associated with homologous recombination (RAD51, XRCC2, XRCC3) and non-homologous end joining (XRCC4, XRCC5, PRKDC). Next, we treated the cell fractions with daunorubicin, an intercalating anthracycline that causes double stranded breaks. DNA damage and repair were evaluated by measuring foci of 53BP1, RAD51 and γH2AX by fluorescent microscopy and quantified using image J. Compared to bulk cells, 8227 stem cells demonstrated enhanced DNA damage repair with increased foci of 53BP1 and RAD51 and decreased γH2AX foci, compared to their basal levels. Similar findings were noted after exposing the stem and bulk cells to radiation.

We recently discovered that the metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus to maintain stem cell number and function. Therefore, we selectively over-expressed HK2 in the nucleus of 8227 and NB4 cells by tagging HK2 with a nuclear localizing sequence (PAAKRVKLD). We confirmed selective over-expression of HK2 in the nucleus by immunoblotting and confocal microscopy. Over-expressing HK2 increased stem cell function as shown by clonogenic growth assays and engraftment into mouse marrow. We then treated these cells with daunorubicin and measured DNA damage repair. Over-expression of nuclear HK2 increased 53BP1 and RAD51 foci with decreased γH2AX foci, similar to the phenotype observed in LSCs. In addition, over-expression of nuclear HK2 conferred resistance to daunorubicin as measured by clonogenic growth assays.

In summary, LSCs appear to be primed for DNA repair with increased levels of DNA damage repair genes. After exposure to chemotherapy and radiation, LSCs have increased repair of double strand DNA breaks compared to more differentiated blasts. This accelerated DNA damage repair may partly explain the increased chemoresistance seen in LSCs.

Disclosures

Schimmer: Takeda:Honoraria, Research Funding;Novartis:Honoraria;Jazz:Honoraria;AbbVie Pharmaceuticals:Other: owns stock ;Otsuka:Honoraria;Medivir AB:Research Funding.
Nuclear Protein DEK Governs Quiescence and Metabolic Homeostasis of Hematopoietic Stem Cells By Shaping Chromatin Accessibility
Authors: Chen Zhe , Li Lei , Chen Jieping , Hou Yu
Published: November 2020

Hematopoietic stem cells (HSCs) must achieve a balance between quiescence and activation that fulfils the demands for hematopoiesis without compromising long-term maintenance of HSCs. DEK, a chromatin architectural factor, is involved in chromatin remodeling, transcriptional regulation and DNA replication, and is implicated in genetic and epigenetic regulation of gene expression. Here, we identified that DEK is a critical regulator of HSCs quiescence. Deletion of DEK in mice resulted in abnormal hematopoiesis with an obvious decreased HSC pool size (~3700 to ~1700 cells/mouse), associated with apparent reduction in the proportion of HSCs in G0 phase as compared to control HSCs (~72% to ~57%). As shown by serial bone marrow transplantation and competitive repopulation assays, deletion of DEK impaired the self-renewal capacity of HSCs. Mechanistically, deficiency of DEK in HSC altered chromatin accessibility landscape, resulting in increased transcription of activation-specific genes (including Akt1/2,Ccnb2, and Rps6) and decreased transcription of quiescence-specific genes (including p21 and Gata2), leading to excessively activated Akt-mTOR signaling and elevated metabolism of HSC. Targeting the Akt-mTOR pathway efficiently abrogated the impaired quiescence and the increased metabolism of HSC in DEK-deficient mice, and partially rescued the long-term functions of HSC. Further, DEK regulated chromatin accessibility of HSC by recruiting the co-repressor NCoR1 to repress acetylation of histone 3 at lysine 27. Collectively, our findings revealed crucial functions of DEK in HSC quiescence maintenance and disclosed a new link between chromatin remodelers, epigenetic modification, gene transcription, and HSC homeostasis.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of Direct Oral Anticoagulants in Extremes Weights
Authors: Huang Julie , Chin Jamie , Hindenburg Alexander , Davenport Lilia , Willner Debra
Published: November 2020

Background: The clinical use of Direct oral anticoagulants (DOACs), as opposed to warfarin, has become more prevalent in patients with extremes in body weight. However, both the International Society on Thrombosis and Haemostasis' (ISTH) and anti-thrombotic therapy guidelines state that DOACs should be avoided in patients with a body mass index (BMI) >40 kg/m2, weight >120 kg, or weight < 50 kg. The purpose of this study was to analyze the efficacy and safety of DOACs in extremes of weight compared to patients treated with warfarin. Warfarin may be a safer and more effective oral anticoagulant for patients in extremes of weight, due to the availability of dosing based on INR. DOAC standard dosing may either overdose/underdose in patients with low/high BMI respectively.

Study Design and Methods: A retrospective, single-institution study evaluated patients with extreme weights receiving a DOAC or warfarin for either venous thromboembolism (VTE) or atrial fibrillation/atrial flutter between October 2016 and October 2020. Inclusion criteria consisted of patients admitted to NYU Langone Hospitals continued on a DOAC or warfarin for VTE or atrial fibrillation/atrial flutter with BMI < 18 kg/m2 or BMI > 30 kg/m2. Patients newly initiated on oral anticoagulation or received anticoagulation other than atrial fibrillation/atrial flutter or VTE were excluded. Primary endpoints include incidence of VTE or bleeding events in anticoagulated patients who meet extreme weight criteria.

Disclosures

No relevant conflicts of interest to declare.
Measles Reactivity in Windsor Patients Post Autologous Versus Allogeneic Hematopoietic Cell Transplantation: A Retrospective Review
Authors: Negus Kayla , Jarrar Mohammad , Woldie Indryas L. , Kanjeekal Sindu M. , McCann Kit , Hamm Caroline
Published: November 2020

Background

As the antivaccine movement has increased, vaccine preventable illnesses have also increased. The resurgence of measles globally has been noted, specifically the United States received 1200 new cases of measles in 2019, which is the highest number of cases since 1994. Measles is a highly contagious pathogen; the virus has an attack rate of up to 90% in susceptible individuals. Standard of care for patients post hematopoietic cell transplant (HCT) includes repeating all childhood vaccinations. However, compliance with recommendations is unknown. No previous reports have been created measuring the difference in measles, mumps, and rubella (MMR) reactivity between autologous and allogeneic HCT patients post treatment.

Methods

A retrospective chart review investigated HCT patients between 2000-2019 from the Windsor Regional Hospital (WRH) cancer centre. Patients were excluded from data collection if they were deceased before an MMR reactivity test could be done or if they were lost to follow up. A total of 83% of autologous HCT (N=57) and 66% of allogeneic HCT (N=47) patients had serology tested to measure MMR reactivity post-transplant prior to live vaccinations. MMR titres were drawn from autologous patients a median of 395 days after HCT and a median of 907 days after HCT for allogeneic patients.

Results

Overall, allogeneic HCT patients had more reactivity than autologous HCT patients as seen in Table 1.

Conclusion

All patients not reactive to measles need to be re-vaccinated 24 months after treatment according to 2019 American Society for Transplantation and Cellular Therapy guidelines. Our patients are treated in a variety of transplant centers in Ontario, Canada as well as Detroit, Michigan; which is of concern because measles cases have been reported in Detroit. The majority (66%) of allogeneic HCT patients had a myeloid malignancy, while 70% of autologous patients has a diagnosis of multiple myeloma. As evidenced by the poor MMR response, less robust immune systems may be accounted for by multiple myeloma patients. This does emphasize the need for MMR vaccinations post HCT for multiple myeloma patients and raises the question regarding immunization for at risk non-transplant eligible patients. We suggest that it may be reasonable to assess MMR immune status in all myeloma patients to determine if this is a transplant effect or an effect of the underlying immune status of the myeloma patient. This study does emphasize the need to assess MMR status post transplant in all myeloma patients, as the vast majority in our study did not demonstrate immunity post stem cell transplant.

Figure

Disclosures

Hamm: Amgen: Consultancy.
RNA Sequencing Analysis in Primary Mediastinal B Cell Lymphoma: Identification of Different Gene Expression Related to Chemoresistance
Authors: Parvis Guido Eugenio , Incarnato Danny , Torti Davide , Familiari Ubaldo , Vassallo Francesco , Carrà Giovanna , Oliviero Salvatore , Volante Marco , Guerrasio Angelo , Saglio Giuseppe , Morotti Alessandro
Published: November 2020

Background: Primary mediastinal large B cell lymphoma (PMLBCL) is a rare subtype of non-Hodgkin lymphoma mostly diagnosed in young women and is currently recognized as a distinct clinical and biological entity. First line therapy with R-CHOP allows to achieve good remission rates even if chemoresistant cases remain highly challenging from the therapeutic standpoint. As such, we aimed to compare the transcriptome of R-CHOP resistant PMBCL patients to those of chemosensitive patients.

Methods:We extracted RNA from embedded paraffin samples and then we performed whole RNA sequencing on 7 patients. Four of them were selected as chemoresistant (Group A), while three of them were classified as responder to R-CHOP (Group B). A First bioinformatics analysis selected a panel of 200 genes significantly differentially expressed in chemoresistant (A) samples versus chemosensitive (B). An unbiased analysis based on different ontology of the genes led to easily identify common signatures that may better profile the two groups of patients. Finally, on a bias analysis, genes were divided into categories in order to identify potential new targets and/or mechanisms of chemoresistance.

Results:We identified three genes which may be frankly related to chemoresistance in PMLBCLs due to an overexpression in the group A or a suppression of expression in group B. We selected NFKBIA, the gene which encodes for the IκBα protein, mutated in numerous Hodgkin's lymphoma cells, which cause NFkB to be chronically active in the lymphoma tumor cells. For this reason, we imagine that it could have a major role in the modulation of PMLBCLs sensitivity to chemotherapy.

EPHB1 was selected for its very strong expression in the poor prognosis group, since it is one of the most expressed genes and for his association with numerous cancers. The kinase STK 33 appeared overexpressed in group A. A more thorough investigation of this gene might lead to new, significant findings.

Conclusions:

Our in-silico analyses allowed to identify in PMBCL an unique profile that may modulate sensitivity to chemotherapy. Further analyses may address whether this unique phenotype has clinical implications. We may expect to: i) develop specific therapeutic strategies to target NFkB, EPHB1 and STK33 pathways in PMBCL with a chemoresistant behaviour; ii) correlate the expression profile of resistant PMBCL to other transcriptomes, including those of Hodgkin Lymphomas, Diffuse Large B cell Lymphomas, in order to better profile clinical and biological overlapping features.

Disclosures

Saglio: Ariad:Research Funding;Incyte:Research Funding;Roche:Research Funding;Bristol-Myers Squibb:Research Funding;Pfizer:Research Funding;Novartis:Research Funding.
Bleeding Diathesis in Mice Lacking JAK2 in Platelets
Authors: Eaton Nathan , Subramaniam Saravanan , Schulte Marie L , Drew Caleb , Jakab David , Haberichter Sandra L , Weiler Hartmut , Falet Herve
Published: November 2020

The tyrosine kinase JAK2 is a critical component of intracellular JAK/STAT cytokine signaling cascades that is prevalent in hematopoietic cells such as hematopoietic stem and progenitor cells (HSPCs), megakaryocytes (MKs), and platelets. Individuals expressing somatic activating JAK2 mutations such as JAK2V617F commonly develop myeloproliferative neoplasms (MPNs) associated with serious complications, including venous and arterial thrombosis, a leading cause of mortality. Here, we investigated the role of JAK2 in hemostasis and thrombosis using Jak2fl/flPf4-Cre (Jak2Plt-/-) mice specifically lacking JAK2 within the platelet lineage. Jak2Plt-/- mice developed severe thrombocytosis with a 5-fold increase in circulating platelet number, MK hyperplasia, and splenomegaly. Jak2Plt-/-platelets were of normal size and the expression of major membrane surface glycoproteins was indistinguishable from controls, except for the integrin β3, which was reduced by 20%. Despite the thrombocytosis, Jak2Plt-/- mice had a severe bleeding diathesis, as evidenced by: 1) prolonged tail bleeding time; 2) failure to occlude in a ferric chloride-induced carotid artery injury model; and 3) failure to form stable thrombi in a laser-induced cremaster muscle injury model. Jak2Plt-/- platelets spread poorly on immobilized collagen or on immobilized fibrinogen following GPVI stimulation with the collagen-related peptide (CRP). Jak2Plt-/- platelets had defective α-granule secretion and integrin αIIbβ3 activation following stimulation with CRP, but not thrombin, and showed aggregation defects with low-doses of CRP. Together, the data support a GPVI-specific impairment in platelets lacking JAK2, a notion that was supported by impaired intracellular signaling following GPVI stimulation, as assessed by protein tyrosine phosphorylation. Jak2Plt-/- platelets adhered poorly to type I collagen under arterial shear rates in whole blood. However, JAK2 deletion in platelets did not alter plasma von Willebrand factor (VWF) levels or botrocetin-mediated binding of plasma VWF to GPIbα. Together, the results underline a critical role for JAK2 in platelet GPVI signaling and hemostatic function, which likely contributes to venous and arterial thrombosis observed in patients with MPNs with the activating JAK2V617F mutation.

Disclosures

No relevant conflicts of interest to declare.
Stratification of Vascular Profile in Multiple Myeloma Patients Using Thrombin Generation Test
Authors: Papageorgiou Loula , Van Dreden Patrick , Garderet Laurent , Grusse Matthieu , Elalamy Ismail , Gerotziafas Grigoris
Published: November 2020

Introduction: Multiple myeloma (MM) is an hematological disease linked to a high thrombotic risk, estimated at around 10%/year, irrespective to disease onset. An important proportion of MM patients presents at least one of the well-defined vascular risk factors, such as diabetes, cardiac disease, hypertension or hyperlipidemia, which contribute to thrombotic risk. Thrombin Generation Test (TGT) could be an useful biomarker reflecting the prothrombotic profile of MM patients.

Aim: To evaluate the potential correlation between vascular risk factors and TGT in MM patients.

Materials and methods: This is a monocentric, prospective, non-interventional study on a cohort of 82 MM patients referred to the Hemostasis Center at Tenon University Hospital. Patients receiving already anticoagulant treatment of any kind were excluded. Thrombin generation was performed at their first visit using the Calibrated Thrombogram Assay (CAT®,Stago, Genevilliers, France), according to manufacturer's instructions. We collected all TGT parameters: lag time (LT), Endogenous Thrombin Potential (ETP) and Mean Rate Index (MRI).We also measured factor VIII activity (FVIII). Results were statistically analyzed using a two-sample t-test.

Results: Among 82 patients with a male/female ratio of 44/35 and a median age at 65.2 years, 39 patients (48%) presented at least one cardiovascular risk factor (group A) and 42 had no vascular risk factors (group B) The LT value was reduced but not reaching a statistical difference between groups A and B (3 vs 3.95 sec, p= 0.8). MRI representing velocity was statistically shorter in group A (100 vs 118 nmol/min , p< 0.001). Surprisingly, ETP was significantly reduced in group A (1392 vs 1717 nmol/l x min, p < 0.001). FVIII levels were increased in group A (216% vs 192 %, p<0.05).

Conclusion: MM hypercoagulability can be easily identified with MRI, a chronometric TGT parameter. Increased FVIII levels observed in vascular patients are also facilitating an accelerated thrombin generation and are correlated with an endothelial activation. ETP decrease, reflecting the link between both content and container, must be seen as an adaptative response. Thus, endothelial activation could lead to TFPI release and this particular TGT profile in high vascular risk MM patients with a hypercoagulable state.

Disclosures

No relevant conflicts of interest to declare.
Primary Mediastinal B-Cell Lymphoma: The Dilemma of Radiotherapy
Authors: Saraiva Filipa , Saunders Christopher J. , Fevereiro Margarida , Monteiro Alexandra , Sousa Aida B
Published: November 2020

Introduction: According to the WHO classification, primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a distinct entity, which has a close relationship with nodular sclerosing classical Hodgkin's lymphoma (cHL) in terms of clinical and molecular characteristics and sharing an excellent prognosis. When PMBCL is treated with R-CHOP, the addition of radiotherapy (RT) turns more than 90% of positron emission tomography (PET) positive cases into complete remissions (CR) and increases 5-year overall survival (OS) to 93%. However, the fear of potential late toxicities due to RT, has led an increasing number of centers to favor more intensive regimens like DA-EPOCH-R without RT. This controversy is deepened by the recent comparison between the latter regime with R-CHOP, unfavorable to the DA-EPOCH-R for toxicity reasons.

Objective: Evaluate the effectiveness and late toxicities of R-CHOP plus RT in our center and secondarily compare these results with the ones obtained in our cHL patients with bulky and early stage disease.

Methods: Retrospective analysis of patients with PMBCL treated between Jan/2007 and Dec/2017 according to clinical characteristics, late toxicities, rate of CR, OS and disease-free survival (DFS) estimated by Kaplan-Meier method.

Results: In 32 patients with a median age of 34 years (23-70), 56% were male, 91% had limited stage and 6% had an unfavorable IPI. The rate of CR was 91% (2 patients needed second line therapy to achieve CR) with 2 relapses (at 6 and 11 months, respectively) rescued with autologous transplantation. Three deaths were recorded due to disease progression. With a median follow-up of 86 months, OS and DFS at 10 years were 91% and 93%, respectively. As for late toxicities, besides 2 cases of severe pulmonary fibrosis, there were no other relevant late toxicities registered. These results overlap those obtained in our cHL patients with bulky and early stage disease treated with Stanford V plus RT with an OS and an event free survival of 93% and 84%, respectively.

Conclusion: These results support PMBCL's excellent prognosis, parallel to that of cHL. Given the low probability of late toxicities with this regimen our data uphold against the therapeutic strategy of more intensive regimens, that have an increased management complexity and are clinically more toxic.

Disclosures

No relevant conflicts of interest to declare.
Echocardiographic Changes of Carfilzomib Therapy in Multiple Myeloma Patients
Authors: Bahaj Waled , Albawaliz Anas , Begemann Madeline E , Shrestha Anuj , Sperry Brett , Raza Shahzad
Published: November 2020

Introduction: Carfilzomib is a proteasome inhibitor that is known to be associated with cardiotoxicity. Current clinical data on Carfilzomib associated with cardiotoxicity is generated in clinical trials from which patients with severe cardiovascular comorbidities were excluded. In this study, we have reported real-word experience on outcome of cardiotoxicity in patients managed by physicians in a community setting.

Methods: We performed a retrospective analysis evaluating for cardiac complications in MM patients who received Carfilzomib at our institution in the last 5 years. Pre- and post-therapy echocardiogram findings were compared. Chi-square tests were used to compare categorical variables with an α level set at 0.05 for statistical significance.

Results: Among the 28 identified patients who had pre- and post- Carfilzomib therapy echocardiogram imaging, (18 patients, 64%) had at least one echocardiographic abnormality. The main changes were in heart functions (10/28), whereas systolic dysfunction is seen in 9 patients while only one patient had diastolic dysfunction, pulmonary artery pressure (6/28), and wall motion abnormalities (5/28). (11/28) patients had disease progression. We did not notice any correlation to variables such as; age, duration of therapy, dose differences, and number of lines of therapies. Furthermore, two patients were rechallenged with Carfilzomib after echocardiographic worsening; one of them tolerated the treatment well, while the other had further worsening that led to holding the therapy.

Conclusion: Several echocardiographic changes could be related to Carfilzomib therapy. Our study was limited due to the sample size and the retrospective nature of the analysis. Larger studies are needed to detect and correlate more echocardiogram variables in this population. Rechallenging these patients with Carfilzomib, particularly during relapse stages, will remain a difficult decision especially if the therapy was effective.

Disclosures

Raza: Advisory board Incyte, Amgen, Celgene, Kite, Janseen, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Moderna: Current equity holder in publicly-traded company; Drrx: Divested equity in a private or publicly-traded company in the past 24 months; Gilead, Sierra, Abbot, Acasti, Amicus: Current equity holder in private company; Received Honorarium/speaker bureu from Janseen, Celgene, Takeda: Ended employment in the past 24 months, Honoraria, Speakers Bureau.