bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic Risk Factors Associated with Early-Onset Colorectal Adenocarcinoma: A Case–Control Study at Kaiser Permanente Southern California
Authors: Schumacher Andrew J. , Chen Qiaoling , Attaluri Vikram , McLemore Elisabeth C. , Chao Chun R. 
Published: July 2021

Abstract

Background:
The incidence of early-onset colorectal cancer (eoCRC) diagnosed among individuals under age 50 has been rising. However, risk factors for eoCRC are unclear. We investigated whether metabolic abnormalities are risk factors for eoCRC adenocarcinoma.

Methods:
Invasive colorectal adenocarcinoma cases diagnosed between ages 15 and 49 from 2008 to 2018 at Kaiser Permanente Southern California (KPSC) were identified. Those with a history of inflammatory bowel disease were excluded. Noncancer controls were selected 5:1 for each case matched by age, sex, and length of membership prior to index date. Data were collected from KSPC's electronic medical records. The exposures of interest included obesity, type II diabetes, hypertension, and dyslipidemia, assessed from ≥1 year prior to eoCRC diagnosis/index date. Conditional logistic regressions were used to evaluate the associations between these metabolic risk factors and risk of eoCRC adenocarcinoma, adjusting for race/ethnicity, smoking, family history, neighborhood socioeconomic status, and health care utilization.

Results:
A total of 1,032 cases and 5,128 controls were included. Risk of colorectal adenocarcinoma was significantly associated with obesity [odds ratio (OR) = 1.41; 95% confidence interval (CI), 1.15–1.74], but not diabetes, hypertension or dyslipidemia. In analysis stratified by tumor location, obesity was significantly associated with risk of colon adenocarcinoma OR = 1.56 (1.17–2.07), but its association with rectal adenocarcinoma was less clear OR = 1.19 (0.85–1.68). No significant interaction was detected between obesity and age (≥40 vs. &lt;40), and obesity and sex.

Conclusions:
Obesity was associated with risk for eoCRC adenocarcinoma.

Impact:
This finding could help inform early-onset colorectal adenocarcinoma screening and prevention recommendations.
See related commentary by Hayes, p. 1775
Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing
Authors: Newman Scott , Nakitandwe Joy , Kesserwan Chimene A. , Azzato Elizabeth M. , Wheeler David A. , Rusch Michael , Shurtleff Sheila , Hedges Dale J. , Hamilton Kayla V. , Foy Scott G. , Edmonson Michael N. , Thrasher Andrew , Bahrami Armita , Orr Brent A. , Klco Jeffery M. , Gu Jiali , Harrison Lynn W. , Wang Lu , Clay Michael R. , Ouma Annastasia , Silkov Antonina , Liu Yanling , Zhang Zhaojie , Liu Yu , Brady Samuel W. , Zhou Xin , Chang Ti-Cheng , Pande Manjusha , Davis Eric , Becksfort Jared , Patel Aman , Wilkinson Mark R. , Rahbarinia Delaram , Kubal Manish , Maciaszek Jamie L. , Pastor Victor , Knight Jay , Gout Alexander M. , Wang Jian , Gu Zhaohui , Mullighan Charles G. , McGee Rose B. , Quinn Emily A. , Nuccio Regina , Mostafavi Roya , Gerhardt Elsie L. , Taylor Leslie M. , Valdez Jessica M. , Hines-Dowell Stacy J. , Pappo Alberto S. , Robinson Giles , Johnson Liza-Marie , Pui Ching-Hon , Ellison David W. , Downing James R. , Zhang Jinghui , Nichols Kim E. 
Published: July 2021

Abstract

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor–normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers.

Significance:
Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers.
This article is highlighted in the In This Issue feature, p. 2945
Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy
Authors: Wu Hsin-Chieh , Rérolle Domitille , Berthier Caroline , Hleihel Rita , Sakamoto Takashi , Quentin Samuel , Benhenda Shirine , Morganti Claudia , Wu Chengchen , Conte Lidio , Rimsky Sylvie , Sebert Marie , Clappier Emmanuelle , Souquere Sylvie , Gachet Stéphanie , Soulier Jean , Durand Sylvère , Trowbridge Jennifer J. , Bénit Paule , Rustin Pierre , El Hajj Hiba , Raffoux Emmanuel , Ades Lionel , Itzykson Raphael , Dombret Hervé , Fenaux Pierre , Espeli Olivier , Kroemer Guido , Brunetti Lorenzo , Mak Tak W. , Lallemand-Breitenbach Valérie , Bazarbachi Ali , Falini Brunangelo , Ito Keisuke , Martelli Maria Paola , de Thé Hugues 
Published: July 2021

AbstractAcute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear bodies (NB), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mitochondrial DNA, activating cyclic GMP-AMP synthase signaling, and boosting reactive oxygen species (ROS) production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies.Significance:ActD induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML NBs. ActD targets mitochondria, yielding ROS which enforce PML NB biogenesis and restore senescence. Dual targeting of mitochondria with ActD and venetoclax sharply potentiates their anti-AML activities in vivo.This article is highlighted in the In This Issue feature, p. 2945
Contesting Aristotle: Science, Theology and the Resurrection of the Body in Methodius of Olympus’ De Resurrectione and the Dialogue of Adamantius
Authors: LaValle Norman Dawn 
Published: July 2021

Abstract
The contest over the resurrection of the body used the scientific authority of Aristotle as ammunition on both sides. Past scholars have read Methodius of Olympus as displaying an anti-Aristotelian bias. In contrast, through close reading of the entire text with attention to characterization and development of argument, I prove that Methodius of Olympus’ dialogue the De Resurrectione utilizes Aristotelian biology as a morally neutral tool. To put this into higher relief, I compare Methodius’ dialogue with the anonymous Dialogue of Adamantius, a text directly dependent upon the Methodius’ De Resurrectione, but which rejects arguments based on scientific reasoning. Reading Methodius’ De Resurrectione with greater attention to the whole and putting it in the context of its nearest parallel text retells the traditional story of early Christian resistance to Aristotle. Methodius of Olympus’ characters, although they view scientific knowledge as subordinate to philosophy, see it as neutral in and of itself.
Development of pragmatic competence among L2 learners
Authors: Hilliker Shannon M. , Lenkaitis Chesla Ann , Loranc-Paszylk Barbara 
Published: July 2021

Abstract
Although compliments and compliment responses seem to play an important role in discourse of second language (L2) classrooms (Khaneshan & Bonyadi, 2016), the influence of virtual exchanges on enhancing the use of compliment responses remains unexplored. Twelve L2 learners of English from Poland met in groups for six weeks, via video conferencing, with Teaching English to Speakers of Other Languages (TESOL) teacher candidates from a university in the USA. During online sessions, the L2 learners’ primary focus was on discussion in English regarding assigned TED Talks. Data analysis consisted of statistical analyses using SPSS on Likert-scale questions while open-ended responses were coded using NVivo 12 into researcher-created categories. In addition, transcripts were analyzed. It is evident from this study that L2 learners have opportunities to utilize virtual exchange to develop L2 pragmatic awareness related to compliment responses.
How to riddle by Chinese names
Authors: Hou Guojin , Ye Yuhua 
Published: July 2021

Abstract
This paper studies how Chinese riddles, esp. how to riddle by a name. Based on lexico-constructional pragmatics, a Chinese riddle is a construction, with the configuration of FACE (P), EYE and BOTTOM (Q). P and Q are to hold a tension between identity and heterogeneity, and the entire riddle is to meet the (six) felicity conditions of riddles. Old means of Chinese riddles are discussed, to seek new riddling manners like use of foreign loans, material props, and face-bottom reversions. It is hypothesised that a rhetor with humour-consciousness, in informal or weak communication, can in principle generate a riddle, for instance, by names of places, people, and things. By some pragmatic constraint or even coercion, the riddler can boost expressibility and processibility of a riddle. With a case study, liberal use of riddles in more ways, for more occasions, is suggested to elevate communicators’ humour competence and humour happiness.
Effects of Suppressed Transient Eddies by the Tibetan Plateau on the East Asian Summer Monsoon
Authors: Ren Qiaoling , Jiang Xingwen , Zhang Yang , Li Zhenning , Yang Song 
Published: July 2021

AbstractIt is known that the Tibetan Plateau (TP) can weaken the transient eddies (TEs) transported along the westerly jet stream. This study investigates the effects of the persistently suppressed TEs by the TP on the East Asian summer monsoon and the associated mechanisms using the NCAR Community Earth System Model. A nudging method is used to modify the suppression of the TEs without changing the steady dynamic and thermodynamic effects of the TP. The suppressed TEs by the TP weaken the East Asian westerly jet stream through the weakened poleward TE vorticity flux. On the one hand, the weakened jet stream leads to less (more) rainfall in northern (southern) East Asia by inducing anomalous moisture convergence, midtropospheric warm advection, and upper-level divergence, particularly in early summer when the eastward propagation of TE suppression by the TP is strong. On the other hand, the precipitation anomalies can shift the East Asian westerly jet stream southward and promote the moisture convergence in southern East Asia through latent heat release. Therefore, the persistent suppression of the TEs leads to a southward shift of the East Asian rain belt by a convective feedback, as it was previously found that the steady thermodynamic and dynamic forcings of the TP favored a northward shift of the rain belt. This study suggests that the anomalously weak TEs can lead to a rainfall change (more in the south, less in the north) over East Asia.
Changes in lengths of the four seasons over the drylands in the Northern Hemisphere mid-latitudes
Authors: Wang Jiamin , Guan Xiaodan , Guan Yuping , Zhu Kaiwei , Shi Rui , Kong Xiangning , Guo Shuyang 
Published: July 2021

AbstractDue to global warming, the lengths of the four seasons, which are always taken as constant values, have experienced significant variations with rising temperature. Such changes play different roles on regional climate change, with the most significant effect on drylands. To guarantee local crop yields and preserve ecosystems, the identification of the changes of the four seasons in drylands is important. Our results show that, relative to humid lands, changing trends in lengths of spring, summer and autumn were particularly enhanced in drylands of the Northern Hemisphere mid-latitudes during 1951-2020. In this period, summer length has increased by 0.51 day per year, while spring and autumn lengths have contracted by 0.14 and 0.14 day per year, respectively. However, the enhanced changes in drylands did not appear in winter length. Such changes of spring, summer and autumn in drylands are dominated by internal variability over the entire study period, with a stronger external forcing effect on drylands than on humid lands. In drylands, the external forcing contributed to the changes in lengths of spring, summer and autumn by 30.1%, 42.2% and 29.4%, respectively. The external forcing has become an increasingly important component since 1990, with the ability to dominate all seasons in drylands after 2010. Nevertheless, only one out of the 16 Coupled Model Intercomparison Project Phase 6 (CMIP6) models used in this study can capture the enhanced changes in the lengths of spring, summer and autumn in drylands. Further investigation on the local effects of changes in seasons on agriculture and ecosystem would be needed, especially for the fragile regions.
Peripheral B cells repress B-cell regeneration in aging through a TNF-α/IGFBP-1/IGF-1 immune-endocrine axis
Authors: Dowery Reem , Benhamou David , Benchetrit Eli , Harel Ofer , Nevelsky Alex , Zisman-Rozen Simona , Braun-Moscovici Yolanda , Balbir-Gurman Alexandra , Avivi Irit , Shechter Arik , Berdnik Daniela , Wyss-Coray Tony , Melamed Doron 
Published: July 2021

AbstractLoss of B lymphocyte regeneration in the bone marrow (BM) is an immunologic hallmark of advanced age, which impairs the replenishment of peripheral B-cell subsets and results in impaired humoral responses, thereby contributing to immune system dysfunction associated with aging. A better understanding of the mechanism behind this loss may suggest ways to restore immune competence and promote healthy aging. In this study, we uncover an immune-endocrine regulatory circuit that mediates cross-talk between peripheral B cells and progenitors in the BM, to balance B-cell lymphopoiesis in both human and mouse aging. We found that tumor necrosis factor α (TNF-α), which is increasingly produced by peripheral B cells during aging, stimulates the production of insulin-like growth factor-binding protein 1 (IGFBP-1), which binds and sequesters insulin-like growth factor 1 (IGF-1) in the circulation, thereby restraining its activity in promoting B-cell lymphopoiesis in the BM. Upon B-cell depletion in aging humans and mice, circulatory TNF-α decreases, resulting in increased IGF-1 and reactivation of B-cell lymphopoiesis. Perturbation of this circuit by administration of IGF-1 to old mice or anti–TNF-α antibodies to human patients restored B-cell lymphopoiesis in the BM. Thus, we suggest that in both human and mouse aging, peripheral B cells use the TNF-α/IGFBP-1/IGF-1 axis to repress B-cell lymphopoiesis. This trial was registered at www.clinicaltrials.govas#NCT00863187.
Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial
Authors: Niemeyer Charlotte M. , Flotho Christian , Lipka Daniel B. , Starý Jan , Rössig Claudia , Baruchel André , Klingebiel Thomas , Micalizzi Concetta , Michel Gérard , Nysom Karsten , Rives Susana , Schmugge Liner Markus , Zecca Marco , Schönung Maximilian , Baumann Irith , Nöllke Peter , Benettaib Bouchra , Biserna Noha , Poon Jennifer , Simcock Mathew , Patturajan Meera , Menezes Daniel , Gaudy Allison , van den Heuvel-Eibrink Marry M. , Locatelli Franco 
Published: July 2021

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
Research on the drought tolerance mechanism of Pennisetum glaucum (L.) in the root during the seedling stage
Authors: Zhang Ailing , Ji Yang , Sun Min , Lin Chuang , Zhou Puding , Ren Juncai , Luo Dan , Wang Xiaoshan , Ma Congyu , Zhang Xinquan , Feng Guangyan , Nie Gang , Huang Linkai 
Published: July 2021

Abstract
Background
Drought is one of the major environmental stresses resulting in a huge reduction in crop growth and biomass production. Pearl millet (Pennisetum glaucum L.) has excellent drought tolerance, and it could be used as a model plant to study drought resistance. The root is a very crucial part of plant that plays important roles in plant growth and development, which makes it a focus of research.

Results
In this study, we explored the mechanism of drought tolerance of pearl millet by comparing physiological and transcriptomic data under normal condition and drought treatment at three time points (1 h, 3 h and 7 h) in the root during the seedling stage. The relative electrical conductivity went up from 1 h to 7 h in both control and drought treatment groups while the content of malondialdehyde decreased. A total of 2004, 1538 and 605 differentially expressed genes were found at 1 h, 3 h and 7 h respectively and 12 genes showed up-regulation at all time points. Some of these differentially expressed genes were significantly enriched into ‘metabolic processes’, ‘MAPK signaling pathway’ and ‘plant hormone signal transduction’ such as the ABA signal transduction pathway in GO and KEGG enrichment analysis.

Conclusions
Pearl millet was found to have a quick drought response, which may occur before 1 h that contributes to its tolerance against drought stress. These results can provide a theoretical basis to enhance the drought resistance in other plant species.
Poor clinical outcomes associated with suboptimal antibiotic treatment among older long-term care facility residents with urinary tract infection: a retrospective cohort study
Authors: Appaneal Haley J. , Shireman Theresa I. , Lopes Vrishali V. , Mor Vincent , Dosa David M. , LaPlante Kerry L. , Caffrey Aisling R. 
Published: July 2021

Abstract
Background
Antibiotic use is associated with several antibiotic-related harms in vulnerable, older long-term care (LTC) residents. Suboptimal antibiotic use may also be associated with harms but has not yet been investigated. The aim of this work was to compare rates of poor clinical outcomes among LTC residents with UTI receiving suboptimal versus optimal antibiotic treatment.

Methods
We conducted a retrospective cohort study among residents with an incident urinary tract infection (UTI) treated in Veterans Affairs LTC units (2013–2018). Potentially suboptimal antibiotic treatment was defined as use of a suboptimal initial antibiotic drug choice, dose frequency, and/or excessive treatment duration. The primary outcome was time to a composite measure of poor clinical outcome, defined as UTI recurrence, acute care hospitalization/emergency department visit, adverse drug event, Clostridioides difficile infection (CDI), or death within 30 days of antibiotic discontinuation. Shared frailty Cox proportional hazard regression models were used to compare the time-to-event between suboptimal and optimal treatment.

Results
Among 19,701 LTC residents with an incident UTI, 64.6% received potentially suboptimal antibiotic treatment and 35.4% experienced a poor clinical outcome. In adjusted analyses, potentially suboptimal antibiotic treatment was associated with a small increased hazard of poor clinical outcome (aHR 1.06, 95% CI 1.01–1.11) as compared with optimal treatment, driven by an increased hazard of CDI (aHR 1.94, 95% CI 1.54–2.44).

Conclusion
In this national cohort study, suboptimal antibiotic treatment was associated with a 6% increased risk of the composite measure of poor clinical outcomes, in particular, a 94% increased risk of CDI. Beyond the decision to use antibiotics, clinicians should also consider the potential harms of suboptimal treatment choices with regards to drug type, dose frequency, and duration used.