bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapamycin Pretreatment Rescues the Bone Marrow AML Cell Elimination Capacity of CAR-T Cells
Authors: Nian Zhigang , Zheng Xiaohu , Dou Yingchao , Du Xianghui , Zhou Li , Fu Binqing , Sun Rui , Tian Zhigang , Wei Haiming 
Published: July 2021

Abstract

Purpose:
Ongoing clinical trials show limited efficacy for Chimeric antigen receptor (CAR) T treatment for acute myeloid leukemia (AML). The aim of this study was to identify potential causes of the reported limited efficacy from CAR-T therapies against AML.

Experimental Design:
We generated CAR-T cells targeting Epithelial cell adhesion molecule (EpCAM) and evaluated their killing activity against AML cells. We examined the impacts of modulating mTORC1 and mTORC2 signaling in CAR-T cells in terms of CXCR4 levels. We examined the effects of a rapamycin pretreatment of EpCAM CAR-T cells (during ex vivo expansion) and assessed the in vivo antitumor efficacy of rapamycin-pretreated EpCAM CAR-T cells (including CXCR4 knockdown cells) and CD33 CAR-T cells in leukemia xenograft mouse models.

Results:
EpCAM CAR-T exhibited killing activity against AML cells but failed to eliminate AML cells in bone marrow. Subsequent investigations revealed that aberrantly activated mTORC1 signaling in CAR-T cells results in decreased bone marrow infiltration and decreased the levels of the rapamycin target CXCR4. Attenuating mTORC1 activity with the rapamycin pretreatment increased the capacity of CAR-T cells to infiltrate bone marrow and enhanced the extent of bone marrow AML cell elimination in leukemia xenograft mouse models. CXCR4 knockdown experiments showed that CXCR4 contributes to the enhanced bone marrow infiltration capacity of EpCAM CAR-T cells and the observed reduction in bone marrow AML cells.

Conclusions:
Our study reveals a potential cause for the limited efficacy of CAR-T reported from current AML clinical trials and illustrates an easy-to-implement pretreatment strategy, which enhances the anti-AML efficacy of CAR-T cells.
See related commentary by Maiti and Daver, p. 5739
Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in a TP53- and BAX-Dependent Manner
Authors: Liu Tingting , Lam Vi , Thieme Elana , Sun Duanchen , Wang Xiaoguang , Xu Fei , Wang Lili , Danilova Olga V. , Xia Zheng , Tyner Jeffrey W. , Kurtz Stephen E. , Danilov Alexey V. 
Published: July 2021

Abstract

Purpose:
Bcl-2 has been effectively targeted in lymphoid malignancies. However, resistance is inevitable, and novel approaches to target mitochondrial apoptosis are necessary. AZD5991, a selective BH3-mimetic in clinical trials, inhibits Mcl-1 with high potency.

Experimental Design:
We explored the preclinical activity of AZD5991 in diffuse large B-cell lymphoma (DLBCL) and ibrutinib-resistant mantle cell lymphoma (MCL) cell lines, MCL patient samples, and mice bearing DLBCL and MCL xenografts using flow cytometry, immunoblotting, and Seahorse respirometry assay. Cas9 gene editing and ex vivo functional drug screen assays helped identify mechanisms of resistance to Mcl-1 inhibition.

Results:
Mcl-1 was expressed in DLBCL and MCL cell lines and primary tumors. Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition. Induction of prosurvival proteins (e.g., Bcl-xL) in stromal conditions that mimic the tumor microenvironment rendered protection of primary MCL cells from Mcl-1 inhibition, while BH3-mimetics targeting Bcl-2/xL sensitized lymphoid cells to AZD5991. Treatment with AZD5991 reduced tumor growth in murine lymphoma models and prolonged survival of MCL PDX mice.

Conclusions:
Selective targeting Mcl-1 is a promising therapeutic approach in lymphoid malignancies. TP53 apoptotic network and metabolic reprogramming underlie susceptibility to Mcl-1 inhibition.
Clinical Conditions and Their Impact on Utility of Genetic Scores for Prediction of Acute Coronary Syndrome
Authors: Lee Jiwoo , Kiiskinen Tuomo , Mars Nina , Jukarainen Sakari , Ingelsson Erik , Neale Benjamin , Ripatti Samuli , Natarajan Pradeep , Ganna Andrea 
Published: July 2021

Background:
Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease. Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual’s genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS.

Methods:
We explored the association between 405 clinical conditions diagnosed before baseline and 9080 incident cases of ACS in 387 832 individuals from the UK Biobank. Results were replicated in 6430 incident cases of ACS in 177 876 individuals from FinnGen.

Results:

We identified 80 conventional (eg, stable angina pectoris and type 2 diabetes) and unconventional (eg, diaphragmatic hernia and inguinal hernia) associations with ACS. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of stable angina pectoris yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction
P
=2.87×10
−8
) risk for ACS in individuals with stable angina pectoris (hazard ratio, 1.163 [95% CI, 1.082–1.251]) compared with individuals without stable angina pectoris (hazard ratio, 1.531 [95% CI, 1.497–1.565]). These findings were replicated in FinnGen (interaction
P
=1.38×10
−6
).

Conclusions:
In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable coronary heart disease. PS may be more appropriate for prediction of ACS in asymptomatic individuals than symptomatic individuals with clinical suspicion for coronary heart disease.
Disturbance in the Outlines of Sextus Empiricus
Authors: Svavarsson Svavar Hrafn 
Published: July 2021

Abstract
Sextus seems to offer inconsistent accounts of the sceptics’ achievement of tranquillity, apparently saying both that the sceptics’ tranquillity is achieved by suspending judgement on all issues and that it is achieved by suspending judgement only on the issue of there being objective goods and evils. It is argued that Sextus does not make the latter claim. The reason for the sceptics’ achievement of tranquillity is to be found in the original perplexity that instigated scepticism and left them immune to the value beliefs that disturb everyone else. After discussing this perplexity that gave rise to scepticism, the paper focuses on Sextus’ explanation of sceptical tranquillity and dogmatic disturbance.
The Vow to Kill Elisha: Function and Meaning in 2 Kings 6:31–33
Authors: Kislev Itamar 
Published: July 2021

Abstract
In the story of the siege of Samaria (2 Kgs 6:24–7:20), the passage in which the king surprisingly threatens to kill Elisha (6:31–33) is problematic. This passage also recounts the preparations by Elisha and the elders who are with him for the arrival of the king’s messenger who comes to kill the prophet (6:32). Eventually, and without explanation, the king abandons his initial intention to kill Elisha (6:33). This strange passage does not promote the plot and its function in the story is not clear.
An analysis of this passage in its context leads to the recognition that the story is not unified and reveals the stages of its development. Understanding the motivation for developing the story leads to another conclusion: that the formation of this story is closely related to the wider context, namely the redaction of the Elisha cycle.
1 Samuel 2:6: Time and Wayyiqtol in Hannah’s Song
Authors: Jones Ethan C. 
Published: July 2021

Abstract
This article challenges the ideas that we should either re-read the form or appeal to a present tense rendering of וַיָּעַל in 1 Sam 2:6. Instead, I argue that the prospect of gnomic semantics due to the surrounding participles is leveraged to highlight a past time wayyiqtol “he raised up.” This past time makes sense of the context both within the poem itself (1 Sam 2) and the preceding narrative (1 Sam 1). What is more, a past tense meaning of וַיָּעַל is corroborated by recent robust linguistic research of the form. Reading the wayyiqtol as past makes reference to a specific, historical action done to Hannah. This reference to the past tightens the cohesion of and provides further coherence for Hannah’s narrative (1 Sam 1) and her song (1 Sam 2).
Tu, felix Salomon, nube: Solomon’s Marriages in Early Christian and East Syrian Biblical Interpretation
Authors: Pragt Marion 
Published: July 2021

Abstract
This article explores the political portrayal of Solomon’s marriages presented by three East Syrian authors. It will be shown that whereas Jewish and early Christian interpreters often pointed to desire and demonic influence to explain Solomon’s many marriages, Theodore bar Koni, Ishoʿdad of Merv and the commentators of the anonymous manuscript olim Diyarbakır 22 instead portrayed the marriages as a form of nuptial politics intended to provide peace. The article examines the role of this political motif against the background of Theodore of Mopsuestia’s views on Solomon and the Song of Songs. It will be argued that the ways in which the East Syrian authors evaluated Solomon’s marriages are related to their different attitudes to the Song. The article illustrates how Greek exegesis could be transmitted and transformed in the East Syrian tradition of scriptural interpretation.
The Unity and Multiplicity of the Holy Spirit in Origen of Alexandria
Authors: Miller Micah M. 
Published: July 2021

Abstract
In his study on angelomorphic traditions in early Christian pneumatology, Bogdan Bucur suggests that Origen is both indebted to and develops upon Clement of Alexandria’s pneumatology. This article takes up Bucur’s claim, offering the first examination of Origen’s pneumatology in light of previous research on early Christian angelomorphic traditions. It argues that Origen interprets the traditional understanding of the Holy Spirit as one and seven in terms of a philosophical notion of power, allowing him to explain how the one Holy Spirit can distribute many different gifts.
Landscapes of Memories: A Study of Representation for Translocal Chinese Cultural Heritage in Kaiping, Guangdong, China
Authors: Chiang Bo-wei 
Published: July 2021

Abstract
Beginning in the mid-nineteenth century, many young people emigrated from Guangdong to the American West in search of a better living, mainly through building the Pacific Railroad and panning for gold in California. Some of these overseas Chinese who eventually accumulated wealth sent remittances back to their hometowns to provide their families with a better life, or they built mansions for their own retirement. They also used their wealth to renovate ancestral halls, establish schools, get involved in local politics and issues of local public security, public hygiene, etc. The overseas Chinese were one of the important new rising social strata in modern China before the 1960s.
This paper will focus on translocal Chinese cultural heritage in Guangdong and try to discuss how people memorize, narrate, preserve, and represent their migration history in these hometowns. Meanwhile, the meaning of the tangible cultural heritage as a landscape of memories in local society in China will also be discussed. Firstly, I think that there are three types of overseas Chinese memories: the memory of suffering, the memory of making fortunes, and the memory of a philanthropic image; secondly, I will deal with the narrative and representation of the collective memories since the 1990s and check how the collective memory became the cultural heritage beneath the state’s discourse; and finally, I will analyze how the overseas Chinese cultural heritage became resources for cultural tourism and local economic development, and show a process of commercialization of those landscapes.
Across, Between, and Beyond Nation States: Overseas Chinese Private Remittance Networks, 1850s–1930s
Authors: Mah-Gricuk Ania 
Published: July 2021

Abstract
This paper examines the development of private remittance networks that came into being in response to the practice of migrants sending financial resources back to their families in China from 1850 to 1930s and analyses them through the lens of transnational space. It discusses the transnational space between the diaspora and the homeland and the structures that link them. My research has shown that these networks contributed to a space transcending national borders. The material comprising the basis of this research project includes newspapers from the diaspora, remittance letters and receipts, and reports conducted by the Taiwanese governmental institutions and secondary material focused on both emigrant home villages in China and communities in destinations. In the diasporic context, space is created through shared experiences of migrants, who are physically separated from their families but remain linked through networks such as the remittance trade.
Still an Outsider? A Preliminary Study on the Political Culture of Ethnic Chinese in Myanmar
Authors: Szu-Tu Yu 
Published: July 2021

Abstract
The ethnic Chinese in Myanmar used to be strongly averse to political engagement, while some third-generation Burmese of Chinese descent had run for the 2015 general election, which indicated that the time-honored political culture embraced by ethnic Chinese in Myanmar seems to be evolving instead of remaining invariable. Nonetheless, what their political culture has truly become is well deserving of thorough analysis. The connotations of political culture are twofold: people’s attitudes towards the hierarchical structure of the government, and people’s attitudes towards their own political actions. Treating these two aspects of political culture as points of departure and employing various methods including field research and in-depth interviews, this article seeks to address the key question as to whether the political culture of ethnic Chinese in Myanmar is actually evolving.
A New Page of Literati Painting from Singapore and Malaysia: A Study of Chen Wen Hsi and Chung Chen Sun
Authors: Chiu Ling-Ting 
Published: July 2021

Abstract
In the early twentieth century, Chinese literati painting was embroiled in arguments on the relationship between ancient and modern or east and west. Therefore, the artistic practices of Wu Changshuo, Chen Shizeng, Qi Baishi, Xu Beihong and so on, were in response to this development. However, with the occurrence of World War ii and changes in the post-war situation, literati painting underwent further, new changes in different regions. This article intends to discuss the overseas Chinese painters Chen Wen Hsi and Chung Chen Sun as examples in exploring the new development of literati painting in Singapore and Malaysia in the second half of the twentieth century. Chen Wen Hsi was born in Jieyang County, Guangdong Province in 1906. He studied at Shanghai Fine Arts College and Xinhua Art College. He went to Singapore and held an exhibition in 1948. In 1950, he taught at The Chinese High School, and the following year also began teaching Chinese ink painting at Nanyang Fine Arts College. Chung Chen Sun, a native of Mei County, Guangdong Province, was born in 1935 in Malacca, Malaysia. In 1953, he entered the Department of Art Education of Nanyang Academy of Fine Arts, which was founded by Lim Hak Tai. Chung was inspired by predecessors such as Cheong Soo-pien, Chen Wen Hsi and Chen Chong-swee who had pursued the Nanyang style. In 1967, Chung founded the Malaysian Academy of Art. Their styles of painting not only incorporate the Eastern aesthetics and Western theory but also include diverse elements. Their paintings wrote a new page in the history of literati painting during the Cold War era.
A new combined detection algorithm for blocking and subtropical ridges
Authors: Sousa Pedro M. , Barriopedro David , García-Herrera Ricardo , Woollings Tim , Trigo Ricardo M. 
Published: July 2021

AbstractBlockings are high-impact atmospheric systems of mid/high-latitudes and have been widely addressed in meteorological and climatological studies. However, the diversity of blocking definitions makes comparison across studies not straightforward. Here, we propose a conceptual model for the life-cycle of high-pressure systems that recognizes the multifaceted and transient characteristics of these events. A detection scheme identifies and classifies daily structures, discriminating between subtropical ridges and different types of well-established blocking patterns (omega and dipole-like Rex). This is complemented by a spatio-temporal tracking algorithm, which accounts for transitions between patterns, providing a global catalogue of events for 1950-2020. Criteria rely on simple metrics retrieved from one single-level field, and allow implementation in different datasets and climatic realms. Using reanalyses data, we provide illustrative examples, the first global and seasonal climatological assessment of the diversity of high-pressure events, their associated impacts and recent frequency changes.Results reveal that ridge and blocking events affect widespread regions from the subtropics to high-latitudes. We find remarkably distinct regional impacts among the considered types, which had been hindered in previous studies by restricted focus on Rex-like structures. This plethora of high-pressure systems is much less evident in the Southern Hemisphere, where activity is dominated by subtropical ridges and secluded blocking-like patterns. We report increasing frequencies of low-latitude systems, although with hemispheric and seasonal differences that can only be partially interpreted as a consequence of subtropical expansion. Blocking frequency trends exhibit more heterogeneous and complex spatial patterns, with no evidence of generalized significant changes.
Coherent Velocity Structures in the Mixed Layer: Characteristics, Energetics, and Turbulent Kinetic Energy Budget
Authors: Jarosz Ewa , Wijesekera Hemantha W. , Wang David W. 
Published: July 2021

AbstractVelocity, hydrographic, and microstructure observations collected under moderate to high winds, large surface waves, and significant ocean-surface heat losses were utilized to examine coherent velocity structures (CVS) and turbulent kinetic energy (TKE) budget in the mixed layer on the outer shelf in the northern Gulf of Mexico in February 2017. The CVS exhibited larger downward velocities in downwelling regions and weaker upward velocities in broader upwelling regions, elevated vertical velocity variance, vertical velocity maxima in the upper part of the mixed layer, and phasing of crosswind velocities relative to vertical velocities near the base of the mixed layer. Temporal scales ranged from 10 to 40 min, and estimated lateral scales ranged from 90 to 430 m, which were 1.5–6 times as large as the mixed layer depth. Nondimensional parameters, Langmuir and Hoenikker numbers, indicated that plausible forcing mechanisms were surface-wave-driven Langmuir vortex and destabilizing surface buoyancy flux. The rate of change of TKE, shear production, Stokes production, buoyancy production, vertical transport of TKE, and dissipation in the TKE budget were evaluated. The shear and Stokes productions, dissipation, and vertical transport of TKE were the dominant terms. The buoyancy production term was important at the sea surface, but it decreased rapidly in the interior. A large imbalance term was found under the unstable, high-wind, and high–sea state conditions. The cause of this imbalance cannot be determined with certainty through analyses of the available observations; however, our speculation is that the pressure transport is significant under these conditions.
Prevalence of and risk factors for high-altitude hyperuricaemia in Bai individuals: a cross-sectional study
Authors: Gao Chenni , Chen Zijin , Ma Jun , Xie Jingyuan , Zhang Wen , Ren Hong , Chen Xiaonong 
Published: July 2021

Objective Hyperuricaemia is common in Bai individuals; however, its prevalence remains unclear. This work aimed to investigate high-altitude hyperuricaemia prevalence and risk factors in Bai individuals. Methods All eligible participants of Bai ethnicity (aged ≥18 years and undergoing routine medical examination at the People’s Hospital of Jianchuan County between January and December 2019) were consecutively enrolled. Demographic and laboratory data were collected to investigate hyperuricaemia prevalence and associated risk factors. Results A total of 1393 participants were assessed, comprising 345 (24.8%) with hyperuricaemia showing a male predominance (287/865 [33.2%] males versus 58/528 [11.0%] females). Hyperuricaemia prevalence was significantly higher in participants aged ≥50 years (100/332 [30.1%]) versus those aged 30–40 years (59/308 [19.2%]), and in overweight/obese individuals compared with those showing an underweight or normal body mass index (BMI; 267/885 [30.2%] versus 78/508 [15.4%]). Finally, haemoglobin concentrations and serum uric acid levels were positively correlated. Conclusion Besides traditional risk factors, including age, sex and BMI, polycythaemia due to prolonged exposure to high altitude may also cause hyperuricaemia in Bai individuals residing in Yunnan Province.
The Influence of Breastfeeding Educational Interventions on Breast Engorgement and Exclusive Breastfeeding: A Systematic Review and Meta-Analysis
Authors: Huda Mega Hasanul , Chipojola Roselyn , Lin Yen Miao , Lee Gabrielle T. , Shyu Meei-Ling , Kuo Shu-Yu 
Published: July 2021

Background Breast engorgement and breast pain are the most common reasons for the early cessation of exclusive breastfeeding by mothers. Research Aims (1) To examine the influence of breastfeeding educational interventions on breast engorgement, breast pain, and exclusive breastfeeding; and (2) to identify effective components for implementing breastfeeding programs. Methods Randomized controlled trials of breastfeeding educational interventions were searched using five English and five Chinese databases. Eligible studies were independently evaluated for methodological quality, and data were extracted by two investigators. In total, 22 trials were identified, and 3,681 participants were included. A random-effects model was used to pool the results, and a subgroup analysis and meta-regression analysis were conducted. Results Breastfeeding education had a significant influence on reducing breast engorgement at postpartum 3 days (odds ratio [OR]: 0.27, 95% CI [0.15, 0.48] p < .001), 4 days (OR: 0.16, 95% CI [0.11, 0.22], p < .001), and 5–7 days (OR: 0.24, 95% CI [0.08, 0.74], p = .013) and breast pain (standardized mean difference: −1.33, 95% CI [−2.26, −0.40]) at postpartum 4–14 days. Participants who received interventions had higher odds of exclusive breastfeeding. Breastfeeding educational interventions provided through lecture combined with skills practical effectively reduced breast engorgement (OR: 0.21; 95% CI [0.15, 0.28]; p = .001) and improved exclusive breastfeeding at postpartum 1–6 weeks (OR: 2.16; 95% CI [1.65, 2.83]; p = .001). Conclusions Breastfeeding educational interventions have been effective in reducing breast engorgement, breast pain, and improved exclusive breastfeeding. A combination of knowledge and skill-based education has been beneficial for sustaining exclusive breastfeeding by mothers.