bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of BCL-2 in Both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T-cell Immunotherapy against Cancer
Authors: Lee Yong Gu , Guruprasad Puneeth , Ghilardi Guido , Pajarillo Raymone , Sauter Christopher Tor , Patel Ruchi , Ballard Hatcher J. , Hong Seok Jae , Chun Inkook , Yang Nicholas , Amelsberg Kimberly V. , Cummins Katherine D. , Svoboda Jakub , Gill Saar , Chong Elise A. , North Khrystyna , Church Sarah E. , Fraietta Joseph A. , Chang Wan-Jung , Lacey Simon F. , Lu Xueqing Maggie , Zhang Yunlin , Whig Kanupriya , Schultz David C. , Cherry Sara , Gerson James , Schuster Stephen J. , Porazzi Patrizia , Ruella Marco 
Published: July 2022

AbstractChimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence.Significance:This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies—the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies.This article is highlighted in the In This Issue feature, p. 2221
Cost-Effectiveness of Polygenic Risk Scores to Guide Statin Therapy for Cardiovascular Disease Prevention
Authors: Kiflen Michel , Le Ann , Mao Shihong , Lali Ricky , Narula Sukrit , Xie Feng , Paré Guillaume 
Published: July 2022

Background:
Atherosclerotic cardiovascular diseases (CVDs) are leading causes of death despite effective therapies and result in unnecessary morbidity and mortality throughout the world. We aimed to investigate the cost-effectiveness of polygenic risk scores (PRS) to guide statin therapy for Canadians with intermediate CVD risk and model its economic outlook.

Methods:
This cost-utility analysis was conducted using UK Biobank prospective cohort study participants, with recruitment from 2006 to 2010, and at least 10 years of follow-up. We included nonrelated white British-descent participants (n=96 116) at intermediate CVD risk with no prior lipid lowering medication or statin-indicated conditions. A coronary artery disease PRS was used to inform decision to use statins. The effects of statin therapy with and without PRS, as well as CVD events were modelled to determine the incremental cost-effectiveness ratio from a Canadian public health care perspective. We discounted future costs and quality-adjusted life-years by 1.5% annually.

Results:
The optimal economic strategy was when intermediate risk individuals with a PRS in the top 70% are eligible for statins while the lowest 1% are excluded. Base-case analysis at a genotyping cost of $70 produced an incremental cost-effectiveness ratio of $172 906 (143 685 USD) per quality-adjusted life-year. In the probabilistic sensitivity analysis, the intervention has approximately a 50% probability of being cost-effective at $179 100 (148 749 USD) per quality-adjusted life-year. At a $0 genotyping cost, representing individuals with existing genotyping information, PRS-guided strategies dominated standard care when 12% of the lowest PRS individuals were withheld from statins. With improved PRS predictive performance and lower genotyping costs, the incremental cost-effectiveness ratio demonstrates possible cost-effectiveness under thresholds of $150 000 and possibly $50 000 per quality-adjusted life-year.

Conclusions:
This study suggests that using PRS alongside existing guidelines might be cost-effective for CVD. Stronger predictiveness combined with decreased cost of PRS could further improve cost-effectiveness, providing an economic basis for its inclusion into clinical care.
Cardiac Comorbidity Risk Score: Zero‐Burden Machine Learning to Improve Prediction of Postoperative Major Adverse Cardiac Events in Hip and Knee Arthroplasty
Authors: Onishchenko Dmytro , Rubin Daniel S. , van Horne James R. , Ward R. Parker , Chattopadhyay Ishanu 
Published: July 2022

Background
In this retrospective, observational study we introduce the Cardiac Comorbidity Risk Score, predicting perioperative major adverse cardiac events (MACE) after elective hip and knee arthroplasty. MACE is a rare but important driver of mortality, and existing tools, eg, the Revised Cardiac Risk Index demonstrate only modest accuracy. We demonstrate an artificial intelligence‐based approach to identify patients at high risk of MACE within 4 weeks (primary outcome) of arthroplasty, that imposes zero additional burden of cost/resources.

Methods and Results
Cardiac Comorbidity Risk Score calculation uses novel machine learning to estimate MACE risk from patient electronic health records, without requiring blood work or access to any demographic data beyond that of sex and age, and accounts for variable/missing/incomplete information across patient records. Validated on a deidentified cohort (age >45 years, n=445 391), performance was evaluated using the area under the receiver operator characteristics curve (AUROC), sensitivity/specificity, positive predictive value, and positive/negative likelihood ratios. In our cohort (age 63.5±10.5 years, 58.2% women, 34.2%/65.8% hip/knee procedures), 0.19% (882) experienced the primary outcome. Cardiac Comorbidity Risk Score achieved area under the receiver operator characteristics curve=80.0±0.4% (95% CI) for women and 80.1±0.5% (95% CI) for males, with 36.4% and 35.1% sensitivities, respectively, at 95% specificity, significantly outperforming Revised Cardiac Risk Index across all studied age‐, sex‐, risk‐, and comorbidity‐based subgroups.

Conclusions
Cardiac Comorbidity Risk Score, a novel artificial intelligence‐based screening tool using known and unknown comorbidity patterns, outperforms state‐of‐the‐art in predicting MACE within 4 weeks postarthroplasty, and can identify patients at high risk that do not demonstrate traditional risk factors.
Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts
Authors: Lamprea‐Montealegre Julio A. , Arnold Alice M. , McCLelland Robyn L. , Mukamal Kenneth J. , Djousse Luc , Biggs Mary L. , Siscovick David S. , Tracy Russell P. , Beisswenger Paul J. , Psaty Bruce M. , Ix Joachim H. , Kizer Jorge R. 
Published: July 2022

Background
Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α‐dicarbonyl‐derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new‐onset CVD in 2 population‐based cohorts of differing age and comorbidities.

Methods and Results
Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case‐cohort sample (n=1631) from the Multi‐Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi‐Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow‐up of 11 years, 439 participants in the Multi‐Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl‐lysine, 3‐deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi‐Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort.

Conclusions
We found α‐dicarbonyl‐derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle‐aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α‐dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high‐risk older populations.
Can You Hear What’s Coming? Failure to Replicate ERP Evidence for Phonological Prediction
Authors: Poulton Victoria R. , Nieuwland Mante S. 
Published: July 2022

Abstract
Prediction-based theories of language comprehension assume that listeners predict both the meaning and phonological form of likely upcoming words. In alleged event-related potential (ERP) demonstrations of phonological prediction, prediction-mismatching words elicit a phonological mismatch negativity (PMN), a frontocentral negativity that precedes the centroparietal N400 component. However, classification and replicability of the PMN has proven controversial, with ongoing debate on whether the PMN is a distinct component or merely an early part of the N400. In this electroencephalography (EEG) study, we therefore attempted to replicate the PMN effect and its separability from the N400, using a participant sample size (N = 48) that was more than double that of previous studies. Participants listened to sentences containing either a predictable word or an unpredictable word with/without phonological overlap with the predictable word. Preregistered analyses revealed a widely distributed negative-going ERP in response to unpredictable words in both the early (150–250 ms) and the N400 (300–500 ms) time windows. Bayes factor analysis yielded moderate evidence against a different scalp distribution of the effects in the two time windows. Although our findings do not speak against phonological prediction during sentence comprehension, they do speak against the PMN effect specifically as a marker of phonological prediction mismatch. Instead of an PMN effect, our results demonstrate the early onset of the auditory N400 effect associated with unpredictable words. Our failure to replicate further highlights the risk associated with commonly employed data-contingent analyses (e.g., analyses involving time windows or electrodes that were selected based on visual inspection) and small sample sizes in the cognitive neuroscience of language.
Understanding the Framework of Civil Conflicts and External Support for Insurgents in Africa South of the Sahara
Authors: Ameyaw-Brobbey Thomas 
Published: July 2022

Abstract
Since independence in Africa south of the Sahara, deadly internal conflicts have wracked the region more than any other in the world. Some of these conflicts transcended national boundaries because external states became involved in supporting rebel movements. The purpose of this paper is to contribute to an understanding of this international dimension of civil conflict. It develops a framework—unholy alignment, referring to the cooperative relationship between states and rebels—to examine how external support leads to the onset and intensification of civil conflict. I argue that external state support augments rebels’ capabilities to intensify violent demands that threaten the target government. I use data from secondary sources through historical process tracing and observation of congruence, and the case studies method, to explore three instances of Rwanda’s cooperative relations with rebels between 1994 and 1999, to show how they shaped civil wars in the DRC.
“Bel Crouches; Nebo Travails”: Reading Birth Imagery in Isaiah 46:1–4
Authors: Schoening Zachary 
Published: July 2022

Abstract
The traditional reading of Isa 46:1–4 understands the Babylonian gods as falling or toppling. Interpretation of the nature of their actions depends upon how one reads the verbiage applied to the deities, which hinges upon the translation of a series of either difficult or semantically diverse Hebrew terms. This essay analyzes these terms in light of comparative Semitic evidence. It also considers the passage in light of broader ancient Near Eastern ideological and mythological patterns. Finally, it explores some prominent motifs in the traditions of the Akītu festival, which constitutes the immediate frame of reference for the oracle’s imagery and against which Deutero-Isaiah was framing his rhetoric. Birth imagery, this essay contends, constitutes the primary rhetorical vehicle by which the prophet ridicules the Babylonian gods, portraying them as crouching in labor, and depicting them as inferior to Yahweh.
Benjamin and the Anonymous Ten Tribes of Israel: A Holistic Approach to Tribal Confusions
Authors: Tobolowsky Andrew 
Published: July 2022

Abstract
This article weighs in on new debates about the affiliation of the tribe of Benjamin between Israel and Judah in the early monarchy. It points to two underappreciated aspects of the Hebrew Bible’s account of tribal realities in the books of Kings: the anonymity of the ten tribes attributed to Israel in 1 Kgs 11–12, and how unusual the absence of a complete and detailed account of tribal arrangements in Kings is in the context of a Primary History as a whole. It argues that both of these realities reflect a deliberate effort to obscure Benjamin’s northern origins and that, in fact, it is impossible to come up with a plausible list of ten Israelite tribes without Benjamin.
Rethinking ‘August Meeting’ in Southeastern Nigeria
Authors: Onwuzuruigbo Ifeanyi 
Published: July 2022

Abstract
‘August Meeting’ is the annual homecoming or convention of Igbo women hometown associations of Southeastern Nigeria. For local communities in Southeastern Nigeria, August Meeting is a veritable platform for driving development, managing conflicts and building peace. But August Meeting is also a tool for hatching and promoting conflicts. While the conflict resolution and peacebuilding role of August Meeting has been acknowledged and applauded, its capacity for producing conflicts has been largely ignored. Drawing on a Nollywood film, August Meeting, and empirical research findings, this article exposes the ways in which August Meeting promotes interpersonal and intracommunal conflicts in Southeastern Nigeria.
Decolonizing the African University
Authors: Olutayo Akinpelu Olanrewaju , Olutayo Oluwaseun , Liadi Olusegun Fariudeen 
Published: July 2022

Abstract
This article focuses on the higher education system as an object of developmental analysis by examining the challenges and prospects of decolonizing the knowledge base of higher education systems across the Continent of Africa. The purpose of the article is to show that African countries’ seeming lack of progress relates to the character of her education system, which is deeply rooted in the context of coloniality and ‘metacolonialism.’ Using an analogical approach, the article discusses the attachment problem, which forms the pedestal for the continued undermining of indigenous knowledge as the basis of the pursuit of developmental goals. Universities in Africa have developed several kinds of attachments to and have been uncritical of received knowledge from the Western societies through their colonial roots. What African societies need at this moment is a knowledge system that integrates with the existential realities of African students and intellectuals.
The Jakabaring Sport City in Palembang, Indonesia
Authors: Trotier Friederike 
Published: July 2022

Abstract
A sports-themed zone—a concentrated site of sports facilities—embodies both an ambitious vision and a rather speculative and risky building project. This nature of combining visionary ideas, risk, competition and contestation makes these zones sites of worlding practices. This paper investigates the role of the sports-themed zone Jakabaring Sport City, situated in the South Sumatran capital Palembang, as a worlding site of sports, modernity, urban development and competitiveness. As a venue of prestigious sports events, Jakabaring Sport City has gained international attention and has entered the competition with other sports complexes and cities. The analysis reveals the ambitious visions and pitfalls to turn a formerly neglected and “haunted” place into a symbol of modernity and success for the city and its political leaders. It also identifies the new meanings of connectivity and competition attached to the sports complex as a site of experiments and aspirations as well as the alternation of rural, urban and global elements that characterise Jakabaring Sport City.
The Absent Player: The Soviet Union and the Genesis of the Allied War Crimes Trials Program, 1941–1943
Authors: Polunina Valentyna 
Published: July 2022

Abstract
During World War II, it was important for the Kremlin to be a part of the Allied effort to prosecute war criminals, and initially Moscow planned to join the UNWCC. However, attempts by the Soviet Union to increase its influence on the Commission led to the opposition of the Western Allies. The USSR wanted to demonstrate that they were capable of conducting their own investigations. With this task in mind, Moscow founded their alternative to the UNWCC – the Extraordinary State Commission. This article seeks to address the influence of Soviet legal innovations on the UNWCC – in particular on the Czechoslovak representative Bohuslav Ečer – as well as Moscow’s own attempts to investigate Nazi war crimes.
Dispute Settlement in the Law of the Sea: Survey for 2021
Authors: Churchill Robin 
Published: July 2022

Abstract
This is the latest in a series of annual surveys in this Journal reviewing dispute settlement in the law of the sea, both under Part XV of the United Nations Convention on the Law of the Sea and outside the framework of the Convention. The most significant developments during 2021 were a judgment of a Special Chamber of the International Tribunal for the Law of the Sea finding that it had jurisdiction to delimit a maritime boundary between Mauritius and the Maldives and a judgment of the International Court of Justice delimiting the maritime boundary between Somalia and Kenya.
Backsliding into Judicial Oligarchy? The Cautionary Tale of Georgia’s Failed Judicial Reforms, Informal Judicial Networks and Limited Access to Leadership Positions
Authors: Tsereteli Nino 
Published: July 2022

Abstract
This article investigates the formal and informal factors behind the persistence of judicial oligarchies in post-communist countries despite large-scale reforms. This case study on Georgia reveals that formal positions of power in these judiciaries can be monopolized by a close-knit group, with a handful of influential judges (i.e. judicial oligarchs) at the top of its hierarchical structure. Drawing on in-depth interviews with sitting as well as former judges and other stakeholders of reform processes, the article attributes the failure to dismantle the rule of judicial oligarchs at least partly to legislative flaws and loopholes. More importantly, it warns about the reliance of judicial oligarchs on informal rules and practices to undermine formal rules and procedures meant to facilitate the meaningful participation of all judges in governing the judiciary. It uncovers informal mechanisms allowing the network of powerful judges to suppress the emergence of competing judicial networks and cement itself into leadership positions. Finally, the article reflects on the implications of these findings for designing and implementing judicial reforms in Georgia and beyond.
Policy-Making in Tanzania: A Critical Analysis of Emerging Trends and Challenges in the Context of Health Policy
Authors: Marijani Ramadhani , Hussein Lufunyo 
Published: July 2022

Abstract
Today’s challenges such as automation, climate change, ageing populations, pandemics and deployment of artificial intelligence, have unpredictable and unintended consequences at both global and individual levels. Similarly, complex systems have become the norm rather than the exception. In this environment, “reactive” approaches to policy-making have increasingly proven ineffective. We need, therefore, to invest in anticipation policy for sustainable development. Formulating sustainable policies in developing states has been a challenge. This paper builds on Sociological Institutionalism in its attempt to discern the role of institutions in policy-making in Tanzania. The study used archival data from the Ministry of Health, Community Development, Gender, the Elderly and Children (MHCDGEC) with the National Health Policy of 2007 as the case study guided by Boomerang, Earthquake, Stalactite, and Tortoise (BEST) scheme for studying patterns of institutional change. The findings indicate that the policy-making process in Tanzania failed to domesticate some regional guidelines such as the African Agenda 2063, especially goal number three (3). However, pragmatically, the policy has registered stead increase in health facilities and improved services while politically the policy is viewed as a success as one of the pledges made in the ruling party’s manifesto that is being implemented in Tanzania. This paper concludes that Tanzania still embraces the pattern; and that it is the fidelity to the erstwhile policy-making style, which is centralized, hierarchical and managerial-a typical coercive isomorphism. Policy-making is still dominated by the central government while excluding other stakeholders such as communities. To improve policy-making in Tanzania, the paper recommends enhancement of the space for grassroots participation, domestication of regional and global policy agenda and imposition of a limitation upon the power of the elite.
Socrates’ Tomb in Antisthenes’ Kyrsas and its Relationship with Plato’s Phaedo
Authors: Luz Menahem 
Published: July 2022

Abstract
Socrates’ burial is dismissed as philosophically irrelevant in Phaedo 115c-e although it had previously been discussed by Plato’s older contemporaries. In Antisthenes’ Kyrsas dialogue describes a visit to Socrates’ tomb by a lover of Socrates who receives protreptic advice in a dream sequence while sleeping over Socrates’ grave. The dialogue is a metaphysical explanation of how Socrates’ spiritual message was continued after death. Plato underplays this metaphorical imagery by lampooning Antisthenes philosophy and his work (Phd. 81b-82e) and subsequently precludes him from an active role in the Phaedo. A similar case is the exclusion of Euclides of Megara. Fragments of a lost Socratic dialogue depict Apollodorus citing an unnamed Megarian in order to justify care for the remains of the dead. Similar mistaken notions explain Kyrsas’ belief when he lusts after Socrates even though he was dead. In spite of these disputes, the philosophers (Euclides, Antisthenes and Plato) each attempted to present Socrates’ moral influence as a force that continued after his death and burial.