bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational Identification of Preneoplastic Cells Displaying High Stemness and Risk of Cancer Progression
Authors: Liu Tianyuan , Zhao Xuan , Lin Yuan , Luo Qi , Zhang Shaosen , Xi Yiyi , Chen Yamei , Lin Lin , Fan Wenyi , Yang Jie , Ma Yuling , Maity Alok K. , Huang Yanyi , Wang Jianbin , Chang Jiang , Lin Dongxin , Teschendorff Andrew E. , Wu Chen 
Published: May 2022

Abstract

Evidence points toward the differentiation state of cells as a marker of cancer risk and progression. Measuring the differentiation state of single cells in a preneoplastic population could thus enable novel strategies for early detection and risk prediction. Recent maps of somatic mutagenesis in normal tissues from young healthy individuals have revealed cancer driver mutations, indicating that these do not correlate well with differentiation state and that other molecular events also contribute to cancer development. We hypothesized that the differentiation state of single cells can be measured by estimating the regulatory activity of the transcription factors (TF) that control differentiation within that cell lineage. To this end, we present a novel computational method called CancerStemID that estimates a stemness index of cells from single-cell RNA sequencing data. CancerStemID is validated in two human esophageal squamous cell carcinoma (ESCC) cohorts, demonstrating how it can identify undifferentiated preneoplastic cells whose transcriptomic state is overrepresented in invasive cancer. Spatial transcriptomics and whole-genome bisulfite sequencing demonstrated that differentiation activity of tissue-specific TFs was decreased in cancer cells compared with the basal cell-of-origin layer and established that differentiation state correlated with differential DNA methylation at the promoters of these TFs, independently of underlying NOTCH1 and TP53 mutations. The findings were replicated in a mouse model of ESCC development, and the broad applicability of CancerStemID to other cancer-types was demonstrated. In summary, these data support an epigenetic stem-cell model of oncogenesis and highlight a novel computational strategy to identify stem-like preneoplastic cells that undergo positive selection.

Significance:
This study develops a computational strategy to dissect the heterogeneity of differentiation states within a preneoplastic cell population, allowing identification of stem-like cells that may drive cancer progression.
Delineating the RAS Conformational Landscape
Authors: Parker Mitchell I. , Meyer Joshua E. , Golemis Erica A. , Dunbrack, Roland L. 
Published: May 2022

Abstract

Mutations in RAS isoforms (KRAS, NRAS, and HRAS) are among the most frequent oncogenic alterations in many cancers, making these proteins high priority therapeutic targets. Effectively targeting RAS isoforms requires an exact understanding of their active, inactive, and druggable conformations. However, there is no structural catalog of RAS conformations to guide therapeutic targeting or examining the structural impact of RAS mutations. Here we present an expanded classification of RAS conformations based on analyses of the catalytic switch 1 (SW1) and switch 2 (SW2) loops. From 721 human KRAS, NRAS, and HRAS structures available in the Protein Data Bank (206 RAS–protein cocomplexes, 190 inhibitor-bound, and 325 unbound, including 204 WT and 517 mutated structures), we created a broad conformational classification based on the spatial positions of Y32 in SW1 and Y71 in SW2. Clustering all well-modeled SW1 and SW2 loops using a density-based machine learning algorithm defined additional conformational subsets, some previously undescribed. Three SW1 conformations and nine SW2 conformations were identified, each associated with different nucleotide states (GTP-bound, nucleotide-free, and GDP-bound) and specific bound proteins or inhibitor sites. The GTP-bound SW1 conformation could be further subdivided on the basis of the hydrogen bond type made between Y32 and the GTP γ-phosphate. Further analysis clarified the catalytic impact of G12D and G12V mutations and the inhibitor chemistries that bind to each druggable RAS conformation. Overall, this study has expanded our understanding of RAS structural biology, which could facilitate future RAS drug discovery.

Significance:
Analysis of &gt;700 RAS structures helps define an expanded landscape of active, inactive, and druggable RAS conformations, the structural impact of common RAS mutations, and previously uncharacterized RAS inhibitor–binding modes.
Serum Pepsinogen as a Biomarker for Gastric Cancer in the United States: A Nested Case–Control Study Using the PLCO Cancer Screening Trial Data
Authors: In Haejin , Sarkar Srawani , Ward Jessica , Friedmann Patricia , Parides Michael , Yang Julie , Epplein Meira 
Published: May 2022

Abstract

Background:
Gastric cancer lacks specific symptoms, resulting in diagnosis at later stages and high mortality. Serum pepsinogen is a biomarker for atrophic gastritis, a gastric cancer precursor, and may be useful to detect persons at increased risk of gastric cancer.

Methods:
The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was conducted in the United States between 1993 and 2001. ELISA-based pepsinogen tests were conducted on prediagnostic serum samples of 105 PLCO participants who developed gastric cancer and 209 age, sex, and race-matched controls. Pepsinogen positive (PG+) was defined as pepsinogen I ≤ 70 μg/L and pepsinogen I/II ratio ≤3.0. Results of conditional logistic regression models, and sensitivity and specificity, of PG+ for gastric cancer are reported.

Results:
Gastric cancer cases were more likely to be PG+ (31.4% vs. 5.5%, P &lt; 0.001) at baseline than controls. Compared to PG-, PG+ was associated with an 8.5-fold increased risk for gastric cancer [95% confidence interval (CI) = 3.8–19.4]. This risk remained significant after adjusting for Helicobacter pylori, family history of gastric cancer, education, smoking, and BMI (aOR, 10.6; 95% CI, 4.3–26.2). In subgroup analysis, PG+ individuals were 11-fold more like to develop non-cardia gastric cancer (OR, 11.1; 95% CI, 4.3–28.8); conversely, they were not significantly more likely to develop cardia gastric cancer (OR, 2.0; 95% CI = 0.3–14.2). PG+ status yielded low sensitivity but high specificity for both noncardia (44.3%; 93.6%) and cardia gastric cancer (5.7%; 97.2%).

Conclusions:
Prediagnostic serum pepsinogen levels from a large, prospective cohort study were associated with risk of gastric cancer, particularly noncardia gastric cancer.

Impact:
PG status may identify individuals at higher risk of noncardia gastric cancer for targeted screening or interventions.
See related commentary by Zhou and Huang, p. 1257
Airflow Limitation Increases Lung Cancer Risk in Smokers: The Lifelines Cohort Study
Authors: Du Yihui , Sidorenkov Grigory , Groen Harry J.M. , Heuvelmans Marjolein A. , Vliegenthart Rozemarijn , Dorrius Monique D. , Timens Wim , de Bock Geertruida H. 
Published: May 2022

Abstract

Background:
The relationship between smoking, airflow limitation, and lung cancer occurrence is unclear. This study aims to evaluate the relationship between airflow limitation and lung cancer, and the effect modification by smoking status.

Methods:
We included participants with spirometry data from Lifelines, a population-based cohort study from the Northern Netherlands. Airflow limitation was defined as FEV1/FVC ratio &lt; 0.7. The presence of pathology-confirmed primary lung cancer during a median follow-up of 9.5 years was collected. The Cox regression model was used and hazard ratios (HR) with 95% confidence interval (95% CI) were reported. Adjusted confounders included age, sex, educational level, smoking, passive smoking, asthma status and asbestos exposure. The effect modification by smoking status was investigated by estimating the relative excess risk due to interaction (RERI) and the ratio of HRs with 95% CI.

Results:
Out of 98,630 participants, 14,200 (14.4%) had airflow limitation. In participants with and without airflow limitation, lung cancer incidence was 0.8% and 0.2%, respectively. The adjusted HR between airflow limitation and lung cancer risk was 1.7 (1.4–2.3). The association between airflow limitation and lung cancer differed by smoking status [former smokers: 2.1 (1.4–3.2), current smokers: 2.2 (1.5–3.2)] and never smokers [0.9 (0.4–2.1)]. The RERI and ratio of HRs was 2.1 (0.7–3.4) and 2.5 (1.0–6.5) for former smokers, and 4.6 (95% CI, 1.8–7.4) and 2.5 (95% CI, 1.0–6.3) for current smokers, respectively.

Conclusions:
Airflow limitation increases lung cancer risk and this association is modified by smoking status.

Impact:
Ever smokers with airflow limitation are an important target group for the prevention of lung cancer.
Cardiovascular and Cerebrovascular Disease Mortality in Asian American Subgroups
Authors: Shah Nilay S. , Xi Kevin , Kapphahn Kristopher I. , Srinivasan Malathi , Au Timothy , Sathye Vedant , Vishal Vaibhav , Zhang Han , Palaniappan Latha P. 
Published: May 2022

Background:
Asian American individuals comprise the fastest-growing race and ethnic group in the United States. Certain subgroups may be at disproportionately high cardiovascular risk. This analysis aimed to identify cardiovascular and cerebrovascular disease mortality trends in Asian American subgroups.

Methods:
Age-standardized mortality rates (ASMR), average annual percent change of ASMR calculated by regression, and proportional mortality ratios of ischemic heart disease, heart failure, and cerebrovascular disease were calculated by sex in non-Hispanic Asian American subgroups (Chinese, Filipino, Asian Indian, Japanese, Korean, and Vietnamese), non-Hispanic White, and Hispanic individuals from US death certificates, 2003 to 2017.

Results:
Among 618 004 non-Hispanic Asian American, 30 267 178 non-Hispanic White, and 2 292 257 Hispanic deaths from all causes, ASMR from ischemic heart disease significantly decreased in all subgroups of Asian American women and in non-Hispanic White and Hispanic women; significantly decreased in Chinese, Filipino, Japanese, and Korean men and non-Hispanic White and Hispanic men and remained stagnant in Asian Indian and Vietnamese men. The highest 2017 ASMR from ischemic heart disease among Asian American decedents was in Asian Indian women (77 per 100 000) and men (133 per 100 000). Heart failure ASMR remained stagnant in Chinese, Korean, and non-Hispanic White women, and Chinese and Vietnamese men. Heart failure ASMR significantly increased in both sexes in Filipino, Asian Indian, and Japanese individuals, Vietnamese women, and Korean men, with highest 2017 ASMR among Asian American subgroups in Asian Indian women (14 per 100 000) and Asian Indian men (15 per 100 000). Cerebrovascular disease ASMR decreased in Chinese, Filipino, and Japanese women and men between 2003 and 2017, and remained stagnant in Asian Indian, Korean, and Vietnamese women and men. The highest cerebrovascular disease ASMR among Asian American subgroups in 2017 was in Vietnamese women (46 per 100 000) and men (47 per 100 000).

Conclusions:
There was heterogeneity in cardiovascular and cerebrovascular mortality among Asian American subgroups, with stagnant or increasing mortality trends in several subgroups between 2003 and 2017.
Rapid Exclusion of Acute Myocardial Injury and Infarction With a Single High-Sensitivity Cardiac Troponin T in the Emergency Department: A Multicenter United States Evaluation
Authors: Sandoval Yader , Lewis Bradley R. , Mehta Ramila A. , Ola Olatunde , Knott Jonathan D. , De Michieli Laura , Akula Ashok , Lobo Ronstan , Yang Eric H. , Gharacholou S. Michael , Dworak Marshall , Crockford Erika , Rastas Nicholas , Grube Eric , Karturi Swetha , Wohlrab Scott , Hodge David O. , Tak Tahir , Cagin Charles , Gulati Rajiv , Jaffe Allan S. 
Published: May 2022

Background:
There are good data to support using a single high-sensitivity cardiac troponin T (hs-cTnT) below the limit of detection of 5 ng/L to exclude acute myocardial infarction. Per the US Food and Drug Administration, hs-cTnT can only report to the limit of quantitation of 6 ng/L, a threshold for which there are limited data. Our goal was to determine whether a single hs-cTnT below the limit of quantitation of 6 ng/L is a safe strategy to identify patients at low risk for acute myocardial injury and infarction.

Methods:
The efficacy (proportion identified as low risk based on baseline hs-cTnT<6 ng/L) of identifying low-risk patients was examined in a multicenter (n=22 sites) US cohort study of emergency department patients undergoing at least 1 hs-cTnT (CV Data Mart Biomarker cohort). We then determined the performance of a single hs-cTnT<6 ng/L (biomarker alone) to exclude acute myocardial injury (subsequent hs-cTnT >99th percentile in those with an initial hs-cTnT<6 ng/L). The clinically intended rule-out strategy combining a nonischemic ECG with a baseline hs-cTnT<6 ng/L was subsequently tested in an adjudicated cohort in which the diagnostic performance for ruling out acute myocardial infarction and safety (myocardial infarction or death at 30 days) were evaluated.

Results:

A total of 85 610 patients were evaluated in the CV Data Mart Biomarker cohort, among which 24 646 (29%) had a baseline hs-cTnT<6 ng/L. Women were more likely than men to have hs-cTnT<6 ng/L (38% versus 20%,
P
<0.0001). Among 11 962 patients with baseline hs-cTnT<6 ng/L and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% (95% CI, 98.6–99.0) and sensitivity of 99.6% (95% CI, 99.5–99.6). In the adjudicated cohort, a nonischemic ECG with hs-cTnT<6 ng/L identified 33% of patients (610/1849) as low risk and resulted in a negative predictive value and sensitivity of 100% and a 30-day rate of 0.2% for myocardial infarction or death.

Conclusions:
A single hs-cTnT below the limit of quantitation of 6 ng/L is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.
Myeloid Poldip2 Contributes to the Development of Pulmonary Inflammation by Regulating Neutrophil Adhesion in a Murine Model of Acute Respiratory Distress Syndrome
Authors: Ou Ziwei , Dolmatova Elena , Mandavilli Rohan , Qu Hongyan , Gafford Georgette , White Taylor , Valdivia Alejandra , Lassègue Bernard , Hernandes Marina S. , Griendling Kathy K. 
Published: May 2022

Background

Lung injury, a severe adverse outcome of lipopolysaccharide‐induced acute respiratory distress syndrome, is attributed to excessive neutrophil recruitment and effector response. Poldip2 (polymerase δ‐interacting protein 2) plays a critical role in regulating endothelial permeability and leukocyte recruitment in acute inflammation. Thus, we hypothesized that
myeloid
Poldip2 is involved in neutrophil recruitment to inflamed lungs.

Methods and Results

After characterizing myeloid‐specific
Poldip2
knockout mice, we showed that at 18 hours post‐lipopolysaccharide injection, bronchoalveolar lavage from myeloid Poldip2‐deficient mice contained fewer inflammatory cells (8 [4–16] versus 29 [12–57]×10
4
/mL in wild‐type mice) and a smaller percentage of neutrophils (30% [28%–34%] versus 38% [33%–41%] in wild‐type mice), while the main chemoattractants for neutrophils remained unaffected. In vitro, Poldip2‐deficient neutrophils responded as well as wild‐type neutrophils to inflammatory stimuli with respect to neutrophil extracellular trap formation, reactive oxygen species production, and induction of cytokines. However, neutrophil adherence to a tumor necrosis factor‐α stimulated endothelial monolayer was inhibited by Poldip2 depletion (225 [115–272] wild‐type [myePoldip2
+/+
] versus 133 [62–178] myeloid‐specific
Poldip2
knockout [myePoldip2
‐/‐
] neutrophils) as was transmigration (1.7 [1.3–2.1] versus 1.1 [1.0–1.4] relative to baseline transmigration). To determine the underlying mechanism, we examined the surface expression of β2‐integrin, its binding to soluble intercellular adhesion molecule 1, and Pyk2 phosphorylation. Surface expression of β2‐integrins was not affected by Poldip2 deletion, whereas β2‐integrins and Pyk2 were less activated in Poldip2‐deficient neutrophils.

Conclusions
These results suggest that myeloid Poldip2 is involved in β2‐integrin activation during the inflammatory response, which in turn mediates neutrophil‐to‐endothelium adhesion in lipopolysaccharide‐induced acute respiratory distress syndrome.
Effect of Heart Rate on 1‐Year Outcome for Patients With Acute Ischemic Stroke
Authors: Lee Keon‐Joo , Kim Beom Joon , Han Moon‐Ku , Kim Joon‐Tae , Choi Kang‐Ho , Shin Dong‐Ick , Cha Jae‐Kwan , Kim Dae‐Hyun , Kim Dong‐Eog , Ryu Wi‐Sun , Park Jong‐Moo , Kang Kyusik , Lee Soo Joo , Kim Jae Guk , Oh Mi‐Sun , Yu Kyung‐Ho , Lee Byung‐Chul , Hong Keun‐Sik , Cho Yong‐Jin , Choi Jay Chol , Park Tai Hwan , Park Sang‐Soon , Lee Kyung Bok , Kwon Jee‐Hyun , Kim Wook‐Joo , Sohn Sung Il , Hong Jeong‐Ho , Lee Jun , Lee Ji Sung , Lee Juneyoung , Gorelick Philip B. , Bae Hee‐Joon ,   the CRCS‐K (Clinical Research Collaboration for Stroke in Korea) Investigators
Published: May 2022

Background
Previous literature about the effect of heart rate on poststroke outcomes is limited. We attempted to elucidate (1) whether heart rate during the acute period of ischemic stroke predicts subsequent major clinical events, (2) which heart rate parameter is best for prediction, and (3) what is the estimated heart rate cutoff point for the primary outcome.

Methods and Results

Eight thousand thirty‐one patients with acute ischemic stroke who were hospitalized within 48 hours of onset were analyzed retrospectively. Heart rates between the 4th and 7th day after onset were collected and heart rate parameters including mean, time‐weighted average, maximum, and minimum heart rate were evaluated. The primary outcome was the composite of recurrent stroke, myocardial infarction, and mortality up to 1 year after stroke onset. All heart rate parameters were associated with the primary outcome (
P
’s<0.001). Maximum heart rate had the highest predictive power. The estimated cutoff point for the primary outcome was 81 beats per minute for mean heart rate and 100 beats per minute for maximum heart rate. Patients with heart rates above these cutoff points had a higher risk of the primary outcome (adjusted hazard ratio, 1.80 [95% CI, 1.57–2.06] for maximum heart rate and 1.65 [95% CI, 1.45–1.89] for mean heart rate). The associations were replicated in a separate validation dataset (N=10 000).

Conclusions
These findings suggest that heart rate during the acute period of ischemic stroke is a predictor of major clinical events, and optimal heart rate control might be a target for preventing subsequent cardiovascular events.
Psilocybe ningshanensis (Hymenogastraceae, Agaricales), a new species from China
Authors: HE XUE-LIAN , HUO WEN-YAN , ZHANG LI-GUANG , LIU YU , QI PENG , DAI LU , QIAO TING , LU PENGPENG , LI JUN-ZHI 
Published: May 2022

The Qinling Mountains are the geographic boundary between northern and southern China. In our current study, we investigated the biodiversity of macrofungi in the Qinling Mountains of Shaanxi and discovered a new species, Psilocybe ningshanensis.
The phylogenetic tree shows its position in a group composed by P. hopii and P. mescaleroensis. They differ in some macro- and microscopic features, such as the presence or absence of an annulus or veil, the surface characteristics of the pileus, and the sizes and shapes of basidiospores and cheilocystidia. In addition, they are geographically distanced. P. ningshanensis was first discovered in Ningshan, China, whereas P. hopii and P. mescaleroensis were both found in the United States. In this article, we introduce the new species with illustrated description, ITS sequences, and comparisons with similar species.
Does the History of Tracheoesophageal Fistula Repair Alter Outcomes of Laryngeal Cleft Repair?
Authors: Nebor Ivanna , Katz Kadosh Orna , Tabangin Meredith E. , Hart Catherine K. , Myer Charles M. , Smith Matthew M. , Meinzen-Derr Jareen K. , Rutter Michael , de Alarcón Alessandro 
Published: May 2022

AbstractObjectiveTracheoesophageal fistula and esophageal atresia (TEA) and laryngeal cleft (LC) can coexist in some patients. The surgery‐specific success rate of LC repair in children with associated TEA has not been well described. The aim of the study is to determine if the history of TEA alters the LC repair outcomes.Study DesignCase series with chart review.SettingSingle‐institution academic medical center.MethodA retrospective review was conducted of patients with LC with and without TEA repair between January 2001 and November 2020. Data collected and analyzed included demographics and clinical characteristics, LC type, and LC with TEA timing of repairs.ResultsAn overall 282 patients met the inclusion criteria of LC repair: LC (n = 242, 85.8%) and LC + TEA (n = 40, 14.2%). Revision repair was required in 43 patients (15.2%) with 8 (2.8%) needing a second revision repair. The first LC revision rate in the LC group was 36/242 (14.9%) as compared with 7/40 (17.5%) in the LC + TEA group (P = .67). The second LC revision rate in the LC and LC + TEA groups was 7 (2.9%) and 1 (2.4%), respectively. The median time to revision was 5.1 months (interquartile range, 3.45–10.6) in the LC group as compared with 29.2 months (interquartile range, 4.8–44.2) in the LC + TEA group (P = .06).ConclusionThe incidence of TEA and LC was 14.2% in our study. Based on our findings, history of TEA repair is not associated with a higher revision rate vs LC alone. The history of TEA repair did not alter the outcomes of LC repair.
Effects of low-intensity pulsed ultrasound on knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials
Authors: Chen Haoqian , Wang Zheng , Zhang Xinan , Sun Mingli 
Published: May 2022

Objective To systemically review the effects of low-intensity pulsed ultrasound (LIPUS) on pain relief and functional recovery in patients with knee osteoarthritis (KOA). Data sources PubMed, Web of Science, Cochrane Library, Physiotherapy Evidence Database (PEDro), and China National Knowledge Infrastructure (CNKI) were used from inception to 18 March 2022. Review Methods Meta-analysis was performed to evaluate pain and function recovery between control and LIPUS groups. Standardized mean difference (SMD) or mean difference (MD) and 95% confidence interval (CI) were calculated, and data were combined using the fixed or random-effect model. Results Thirteen studies involving 807 patients with KOA were included. Patients’ outcomes treated by LIPUS were improved significantly, including Visual analog scale (VAS) score (MD = −0.95, 95% CI: −1.43 to −0.48， P < 0.001), Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) score (MD = −4.35, 95% CI: −8.30 to −0.40, P = 0.0309), Lysholm score (SMD = 1.59, 95% CI: 1.29 to 1.90, P < 0.001), Lequesne index (MD = −1.33, 95% CI: −1.69 to −0.96, P < 0.001), Range of motion (ROM) (MD = 2.43, 95% CI: 0.39 to 4.46, P = 0.0197) and 50 meter walking time (SMD = 1.48, 95% CI: 0.46 to 2.49, P = 0.0044). Subgroup analyses showed monotherapy of LIPUS produced a better effect on reducing VAS score ( P = 0.0213), and the shorter therapeutic period (≤4 weeks) produced a more significant effect on raising the WOMAC score ( P = 0.0083). Conclusion LIPUS was beneficial for pain relief and functional knee recovery and maybe as an alternative therapy in KOA rehabilitation.