bluuebunny/crossref_metadata_2025 huggingface dataset:
Seismic Sequence Effects on Buried Pipelines Crossing Nonuniform Sites with Ground Settlement by Dynamic Centrifuge Test
Authors: Zhang Hongtao , Zhao Yufei , Gao Mingxu
Published: April 2022

The deformation and residual strength of the buried pipeline caused by the earthquake in nonuniform sites has an important influence on the safety of the pipeline. Most of the previous research focuses on the permanent ground deformation (PGD) caused by fault or transient ground deformation (TGD) due to seismic wave propagation independently. The mechanical character of buried pipelines crossing nonuniform sites during seismic sequence after ground settlement has not been studied. This article carried out a dynamic centrifuge experiment to simulate the seismic response of buried pipelines of polyvinyl chloride (PVC) and aluminum alloy (AL) horizontally crossing the loose and dense site and study the residual strength of pipelines after an earthquake. Two simulated seismic waves with 0.6 g and 0.3 g of input peak ground accelerations (PGAs) were inputted in sequence to simulate the strong and weak earthquakes. The deformations of ground and pipelines were obtained during and after seismic. The numerical model consistent with the experiment was established and compared with test, and it was found that the strain of pipeline caused by TGD was different between numerical and experimental results, especially in the loose site. The mechanical model of the pipeline by earthquake indicated that the total strain of the pipeline was composed of bending deformation by PGD and axial deformation by TGD. PGD caused by a strong earthquake had great effects on the deformation and residual strength of the pipeline. The strain of pipeline by TGD was compressive‐extensional alternating mode between the loose and dense site and the strain amplitude reached peaks near the block interface in the loose site. The residual strain of pipeline in the dense site was a compressive strain, while in the loose site, it was compressive‐extensional alternating mode and varied with the stiffness of the pipeline.
Construction and Validation of Angiogenesis-Related Prognostic Risk Signature to Facilitate Survival Prediction and Biomarker Excavation of Breast Cancer Patients
Authors: Xu Yingkun , Peng Yang , Shen Meiying , Liu Li , Lei Jinwei , Gao Shun , Wang Yuan , Lan Ailin , Li Han , Liu Shengchun
Published: April 2022

This study is aimed at exploring the potential mechanism of angiogenesis, a biological process-related gene in breast cancer (BRCA), and constructing a risk model related to the prognosis of BRCA patients. We used multiple bioinformatics databases and multiple bioinformatics analysis methods to complete our exploration in this research. First, we use the RNA-seq transcriptome data in the TCGA database to conduct a preliminary screening of angiogenesis-related genes through univariate Cox curve analysis and then use LASSO regression curve analysis for secondary screening. We successfully established a risk model consisting of seven angiogenesis-related genes in BRCA. The results of ROC curve analysis show that the risk model has good prediction accuracy. We can successfully divide BRCA patients into the high-risk and low-risk groups with significant prognostic differences based on this risk model. In addition, we used angiogenesis-related genes to perform cluster analysis in BRCA patients and successfully divided BRCA patients into three clusters with significant prognostic differences, namely, cluster 1, cluster 2, and cluster 3. Subsequently, we combined the clinical-pathological data for correlation analysis, and there is a significant correlation between the risk model and the patient’s T and stage. Multivariate Cox regression curve analysis showed that the age of BRCA patients and the risk score of the risk model could be used as independent risk factors in the progression of BRCA. In particular, based on this angiogenesis-related risk model, we have drawn a matching nomogram that can predict the 5-, 7-, and 10-year overall survival rates of BRCA patients. Subsequently, we performed a series of pan-cancer analyses of CNV, SNV, OS, methylation, and immune infiltration for this risk model gene and used GDSC data to explore drug sensitivity. Subsequently, to gain insight into the protein expression of these risk model genes in BRCA, we used the immunohistochemical data in the THPA database for verification. The results showed that the protein expressions of IL18, RUNX1, SCG2, and THY1 molecules in BRCA tissues were significantly higher than those in normal breast tissues, while the protein expressions of PF4 and TNFSF12 molecules in BRCA tissues were significantly lower than those in normal breast tissues. Finally, we conducted multiple GSEA analyses to explore the biological pathways these risk model genes can cross in cancer progression. In summary, we believe that this study can provide valuable data and clues for future studies on angiogenesis in BRCA.
Deep Learning-Based Ultrasound Combined with Gastroscope for the Diagnosis and Nursing of Upper Gastrointestinal Submucous Lesions
Authors: Xia Lima , Sun Suhua , Dai Weijie
Published: April 2022

The study focused on the diagnostic value of deep learning-based ultrasound combined with gastroscope examination for upper gastrointestinal submucous lesions and nursing. A total of 104 patients with upper gastrointestinal submucous lesions diagnosed in hospital were selected as the research subjects. In this study, the feed forward denoising convulsive neural network (DnCNN) was improved, and the n-DnCNN model was designed and applied to ultrasonic image processing. The peak signal-to-noise ratio (PSNR) and structural similarity (SSIM) of Gaussian filtering, NL-means, and DnCNN were then compared with n-DnCNN. Subsequently, the distribution and types of submucosal lesions in different parts of the upper digestive tract were analyzed by ultrasound combined with gastroscope and gastroscope examination alone, and the diagnostic performance of this method was evaluated. The results showed that the average PSNR and SSIM of the n-DnCNN model were 33.01 dB and 0.87, respectively, which were significantly higher than GF, NL-means, and DnCNN algorithms, and the difference was statistically significant (

P
<
0.05

). Of the 116 lesions detected, 49 were located in the esophagus (42.24%), 52 in the stomach (44.83%), and 15 in the duodenum (12.93%). Of the 49 esophageal submucosal lesions, 6.12% were located in the upper esophagus, 55.1% in the middle esophagus, and 38.79% in the lower esophagus, and the difference was statistically significant (

P
<
0.05

). Of the gastric submucosal lesions, the lesions in the gastric cardia were significantly less than in other parts, and the difference was statistically significant (

P
<
0.05

). The accuracy of ultrasound combined with gastroscope in the diagnosis of upper gastrointestinal submucous episodes was 82.32%, higher than that of gastroscope examination, and the difference was statistically significant (

P
<
0.05

). In conclusion, the n-DnCNN model has a good noise reduction effect, and the obtained image is of high quality. Ultrasound combined with gastroscope examination can effectively improve the accuracy of diagnosis of upper gastrointestinal submucous lesions.
Multiview Gait Recognition Based on Slack Allocation Generation Adversarial Network
Authors: Gao Jing , Zhang Shuyue , Guan Xin , Meng Xiao
Published: April 2022

Through the in-depth study of biological characteristics, the gait information of each person is found to be unique. Therefore, gait characteristics can be used to identify a person’s identity information. However, pedestrian gait information is often affected by various interference factors such as viewing angle, dress, and carrying objects. To solve this problem, the idea of perspective transformation is proposed to transform gait images from different perspectives and different states to gait images under standard conditions on one side. Generative adversarial network (GAN) is adopted for perspective transformation. Moreover, in order to solve the difficulty and instability to converge characteristics of GAN in the training process, we introduced a slack module to adjust the shortcomings of the GAN. Experiments show that under normal walking conditions, our method achieves an average accuracy of 98.32% on the CASIA-B gait dataset.
An Image Saliency Detection Method Based on Combining Global and Local Information
Authors: Yang Hangxu , Gong Yongjian , Wang Kai
Published: April 2022

In the field of computer vision, image saliency target detection can not only improve the accuracy of image detection but also accelerate the speed of image detection. In order to solve the existing problems of the saliency target detection algorithms at present, such as inconspicuous texture details and incomplete edge contour display, this paper proposes a saliency target detection algorithm integrating multiple information. The algorithm consists of three processes: preprocessing process, multi-information extraction process, and fusion optimization process. The frequency domain features of the image are calculated, the algorithm calculates the frequency domain features of the image, introduces power law transform and feature normalization, improves the frequency domain features of the image, saves the information of the target region, and inhibits the information of the background region. On three public MSRA, SED2, and ECSSD image datasets, the proposed algorithm is compared with other classical algorithms in subjective and objective comparison experiments. Experimental results show that the proposed algorithm can not only accurately and comprehensively extract significant target regions but also retain more texture information and complete edge information while satisfying the human visual experience. All evaluation indexes are significantly better than the comparison algorithm, showing good reliability and adaptability.
Modelling the Impact of Media‐Induced Social Distancing on the Containment of COVID‐19 in Beijing
Authors: Gong Yinjiao , Wang Aili , Guo Jin , Smith? Stacey R.
Published: April 2022

With the multiple waves of COVID‐19 in China and other countries, there is an urgent need to design effective containment, especially nonpharmaceutical interventions, to combat the transmission. Media reports on COVID‐19—which can induce precautionary behaviour such as social distancing, by providing disease‐related information to the public—are thought to be effective in containing the spread. We include the media‐reporting data collected from authoritative and popular websites, along with the corresponding IP‐visiting data, to study the effects of media reports in curbing the outbreak of COVID‐19 in Beijing. To quantify how social distancing affects the spread of COVID‐19, we differentiate the fully susceptible from those susceptibles who are media aware and practice social distancing or are quarantined. We propose a discrete compartment model with the fully susceptible, the media‐aware susceptible, and the quarantined susceptible as three separate classes. We adopt functions dependent on the media reports and the contacts of media‐aware susceptibles to describe the progression rate of susceptibles to media‐aware susceptibles. By fitting the targeted model to data on the two Beijing outbreaks, we estimated the reproduction numbers for the two outbreaks as R0 = 1.6818 and R0 = 1.3251, respectively. Cross‐correlation analysis on our collected data suggests a strong correlation between the media reporting and epidemic case data. Sensitivity and uncertainty analysis show that even with the intensified interventions in force, reducing either the social distancing uptake rate or the average duration of social distancing for media‐aware susceptibles could aggravate the severity of the two outbreaks in Beijing by magnifying the final confirmed cases and lengthening the end time of the pandemic. Our findings demonstrate that enhancing social distancing and media reporting alone, if done in sufficient measures, are enough to alleviate the COVID‐19 epidemic.
Multi-Feature Multi-Sensor Fusion for Emitter Identification Based on a Modified DS Application
Authors: Chen Jie , Xiao Kai , You Kai , Duan Feng , Qing Xianguo
Published: April 2022

Emitter identification is a crucial task in electronic countermeasure technology area, which deeply affects the accuracy of subsequent threat estimation. In emitter identification system, sensors (transmitter and receiver) have inevitable inconsistency and fuzziness, along with possible ambiguity and instability under interference and malfunction. To manage the uncertainty in emitter identification system, we propose a multi-feature multi-sensor fusion algorithm based on a modified DS application. The modified DS application for emitter identification system is accomplished by two parts—multi-feature fusion based on the improved proximity approach to obtain basic probability assignment (

B
P
A

) and multi-sensor fusion based on the combination of two revised evidences to solve potential evidence conflicts. Firstly, the multi-feature fusion method based on the improved proximity approach is raised to produce the identification result for each receiver, which simultaneously build

B
P
A
s

for DS application. Four entropies are extracted to establish the multi-feature description of received signal. Then, in order to solve the inconsistency among different receivers and realize multi-sensor fusion for emitter identification, the multi-sensor fusion method based on the combination of two revised evidences is proposed. Two revised evidences are put forward, respectively, by the introduction of Lance distance function and spectral angle cosine function before applying DS combination. Experiments and analyses comprehensively demonstrate the great uncertainty management performance and favorable emitter identification effect of the proposed algorithm.
Role of T Regulatory Cells and Myeloid-Derived Suppressor Cells in COVID-19
Authors: Alsalman Alhasan , Al-Mterin Mohammad A. , Elkord Eyad
Published: April 2022

Coronavirus disease 2019 (COVID-19) has been raised as a pandemic disease since December 2019. Immunosuppressive cells including T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are key players in immunological tolerance and immunoregulation; however, they contribute to the pathogenesis of different diseases including infections. Tregs have been shown to impair the protective role of CD8+ T lymphocytes against viral infections. In COVID-19 patients, most studies reported reduction, while few other studies found elevation in Treg levels. Moreover, Tregs have a dual role, depending on the different stages of COVID-19 disease. At early stages of COVID-19, Tregs have a critical role in decreasing antiviral immune responses, and consequently reducing the viral clearance. On the other side, during late stages, Tregs reduce inflammation-induced organ damage. Therefore, inhibition of Tregs in early stages and their expansion in late stages have potentials to improve clinical outcomes. In viral infections, MDSC levels are highly increased, and they have the potential to suppress T cell proliferation and reduce viral clearance. Some subsets of MDSCs are expanded in the blood of COVID-19 patients; however, there is a controversy whether this expansion has pathogenic or protective effects in COVID-19 patients. In conclusion, further studies are required to investigate the role and function of immunosuppressive cells and their potentials as prognostic biomarkers and therapeutic targets in COVID-19 patients.
Mitochondrial Dysfunction Pathway Alterations Offer Potential Biomarkers and Therapeutic Targets for Ovarian Cancer
Authors: Shen Liang , Zhan Xianquan
Published: April 2022

The mitochondrion is a very versatile organelle that participates in some important cancer-associated biological processes, including energy metabolism, oxidative stress, mitochondrial DNA (mtDNA) mutation, cell apoptosis, mitochondria-nuclear communication, dynamics, autophagy, calcium overload, immunity, and drug resistance in ovarian cancer. Multiomics studies have found that mitochondrial dysfunction, oxidative stress, and apoptosis signaling pathways act in human ovarian cancer, which demonstrates that mitochondria play critical roles in ovarian cancer. Many molecular targeted drugs have been developed against mitochondrial dysfunction pathways in ovarian cancer, including olive leaf extract, nilotinib, salinomycin, Sambucus nigra agglutinin, tigecycline, and eupatilin. This review article focuses on the underlying biological roles of mitochondrial dysfunction in ovarian cancer progression based on omics data, potential molecular relationship between mitochondrial dysfunction and oxidative stress, and future perspectives of promising biomarkers and therapeutic targets based on the mitochondrial dysfunction pathway for ovarian cancer.
The Impact of Telemonitoring on Improving Glycemic and Metabolic Control in Previously Lost-to-Follow-Up Patients with Type 2 Diabetes Mellitus: A Single-Center Interventional Study in the United Arab Emirates
Authors: Farooqi Muhammad Hamed , Abdelmannan Dima Kamal , Al buflasa Manal Mubarak , Abbas Hamed Moataz Abdalla , Xavier Maxon , Santos Cadiz Tessa Joyce , Nawaz Faisal Amir
Published: April 2022

Background. Telemonitoring (TM), mobile-phone technology for health, and bluetooth-enabled self-monitoring devices represent innovative solutions for proper glycemic control, compliance and monitoring, and access to providers. Objective. In this study, we evaluated the impact of TM devices on glycemic control and the compliance of 38 previously lost-to-follow-up (LTFU) patients with type 2 diabetes mellitus (T2DM). Methods. This was an interventional single-center study that randomly recruited LTFU patients from the Dubai Diabetes Center (DDC), UAE. After contact and recruitment by phone, patients had an initial visit at which they were provided with home-based TM devices. A follow-up visit was conducted three months later. Results. The mean HbA1c decreased significantly from 10.3 ± 1.9% at baseline to 7.4 ± 1.5% at the end of follow-up, with a mean difference (MD) of −2.9% [95% CI: −3.6 to −2.2]. The percentage of patients with HbA1c <7% was 50% after three months. Home-based blood sugar monitor devices showed a significant reduction in fasting blood glucose (FBG) after three months (MD = -40.1 mg/dL, 95% CI: −70.8 to −9.3). A significant reduction was observed in terms of body weight after three months (MD = −1.3 kg, 95% CI: −2.5 to −0.08). The mean number of days the participants used a device was the highest for portable pill dispensers (86.5 ± 22.8 days), followed by a OneTouch® blood glucose monitor (72.9 ± 23.5 days). Conclusions. TM led to significant improvements in overall diabetes outcomes, including glycemic control and body weight, indicating its effectiveness in a challenging population of T2DM patients who had previously been lost to follow-up.
Decomposition Dynamics of Leaf Litter Mixtures Enriched with NPS Fertilizer and Resultant Effects on Common Bean Productivity in Nutrient Depleted Soil
Authors: Laekemariam Fanuel , Elka Ermias
Published: April 2022

Organic materials have a nonreplaceable role to improve soil quality and productivity. Yet, processes related to decomposition and nutrient supply capacity are restricted under nutrient-depleted soils. Thus, a field experiment was conducted to evaluate the decomposition rate of leaf litter mixtures treated with mineral nitrogen (N), phosphorous (P), and sulfur (S) fertilizer in the form of NPS (19N38P2O57S), and their effects on agronomic performance of common bean (Phaseolus vulgaris L.). The mixtures of croton (Croton macrostachyus) and erythrina (Erythrina brucei) leaf litters (LLs) were placed at 20 cm depth in a litterbag at a rate equivalent to 2.5 and 5 t/ha, and treated with four NPS rates (0, 50, 100, and 150 kg/ha). The leaf litters have low carbon (C) to N ratio. The experiments (litterbag and crop response) were laid out in a randomized complete block design with three replications. The decomposition pattern was monitored at a two week interval (15, 30, 45, and 56 days after application) and assessed for daily decomposition rate (k), weight loss, and time required to decompose half of the residue (t50). For the crop response experiment, selected growth and yield component parameters, and grain yield data were recorded. The results indicated that NPS fertilizer and the amount of LL were significantly (

p
<
0.01

) influenced the k values and weight loss. The k at 14 days varied from 4.47% day−1 (150 NPS kg/ha × 2.5 t LL/ha) and 2.75% day−1 (sole 2.5 t/ha LL) in which application of mineral NPS fertilizer enhanced k by 62.5%. The k values, averaged over 56 days, revealed 2.68% day−1 (150 kg NPS/ha × 2.5 t LL/ha), and 1.78% day−1 in the unfertilized 2.5 LL. The decay rate was faster within 14 days and declined afterward. Over 56 days, 60.4% and 46.6% of the original mass remained in litters without NPS fertilizer, and 150 NPS kg/ha x 2.5 t LL/ha, respectively. The residue weight loss also significantly decreased with time (r2 > 0.98). Half-lifetime was significantly (

p
<
0.001

) decreased with the increasing rate of NPS application (r = −0.86). The t50 values, averaged over 56 days, were between 38.9 days (nontreated LL) and 27.8 days (150 kg NPS/ha), respectively. The result regarding agronomic performance indicated that the application of NPS fertilizer on the leaf litters significantly (

p
<
0.01

) increased the growth, yield component, and grain yield of common bean. For instance, 150 kg NPS/ha on 2.5 t/ha LL has resulted in a 79% grain yield advantage over LL without NPS. Grain yield also showed significant relationship (

p
<
0.01

) with k (r = 0.67), mass loss (r = −0.67), and t50 (r = −0.66). The finding suggests that for plant residues with a narrow C/N ratio in nutrient-depleted soils, the addition of mineral NPS fertilizer is advantageous for increased decomposition and yield of legume crops.
Measuring the Possibility of Middle Ear Discharge for COVID-19 Test Material
Authors: Kadriyan Hamsu , Rizkika Abtartu Lalu Hizrian , Wardoyo Eustachius Hagni , Andiwijaya Fahrin Ramadan
Published: April 2022

The COVID-19 pandemic is still ongoing, and new variants continue to emerge. Various examination methods and sampling specimens are continuously being developed and published. The standard for sampling is in the nasopharynx. However, in children, this is often uncomfortable and at risk of eliciting complications. Therefore, it is necessary to look for other alternative sampling sites such as fluid from the middle ear. Scientific evidence shows that the middle ear can be a place for the attachment and growth of the SARS-CoV-2 virus. Currently, to the best of the author's knowledge, there have been no publications on middle ear discharge as a sample for the determination of the diagnosis of COVID-19. Based on this, the authors would like to explore the possibility of middle ear discharge for COVID-19 test material. A narrative review on the use of middle ear discharge as a potential diagnostic specimen for COVID-19 was conducted. The searches were conducted in the PubMed and ProQuest databases.
Complex Survival System Modeling for Risk Assessment of Infant Mortality Using a Parametric Approach
Authors: Chen Hang , Sadiq Maryam , Song Zishen
Published: April 2022

Pakistan is still one of the five countries contributing to half of the child deaths worldwide and holds a low ratio of infant survival. A high rate of poverty, low level of education, limited health facilities, rural-urban inequalities, and political uncertainty are the main reasons for this condition. Survival models that evaluate the performance of models over simulated and real data set may serve as an effective technique to determine accurate complex systems. The present study proposed an efficient extension of the recent parametric technique for risk assessment of infant mortality to address complex survival systems in the presence of extreme observations. This extended method integrated four distributions with the basic algorithm using a real data set of infant survival without extreme observations. The proposed models are compared with the standard partial least squares-Cox regression (PLS-CoxR), and higher efficiency of these proposed algorithms is observed for handling complex survival time systems for risk assessment. The algorithm is also used to analyze simulated data set for further verification of results. The optimal model revealed that the mother’s age, type of residence, wealth index, permission to go to a medical facility, distance to a health facility, and awareness about tuberculosis significantly affected the survival time of infants. The flexibility and continuity of extended parametric methods support the implementation of public health surveillance data effectively for data-oriented evaluation. The findings may support projecting targeted interventions, producing awareness, and implementing policies planned to reduce infant mortality.
Long Noncoding RNA TUG1 Aggravates Cerebral Ischemia/Reperfusion Injury by Acting as a ceRNA for miR-3072-3p to Target St8sia2
Authors: Chen Miao , Wang Feng , Fan Limin , Wang Hairong , Gu Shuo
Published: April 2022

Long noncoding RNA taurine-upregulated gene 1 (TUG1) is considered to be involved in postischemic cerebral inflammation, whereas polysialic acid (polySia, PSA), the product of St8sia2, constitutes polysialylated neural adhesion cell molecule (PSA-NCAM) in both mice and humans and that cerebral PSA-NCAM level is elevated in neuronal progenitor cells in response to transient focal ischemia. Herein, we aim to identify novel miRNAs that bridge the functions of St8sia2 and TUG1 in ischemia-associated injuries. In both in vivo (C57BL/6J mouse ischemia/reperfusion, I/R model) and in vitro (mouse neuroblastoma N2A cell oxygen glucose deprivation/reoxygenation, OGD model) settings, we observed upregulated TUG1 and St8sia2 after the induction of ischemic injury, accompanied by reduced miR-3072-3p expression. We performed siRNA-induced TUG1 knockdown combined with the induction of ischemic injury; the results showed that inhibiting TUG1 expression led to the reduced infarct area and improved neurological deficit. Through bioinformatics analysis, miR-3072-3p was found to target both St8sia2 and TUG1, which was subsequently verified by the luciferase reporter system and RNA binding protein immunoprecipitation assay. Also, the addition of miR-3072-3p mimic/inhibitor resulted in reduced/elevated St8sia2 expression at the protein level. Further studies revealed that in both in vivo and in vitro settings, TUG1 bound competitively to miR-3072-3p to regulate St8sia2 expression and promote apoptosis. In summary, targeting the TUG1/miR-3072-3p/St8sia2 regulatory cascade, a novel cascade we identified in cerebral ischemia injury, may render feasible therapeutic possibilities for overcoming cerebral ischemic insults.
FOXA1 Leads to Aberrant Expression of SIX4 Affecting Cervical Cancer Cell Growth and Chemoresistance
Authors: Wang Zhuo , Sun Bao-Sheng , Chen Zhi-Shen , Zhao Kang-Kang , Wang Yun-Long , Meng Fan-Xu , Zhang Yang
Published: April 2022

Cervical cancer (CC) is among the most prevalent cancers among female populations with high recurrence rates all over the world. Cisplatin (DDP) is the first-line treatment for multiple cancers, including CC. The main problem associated with its clinical application is drug resistance. This study is aimed at investigating the function and downstream regulation mechanism of forkhead-box A1 (FOXA1) in CC, which was verified as an oncogene in several cancers. Using GEO database and bioinformatics analysis, we identified FOXA1 as a possible oncogene in CC. Silencing of FOXA1 inhibited CC cell growth, invasion, and chemoresistance. Afterwards, the downstream gene of FOXA1 was predicted using a bioinformatics website and validated using ChIP and dual-luciferase assays. SIX4, a possible target of FOXA1, promoted CC cell malignant aggressiveness and chemoresistance. In addition, overexpression of SIX4 promoted phosphorylation of PI3K and AKT proteins and activated the PI3K/AKT signaling pathway. Further overexpression of SIX4 reversed the repressive effects of FOXA1 knockdown on CC cell growth, invasion, and chemoresistance in DDP-resistant cells. FOXA1-induced SIX4 facilitates CC progression and chemoresistance, highlighting a strong potential for FOXA1 to serve as a promising therapeutic target in CC.
SETD2 Haploinsufficiency Enhances Germinal Center–Associated AICDA Somatic Hypermutation to Drive B-cell Lymphomagenesis
Authors: Leung Wilfred , Teater Matt , Durmaz Ceyda , Meydan Cem , Chivu Alexandra G. , Chadburn Amy , Rice Edward J. , Muley Ashlesha , Camarillo Jeannie M. , Arivalagan Jaison , Li Ziyi , Flowers Christopher R. , Kelleher Neil L. , Danko Charles G. , Imielinski Marcin , Dave Sandeep S. , Armstrong Scott A. , Mason Christopher E. , Melnick Ari M.
Published: April 2022

SETD2 is the sole histone methyltransferase responsible for H3K36me3, with roles in splicing, transcription initiation, and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is typically heterozygous in diffuse large B-cell lymphomas. Here we show that heterozygous Setd2 deficiency results in germinal center (GC) hyperplasia and increased competitive fitness, with reduced DNA damage checkpoint activity and apoptosis, resulting in accelerated lymphomagenesis. Impaired DNA damage sensing in Setd2-haploinsufficient germinal center B (GCB) and lymphoma cells associated with increased AICDA-induced somatic hypermutation, complex structural variants, and increased translocations including those activating MYC. DNA damage was selectively increased on the nontemplate strand, and H3K36me3 loss was associated with greater RNAPII processivity and mutational burden, suggesting that SETD2-mediated H3K36me3 is required for proper sensing of cytosine deamination. Hence, Setd2 haploinsufficiency delineates a novel GCB context–specific oncogenic pathway involving defective epigenetic surveillance of AICDA-mediated effects on transcribed genes.

Significance:

Our findings define a B cell–specific oncogenic effect of SETD2 heterozygous mutation, which unleashes AICDA mutagenesis of nontemplate strand DNA in the GC reaction, resulting in lymphomas with heavy mutational burden. GC-derived lymphomas did not tolerate SETD2 homozygous deletion, pointing to a novel context-specific therapeutic vulnerability.

This article is highlighted in the In This Issue feature, p. 1599
GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus
Authors: Lorenz Georg , Ribeiro Andrea , von Rauchhaupt Ekatharina , Würf Vivian , Schmaderer Christoph , Cohen Clemens D. , Vohra Twinkle , Anders Hans-Joachim , Lindenmeyer Maja , Lech Maciej
Published: April 2022

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β superfamily, has been associated with acute and chronic inflammatory conditions including autoimmune disease, i.e., type I diabetes and rheumatoid arthritis. Still, its role in systemic autoimmune disease remains elusive. Thus, we studied GDF15-deficient animals in Fas-receptor intact (C57BL/6) or deficient (C57BL/6lpr/lpr) backgrounds. Further, lupus nephritis (LN) microdissected kidney biopsy specimens were analyzed to assess the involvement of GDF15 in human disease. GDF15-deficiency in lupus-prone mice promoted lymphoproliferation, T-, B- and plasma cell-expansion, a type I interferon signature, and increased serum levels of anti-DNA autoantibodies. Accelerated systemic inflammation was found in association with a relatively mild renal phenotype. Splenocytes of phenotypically overall-normal Gdf15−/− C57BL/6 and lupus-prone C57BL/6lpr/lpr mice displayed increased in vitro lymphoproliferative responses or interferon-dependent transcription factor induction in response to the toll-like-receptor (TLR)-9 ligand CpG, or the TLR-7 ligand Imiquimod, respectively. In human LN, GDF15 expression was downregulated whereas type I interferon expression was upregulated in glomerular- and tubular-compartments versus living donor controls. These findings demonstrate that GDF15 regulates lupus-like autoimmunity by suppressing lymphocyte-proliferation and -activation. Further, the data indicate a negative regulatory role for GDF15 on TLR-7 and -9 driven type I interferon signaling in effector cells of the innate immune system.
Einsatz von exklusiver enteraler Ernährung bei Erwachsenen mit Morbus Crohn
Authors: Blumenstein Irina
Published: April 2022

Background: Exclusive enteral nutrition (EEN) is a potentially effective but underused therapy for Crohn’s disease (CD) in adults. It is first-line induction treatment for paediatric patients but remains a second-line or third-line therapy in adults. Objective: To analyse the evidence for EEN in adult patients with CD, and summarise this in a narrative review. Methods: In April/May 2020 and July 2021, a literature search was performed using the Medical Subject Headings (MeSH) terms: ‘Crohn’s disease’, ‘CD’, ‘inflammatory bowel disease’, ‘IBD’, ‘exclusive enteral nutrition’, ‘enteral nutrition’, ‘EEN’, in PubMed, Scopus, Cochrane. Additional studies were obtained from references of search result articles as well as general reading. Studies with adult patients with CD treated with EEN were selected. 79 articles of relevance were found. Where data in adults were lacking, data from paediatric studies as extrapolated with care. Results: EEN in adult patients been shown to improve clinical, biomarker, endoscopic and radiologic measures of disease activity. EEN avoids the potential adverse effects of recurrent corticosteroids for induction such as metabolic derangements and opportunistic infections. EEN has also demonstrated benefits among adult patients with fistulising and stricturing CD. It may avoid surgery in such patients. Preoperative EEN has also been shown to reduce postoperative complications and recurrence. There appears to be benefits in combing EEN with antitumour necrosis factor agents, however, benefits of combination therapy with other biologics are less clear. A major drawback of EEN therapy in adults has been poor compliance. More palatable polymeric formulations improved patient education and dietitian support may overcome this. Evidence in adults is limited to small studies, often with suboptimal control arms and lack of blinding. Larger scale studies with improved study design are needed to confirm these beneficial effects. Conclusion: Despite limitations in evidence EEN should be considered in treating adults with CD.
Long-Term Results after Intraocular Surgery in Treated Retinoblastoma Eyes
Authors: Rating Philipp , Bornfeld Norbert , Schlüter Sabrina , Westekemper Henrike , Kiefer Tobias , Stuschke Martin , Göricke Sophia , Ketteler Petra , Ting Saskia , Metz Klaus A. , Bechrakis Nikolaos E. , Biewald Eva
Published: April 2022

Introduction: The aim of the study was to analyze the results of intraocular surgery in treated retinoblastoma eyes and to assess the long-term results with a priority on local recurrences, secondary enucleation, and metastases. Methods: Retrospective noncomparative case series. Results: From March 1964 to January 2020, 42 eyes of 40 retinoblastoma patients underwent intraocular surgery. Time interval between the last therapy and surgery was 9.5 years (mean: 114 months; median: 54.5 months). 31 eyes were treated for radiogenic cataract formation with a gain in visual acuity of 61.3%. One child developed an upper eyelid metastasis, 3 showed second primary malignancies (SPM), one a late recurrence, and 2 eyes were enucleated. Retinal surgery was performed in 17 eyes; 6 eyes were done as a combined procedure. Indications were radiogenic complications in the sense of a vitreous hemorrhage in 11 eyes and a rhegmatogenous retinal detachment in 6 eyes. 41.2% of the treated eyes had a postoperative gain in visual acuity, whereas 9.5% of the eyes could not be preserved in the long term. Regarding systemic involvement 2 patients developed late recurrences and one a SPM. Conclusion: Surgical therapy in treated retinoblastoma is necessary in isolated cases. In our series, cataract surgery was a safe procedure with a good option of a significant increase in visual acuity. As expected, vitreoretinal treated eyes showed a limited gain in visual acuity, a higher risk of late recurrences, and a lower globe retention rate. Therefore, a careful indication and individual risk-benefit analysis are mandatory.
Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights From DAPA-HF
Authors: Adamson Carly , Docherty Kieran F. , Heerspink Hiddo J.L. , de Boer Rudolf A. , Damman Kevin , Inzucchi Silvio E. , Køber Lars , Kosiborod Mikhail N. , Martinez Felipe A. , Petrie Mark C. , Ponikowski Piotr , Sabatine Marc S. , Schou Morten , Solomon Scott D. , Verma Subodh , Bengtsson Olof , Langkilde Anna Maria , Sjöstrand Mikaela , Vaduganathan Muthiah , Jhund Pardeep S. , McMurray John J.V.
Published: April 2022

Background:

In a post hoc analysis, the frequency of occurrence of an early decline (dip) in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin and its association with outcomes were evaluated in patients with heart failure and reduced ejection fraction randomized in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial.

Methods:

Patients with heart failure with reduced ejection fraction with or without type 2 diabetes and an eGFR ≥30 mL·min
−1
·1.73 m
−2
were randomized to placebo or dapagliflozin 10 mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed with repeated-measures mixed-effect models.

Results:

The mean change in eGFR between day 0 and 14 was −1.1 mL·min
−1
·1.73 m
−2
(95% CI, −1.5 to −0.7) with placebo and −4.2 mL·min
−1
·1.73 m
−2
(95% CI, −4.6 to −3.9) with dapagliflozin, giving a between-treatment difference of 3.1 mL·min
−1
·1.73 m
−2
(95% CI, 2.6–3.7). The proportions of patients randomized to dapagliflozin experiencing a >10%, >20%, and >30% decline in eGFR were 38.2%, 12.6%, and 3.4%, respectively; for placebo, they were 21.0%, 6.4%, and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin compared with placebo was 2.36 (95% CI, 2.07–2.69;
P
<0.001). Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR was 1.45 (95% CI, 1.19–1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI, 0.59–0.91;
P
interaction
<0.001). A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events.

Conclusions:

The average dip in eGFR after dapagliflozin was started was small and associated with better clinical outcomes compared with a similar decline on placebo in patients with heart failure with reduced ejection fraction. Large declines in eGFR were uncommon with dapagliflozin.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03036124.
Association of Change in Alcohol Consumption With Risk of Ischemic Stroke
Authors: Jeong Su-Min , Lee Han Rim , Han Kyungdo , Jeon Keun Hye , Kim Dahye , Yoo Jung Eun , Cho Mi Hee , Chun Sohyun , Lee Seung Pyo , Nam Ki-Woong , Shin Dong Wook
Published: April 2022

Background:

The effect of serial change in alcohol consumption on stroke risk has been limitedly evaluated. We investigated the association of change in alcohol consumption with risk of stroke.

Methods:

This study is a population-based retrospective cohort study from National Health Insurance Service database of all Koreans. Four lakh five hundred thirteen thousand seven hundred forty-six participants aged ≥40 years who underwent 2 subsequent national health examinations in both 2009 and 2011. Alcohol consumption was assessed by average alcohol intake (g/day) based on self-questionnaires and categorized into non-, mild, moderate, and heavy drinking. Change in alcohol consumption was defined by shift of category from baseline. Cox proportional hazards model was used with adjustment for age, sex, smoking status, regular exercise, socioeconomic information, and comorbidities, Charlson Comorbidity Index, systolic blood pressure, and laboratory results. Subgroup analysis among those with the third examination was conducted to reflect further change in alcohol consumption.

Results:

During 28 424 497 person-years of follow-up, 74 923 ischemic stroke events were identified. Sustained mild drinking was associated with a decreased risk of ischemic stroke (adjusted hazard ratio, 0.88 [95% CI, 0.86–0.90]) compared with sustained nondrinking, whereas sustained heavy drinking was associated with an increased risk of ischemic stroke (adjusted hazard ratio, 1.06 [95% CI, 1.02–1.10]). Increasing alcohol consumption was associated with an increased risk of ischemic stroke (adjusted hazard ratio, 1.11 [95% CI, 1.06–1.17] from mild to moderate; adjusted hazard ratio, 1.28 [95% CI, 1.19–1.38] from mild to heavy) compared with sustained mild drinkers. Reduction of alcohol consumption from heavy to mild level was associated with 17% decreased risk of ischemic stroke through 3× of examinations.

Conclusions:

Light-to-moderate alcohol consumption is associated with a decreased risk of ischemic stroke, although it might be not causal and could be impacted by sick people abstaining from drinking. Reduction of alcohol consumption from heavy drinking is associated with a decreased risk of ischemic stroke.
Impact of Previous Stroke on Clinical Outcome in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Registry
Authors: Yoshimoto Takeshi , Toyoda Kazunori , Ihara Masafumi , Inoue Hiroshi , Yamashita Takeshi , Suzuki Shinya , Akao Masaharu , Atarashi Hirotsugu , Ikeda Takanori , Okumura Ken , Koretsune Yukihiro , Shimizu Wataru , Tsutsui Hiroyuki , Hirayama Atsushi , Yasaka Masahiro , Maruyama Hirofumi , Teramukai Satoshi , Kimura Tetsuya , Morishima Yoshiyuki , Takita Atsushi , Yamaguchi Takenori
Published: April 2022

Background:

We determined the long-term event incidence among elderly patients with nonvalvular atrial fibrillation in terms of history of stroke/transient ischemic attack (TIA) and oral anticoagulation.

Methods:

Patients aged ≥75 years with documented nonvalvular atrial fibrillation enrolled in the prospective, multicenter, observational All Nippon Atrial Fibrillation in the Elderly Registry between October 2016 and January 2018 were divided into 2 groups according to history of stroke/TIA. The primary end point was the occurrence of stroke/systemic embolism within 2 years, and secondary end points were major bleeding and all-cause death within 2 years. Cox models were used to determine whether there was a difference in the hazard of each end point in patients with/without history of stroke/TIA, and in ischemic stroke/TIA survivors taking direct oral anticoagulants versus those taking warfarin.

Results:

Of 32 275 evaluable patients (13 793 women [42.7%]; median age, 81.0 years), 7304 (22.6%) had a history of stroke/TIA. The patients with previous stroke/TIA were more likely to be male and older and had higher hazard rates of stroke/systemic embolism (adjusted hazard ratio, 2.25 [95% CI, 1.97–2.58]), major bleeding (1.25, 1.05–1.49), and all-cause death (1.13, 1.02–1.24) than the other groups. Of 6446 patients with prior ischemic stroke/TIA, 4393 (68.2%) were taking direct oral anticoagulants and 1668 (25.9%) were taking warfarin at enrollment. The risk of stroke/systemic embolism was comparable between these 2 groups (adjusted hazard ratio, 0.90 [95% CI, 0.71–1.14]), while the risk of major bleeding (0.67, 0.48–0.94), intracranial hemorrhage (0.57, 0.39–0.85), and cardiovascular death (0.71, 0.51–0.99) was lower among those taking direct oral anticoagulants.

Conclusions:

Patients aged ≥75 years with nonvalvular atrial fibrillation and previous stroke/TIA more commonly had subsequent ischemic and hemorrhagic events than those without previous stroke/TIA. Among patients with previous ischemic stroke/TIA, the risk of hemorrhagic events was lower in patients taking direct oral anticoagulants compared with warfarin.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique Identifier: UMIN000024006.
The Satanic Verses and Evil in Babylonia
Authors: Boyarin Daniel
Published: April 2022

In this article, I study several midrashic passages preserved in the Babylonian Talmud that deal with Satan. The verses that they are based on are nearly all drawn from the book of Job. I find that these midrashim strongly support the conclusions of Ishay Rosen-Zvi’s monograph Demonic Desires in several ways, notably that Satan is not the font and origin of evil in the world as he is in other branches or wings of the ancient Jewish imagination.
Secrets of Qohelet: Toward an Exegetical History of a Biblical Text during the Middle Ages
Authors: Robinson James Theodore
Published: April 2022

During the middle ages and early modern period, dozens of Jewish commentaries were written on Qohelet, in Arabic and Hebrew, and representing a very full range of methods and approaches, from Karaite to Rabbanite, grammatical to pietistic, Neoplatonic, Aristotelian, and anti-Aristotelian, even kabbalistic. The purpose of this article – dedicated to the memory of Kalman Bland – is to present some experiments related to the telling of the history of medieval Jewish exegesis of Qohelet in hermeneutical context.
Spiritual Pedagogy and Rhetoric in a Ḥasidic Homily: The Maʾor va-Shemesh on Parshat Qedoshim
Authors: Fishbane Michael
Published: April 2022

A close analysis of a Ḥasidic homily by R. Kalonymos Kalman Epstein of Krakow, author of Maʾor va-Shemesh. The essay focuses on rhetoric, structure, and thematic content. The role of hermeneutics is engaged throughout.