bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-36: Functional bypass of cell cycle entry checkpoints by MYC T58A mutation in germinal center-derived lymphomas
Authors: Lee Jongkuen , Dominguez-Sola David 
Published: December 2020

Abstract
Somatic missense mutations targeting MYC's coding sequence are found in &gt;50% of Burkitt lymphomas and in a small fraction of diffuse large B-cell lymphomas. These mutations typically arise in translocated MYC alleles and cluster at specific protein residues, particularly Threonine 58 (T58). Previous studies in non-B cell models suggested that MYC mutations enhance oncogenic properties by escaping MYC-induced apoptosis. However, the functional impact of these mutations on the biology of germinal center (GC) B cells, where these mutations arise, has never been investigated. In GC B cells, MYC expression is induced by positive selection signals during cognate interactions with T follicular helper cells, concurrent with activation of PI3K and mTOR signaling. PI3K and mTOR are activated upon CD40 and B-cell receptor co-engagement and are critically required for positive selection and clonal expansion of GC B cells. Using newly generated MYC T58A knock-in mouse models, we found that MYC T58A mutation allows B cells to bypass a cell cycle entry checkpoint dependent on PI3K and mTOR activities. Exposure of wild-type (WT) B cells to rapamycin or, less markedly, to PI3K inhibitors, prevented the proliferation upon CD40 and IL4 stimulation ex vivo (a cytokine combination mimicking T-cell help) whereas MYC T58A mutant B cells divided multiple times and maintained adequate rates of active biosynthesis. Similarly, administration of rapamycin to immunized WT mice collapsed formed GCs while MYC T58A GCs maintained normal size and proliferation rates in vivo. These phenotypes were in part explained by the effects of PI3K/mTOR signaling on GSK3-beta, a kinase that normally phosphorylates MYC T58 to control protein turnover. Differences in metabolic and gene expression profiles between MYC WT and T58A cells offered additional insights into the mechanisms by which this mutation bypasses PI3K/mTOR checkpoint. Finally, we found that GC B cell-specific overexpression of MYC T58A, resulted in abnormally enlarged GCs upon immunization, a phenotype common to lymphoma models. Altogether, these results indicate that MYC somatic mutations confer competitive advantages to B cells by bypassing a strict requirement for upstream signals during cell cycle entry, which may support the clonal expansion of MYC mutant B cells during GC responses. These results have important translational implications, particularly given the increasing interest in the potential use of PI3K and/or mTOR inhibitors in the treatment of lymphomas.
Citation Format: Jongkuen Lee, David Dominguez-Sola. Functional bypass of cell cycle entry checkpoints by MYC T58A mutation in germinal center-derived lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-36.
Abstract PO-54: Mechanistic consequences of histone-deacetylase inhibition towards sensitizing PD1 blockade-resistant B-cell lymphomas
Authors: Wang Xiaoguang , Waschke Brittany C. , Woolaver Rachel A. , Chen Zhangguo , Zhang Gan , Piscopio Anthony D. , Liu Xuedong , Wang Jing H. 
Published: December 2020

Abstract
PD1 blockade is effective in a subset of B-cell lymphoma patients (e.g., classical Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To overcome PD1 resistance, we employ a newly developed isoform-selective histone-deacetylase-inhibitor (HDACi) (OKI-179) and a novel mouse mature B-cell lymphoma, G1XP lymphoma, that resembles immunosuppressive features of human B-cell lymphomas including downregulation of major histocompatibility complex (MHC) class I and II, exhaustion of CD8 and CD4 tumor-infiltrating lymphocytes (TILs), and PD1-blockade resistance. Using multiple lymphoma models, we show that combined treatment of OKI-179/anti-PD1 significantly inhibited growth of B-cell lymphomas refractory to PD1 blockade; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated to MHC class II level. We conclude that OKI-179 sensitizes lymphomas to PD1 blockade by enhancing tumor immunogenicity. Additionally, we found that different HDACi exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas. Thus, our study highlights the importance of immunologic effects of HDACi on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and unique profiles of HDACi.
Citation Format: Xiaoguang Wang, Brittany C. Waschke, Rachel A. Woolaver, Zhangguo Chen, Gan Zhang, Anthony D. Piscopio, Xuedong Liu, Jing H. Wang. Mechanistic consequences of histone-deacetylase inhibition towards sensitizing PD1 blockade-resistant B-cell lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-54.
Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19
Authors: Ng Henry , Havervall Sebastian , Rosell Axel , Aguilera Katherina , Parv Kristel , von Meijenfeldt Fien A. , Lisman Ton , Mackman Nigel , Thålin Charlotte , Phillipson Mia 
Published: December 2020

Objective:
The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy. The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression. Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis.

Approach and Results:
One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months. Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase). We found that all plasma levels of NET markers were elevated in patients with COVID-19 relative to healthy controls, that they were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection. The levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage.

Conclusions:
Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state. Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19.
NADPH Oxidases Are Required for Full Platelet Activation In Vitro and Thrombosis In Vivo but Dispensable for Plasma Coagulation and Hemostasis
Authors: Vara Dina , Mailer Reiner K. , Tarafdar Anuradha , Wolska Nina , Heestermans Marco , Konrath Sandra , Spaeth Manuela , Renné Thomas , Schröder Katrin , Pula Giordano 
Published: December 2020

Objective:

Using 3KO (triple NOX [NADPH oxidase] knockout) mice (ie, NOX1
−/−
/NOX2
−/−
/NOX4
−/−
), we aimed to clarify the role of this family of enzymes in the regulation of platelets in vitro and hemostasis in vivo.

Approach and Results:
3KO mice displayed significantly reduced platelet superoxide radical generation, which was associated with impaired platelet aggregation, adhesion, and thrombus formation in response to the key agonists collagen and thrombin. A comparison with single-gene knockouts suggested that the phenotype of 3KO platelets is the combination of the effects of the genetic deletion of NOX1 and NOX2, while NOX4 does not show any significant function in platelet regulation. 3KO platelets displayed significantly higher levels of cGMP—a negative platelet regulator that activates PKG (protein kinase G). The inhibition of PKG substantially but only partially rescued the defective phenotype of 3KO platelets, which are responsive to both collagen and thrombin in the presence of the PKG inhibitors KT5823 or Rp-8-pCPT-cGMPs, but not in the presence of the NOS (NO synthase) inhibitor L-NG-monomethyl arginine. In vivo, triple NOX deficiency protected against ferric chloride–driven carotid artery thrombosis and experimental pulmonary embolism, while hemostasis tested in a tail-tip transection assay was not affected. Procoagulatory activity of platelets (ie, phosphatidylserine surface exposure) and the coagulation cascade in platelet-free plasma were normal.

Conclusions:
This study indicates that inhibiting NOXs has strong antithrombotic effects partially caused by increased intracellular cGMP but spares hemostasis. NOXs are, therefore, pharmacotherapeutic targets to develop new antithrombotic drugs without bleeding side effects.
Number of Social Determinants of Health and Fatal and Nonfatal Incident Coronary Heart Disease in the REGARDS Study
Authors: Safford Monika M. , Reshetnyak Evgeniya , Sterling Madeline R. , Richman Joshua S. , Muntner Paul M. , Durant Raegan W. , Booth John , Pinheiro Laura C. 
Published: December 2020

Background:
Social determinants of health (SDH) are individually associated with incident coronary heart disease (CHD) events. Indices reflecting social deprivation have been developed for population management, but are difficult to operationalize during clinical care. We examined whether a simple count of SDH is associated with fatal incident CHD and nonfatal myocardial infarction (MI).

Methods:
We used data from the prospective longitudinal REGARDS cohort study (Reasons for Geographic and Racial Differences in Stroke), a national population-based sample of community-dwelling Black and White adults age ≥45 years recruited from 2003 to 2007. Seven SDH from the 5 Healthy People 2020 domains included social context (Black race, social isolation); education (educational attainment); economic stability (annual household income); neighborhood (living in a zip code with high poverty); and health care (lacking health insurance, living in 1 of the 9 US states with the least public health infrastructure). Outcomes were expert adjudicated fatal incident CHD and nonfatal MI.

Results:
Of 22 152 participants free of CHD at baseline, 58.8% were women and 42.0% were Black; 20.6% had no SDH, 30.6% had 1, 23.0% had 2, and 25.8% had ≥3. There were 463 fatal incident CHD events and 932 nonfatal MIs over a median of 10.7 years (interquartile range, 6.6 to 12.7). Fewer SDHs were associated with nonfatal MI than with fatal incident CHD. The age-adjusted incidence per 1000 person-years increased with the number of SDH for both fatal incident CHD (0 SDH, 1.30; 1 SDH, 1.44; 2 SDH, 2.05; ≥3 SDH, 2.86) and nonfatal MI (0 SDH, 3.91; 1 SDH, 4.33; ≥2 SDH, 5.44). Compared with those without SDH, crude and fully adjusted hazard ratios for fatal incident CHD among those with ≥3 SDH were 3.00 (95% CI, 2.17 to 4.15) and 1.67 (95% CI, 1.18 to 2.37), respectively; hazard ratios for nonfatal MI among those with ≥2 SDH were 1.57 (95% CI, 1.30 to 1.90) and 1.14 (95% CI, 0.93 to 1.41), respectively.

Conclusions:
A greater burden of SDH was associated with a graded increase in risk of incident CHD, with greater magnitude and independent associations for fatal incident CHD. Counting the number of SDHs may be a promising approach that could be incorporated into clinical care to identify individuals at high risk of CHD.
Digging Deeper into the “Plausibility of Rights”-Criterion in the Provisional Measures Jurisprudence of the ICJ
Authors: Kolb Robert 
Published: December 2020

Abstract
Since 2009, the ICJ has included a plausibility requirement as a condition for indicating provisional measures as demanded by the applicant. What that criterion exactly means and how it is to be applied remains uncertain. This short contribution delves into some blind spots, which have not to date been meaningfully discussed either by the Court or in legal writings. The two main issues turn around the meaning of “preservation of rights” and the applicable standard for determining plausibility. In particular the rights-limb is replete with legal intricacies. Further, some ancillary aspects are discussed, e.g. the link of plausibility with jurisdictional issues. Various conclusions are drawn and some preferred interpretations uttered on these questions.
Ethnic nationalism and gendered morality in the semiotic construction of the Moro language of Sudan
Authors: Lamoureaux Siri 
Published: December 2020

Abstract
This paper brings together discussions on language and nationalism, with gender and nationalism. Drawing from ‘language ideology’ and ‘indexical gender’ from a linguistic anthropological approach, it traces the emergence of the “Moro language”, in the context of a Moro ethnic national movement, originating in the Nuba Mountains of Sudan, and how it became indexically linked with masculine authority. Moro identify as Nuba and Christian, as opposed to Arab and Muslim, the dominant identities. Christian literacy, spearheaded by patriarchal leadership became the frame through which Moro organized ethnic identity and unity. The constructed language, as the object of metapragmatic evaluation, is also tightly woven into norms of morality and gender within the community. Two registers are identified: textuality is normatively masculine and orality is normatively feminine. The Moro community draws on gendered ideologies to produce a new writing and speaking style, the “Moro Bible Language” (MBL). MBL results from the interweaving of the two registers in language standardization practices. Negotiating the ideologies that bring MBL to life occurs in metalinguistic discourse, teaching, learning and speaking styles. Since the politics of standardization are foregrounded, even seeming apolitical projects are laden with moral worth in the turbulent context of rapid cultural change.
Contextualising the Socialisation of Muslim Minorities within Parental Upbringing Values in the Netherlands
Authors: Chafai Habiba 
Published: December 2020

Abstract
The objective of the present review article is to position the role of parents from Muslim backgrounds in shaping the participation and socialisation of their children in Dutch society. It particularly seeks to contextualise the topic among Moroccan-Dutch parents from a cultural perspective by discussing gender issues, religiosity, identity and parental upbringing. The review begins by providing a context on Moroccan-Dutch migration history, religious and cultural background, and socio-economic status. It aims to explore the relationship between the transmission of parental upbringing and the socialisation of children by discussing the representation of Muslims in the media, the portrayal of Muslim women in the integration discourse, markers of identity and sense of belonging, and the impact of parental upbringing values.
Perceived health, adversity, and posttraumatic stress disorder in Syrian and Iraqi refugees
Authors: Javanbakht Arash , Grasser Lana Ruvolo , Kim Soyeong , Arfken Cynthia L , Nugent Nicole 
Published: December 2020

Background: Exposure to armed conflict and fleeing country of origin for refugees has been associated with poorer psychological health. Methods: Within the first month following their arrival in the United States, 152 Syrian and Iraqi refugees were screened in a primary care setting for posttraumatic stress disorder (PTSD), anxiety, and depression and rated their perceived health, and perceived level of adversity of violence, armed conflict/flight. The moderating effects of psychiatric symptoms on the relation between perceived adversity and perceived health were assessed. Results: Three models based on diagnosis (PTSD, anxiety, and depression) were tested. While significant effects were found on perceived adversity negatively influencing perceived health across diagnoses, slightly different patterns emerged based on diagnosis. Discussion: Findings suggest that refugees’ perception regarding adversity of violence, armed conflict, and flight may contribute to perceived health, with a moderating role of clinically significant symptoms of PTSD, anxiety, and depression.
External control mechanisms and red tape: testing the roles of external audit and evaluation on red tape in quasi-governmental organizations
Authors: Oh Youngmin , Lee Kyungeun 
Published: December 2020

Over the past three decades, red tape has been a significant issue in public administration. Several prior studies have discovered the external origins of red tape, noting the roles of external control on increased red tape. Despite the empirical studies, it remains unclear how the particular tools of external controls, such as external audits and evaluations, are associated with employees’ perception of red tape. To answer this question, we measured different external control mechanisms in quasi-governmental organizations in Korea and investigated their effects on red-tape perception. The results show that external audits increase employees’ red-tape perception, whereas external evaluations decrease their perception. However, the positive function of evaluation disappears under a high level of government control because both external audits and evaluations increase red-tape perception when more government control is perceived. Points for practitioners This study sheds theoretical light on the negative impacts of external control in rule management. The impacts of audit and evaluation on red tape are empirically identified in public organizations. Practitioners need to realize that the use of audit and evaluation may produce unintended effects that increase ineffective rules even though such control mechanisms are designed to check mismanagement in quasi-government organizations.
Computed tomography characteristics of multiple myeloma and other osteolytic metastatic bone lesions
Authors: Mutlu Uygar , Balci Ali , Özsan Güner Hayri , Özkal Sermin , Şeyhanli Ahmet , Özgül Hakan Abdullah 
Published: December 2020

Background Differentiation of multiple myeloma (MM) from osteolytic metastatic (OM) bone lesions may be critical in patients with lytic bone lesions but can be challenging for radiologists. Purpose To determine whether computed tomography (CT) can be used to distinguish between MM and other OM bone lesions. Material and Methods In this retrospective study, 320 lesions of 207 patients diagnosed with MM or OM, based on biopsy or clinical examination, were evaluated. Eight qualitative features were evaluated by two radiologists blinded to the diagnoses. The chi-square and Fisher exact tests, and logistic regression analysis, were used to evaluate the relationships between the CT findings and diagnoses. Results High-density areas were more common in OM than MM lesions (85.2% and 19%, P < 0.001), as were perilesional sclerosis (38.9% vs. 13.2%, P < 0.001), heterogeneity (on non-contrast CT images, 60% vs. 19.1%, P < 0.001; on contrast enhanced CT images, 80.6% vs. 28.2%, P < 0.001), and ill-defined margins (34.6% vs. 9.1%, P < 0.001). Similarly, OM lesions showed high-density areas more than MM in evaluation of skeletal system subgroups (vertebrae, 93.8% vs. 29.8%, P < 0.0001; thoracic cage bones, 69.6% vs. 19.2%, P < 0.001; pelvic bones and sacrum, 84.8% vs. 7.7%, P < 0.001; peripheral skeletal bones, 81.5% vs. 8.3%, P < 0.001). Logistic regression analysis revealed that the presence of a high-density area in the lesion increased the probability of a metastasis 25.88-fold (R2 = 0.516, P < 0.001). Conclusion MM and OM lesions can be differentiated by CT; OM lesions exhibit high- density areas.
Effect of Slope and Varus Correction High Tibial Osteotomy in the ACL-Deficient and ACL-Reconstructed Knee on Kinematics and ACL Graft Force: A Biomechanical Analysis
Authors: Imhoff Florian B. , Comer Brendan , Obopilwe Elifho , Beitzel Knut , Arciero Robert A. , Mehl Julian T. 
Published: December 2020

Background: Correction of high posterior tibial slope is an important treatment option for revision of anterior cruciate ligament (ACL) failure as seen in clinical and biomechanical studies. In cases with moderate to severe medial compartment arthritis, an additional varus correction osteotomy may be added to improve alignment. Purpose: To investigate the influence of coronal and sagittal correction high tibial osteotomy in ACL-deficient and ACL-reconstructed knees on knee kinematics and ACL graft load. Study Design: Controlled laboratory study. Methods: Ten cadaveric knees were selected according to previous computed tomography measurements with increased native slope and slight varus tibial alignment (mean ± SD): slope, 9.9°± 1.4°; medial proximal tibia angle, 86.5°± 2.1°; age, 47.7 ± 5.8 years. A 10° anterior closing-wedge osteotomy, as well as an additional 5° of simulated varus correction osteotomy, were created and fixed using an external fixator. Four alignment conditions—native, varus correction, slope correction, and combined varus and slope correction—were randomly tested in 2 states: ACL-deficient and ACL-reconstructed. Compressive axial loads were applied to the tibia while mounted on a free-moving X-Y table and free-rotating tibia in a knee testing fixture. Three-dimensional motion tracking captured anterior tibial translation (ATT) and internal tibial rotation. Change of tensile forces on the reconstructed ACL graft were recorded. Results: In the ACL-deficient knee, an isolated varus correction led to a significant increase of ATT by 4.3 ± 4.0 mm ( P = .04). Isolated slope reduction resulted in the greatest decrease of ATT by 6.2 ± 4.3 mm ( P < .001). In the ACL-reconstructed knee, ATT showed comparable changes, while combined varus and slope correction led to lower ATT by 3.7 ± 2.6 mm ( P = .01) than ATT in the native alignment. Internal tibial rotation was not significantly altered by varus correction but significantly increased after isolated slope correction by 4.0°± 4.1° ( P < .01). Each isolated or combined osteotomy showed decreased forces on the graft as compared with the native state. The combined varus and slope osteotomy led to a mean decrease of ACL graft force by 33% at 200 N and by 58% at 400 N as compared with the native condition ( P < .001). Conclusion: A combined varus and slope correction led to a relevant decrease of ATT in the ACL-deficient and ACL-reconstructed cadaveric knee. ACL graft forces were significantly decreased after combined varus and slope correction. Thus, our biomechanical findings support the treatment goal of a perpendicular-aligned tibial plateau for ACL insufficiencies, especially in cases of revision surgery. Clinical Relevance: This study shows the beneficial knee kinematics and reduced forces on the ACL graft after combined varus and slope correction.