bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk
Authors: Ghoneim Dalia H. , Zhu Jingjing , Zheng Wei , Long Jirong , Murff Harvey J. , Ye Fei , Setiawan Veronica Wendy , Wilkens Lynne R. , Khankari Nikhil K. , Haycock Philip , Antwi Samuel O. , Yang Yaohua , Arslan Alan A. , Beane Freeman Laura E. , Bracci Paige M. , Canzian Federico , Du Mengmeng , Gallinger Steven , Giles Graham G. , Goodman Phyllis J. , Kooperberg Charles , Le Marchand Loïc , Neale Rachel E. , Scelo Ghislaine , Visvanathan Kala , White Emily , Albanes Demetrius , Amiano Pilar , Andreotti Gabriella , Babic Ana , Bamlet William R. , Berndt Sonja I. , Brais Lauren K. , Brennan Paul , Bueno-de-Mesquita Bas , Buring Julie E. , Campbell Peter T. , Rabe Kari G. , Chanock Stephen J. , Duggal Priya , Fuchs Charles S. , Gaziano J. Michael , Goggins Michael G. , Hackert Thilo , Hassan Manal M. , Helzlsouer Kathy J. , Holly Elizabeth A. , Hoover Robert N. , Katske Verena , Kurtz Robert C. , Lee I-Min , Malats Núria , Milne Roger L. , Murphy Neil , Oberg Ann L. , Porta Miquel , Rothman Nathaniel , Sesso Howard D. , Silverman Debra T. , Thompson Ian M. , Wactawski-Wende Jean , Wang Xiaoliang , Wentzensen Nicolas , Yu Herbert , Zeleniuch-Jacquotte Anne , Yu Kai , Wolpin Brian M. , Jacobs Eric J. , Duell Eric J. , Risch Harvey A. , Petersen Gloria M. , Amundadottir Laufey T. , Kraft Peter , Klein Alison P. , Stolzenberg-Solomon Rachel Z. , Shu Xiao-Ou , Wu Lang 
Published: September 2020

Abstract

Background:
Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

Methods:
We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case–Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

Results:
Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98–1.02; arachidonic acid OR = 1.00, 95% CI = 0.99–1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87–1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

Conclusions:
Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

Impact:
These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
Short-term CDK4/6 Inhibition Radiosensitizes Estrogen Receptor–Positive Breast Cancers
Authors: Pesch Andrea M. , Hirsh Nicole H. , Chandler Benjamin C. , Michmerhuizen Anna R. , Ritter Cassandra L. , Androsiglio Marlie P. , Wilder-Romans Kari , Liu Meilan , Gersch Christina L. , Larios José M. , Pierce Lori J. , Rae James M. , Speers Corey W. 
Published: September 2020

Abstract

Purpose:
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have improved progression-free survival for metastatic, estrogen receptor–positive (ER+) breast cancers, but their role in the nonmetastatic setting remains unclear. We sought to understand the effects of CDK4/6 inhibition (CDK4/6i) and radiotherapy in multiple preclinical breast cancer models.

Experimental Design:
Transcriptomic and proteomic analyses were used to identify significantly altered pathways after CDK4/6i. Clonogenic assays were used to quantify the radiotherapy enhancement ratio (rER). DNA damage was quantified using γH2AX staining and the neutral comet assay. DNA repair was assessed using RAD51 foci formation and nonhomologous end joining (NHEJ) reporter assays. Orthotopic xenografts were used to assess the efficacy of combination therapy.

Results:
Palbociclib significantly radiosensitized multiple ER+ cell lines at low nanomolar, sub IC50 concentrations (rER: 1.21–1.52) and led to a decrease in the surviving fraction of cells at 2 Gy (P &lt; 0.001). Similar results were observed in ribociclib-treated (rER: 1.08–1.68) and abemaciclib-treated (rER: 1.19–2.05) cells. Combination treatment decreased RAD51 foci formation (P &lt; 0.001), leading to a suppression of homologous recombination activity, but did not affect NHEJ efficiency (P &gt; 0.05). Immortalized breast epithelial cells and cells with acquired resistance to CDK4/6i did not demonstrate radiosensitization (rER: 0.94–1.11) or changes in RAD51 foci. In xenograft models, concurrent palbociclib and radiotherapy led to a significant decrease in tumor growth.

Conclusions:
These studies provide preclinical rationale to test CDK4/6i and radiotherapy in women with locally advanced ER+ breast cancer at high risk for locoregional recurrence.
Long-term Sculpting of the B-cell Repertoire following Cancer Immunotherapy in Patients Treated with Sipuleucel-T
Authors: Zhang Li , Kandadi Harini , Yang Hai , Cham Jason , He Tao , Oh David Y. , Sheikh Nadeem A. , Fong Lawrence 
Published: September 2020

Abstract
Sipuleucel-T is an autologous cellular immunotherapy, administered as three infusions, for metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T induces T- and B-cell responses to prostatic acid phosphatase (PAP), correlating to improved survival. The long-term impact of sipuleucel-T on tumor antigen–specific immunologic memory remains unknown, in particular, B-cell responses, as measured by antigen-specific antibody responses and B-cell receptor (BCR) sequences. To evaluate whether sipuleucel-T could induce long-term immunologic memory, we examined circulating B-cell responses before and after sipuleucel-T treatment in two groups of patients with mCRPC: those who had previously received sipuleucel-T (treated; median, 8.9 years since the previous treatment) versus those who had not (naïve). Before re-treatment, previously treated patients exhibited persistent antibody responses as well as more focused and convergent BCR repertoires with distinct V(D)J gene usage compared with naïve patients. After re-treatment, previously treated patients maintained high-frequency clones and developed more convergent BCRs at earlier time points unlike naïve patients. With the first sipuleucel-T infusion specifically, previously treated patients had less shuffling within the 100 most abundant baseline clones. In contrast, naïve patients exhibited great BCR turnover with a continued influx of new B-cell clones. Social network analysis showed that previously treated patients had more highly organized B-cell repertoires, consistent with greater clonal maturation. Higher treatment-induced BCR clonality correlated with longer survival for naïve patients. These results demonstrated the capacity of sipuleucel-T to induce long-term immune memory and lasting changes to the B-cell repertoire.
Aging of Preleukemic Thymocytes Drives CpG Island Hypermethylation in T-cell Acute Lymphoblastic Leukemia
Authors: Roels Juliette , Thénoz Morgan , Szarzyńska Bronisława , Landfors Mattias , De Coninck Stien , Demoen Lisa , Provez Lien , Kuchmiy Anna , Strubbe Steven , Reunes Lindy , Pieters Tim , Matthijssens Filip , Van Loocke Wouter , Erarslan-Uysal Büşra , Richter-Pechańska Paulina , Declerck Ken , Lammens Tim , De Moerloose Barbara , Deforce Dieter , Van Nieuwerburgh Filip , Cheung Laurence C. , Kotecha Rishi S. , Mansour Marc R. , Ghesquière Bart , Van Camp Guy , Berghe Wim Vanden , Kowalczyk Jerzy R. , Szczepański Tomasz , Davé Utpal P. , Kulozik Andreas E. , Goossens Steven , Curtis David J. , Taghon Tom , Dawidowska Małgorzata , Degerman Sofie , Van Vlierberghe Pieter 
Published: September 2020

Abstract

Cancer cells display DNA hypermethylation at specific CpG islands in comparison with their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T cells and that display a reciprocal association with H3K27me3 binding. In addition, we reveal that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in preleukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent decitabine. Altogether, we provide conceptual evidence for the involvement of a preleukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.

Significance:
We developed a DNA methylation signature that reveals the epigenetic history of thymocytes during T-cell transformation. This human signature was recapitulated by murine self-renewing preleukemic thymocytes that build an age-related CpG island hypermethylation phenotype, providing conceptual evidence for the involvement of a preleukemic thymic phase in human T-cell leukemia.
This article is highlighted in the In This Issue feature, p. 215
YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis
Authors: Arain Fizza , Abraityte Aurelija , Bogdanova Mariia , Solberg Ole G. , Michelsen Annika E. , Lekva Tove , Aakhus Svend , Holm Sverre , Halvorsen Bente , Finsen Alexandra V. , Vinge Leif-Erik , Nymo Ståle , Espeland Torvald , Ranheim Trine , Aukrust Pål , Vaage Ingvar Jarle , Auensen Andreas , Gullestad Lars , Ueland Thor 
Published: September 2020

Background:
Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS.

Methods:
Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed.

Results:

We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL,
P
<0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37–2.73],
P
<0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice).

Conclusions:
YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01794832.
Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart
Authors: Park David S. , Shekhar Akshay , Santucci John , Redel-Traub Gabriel , Solinas Sergio , Mintz Shana , Lin Xianming , Chang Ernest Whanwook , Narke Deven , Xia Yuhe , Goldfarb Mitchell , Fishman Glenn I. 
Published: September 2020

Rationale:

FHFs (fibroblast growth factor homologous factors) are key regulators of sodium channel (Na
V
) inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced Na
v
availability in
Fhf2
knockout (
Fhf2

KO

) mice predisposes to abnormal excitability at the tissue level are not well defined.

Objective:
Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction.

Methods and Results:

Fhf2

KO

mice were challenged by reducing calcium conductance (gCa
V
) using verapamil or by reducing gap junctional conductance (Gj) using carbenoxolone or by backcrossing into a cardiomyocyte-specific Cx43 (connexin 43) heterozygous background. All conditions produced conduction block in
Fhf2

KO

mice, with
Fhf2
wild-type (
Fhf2

WT

) mice showing normal impulse propagation. To explore the ionic mechanisms of block in
Fhf2

KO

hearts, multicellular linear strand models incorporating FHF2-deficient Na
v
inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced gCa
V
or diminished Gj are very different. Enhanced Na
v
inactivation due to FHF2 deficiency shifts dependence onto calcium current (I
Ca
) to sustain electrotonic driving force, axial current flow, and action potential (AP) generation from cell-to-cell. In the setting of diminished Gj, slower charging time from upstream cells conspires with accelerated Na
v
inactivation in mutant strands to prevent sufficient downstream cell charging for AP propagation.

Conclusions:

FHF2-dependent effects on Na
v
inactivation ensure adequate sodium current (I
Na
) reserve to safeguard against numerous threats to reliable cardiac impulse propagation.
Formation of Calcified Nodule as a Cause of Early In‐Stent Restenosis in Patients Undergoing Dialysis
Authors: Nakamura Norihito , Torii Sho , Tsuchiya Hiroko , Nakano Akihiko , Oikawa Yuji , Yajima Junji , Nakamura Shigeru , Nakano Masataka , Masuda Naoki , Ohta Hiroshi , Yumoto Kazuhiko , Natsumeda Makoto , Ijichi Takeshi , Ikari Yuji , Nakazawa Gaku 
Published: September 2020

Background
Dialysis is an independent risk factor for in‐stent restenosis (ISR) after stent implantation in coronary arteries. However, the characteristics of ISR in patients undergoing dialysis remain unclear, as there are no histological studies evaluating the causes of this condition. The aim of the present study was to investigate the causes of ISR between patients who are undergoing dialysis and those who are not by evaluating tissues obtained from ISR lesions using directional coronary atherectomy.

Methods and Results

A total of 29 ISR lesions from 29 patients included in a multicenter directional coronary atherectomy registry of 128 patients were selected for analysis and divided into a dialysis group (n=8) and a nondialysis group (n=21). Histopathological evaluation demonstrated that an in‐stent calcified nodule was a major histological characteristic of ISR lesions in the dialysis group and the prevalence of an in‐stent calcified nodule was significantly higher in the dialysis group compared with the nondialysis group (75% versus 5%, respectively;
P
<0.01). On the other hand, the prevalence of an in‐stent lipid‐rich plaque was significantly lower in the dialysis group compared with the nondialysis group (0% versus 43%, respectively;
P
=0.03). In all cases with an in‐stent calcified nodule, the underlying calcification before stent implantation was moderate to severe. When tissue characteristics were stratified according to duration post–stent implantation, an in‐stent calcified nodule in the dialysis group was mainly observed within 1 year after stent implantation.

Conclusions
In‐stent calcified nodules are a common cause of ISR in patients undergoing dialysis and are observed within 1 year after stent implantation, suggesting different causes of ISR between patients undergoing dialysis and those who are not.
Hyperoxygenation With Cardiopulmonary Resuscitation and Targeted Temperature Management Improves Post–Cardiac Arrest Outcomes in Rats
Authors: Li Jingru , Wang Jianjie , Shen Yiming , Dai Chenxi , Chen Bihua , Huang Yuanyuan , Xu Senlin , Wu Yi , Li Yongqin 
Published: September 2020

BackgroundOxygen plays a pivotal role in cardiopulmonary resuscitation (CPR) and postresuscitation intervention for cardiac arrest. However, the optimal method to reoxygenate patients has not been determined. This study investigated the effect of timing of hyperoxygenation on neurological outcomes in cardiac arrest/CPR rats treated with targeted temperature management.Methods and ResultsAfter induction of ventricular fibrillation, male Sprague‐Dawley rats were randomized into 4 groups (n=16/group): (1) normoxic control; (2) O2_CPR, ventilated with 100% O2during CPR; (3) O2_CPR+postresuscitation, ventilated with 100% O2during CPR and the first 3 hours of postresuscitation; and (4) O2_postresuscitation, ventilated with 100% O2during the first 3 hours of postresuscitation. Targeted temperature management was induced immediately after resuscitation and maintained for 3 hours in all animals. Postresuscitation hemodynamics, neurological recovery, and pathological analysis were assessed. Brain tissues of additional rats undergoing the same experimental procedure were harvested for ELISA‐based quantification assays of oxidative stress–related biomarkers and compared with the sham‐operated rats (n=6/group). We found that postresuscitation mean arterial pressure and quantitative electroencephalogram activity were significantly increased, whereas astroglial protein S100B, degenerated neurons, oxidative stress–related biomarkers, and neurologic deficit scores were significantly reduced in the O2_CPR+postresuscitation group compared with the normoxic control group. In addition, 96‐hour survival rates were significantly improved in all of the hyperoxygenation groups.ConclusionsIn this cardiac arrest/CPR rat model, hyperoxygenation coupled with targeted temperature management attenuates ischemia/reperfusion‐induced injuries and improves survival rates. The beneficial effects of high‐concentration oxygen are timing and duration dependent. Hyperoxygenation commenced with CPR, which improves outcomes when administered during hypothermia.
Dynamics of Word Production in the Transition from Adolescence to Adulthood
Authors: Atanasova Tanja , Fargier Raphaël , Zesiger Pascal , Laganaro Marina 
Published: September 2020

AbstractChanges in word production occur across the lifespan. Previous studies have shown electrophysiological, temporal, and functional differences between children and adults accompanying behavioral changes in picture-naming tasks (Laganaro, Tzieropoulos, Fraunfelder, & Zesiger, 2015). Thus, a shift toward adult-like processes in referential word production occurs somewhere between the ages of 13 and 20. Our aim was to investigate when and how children develop adult-like behavior and brain activation in word production. Toward this aim, performance and event-related potentials (ERP) in a referential word production task were recorded and compared for two groups of adolescents (aged 14 to 16 and 17 to 18), children (aged 10 to 13), and young adults (aged 20 to 30). Both groups of adolescents displayed adult-like production latencies, which were longer only for children, while accuracy was lower in the younger adolescents and in children, compared to adults. ERP waveform analysis and topographic pattern analysis revealed significant intergroup differences in key time-windows on stimulus-locked ERPs, both early (150–220 ms)—associated with pre-linguistic processes—and late (280–330 ms)—associated with lexical processes. The results indicate that brain activation underlying referential word production is completely adult-like in 17-year-old adolescents, whereas an intermediate pattern is still observed in adolescents aged 14 to 16 years old, although their production speed, but not their accuracy, is already adult-like.
The Innovative Strategies for Observations in the Arctic Atmospheric Boundary Layer Project (ISOBAR): Unique Finescale Observations under Stable and Very Stable Conditions
Authors: Kral Stephan T. , Reuder Joachim , Vihma Timo , Suomi Irene , Haualand Kristine F. , Urbancic Gabin H. , Greene Brian R. , Steeneveld Gert-Jan , Lorenz Torge , Maronga Björn , Jonassen Marius O. , Ajosenpää Hada , Båserud Line , Chilson Phillip B. , Holtslag Albert A. M. , Jenkins Alastair D. , Kouznetsov Rostislav , Mayer Stephanie , Pillar-Little Elizabeth A. , Rautenberg Alexander , Schwenkel Johannes , Seidl Andrew W. , Wrenger Burkhard 
Published: September 2020

AbstractThe Innovative Strategies for Observations in the Arctic Atmospheric Boundary Layer Program (ISOBAR) is a research project investigating stable atmospheric boundary layer (SBL) processes, whose representation still poses significant challenges in state-of-the-art numerical weather prediction (NWP) models. In ISOBAR ground-based flux and profile observations are combined with boundary layer remote sensing methods and the extensive usage of different unmanned aircraft systems (UAS). During February 2017 and 2018 we carried out two major field campaigns over the sea ice of the northern Baltic Sea, close to the Finnish island of Hailuoto at 65°N. In total 14 intensive observational periods (IOPs) resulted in extensive SBL datasets with unprecedented spatiotemporal resolution, which will form the basis for various numerical modeling experiments. First results from the campaigns indicate numerous very stable boundary layer (VSBL) cases, characterized by strong stratification, weak winds, and clear skies, and give detailed insight in the temporal evolution and vertical structure of the entire SBL. The SBL is subject to rapid changes in its vertical structure, responding to a variety of different processes. In particular, we study cases involving a shear instability associated with a low-level jet, a rapid strong cooling event observed a few meters above ground, and a strong wave-breaking event that triggers intensive near-surface turbulence. Furthermore, we use observations from one IOP to validate three different atmospheric models. The unique finescale observations resulting from the ISOBAR observational approach will aid future research activities, focusing on a better understanding of the SBL and its implementation in numerical models.