bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study
Authors: Hua Xinwei , Dai James Y. , Lindström Sara , Harrison Tabitha A. , Lin Yi , Alberts Steven R. , Alwers Elizabeth , Berndt Sonja I. , Brenner Hermann , Buchanan Daniel D. , Campbell Peter T. , Casey Graham , Chang-Claude Jenny , Gallinger Steven , Giles Graham G. , Goldberg Richard M. , Gunter Marc J. , Hoffmeister Michael , Jenkins Mark A. , Joshi Amit D. , Ma Wenjie , Milne Roger L. , Murphy Neil , Pai Rish K. , Sakoda Lori C. , Schoen Robert E. , Shi Qian , Slattery Martha L. , Song Mingyang , White Emily , Marchand Loic Le , Chan Andrew T. , Peters Ulrike , Newcomb Polly A. 
Published: May 2021

Abstract

Background:
A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer–specific survival.

Methods:
We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer–specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.

Results:
Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer–specific survival (HD, −1.15; 95% CI, −2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.

Conclusions:
Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer–specific survival.

Impact:
Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
Combined Inhibition of Rad51 and Wee1 Enhances Cell Killing in HNSCC Through Induction of Apoptosis Associated With Excessive DNA Damage and Replication Stress
Authors: Lindemann Antje , Patel Ameeta A. , Tang Lin , Tanaka Noriaki , Gleber-Netto Frederico O. , Bartels Mason D. , Wang Li , McGrail Daniel J. , Lin Shiaw-Yih , Frank Steven J. , Frederick Mitchell J. , Myers Jeffrey N. , Osman Abdullah A. 
Published: May 2021

AbstractDespite advances in surgery, chemotherapy, and radiation, there are limited treatment options for advanced head and neck squamous cell carcinoma (HNSCC) and survival remains very poor. Therefore, effective therapies are desperately needed. Recently, selective exploitation of DNA damage and replication stress responses has become a novel approach for cancer treatment. Wee1 kinase and Rad51 recombinase are two proteins involved in regulating replication stress and homologous recombination repair in cancer cells. In this study, we investigated the combined effect of Rad51 inhibitor (B02) and Wee1 inhibitor (AZD1775) in vitro and in vivo in various HNSCC cell lines. Clonogenic survival assays demonstrated that B02 synergized with AZD1775 in vitro in all HNSCC cell lines tested. The synergy between these drugs was associated with forced CDK1 activation and reduced Chk1 phosphorylation leading to induction of excessive DNA damage and replication stress, culminating in aberrant mitosis and apoptosis. Our results showed that elevated Rad51 mRNA expression correlated with worse survival in HNSCC patients with HPV-positive tumors. The combination of B02 and AZD1775 significantly inhibited tumor growth in vivo in mice bearing HPV-positive HNSCC tumors as compared to HPV-negative HNSCC. This differential sensitivity appears to be linked to HPV-positive tumors having more in vivo endogenous replication stress owing to transformation by E6 and E7 oncogenes. Furthermore, addition of B02 radiosensitized the HPV-negative HNSCC tumors in vitro and in vivo. In conclusion, our data implicate that a novel rational combination with Rad51 and Wee1 inhibitors holds promise as synthetic lethal therapy, particularly in high-risk HPV-positive HNSCC.
Discovery of Candidate DNA Methylation Cancer Driver Genes
Authors: Pan Heng , Renaud Loïc , Chaligne Ronan , Bloehdorn Johannes , Tausch Eugen , Mertens Daniel , Fink Anna Maria , Fischer Kirsten , Zhang Chao , Betel Doron , Gnirke Andreas , Imielinski Marcin , Moreaux Jérôme , Hallek Michael , Meissner Alexander , Stilgenbauer Stephan , Wu Catherine J. , Elemento Olivier , Landau Dan A. 
Published: May 2021

Abstract

Epigenetic alterations, such as promoter hypermethylation, may drive cancer through tumor suppressor gene inactivation. However, we have limited ability to differentiate driver DNA methylation (DNAme) changes from passenger events. We developed DNAme driver inference–MethSig–accounting for the varying stochastic hypermethylation rate across the genome and between samples. We applied MethSig to bisulfite sequencing data of chronic lymphocytic leukemia (CLL), multiple myeloma, ductal carcinoma in situ, glioblastoma, and to methylation array data across 18 tumor types in TCGA. MethSig resulted in well-calibrated quantile–quantile plots and reproducible inference of likely DNAme drivers with increased sensitivity/specificity compared with benchmarked methods. CRISPR/Cas9 knockout of selected candidate CLL DNAme drivers provided a fitness advantage with and without therapeutic intervention. Notably, DNAme driver risk score was closely associated with adverse outcome in independent CLL cohorts. Collectively, MethSig represents a novel inference framework for DNAme driver discovery to chart the role of aberrant DNAme in cancer.

Significance:
MethSig provides a novel statistical framework for the analysis of DNA methylation changes in cancer, to specifically identify candidate DNA methylation driver genes of cancer progression and relapse, empowering the discovery of epigenetic mechanisms that enhance cancer cell fitness.
This article is highlighted in the In This Issue feature, p. 2113
Abstract 15522: Multiple Brachial ‘Tornado’ Loops Encountered During Transradial Access - A Case Report With Review of Literature
Authors: Vaishnav Aditi S , Vaishnav Avani , Iyer Shankar , Vaishnav Sudhir 
Published: May 2021

Introduction:
Although transradial access (TRA) is widely accepted for cardiac catheterization, technical difficulties may occur due to variations in the radial-brachial-subclavian artery anatomy.

Clinical Vignette:
A 70-year old man presented with typical angina, positive stress test and normal LV function. Elective coronary angiography via TRA was planned since there were no contraindications. A guidewire was inserted and advanced via right radial puncture. Due to resistance above the elbow, the wire was withdrawn and check shoots were taken. These revealed a brachial loop, which was crossed and straightened with a Teflon coated angioplasty wire (0.014BMW wire). On advancing further, resistance was encountered again. Check-shoots at this point revealed multiple tortuous tornado-like brachial loops. Attempts to cross these using a BMW wire and 4F-RCA guiding catheter were unsuccessful as the artery went into spasm, preventing further manipulation. Ipsilateral TRA was abandoned due to risk of arterial perforation and severe pain; contralateral TRA was not attempted due to patient’s refusal. The procedure was completed via femoral access.

Discussion:
To the best of our knowledge, this is the first report of multiple brachial loops, which highlights certain unique challenges-

1. Complex anatomic variations can occur exclusive of signs used to assess TRA amenability
2. No guidelines on procedural techniques
3. No data to guide the alternative access site as it is unknown whether brachial loops tend to occur bilaterally, unlike radial loops
4. Unlike radial and subclavian arteries, there are no data on association of demographic factors with brachial artery variations.

Conclusion:
Anatomic variations of upper limb arteries, although rare, can cause technical difficulties and TRA failure. If resistance is encountered, an angiogram should be performed through the sheath to assess anatomy, to prevent severe spasm and perforation from forceful catheter advancement.
Cardiovascular Risk Factor Trajectories Since Childhood and Cognitive Performance in Midlife: The Cardiovascular Risk in Young Finns Study
Authors: Hakala Juuso O. , Pahkala Katja , Juonala Markus , Salo Pia , Kähönen Mika , Hutri-Kähönen Nina , Lehtimäki Terho , Laitinen Tomi P. , Jokinen Eero , Taittonen Leena , Tossavainen Päivi , Viikari Jorma S.A. , Raitakari Olli T. , Rovio Suvi P. 
Published: May 2021

Background:
Cardiovascular risk factors, such as high blood pressure, adverse serum lipids, and elevated body mass index in midlife, may harm cognitive performance. It is important to note that longitudinal accumulation of cardiovascular risk factors since childhood may be associated with cognitive performance already since childhood, but the previous evidence is scarce. We studied the associations of cardiovascular risk factors from childhood to midlife, their accumulation, and midlife cognitive performance.

Methods:
From 1980, a population-based cohort of 3596 children (3–18 years of age) have been repeatedly followed up for 31 years. Blood pressure, serum lipids, and body mass index were assessed in all follow-ups. Cardiovascular risk factor trajectories from childhood to midlife were identified using latent class growth mixture modeling. Cognitive testing was performed in 2026 participants 34 to 49 years of age using a computerized test. The associations of the cardiovascular risk factor trajectories and cognitive performance were studied for individual cardiovascular risk factors and cardiovascular risk factor accumulation.

Results:

Consistently high systolic blood pressure (β=–0.262 SD [95% CI, –0.520 to –0.005]) and serum total cholesterol (β=–0.214 SD [95% CI, –0.365 to –0.064]) were associated with worse midlife episodic memory and associative learning compared with consistently low values. Obesity since childhood was associated with worse visual processing and sustained attention (β=–0.407 SD [95% CI, –0.708 to –0.105]) compared with normal weight. An inverse association was observed for the cardiovascular risk factor accumulation with episodic memory and associative learning (
P
for trend=0.008; 3 cardiovascular risk factors: β=–0.390 SD [95% CI, –0.691 to –0.088]), with visual processing and sustained attention (
P
for trend<0.0001; 3 cardiovascular risk factors: β=–0.443 SD [95% CI, –0.730 to –0.157]), and with reaction and movement time (
P
for trend=0.048; 2 cardiovascular risk factors: β=–0.164 SD [95% CI, –0.318 to –0.010]).

Conclusions:
Longitudinal elevated systolic blood pressure, high serum total cholesterol, and obesity from childhood to midlife were inversely associated with midlife cognitive performance. It is important to note that the higher the number of cardiovascular risk factors, the worse was the observed cognitive performance. Therefore, launching preventive strategies against cardiovascular risk factors beginning from childhood might benefit primordial promotion of cognitive health in adulthood.
Prediction of Cognitive Recovery After Stroke: The Value of Diffusion-Weighted Imaging–Based Measures of Brain Connectivity
Authors: Aben Hugo P. , De Munter Leonie , Reijmer Yael D. , Spikman Jacoba M. , Visser-Meily Johanna M.A. , Biessels Geert Jan , De Kort Paul L.M. ,   on behalf of the PROCRAS Study Group
Published: May 2021

Background and Purpose:
Prediction of long-term recovery of a poststroke cognitive disorder (PSCD) is currently inaccurate. We assessed whether diffusion-weighted imaging (DWI)–based measures of brain connectivity predict cognitive recovery 1 year after stroke in patients with PSCD in addition to conventional clinical, neuropsychological, and imaging variables.

Methods:
This prospective monocenter cohort study included 217 consecutive patients with a clinical diagnosis of ischemic stroke, aged ≥50 years, and Montreal Cognitive Assessment score below 26 during hospitalization. Five weeks after stroke, patients underwent DWI magnetic resonance imaging. Neuropsychological assessment was performed 5 weeks and 1 year after stroke and was used to classify PSCD as absent, modest, or marked. Cognitive recovery was operationalized as a shift to a better PSCD category over time. We evaluated 4 DWI-based measures of brain connectivity: global network efficiency and mean connectivity strength, both weighted for mean diffusivity and fractional anisotropy. Conventional predictors were age, sex, level of education, clinical stroke characteristics, neuropsychological variables, and magnetic resonance imaging findings (eg, infarct size). DWI-based measures of brain connectivity were added to a multivariable model to assess additive predictive value.

Results:

Of 135 patients (mean age, 71 years; 95 men [70%]) with PSCD 5 weeks after ischemic stroke, 41 (30%) showed cognitive recovery. Three of 4 brain connectivity measures met the predefined threshold of
P
<0.1 in univariable regression analysis. There was no added value of these measures to a multivariable model that included level of education and infarct size as significant predictors of cognitive recovery.

Conclusions:
Current DWI-based measures of brain connectivity appear to predict recovery of PSCD but at present have no added value over conventional predictors.
The Beard as Spectacle and Scandal in a Thirteenth-century Hebrew Maqāma
Authors: Rosen Tova 
Published: May 2021

Abstract
The Eighth Maqāma by Yaʿacov ben Elʿazar (Toledo, ca. 1200) tells the story of ʿAkhbor, a bearded beggar-preacher who is revealed to be rich and lecherous. His sexual preference for a black maid leads his four white/Arab maids to murder him viciously, but not before taking revenge on his beard. In fact, the most notable feature of the false preacher is his gargantuan beard, which occupies a full one-third of the maqāma, and other beards are also excessively described. Following Robert Bartlett, I will relate to the beard as “social text” and explore its abundant symbolical meanings within the surrounding cultures of Islam and Judaism, as well as against the backdrop of Iberian contemporary society. Further, in order to better understand Ben Elʿazar’s manipulation of both the beard and the genre, as well as his emphasis on sexual, anal and scatological humor, I will have recourse to Mikhail Bakhtin’s theoretical discussions of “the grotesque body,” “the carnivalesque,” and to his generic model of the Mennipea.
A New Predictive Framework for Amazon Forest Fire Smoke Dispersion over South America
Authors: Vara-Vela Angel Liduvino , Herdies Dirceu Luís , Alvim Débora Souza , Vendrasco Éder Paulo , Figueroa Silvio Nilo , Pendharkar Jayant , Reyes Fernandez Julio Pablo 
Published: May 2021

AbstractAerosol particles from forest fire events in the Amazon can be effectively transported to urban areas in southeastern South America, thus affecting the air quality over those regions. A combination of observational data and a comprehensive air quality modeling system capable of anticipating acute air pollution episodes is therefore required. A new predictive framework for Amazon forest fire smoke dispersion over South America has been developed based on the Weather Research and Forecasting with Chemistry community (WRF-Chem) model. Two experiments of 48-h simulations over South America were performed by using this system at 20-km horizontal resolution, on a daily basis, during August and September of 2018 and 2019. The experiment in 2019 included the very strong 3-week forest fire event, when the São Paulo metropolitan area, located in southeastern South America, was plunged into darkness on August 19. The model results were satisfactorily compared against satellite-based data products and in situ measurements collected from air quality monitoring sites. The system is executed daily immediately after the CPTEC Satellite Division releases the latest active fire locations data and provides 48-h forecasts of regional distributions of chemical species such as CO, PM2.5, and O3. The new modeling system will be used as a benchmark within the framework of the Chemistry of the Atmosphere–Field Experiment in Brazil (CAFE-Brazil) project, which will take place in 2022 over the Amazon.
Suppression of Baroclinic Eddies by Strong Jets
Authors: Hadas Or , Kaspi Yohai 
Published: May 2021

AbstractThe midlatitude storm tracks are of the most prominent features of extratropical climate. Despite the theoretical expectation, based on baroclinic instability theory, that baroclinic eddies strengthen with jet intensification, there is evidence that this relation breaks when the jet is particularly strong. The most known case is the Pacific midwinter minimum in storm track activity. To isolate the effect of jet strength on storm activity, we conduct a series of GCM experiments systematically varying jet intensity. The simulations are analyzed using Lagrangian tracking to understand the response from a single-eddy perspective. The Lagrangian analysis shows that while the response of upper-level eddies is dominated by a reduction in the amount of tracked features, the lower-level eddies’ response is also affected by a reduction in their lifetime. Analyzing the jet strength effect on the pairing between the upper- and lower-level eddies, we find that the jet intensification increases the relative speed of the upper-level eddies, breaking the baroclinic wave structure and limiting its growth. We show that the Lagrangian response correlates with a shift in the midlatitude spectrum to low wavenumbers. The shift settles these results with linear baroclinic instability theory, as under the stronger jet conditions synoptic-scale eddies are predicted to have a sub-optimal growth rate. These results can potentially explain the midwinter suppression of storm activity over the Pacific and the difference from the Atlantic response.
A Regional Seasonal Forecast Model of Arctic Minimum Sea Ice Extent: Reflected Solar Radiation versus Late Winter Coastal Divergence
Authors: Kim Rachel , Tremblay L. Bruno , Brunette Charles , Newton Robert 
Published: May 2021

AbstractThinning sea ice cover in the Arctic is associated with larger interannual variability in the minimum sea ice extent (SIE). The current generation of forced or fully coupled models, however, has difficulty predicting SIE anomalies from the long-term trend, highlighting the need to better identify the mechanisms involved in the seasonal evolution of sea ice cover. One such mechanism is coastal divergence (CD), a proxy for ice thickness anomalies based on late winter ice motion, quantified using Lagrangian ice tracking. CD gains predictive skill through the positive feedback of surface albedo anomalies, mirrored in reflected solar radiation (RSR), during melt season. Exploring the dynamic and thermodynamic contributions to minimum SIE predictability, RSR, initial SIE (iSIE), and CD are compared as predictors using a regional seasonal sea ice forecast model for 1 July, 1 June, and 1 May forecast dates for all Arctic peripheral seas. The predictive skill of June RSR anomalies mainly originates from open water fraction at the surface; that is, June iSIE and June RSR have equal predictive skill for most seas. The finding is supported by the surprising positive correlation found between June melt pond fraction (MPF) and June RSR in all peripheral seas: MPF anomalies indicate the presence of ice or open water, which is key to creating minimum SIE anomalies. This contradicts models that show correlation between melt onset, MPF, and the minimum SIE. A hindcast model shows that for a 1 May forecast, CD anomalies have better predictive skill than RSR anomalies for most peripheral seas.
Seasonal Prediction and Predictability of Regional Antarctic Sea Ice
Authors: Bushuk Mitchell , Winton Michael , Haumann F. Alexander , Delworth Thomas , Lu Feiyu , Zhang Yongfei , Jia Liwei , Zhang Liping , Cooke William , Harrison Matthew , Hurlin Bill , Johnson Nathaniel C. , Kapnick Sarah B. , McHugh Colleen , Murakami Hiroyuki , Rosati Anthony , Tseng Kai-Chih , Wittenberg Andrew T. , Yang Xiaosong , Zeng Fanrong 
Published: May 2021

AbstractCompared to the Arctic, seasonal predictions of Antarctic sea ice have received relatively little attention. In this work, we utilize three coupled dynamical prediction systems developed at the Geophysical Fluid Dynamics Laboratory to assess the seasonal prediction skill and predictability of Antarctic sea ice. These systems, based on the FLOR, SPEAR_LO, and SPEAR_MED dynamical models, differ in their coupled model components, initialization techniques, atmospheric resolution, and model biases. Using suites of retrospective initialized seasonal predictions spanning 1992–2018, we investigate the role of these factors in determining Antarctic sea ice prediction skill and examine the mechanisms of regional sea ice predictability. We find that each system is capable of skillfully predicting regional Antarctic sea ice extent (SIE) with skill that exceeds a persistence forecast. Winter SIE is skillfully predicted 11 months in advance in the Weddell, Amundsen/Bellingshausen, Indian, and west Pacific sectors, whereas winter skill is notably lower in the Ross sector. Zonally advected upper-ocean heat content anomalies are found to provide the crucial source of prediction skill for the winter sea ice edge position. The recently developed SPEAR systems are more skillful than FLOR for summer sea ice predictions, owing to improvements in sea ice concentration and sea ice thickness initialization. Summer Weddell SIE is skillfully predicted up to 9 months in advance in SPEAR_MED, due to the persistence and drift of initialized sea ice thickness anomalies from the previous winter. Overall, these results suggest a promising potential for providing operational Antarctic sea ice predictions on seasonal time scales.
The physics of ocean wave evolution within tropical cyclones
Authors: Tamizi Ali , Alves Jose-Henrique , Young Ian R. 
Published: May 2021

AbstractA series of numerical experiments with the WAVEWATCH III spectral wave model are used to investigate the physics of wave evolution in tropical cyclones. Buoy observations show that tropical cyclone wave spectra are directionally skewed with a continuum of energy between locally generated wind-sea and remotely generated waves. These systems are often separated by more than 900. The model spectra are consistent with the observed buoy data and are shown to be governed by nonlinear wave-wave interactions which result in a cascade of energy from the wind-sea to the remotely generated spectral peak. The peak waves act in a “parasitic” manner taking energy from the wind-sea to maintain their growth. The critical role of nonlinear processes explains why one-dimensional tropical cyclone spectra have characteristics very similar to fetch-limited waves, even though the generation system is far more complex. The results also provide strong validation of the critical role nonlinear interactions play in wind-wave evolution.