bluuebunny/crossref_metadata_2025_split huggingface dataset:
The BRCA1 Pseudogene Negatively Regulates Antitumor Responses through Inhibition of Innate Immune Defense Mechanisms
Authors: Han Yoo Jane , Zhang Jing , Lee Jung-Hyun , Mason Jennifer M. , Karginova Olga , Yoshimatsu Toshio F. , Hao Qinyu , Hurley Ian , Brunet Laia Paré , Prat Aleix , Prasanth Kannanganattu V. , Gack Michaela U. , Olopade Olufunmilayo I. 
Published: January 2021

Abstract

Innate immune defense mechanisms play a pivotal role in antitumor responses. Recent evidence suggests that antiviral innate immunity is regulated not only by exogenous non–self-RNA but also by host-derived pseudogene RNAs. A growing body of evidence also indicates a biological role for pseudogenes as gene expression regulators or immune modulators. Here, we report an important role for BRCA1P1, the pseudogene of the BRCA1 tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. BRCA1P1 expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA-BRCA1P1 is increased in breast tumors compared with normal breast tissues. Depletion of BRCA1P1 induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, BRCA1P1-deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of BRCA1P1 increases host innate immune responses and restricts virus replication. In converse, overexpression of BRCA1P1 reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA-BRCA1P1 is localized in the nucleus, binds to the NF-κB subunit RelA, and negatively regulates antiviral gene expression. Finally, in a xenograft mouse model of breast cancer, depletion of BRCA1P1 stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for BRCA1P1 in innate immune defense mechanisms and antitumor responses. This mechanism of antiviral immunity regulated by a host-derived pseudogene RNA may guide the development of novel therapies targeting immune responses in breast cancer.

Significance:
This study identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and antitumor responses through regulation of antiviral gene expression.
Concomitant MEK and Cyclin Gene Alterations: Implications for Response to Targeted Therapeutics
Authors: Kato Shumei , Adashek Jacob J. , Shaya Justin , Okamura Ryosuke , Jimenez Rebecca E. , Lee Suzanna , Sicklick Jason K. , Kurzrock Razelle 
Published: January 2021

AbstractPurpose:Cyclin and MAPK/MEK-related gene alterations are implicated in cell-cycle progression and cancer growth. Yet, monotherapy to target the cyclin (CDK4/6) or the MEK pathway has often yielded disappointing results. Because coalterations in cyclin and MEK pathway genes frequently cooccur, we hypothesized that resistance to CDK4/6 or MEK inhibitor monotherapy might be mediated via activation of oncogenic codrivers, and that combination therapy might be useful.Experimental Design:Herein, we describe 9 patients with advanced malignancies harboring concomitant CDKN2A and/or CDKN2B alterations (upregulate CDK4/6) along with KRAS or BRAF alterations (activate the MEK pathway) who were treated with palbociclib (CDK4/6 inhibitor) and trametinib (MEK inhibitor) combination-based regimens.Results:Two patients (with pancreatic cancer) achieved a partial remission (PR) and, overall, 5 patients (56%) had clinical benefit (stable disease ≥ 6 months/PR) with progression-free survival of approximately 7, 9, 9, 11, and 17.5+ months. Interestingly, 1 of these patients whose cancer (gastrointestinal stromal tumor) had progressed on MEK targeting regimen, did well for about 1 year after palbociclib was added.Conclusions:These observations suggest that cotargeting cyclin and MEK signaling can be successful when tumors bear genomic coalterations that activate both of these pathways. Further prospective studies using this matching precision strategy to overcome resistance are warranted.See related commentary by Groisberg and Subbiah, p. 2672
Interleukin 12p40 Deficiency Promotes Abdominal Aortic Aneurysm by Activating CCN2/MMP2 Pathways
Authors: Sharma Neekun , Hans Chetan P. 
Published: January 2021

Background

Development of abdominal aortic aneurysm (AAA) is associated with proinflammatory cytokines including interleukin‐12 (IL12). Deficiency of interleukin 12p40 (IL12p40) increases localized fibrotic events by promoting TGFβ2 (transforming growth factor β)‐dependent anti‐inflammatory response. Here, we determined whether IL12p40 deficiency in apolipoprotein E
‐/‐
mice attenuates the development of AAA by antagonizing proinflammatory response.

Methods and Results

Double knockout (DKO) mice were generated by crossbreeding IL12p40
‐/‐
mice with apolipoprotein E
‐/‐
mice (n=12). Aneurysmal studies were performed using angiotensin II (1 µg/kg/min; subcutaneous). Surprisingly, DKO mice did not prevent the development of AAA with angiotensin II infusion. Immunohistological analysis, however, showed distinct pathological features between apolipoprotein E

‐/‐

and DKO mice. Polymerase chain reaction (7 day) and cytokine arrays (28 day) of the aortic tissues from DKO mice showed significantly increased expression of cytokines related to anti‐inflammatory response (interleukin 5 and interleukin 13), synthetic vascular smooth muscle cell phenotype (Activin receptor‐like kinase‐1 (ALK‐1), artemin, and betacellulin) and T helper 17‐associated response (4‐1BB, interleukin‐17e (Il17e) and Cd40 ligand (Cd‐40L)). Indeed, DKO mice exhibited increased expression of the fibro‐proteolytic pathway in the medial layer of aortae induced by cellular communication network factor 2 (CCN2) and Cd3
+
IL17
+
cells compared with apolipoprotein E

‐/‐

mice. Laser capture microdissection showed predominant expression of CCN2/TGFβ2 in the medial layer of human AAA. Finally,
Ccn2
haploinsufficiency in the mice showed decreased AAA incidence in response to elastase infusion, associated with decreased matrix metalloproteinase‐2 expression.

Conclusions

Our study reveals novel roles for
IL12p40
deficiency in inducing fibro‐proteolytic activities in the aneurysmal mouse model. Mechanistically, these effects of IL12p40 deficiency are mediated by CCN2/matrix metalloproteinase‐2 crosstalk in the medial layer of aneurysmal aortae.
Longitudinal Associations of Midlife Accelerometer Determined Sedentary Behavior and Physical Activity With Cognitive Function: The CARDIA Study
Authors: Whitaker Kara M. , Zhang Dong , Pettee Gabriel Kelley , Ahrens Monica , Sternfeld Barbara , Sidney Stephen , Jacobs David R. , Palta Priya , Yaffe Kristine 
Published: January 2021

Background
To determine if accelerometer measured sedentary behavior (SED), light‐intensity physical activity (LPA), and moderate‐to‐vigorous–intensity physical activity (MVPA) in midlife is prospectively associated with cognitive function.

Methods and Results
Participants were 1970 adults enrolled in the CARDIA (Coronary Artery Risk Development in Young Adults) study who wore an accelerometer in 2005 to 2006 (ages 38–50 years) and had cognitive function assessments completed 5 and/or 10 years later. SED, LPA, and MVPA were measured by an ActiGraph 7164 accelerometer. Cognitive function tests included the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop Test. Compositional isotemporal substitution analysis examined associations of SED, LPA, and MVPA with repeated measures of the cognitive function standardized scores. In men, statistical reallocation of 30 minutes of LPA with 30 minutes of MVPA resulted in an estimated difference of SD 0.07 (95% CI, 0.01–0.14), SD 0.09 (95% CI, 0.02–0.17), and SD −0.11 (95% CI, −0.19 to −0.04) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating better performance. Associations were similar when reallocating time in SED with MVPA, but results were less robust. Reallocation of time in SED with LPA resulted in an estimated difference of SD −0.05 (95% CI, −0.06 to −0.03), SD −0.03 (95% CI, −0.05 to −0.01), and SD 0.05 (95% CI, 0.03– 0.07) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating worse performance. Associations were largely nonsignificant among women.

Conclusions
Our findings support the idea that for men, higher‐intensity activities (MVPA) may be necessary in midlife to observe beneficial associations with cognition.
Procedural Complications During Early Versus Late Endovascular Treatment in Acute Stroke
Authors: Maslias Errikos , Nannoni Stefania , Ricciardi Federico , Bartolini Bruno , Strambo Davide , Puccinelli Francesco , Hajdu Steven David , Eskandari Ashraf , Saliou Guillaume , Michel Patrik 
Published: January 2021

Background and Purpose:
Endovascular treatment (EVT) in acute ischemic stroke is effective in the late time window in selected patients. However, the frequency and clinical impact of procedural complications in the early versus late time window has received little attention.

Methods:
We retrospectively studied all acute ischemic strokes from 2015 to 2019 receiving EVT in the Acute Stroke Registry and Analysis of Lausanne. We compared the procedural EVT complications in the early (<6 hours) versus late (6–24 hours) window and correlated them with short-term clinical outcome.

Results:

Among 695 acute ischemic strokes receiving EVT (of which 202 were in the late window), 113 (16.3%) had at least one procedural complication. The frequency of each single, and for overall procedural complications was similar for early versus late EVT (16.2% versus 16.3%,
P
adj
=0.90). Procedural complications lead to a significantly less favorable short-term outcome, reflected by the absence of National Institutes of Health Stroke Scale improvement in late EVT (delta-National Institutes of Health Stroke Scale-24 hours, −2.5 versus 2,
P
adj
=0.01).

Conclusions:
In this retrospective analysis of consecutive EVT, the frequency of procedural complications was similar for early and late EVT patients but very short-term outcome seemed less favorable in late EVT patients with complications.
Age, Personal Characteristics, and the Speed of Psychological Time
Authors: Gagnon-Harvey Audrey-Anne , McArthur Jamie , Tétreault Émie , Fortin-Guichard Daniel , Grondin Simon 
Published: January 2021

Abstract
Adults often report the impression that time seems to pass more and more quickly as they get older. The purpose of this study is to identify how individual characteristics relate to this impression of acceleration. To do so, 894 participants aged 15 to 97 completed a questionnaire that surveyed sociodemographic characteristics, impulsivity, anxiety, personality, and relation to time. They also indicated how fast different lapses of time seemed to have passed: yesterday, the past week, the past month, the past year, the past three years, the past five years, and the past 10 years. For each period, except for one year, adolescents found that time passes more slowly than participants from older groups (18–29 years, 30–59 years, and 60 years and over). A composite score for all these periods also indicates that female participants found that time passes more rapidly than males. However, a multiple linear regression analysis reveals that the variables that best predict the impression that time passes faster as we get older are high anxiety, the belief in the phenomenon of temporal compression, as well as conscientiousness and agreeableness personality traits, with other factors explaining little variance. These results add further weight to the impression that time seems to pass more quickly as we age, but also indicate that other variables than age play a critical role in explaining this impression.
Using Artificial Neural Networks to Improve CFS Week-3–4 Precipitation and 2-m Air Temperature Forecasts
Authors: Fan Yun , Krasnopolsky Vladimir , van den Dool Huug , Wu Chung-Yu , Gottschalck Jon 
Published: January 2021

Abstract
Forecast skill from dynamical forecast models decreases quickly with projection time due to various errors. Therefore, postprocessing methods, from simple bias correction methods to more complicated multiple linear regression–based model output statistics, are used to improve raw model forecasts. Usually, these methods show clear forecast improvement over the raw model forecasts, especially for short-range weather forecasts. However, linear approaches have limitations because the relationship between predictands and predictors may be nonlinear. This is even truer for extended range forecasts, such as week-3–4 forecasts. In this study, neural network techniques are used to seek or model the relationships between a set of predictors and predictands, and eventually to improve week-3–4 precipitation and 2-m temperature forecasts made by the NOAA/NCEP Climate Forecast System. Benefitting from advances in machine learning techniques in recent years, more flexible and capable machine learning algorithms and availability of big datasets enable us not only to explore nonlinear features or relationships within a given large dataset, but also to extract more sophisticated pattern relationships and covariabilities hidden within the multidimensional predictors and predictands. Then these more sophisticated relationships and high-level statistical information are used to correct the model week-3–4 precipitation and 2-m temperature forecasts. The results show that to some extent neural network techniques can significantly improve the week-3–4 forecast accuracy and greatly increase the efficiency over the traditional multiple linear regression methods.
Eustachian Tube Dysfunction in Children With Adenoid Hypertrophy: The Role of Adenoidectomy for Improving Ear Ventilation
Authors: Manno Alessandra , Iannella Giannicola , Savastano Vincenzo , Vittori Tommaso , Bertin Serena , Pasquariello Benedetta , Pace Annalisa , Rossetti Valeria , Magliulo Giuseppe 
Published: January 2021

Introduction:To our knowledge, few papers have addressed preoperative evaluation of the impact of adenoid hypertrophy (AH) on the pathogenesis of eustachian tube dysfunction (ETD) in children with otitis media with effusion (OME).Aim:The aim of this study was 2-fold: first, to evaluate ETD using tubomanometry and Eustachian Tube Score 7 (ETS-7), in a group of children having AH; second, to assess the clinical impact of adenoidectomy on the ETD of these patients.Methods:Fifty patients, aged 4 to 15 years, underwent adenoidectomy based on various parameters: size of the adenoids causing canal obstruction (grades 1-4), the presence of OME, and recurrent episodes of rhinosinusitis. The function of the eustachian tube was evaluated using ETS-7 before and after surgical treatment. The patients were followed up for 6 months.Results:Forty children presented ETD. Of these, 36 had a grade 4 AH. The preoperative mean value for ETS-7 was 6.62. The mean postoperative ETS-7 score showed a value of 9.60 with a statistical difference compared to the preoperative value ( P = .0015).Conclusions:Adenoid hypertrophy has a high impact on the frequency of ETD. In the patients observed in the present study, the ETS-7 score appeared to be a valid tool for assessing ETD both preoperatively and postoperatively. Adenoidectomy seemed to be effective in improving ETD as well as middle ear ventilation.
Risk factors for poor hemostasis of prophylactic uterine artery embolization before curettage in cesarean scar pregnancy
Authors: Tian Hongan , Li Shunzhen , Jia Wanwan , Yu Kaihu , Wu Guangyao 
Published: January 2021

Objective To observe the hemostatic effect of prophylactic uterine artery embolization (UAE) in patients with cesarean scar pregnancy (CSP) and to examine the risk factors for poor hemostasis. Methods Clinical data of 841 patients with CSP who underwent prophylactic UAE and curettage were retrospectively analyzed to evaluate the hemorrhage volume during curettage. A hemorrhage volume ≥200 mL was termed as poor hemostasis. The risk factors of poor hemostasis were analyzed and complications within 60 days postoperation were recorded. Results Among the 841 patients, 6.30% (53/841) had poor postoperative hemostasis. The independent risk factors of poor hemostasis were gestational sac size, parity, embolic agent diameter (>1000 μm), multivessel blood supply, and incomplete embolization. The main postoperative complications within 60 days after UAE were abdominal pain, low fever, nausea and vomiting, and buttock pain, with incidence rates of 71.22% (599/841), 47.44% (399/841), 39.12% (329/841), and 36.39% (306/841), respectively. Conclusions Prophylactic UAE before curettage in patients with CSP is safe and effective in reducing intraoperative hemorrhage. Gestational sac size, parity, embolic agent diameter, multivessel blood supply, and incomplete embolization of all arteries supplying blood to the uterus are risk factors of poor hemostasis.
Seasonal Influence on the Numbers of Gender-Related Orofacial Cleft Conceptions in the Netherlands
Authors: van der Lek Lisanne M. , Pool Shariselle M.W. , de Jong Kim , Vermeij-Keers Christl , Mouës-Vink Chantal M. 
Published: January 2021

Background: In the multifactorial etiology of orofacial clefts (OFCs), environmental factors play an important role. To trace the influence of these factors, the timing of the cell biological mechanisms that occur during embryological development of the primary and secondary palates must be taken into account. That is, the fusion process of the facial and palatal processes, respectively, followed by their differentiation into bone and musculature, which take place during the first trimester of pregnancy. During this period, harmful seasonal influences such as viral infections and vitamin deficiencies could induce OFC in the embryo. Aims: The aim of this study is to find out whether a seasonal conception period with an increased risk of OFC development exists, particularly gender related. Methods: This was a retrospective cross-sectional study on children with OFC born in the Netherlands from 2006 to 2016. Total conception rates of live births in the Netherlands were used as a control group. χ2 tests were performed to analyze monthly and seasonal differences. Males and females, positive and negative family history and subphenotype groups based on fusion and/or differentiation (F- and/or D-) defects, and their timing in embryogenesis were analyzed separately. Results: In total, 1653 children with OFC, 1041 males and 612 females, were analyzed. Only males with FD-defects showed a significant seasonal variation with an increase in conceptions during spring, most often in May. Conclusions: Males with FD-defects showed a significant seasonal variation with an increase in conceptions during spring. No other seasonal trends could be demonstrated.
Preterm Infant Skin Structure Is Qualitatively and Quantitatively Different From That of Term Newborns
Authors: Reed Robyn C , Johnson Deanna E , Nie Ann Marie 
Published: January 2021

Background The immature skin of preterm infants is uniquely vulnerable to pressure and chemical injury. We sought to qualitatively and quantitatively describe the histopathologic patterns of skin development in preterm infants. Methods Autopsy skin samples were examined for 48 liveborn preterm infants born at 18+ to 36 weeks, and control groups of term neonates and older infants/children. Quantitative variables included thickness of the stratum corneum, epidermis, and dermis. Qualitative features included stratum corneum, rete ridges, and hair follicles. Results Patterns of maturation were reproducible. Compact keratin appeared beginning at 21–22 weeks. Basketweave keratin appeared first around hair follicles, and then became more generalized from ∼28 weeks corrected gestational age (CGA) onward. Rete ridges began to appear at ∼30 weeks. Epidemal and dermal thickness increased with age. Infants who survived ≤7 days had thicker dermis than those who survived longer, even adjusted for CGA. Conclusions Skin development in preterm infants has reproducible milestones. Significant structural changes occurring around 28–30 weeks may improve barrier function, with implications for use of topical compounds such as chlorhexidine. The findings also highlight challenges in evaluating pressure injuries in preterm infants, and postnatal changes in skin parameters.
Ultrasound guided peripheral IV placement: An observational study of the learning curve in pediatric patients
Authors: Anderson Andrea P , Taroc Ann-Marie , Wang Xing , Beardsley Elaine , Solari Patrick , Klein Eileen J 
Published: January 2021

Background: Ultrasound guided peripheral intravenous catheter placement (USGPIV) has demonstrated benefits in children including higher success rates and fewer attempts compared to the traditional technique. Little is known about the experience needed to establish competence with USGPIV in children. In adult patients, nurses with four USGPIV attempts had a subsequent 70% probability of success after training. The objective of this study is to measure the competency of nurses with USGPIV in children after training. Methods: Pediatric nurses completed 2 h of training on USGPIV, after which they used ultrasound at their discretion for children with difficult access. Data was collected prospectively via study forms and retrospectively from medical records. Mixed effects logistic regression models were used to estimate the probability of successful USGPIV placement. Results: Thirty-five nurses underwent training from the pediatric emergency department and intravenous access team. The overall USGPIV success rate was 70%. Participants with less nursing experience made more USGPIV attempts than those with more experience, but had similar success rates. Forty percent of participants performed ten or more attempts during the study period. Mixed effects logistic regression estimated that it took nine USGPIV attempts after training for learners to achieve a 70% probability of success for the subsequent attempt. Conclusion: After training, 40% of participants adopted USGPIV into their practice. When developing training programs for USGPIV for children with difficult access, trainers can anticipate the experience needed to acquire this skill and the fact that not everyone trained will use this skill in their daily practice.