bluuebunny/crossref_metadata_2025 huggingface dataset:
rmvPFBAM: Removing Primers from BAM Files Based on Amplicon-Based Next-Generation Sequencing and Cloud Computing When Analyzing Personal Genome Data
Authors: Ma Yanjun
Published: November 2021

Personal genomic data constitute one important part of personal health data. However, due to the large amount of personal genomic data obtained by the next-generation sequencing technology, special tools are needed to analyze these data. In this article, we will explore a tool analyzing cloud-based large-scale genome sequencing data. Analyzing and identifying genomic variations from amplicon-based next-generation sequencing data are necessary for the clinical diagnosis and treatment of cancer patients. When processing the amplicon-based next-generation sequencing data, one essential step is removing primer sequences from the reads to avoid detecting false-positive mutations introduced by nonspecific primer binding and primer extension reactions. At present, the removing primer tools usually discard primer sequences from the FASTQ file instead of BAM file, but this method could cause some downstream analysis problems. Only one tool (BAMClipper) removes primer sequences from BAM files, but it only modified the CIGAR value of the BAM file, and false-positive mutations falling in the primer region could still be detected based on its processed BAM file. So, we developed one cutting primer tool (rmvPFBAM) removing primer sequences from the BAM file, and the mutations detected based on the processed BAM file by rmvPFBAM are highly credible. Besides that, rmvPFBAM runs faster than other tools, such as cutPrimers and BAMClipper.
Sensory Behaviours and Resting Parasympathetic Functions among Children with and without ADHD
Authors: Gomez Ivan Neil , Domondon Lissa Martha , Tsang Hector WH , Chan Chetwyn CH , Lai Cynthia YY
Published: November 2021

Previous studies suggest that parasympathetic functions support sensory behaviours. However, the relationship between sensory behaviours and parasympathetic functions remain inconclusive and inconsistent among children with and without attention-deficit hyperactivity disorder (ADHD). This research aims to examine the sensory behaviours and resting parasympathetic functions among children with and without ADHD. We compared sensory behaviours and baseline parasympathetic functions of 64 participants, with 42 typically developing and 24 ADHD male children aged 7–12 years. Sensory behaviours were evaluated using the sensory profile. Baseline parasympathetic functions were indexed using the normalized unit of heart rate variability high-frequency bands (HF n.u.). Children underwent an experimental protocol consisting of watching a silent cartoon movie while HF n.u. is continuously monitored, within a controlled environment. The results of this research showed significantly lower HF n.u. (t(64) = 7.84,

p
<
0.01

) and sensory processing total score (t(64) = 14.13 = 

p
<
0.01

) among children with ADHD compared to their typically developing peers. Likewise, a significant moderate positive correlation (r = 0.36,

p
<
0.05

) was found between the HF n.u. and sensory profile total scores among children with ADHD. Children with ADHD have significantly lower resting state parasympathetic functions compared to their typically developing peers.
An Improved Framework for Content‐ and Link‐Based Web‐Spam Detection: A Combined Approach
Authors: Shahzad Asim , Nawi Nazri Mohd , Rehman Muhammad Zubair , Khan Abdullah
Published: November 2021

In this modern era, people utilise the web to share information and to deliver services and products. The information seekers use different search engines (SEs) such as Google, Bing, and Yahoo as tools to search for products, services, and information. However, web spamming is one of the most significant issues encountered by SEs because it dramatically affects the quality of SE results. Web spamming’s economic impact is enormous because web spammers index massive free advertising data on SEs to increase the volume of web traffic on a targeted website. Spammers trick an SE into ranking irrelevant web pages higher than relevant web pages in the search engine results pages (SERPs) using different web‐spamming techniques. Consequently, these high‐ranked unrelated web pages contain insufficient or inappropriate information for the user. To detect the spam web pages, several researchers from industry and academia are working. No efficient technique that is capable of catching all spam web pages on the World Wide Web (WWW) has been presented yet. This research is an attempt to propose an improved framework for content‐ and link‐based web‐spam identification. The framework uses stopwords, keywords’ frequency, part of speech (POS) ratio, spam keywords database, and copied‐content algorithms for content‐based web‐spam detection. For link‐based web‐spam detection, we initially exposed the relationship network behind the link‐based web spamming and then used the paid‐link database, neighbour pages, spam signals, and link‐farm algorithms. Finally, we combined all the content‐ and link‐based spam identification algorithms to identify both types of spam. To conduct experiments and to obtain threshold values, WEBSPAM‐UK2006 and WEBSPAM‐UK2007 datasets were used. A promising F‐measure of 79.6% with 81.2% precision shows the applicability and effectiveness of the proposed approach.
Network Pharmacology and Molecular Docking-Based Analysis on Bioactive Anticoronary Heart Disease Compounds in Trichosanthes kirilowii Maxim and Bulbus allii Macrostemi
Authors: Yu Yi-Ding , Hou Wang-Jun , Zhang Juan , Xue Yi-Tao , Li Yan
Published: November 2021

Trichosanthes kirilowii Maxim. and Bulbus allii Macrostemi are the components of Gualou Xiebai decoction (GLXB), a commonly used herbal combination for the treatment of coronary heart disease (CHD) in traditional Chinese medicine. Although GLXB is associated with a good clinical effect, its active compounds and mechanism of action remain unclear, which limits its clinical application and the development of novel drugs. In this study, we explored key compounds, targets, and mechanisms of action for GLXB in the treatment of CHD using the network pharmacology approach. We identified 18 compounds and 21 action targets via database screening. Enrichment analysis indicated that the effects of GLXB in patients with CHD are primarily associated with the regulation of signalling pathways for tumour necrosis factor, nuclear factor-kappa B, hypoxia-inducible factor-1, arachidonic acid metabolism, and insulin resistance. GLXB thus exerts anti-inflammatory, antihypoxic, and antiagglutinating effects; regulates lipid metabolism; and combats insulin resistance in CHD via these pathways, respectively. After reverse targeting, we observed that the main active compounds of GLXB in the treatment of CHD were quercetin, naringenin, β-sitosterol, ethyl linolenate, ethyl linoleate, and prostaglandin B1. To explore the potential of these compounds in the treatment of CHD, we verified the affinity of the compounds and targets via molecular docking analysis. Our study provides a bridge for the transformation of natural herbs and molecular compounds into novel drug therapies for CHD.
Wardowski’s Contraction and Fixed Point Technique for Solving Systems of Functional and Integral Equations
Authors: Hammad Hasanen A. , Bota Monica-Felicia , Guran Liliana
Published: November 2021

In this manuscript, some tripled fixed point results are presented in the framework of complete metric spaces. Furthermore, Wardowski’s contraction was mainly applied to discuss some theoretical results with and without a directed graph under suitable assertions. Moreover, some consequences and supportive examples are derived to strengthen the main results. In the last part of the paper, the obtained theoretical results are used to find a unique solution to a system of functional and integral equations.
Artificial Intelligence Algorithm-Based Computed Tomography Images in the Evaluation of the Curative Effect of Enteral Nutrition after Neonatal High Intestinal Obstruction Operation
Authors: Dong Yanqing , Wang Zhaolong , Zhang Zhiguang , Niu Bobo , Chen Pan , Zhang Pengju , Niu Huizhong
Published: November 2021

In this study, CT image technology based on level set intelligent segmentation algorithm was used to evaluate the postoperative enteral nutrition of neonatal high intestinal obstruction and analyze the clinical treatment effect of high intestinal obstruction, so as to provide a reasonable research basis for the clinical application of neonatal high intestinal obstruction. 60 children with high intestinal obstruction treated in the hospital were selected as the research objects. Based on the postoperative enteral nutrition treatment, they were divided into control group (noncatheterization group)-parenteral nutrition support. In the observation group, gastric tube was placed through nose for nutritional support. Then, CT images based on level set segmentation algorithm were used to compare the intestinal recovery of the two groups, and the biochemical indexes and hospitalization were compared. The level set algorithm can accurately segment the lesions in CT images. The segmentation time of the level set algorithm was shorter than that of the traditional algorithm (24.34 ± 2.01 s vs. 75.21 ± 5.91 s), and the segmentation accuracy was higher than that of the traditional algorithm (84.71 ± 3.91% vs. 70.04 ± 3.71%,

P

 < 0.05). The weight of children in the observation group (100 ± 7 g) was higher than that in the control group (54 ± 5 g), and the ICU monitoring time (12.01 ± 2.65 days) and the hospital stay (17.82 ± 3.11 days) were shorter than those in the control group (13.42 ± 2.95 days, 19.13 ± 3.22 days, all

P

 < 0.05). The level set segmentation algorithm can accurately segment the CT image, so that the disease location and its contour can be displayed more clearly. Moreover, the nasal placement of jejunal nutrition tube can effectively improve the intestinal function of children, maintain the steady-state environment of intestinal bacterial growth, and significantly improve the clinical treatment effect, which is worthy of clinical application and promotion.
On the Generalized Decreasing Mean Time to Failure or Replaced Ordering
Authors: Wang Haiyan , Kang Diantong , Yan Lei
Published: November 2021

In this paper, we establish two new stochastic orders, DMTFR (decreasing mean time to failure or replaced) and GDMTFR (generalized decreasing mean time to failure or replaced), and mainly investigate properties of the GDMTFR order. Some characterizations of the GDMTFR order are given. The implication relationships between the DMTFR and the GDMTFR orders are considered. Also, closure and reversed closure properties of the new order GDMTFR are investigated. Meanwhile, several illustrative examples that meet the GDMTFR order are shown as well.
Effective Face Detector Based on YOLOv5 and Superresolution Reconstruction
Authors: Xu Qingqing , Zhu Zhiyu , Ge Huilin , Zhang Zheqing , Zang Xu
Published: November 2021

The application of face detection and recognition technology in security monitoring systems has made a huge contribution to public security. Face detection is an essential first step in many face analysis systems. In complex scenes, the accuracy of face detection would be limited because of the missing and false detection of small faces, due to image quality, face scale, light, and other factors. In this paper, a two-level face detection model called SR-YOLOv5 is proposed to address some problems of dense small faces in actual scenarios. The research first optimized the backbone and loss function of YOLOv5, which is aimed at achieving better performance in terms of mean average precision (mAP) and speed. Then, to improve face detection in blurred scenes or low-resolution situations, we integrated image superresolution technology on the detection head. In addition, some representative deep-learning algorithm based on face detection is discussed by grouping them into a few major categories, and the popular face detection benchmarks are enumerated in detail. Finally, the wider face dataset is used to train and test the SR-YOLOv5 model. Compared with multitask convolutional neural network (MTCNN), Contextual Multi-Scale Region-based CNN (CMS-RCNN), Finding Tiny Faces (HR), Single Shot Scale-invariant Face Detector (S3FD), and TinaFace algorithms, it is verified that the proposed model has higher detection precision, which is 0.7%, 0.6%, and 2.9% higher than the top one. SR-YOLOv5 can effectively use face information to accurately detect hard-to-detect face targets in complex scenes.
Outcome Assessment According to the Thickness and Direction of the Acellular Dermal Matrix after Implant‐Based Breast Reconstruction
Authors: Hur Joon , Han Hyun Ho
Published: November 2021

Purpose. The acellular dermal matrix plays an important role in reinforcing thin mastectomy skin and repositioning the implant in prosthetic breast reconstruction. As the concept of prepectoral plane has become widespread, the role of the acellular dermal matrix has become increasingly important. However, evidences and standards for appropriate thickness and direction during placement remain insufficient. This study is aimed at testing the assumption that differences in the acellular dermal matrix thickness and orientation during placement may affect surgical outcomes including the incidence of postoperative complications. Methods. This was a retrospective single‐centered analysis of 43 patients (50 breasts) who underwent implant‐based reconstruction with MegaDerm® (L&C Bio, Seoul, Korea) and 23 patients (23 breasts) who underwent implant‐based reconstruction with DermACELL® (LifeNet Health, Virginia Beach, VA, USA), two types of human‐derived acellular dermal matrix. All surgeries were performed by a single surgeon. Demographic variables, surgery‐related factors, and complications were compared between a thick matrix group (1.5–2.3 mm) and a thin matrix group (1.0–1.5 mm). The same processes were performed in the nonreverse and reverse matrix insertion groups. Results. Baseline demographics and surgery‐related data were summarized according to matrix thickness and direction. There were no significant intergroup differences in the demographic variables such as history of smoking, radiation, or chemotherapy. The mean drain volume was significantly higher in the thick matrix group than that in the thin matrix group (p = 0.0445). However, there were no significant differences in overall complication rates by matrix thickness (p = 0.3139). Additionally, there were no significant differences in complications between the nonreverse and reverse matrix insertion groups (p = 0.538). Conclusion. Our findings suggest that patients with a thick acellular dermal matrix need a prolonged period for engraftment. However, the thickness did not directly affect the surgical outcomes between the thick and thin matrix groups. Likewise, the orientation in which the acellular dermal matrix was inserted did not affect the surgical outcomes including postoperative complications.
Measurement and Analysis of Settlement Induced by Rectangular Pipe Jacking in Silt Stratum
Authors: Tang Jun , Li Shengcai , Zhu Yongfu
Published: November 2021

The large‐scale rectangular pipe jacking technology has attracted more and more attention in the construction of urban underground pipe galleries, especially the problem of prediction and control of the surface settlement. Taking the pipe gallery project of Chengbei Road in Suzhou as an example, the settlement values of three groups of monitoring sections under the conditions of natural settlement and synchronous grouting are monitored, and the measured settlement values are compared with Peck formula and random medium theory. The results show that the Peck formula is more accurate in predicting the natural settlement within 1.5 times the pipe jacking width, while the stochastic medium theory is more accurate in predicting the settlement beyond the width. By comparing the field test and theory, the suggestions on the prediction of ground settlement of rectangular pipe jacking of large scale are put forward. The results of this study provide a basis for subsequent related research work and engineering applications.
Optimal Differential Pricing for Intercity High-Speed Railway Services with Time-Dependent Demand and Passenger Choice Behaviors under Capacity Constraints
Authors: Su Huanyin , Peng Shuting , Deng Lianbo , Xu Weixiang , Zeng Qiongfang
Published: November 2021

Differential pricing of trains with different departure times caters to the taste heterogeneity of the time-dependent (departure time) demand and then improves the ticket revenue of railway enterprises. This paper studies optimal differential pricing for intercity high-speed railway services. The distribution features of the passenger demand regarding departure times are analyzed, and the time-dependent demand is formulated; a passenger assignment method considering departure periods and capacity constraints is constructed to evaluate the prices by simulating the ticket-booking process. Based on these, an optimization model is constructed with the aim of maximizing the ticket revenue and the decision variables for pricing train legs. A modified direct search simulated annealing algorithm is designed to solve the optimization model, and three random generation methods of new solutions are developed to search the solution space efficiently. Experimental analysis containing dozens of trains is performed on Wuhan-Shenzhen high-speed railway in China, and price solutions with different elastic demand coefficients (

ϕ

) are compared. The following results are found: (i) the optimization algorithm converges stably and efficiently and (ii) differentiation is shown in the price solutions, and the optimized ticket revenue is influenced greatly by

ϕ

, increasing by 7%–21%.
Combined Rothia dentocariosa and Streptococcus viridans Corneal Ulcer in an Immunocompromised Patient
Authors: Dietze Jamie , Mauger Thomas
Published: November 2021

Keratitis is a very common condition seen by ophthalmologists. However, many factors can complicate the treatment of this depending on the causative organism and other patient comorbid conditions. The objective of this clinical case report is to highlight the treatment of keratitis caused by Rothia dentocariosa. It also looks at the unique considerations in keratitis presentations for patients immunocompromised by chemotherapy agents. Our patient is a 58 yo female undergoing chemotherapy with folinic acid, fluorouracil, irinotecan, and panitumumab who presented with several days of a red, painful right eye with mucous discharge. Cultures were positive for Rothia dentocariosa and Streptococcus viridans. The patient ultimately underwent a conjunctival flap procedure as medical therapy with proper oral and topical antibiotics failed to resolve keratitis. This case is unique as previously, only a couple of cases of keratitis caused by Rothia dentocariosa have been reported and none of those patients were immunocompromised nor failed antibiotic therapy.
Primary Hyperaldosteronism: A Rare Cause of Malignant Hypertension with Thrombotic Microangiopathy in a Kidney Transplant Recipient
Authors: Ormonde Carolina , Querido Sara , Rombo Nuno , Roque Rita , Clemente Belarmino , Weigert André
Published: November 2021

Thrombotic microangiopathy (TMA) is a rare disease that presents with haemolysis and organ damage. The kidney is one of the main affected organs, and TMA is associated with serious complications and increased mortality. In transplanted patients, TMA is even less common and has a variety of possible causes, including thrombotic thrombocytopenic purpura (TTP) and haemolytic-uremic syndrome (HUS), infections, drugs, autoimmune disease, tumours, and malignant hypertension. Transplant-related causes, such as antibody-mediated rejection, calcineurin inhibitors, and viral infections, need to be considered as well. The authors report a rare case of TMA in a kidney transplant recipient, whose investigation revealed malignant hypertension secondary to primary hyperaldosteronism.
Fine-Tuning Word Embeddings for Hierarchical Representation of Data Using a Corpus and a Knowledge Base for Various Machine Learning Applications
Authors: Alsuhaibani Mohammed , Bollegala Danushka
Published: November 2021

Word embedding models have recently shown some capability to encode hierarchical information that exists in textual data. However, such models do not explicitly encode the hierarchical structure that exists among words. In this work, we propose a method to learn hierarchical word embeddings (HWEs) in a specific order to encode the hierarchical information of a knowledge base (KB) in a vector space. To learn the word embeddings, our proposed method considers not only the hypernym relations that exist between words in a KB but also contextual information in a text corpus. The experimental results on various applications, such as supervised and unsupervised hypernymy detection, graded lexical entailment prediction, hierarchical path prediction, and word reconstruction tasks, show the ability of the proposed method to encode the hierarchy. Moreover, the proposed method outperforms previously proposed methods for learning nonspecialised, hypernym-specific, and hierarchical word embeddings on multiple benchmarks.
Loading History Effect on Stress Relaxation of Rock Joints
Authors: Tian Guanghui , Liu Weijian , Ma Haohao , Zhang Qingzhao
Published: November 2021

In this study, a data analysis method for the relaxation test was proposed under step loading by conducting creep and stress relaxation tests of dentate discontinuity poured by cement mortar using biaxial creep machine under step loading and single‐stage loading. First, a superposition method for the stress relaxation curve was deduced based on the data processing method of creep test by considering the effect of loading history on the relaxation curve and the characteristic of relaxation was analyzed. Second, this superposition method was verified by testing data under step loading and single‐stage loading. Finally, this paper indicate the accurate way for the processing of relaxation test data under step loading. The results show that under the same stress level, the values of relaxation curve after the superposition are different from that under the single‐stage loading test. Furthermore, the relaxation curves in the step loading test under different stress levels are similar to those in single‐stage loading under the same stress level. Furthermore, creep deformation increase monotonically during the creep, but stress do not exhibit such a trend during relaxation, which is inconsistent with the Boltzmann superposition principle. The relaxation curve in the step loading test under different shear stress could reflect the relaxation properties of the single‐stage loading test under the same shear stress, and unlike the data processing method of step loading creep test, superimposition is not needed.
Identification of the circRNA-miRNA-mRNA Regulatory Network in Bladder Cancer by Bioinformatics Analysis
Authors: Lv Jiancheng , Chang Ping-an , Li Xin , Yang Xiao , Han Jie , Yu Hao , Zhou Zijian , Yang Haiwei , Li Pengchao , Zhang Jiexiu , Lu Qiang
Published: November 2021

In recent years, increasing evidence shows that circular RNA (circRNA) disorder is closely related to tumorigenesis and cancer progression. However, the regulatory functions of most circRNAs in bladder cancer (BCa) remain unclear. This study was aimed at exploring the molecular regulatory mechanism of circRNAs in BCa. We obtained four datasets of circRNA, microRNA (miRNA), and messenger (mRNA) expression profiles from the Gene Expression Omnibus and The Cancer Genome Atlas microarray databases and identified 434, 367, and 4799/4841 differentially expressed circRNAs, miRNAs, and mRNAs, respectively. With these differentially expressed RNAs, we established a circRNA-miRNA-mRNA targeted interaction network. A total of 18, 24, and 51 central circRNAs, miRNAs, and mRNAs were identified, respectively. Among them, the top 10 mRNAs that had high connectivity with other circRNAs and miRNAs were regarded as hub genes. We detected the expression levels of these 10 mRNAs in 16 pairs of BCa tissues and adjacent normal tissues through quantitative real-time polymerase chain reaction. The differentially expressed mRNAs and central mRNAs were enriched in the processes and pathways that are associated with the growth, differentiation, proliferation, and apoptosis of tumor cells. The outstanding genes (CDCA4, GATA6, LATS2, RHOB, ZBTB4, and ZFPM2) also interacted with numerous drugs, indicating their potency as biomarkers and drug targets. The findings of this study provide a deep understanding of the circRNA-related competitive endogenous RNA regulatory mechanism in BCa pathogenesis.
The Origins of Phenotypic Heterogeneity in Cancer
Authors: Lenz Guido , Onzi Giovana R. , Lenz Luana S. , Buss Julieti H. , dos Santos Jephesson A. , Begnini Karine R.
Published: November 2021

Heterogeneity is a pervasive feature of cancer, and understanding the sources and regulatory mechanisms underlying heterogeneity could provide key insights to help improve the diagnosis and treatment of cancer. In this review, we discuss the origin of heterogeneity in the phenotype of individual cancer cells. Genotype–phenotype (G–P) maps are widely used in evolutionary biology to represent the complex interactions of genes and the environment that lead to phenotypes that impact fitness. Here, we present the rationale of an extended G–P (eG–P) map with a cone structure in cancer. The eG–P cone is formed by cells that are similar at the genome layer but gradually increase variability in the epigenome, transcriptome, proteome, metabolome, and signalome layers to produce large variability at the phenome layer. Experimental evidence from single-cell-omics analyses supporting the cancer eG–P cone concept is presented, and the impact of epimutations and the interaction of cancer and tumor microenvironmental eG–P cones are integrated with the current understanding of cancer biology. The eG–P cone concept uncovers potential therapeutic strategies to reduce cancer evolution and improve cancer treatment. More methods to study phenotypes in single cells will be the key to better understand cancer cell fitness in tumor biology and therapeutics.
Association between Coffee Consumption and Risk of Prostate Cancer in Japanese Men: A Population-Based Cohort Study in Japan
Authors: Imatoh Takuya , Sawada Norie , Yamaji Taiki , Iwasaki Motoki , Inoue Manami , Tsugane Shoichiro
Published: November 2021

Background:

Although numerous epidemiological studies have examined whether coffee consumption is associated with prostate cancer risk, the results remain controversial. Moreover, there are few studies in Asian populations. Therefore, we investigated the association between coffee consumption and the risk of prostate cancer in a large-scale prospective population-based cohort study in Japan.

Methods:

Study subjects were 48,222 men (40–69 years) who completed a questionnaire that included questions about their coffee consumption in 1990 for Cohort I and 1993 for Cohort II and were followed up until December 31, 2015. Newly diagnosed cases were classified into localized and advanced using information on local staging, the Gleason score, and degree of differentiation. Hazard ratios (HR) and 95% confidential intervals (95% CI) were estimated using Cox regression analysis.

Results:

A total of 1,617 participants were newly diagnosed with prostate cancer during a mean follow-up period of 18.8 years. Of these, 1,099 and 461 patients had localized and advanced cancer, respectively. There was no association between coffee intake and prostate cancer risk. Comparison between the highest and lowest category of coffee consumption produced HRs of 1.08 (95% CI, 0.90–1.30), 1.08 (95% CI, 0.84–1.38), and 1.00 (95% CI, 0.67–1.47) for risk of total, localized, and advanced cancer, respectively. The same results were obtained even when we limited the analysis to patients with subjective symptoms.

Conclusions:

Our findings suggest that coffee consumption has no impact on prostate cancer risk in Japanese men.

Impact:

Coffee has no protective effects against prostate cancer among Japanese men.
Influence of Cancer Susceptibility Gene Mutations and ABO Blood Group of Pancreatic Cancer Probands on Concomitant Risk to First-Degree Relatives
Authors: Antwi Samuel O. , Rabe Kari G. , Bamlet William R. , Meyer Margaret , Chandra Shruti , Fagan Sarah E. , Hu Chunling , Couch Fergus J. , McWilliams Robert R. , Oberg Ann L. , Petersen Gloria M.
Published: November 2021

Background:

ABO blood group is associated with pancreatic cancer risk. Whether ABO blood group alone or when combined with inherited mutation status of index pancreatic cancer cases (probands) can enhance pancreatic cancer risk estimation in first-degree relatives (FDR) is unclear. We examined FDRs' risk for pancreatic cancer based on probands' ABO blood group and probands' cancer susceptibility gene mutation status.

Methods:

Data on 23,739 FDRs, identified through 3,268 pancreatic cancer probands, were analyzed. Probands' ABO blood groups were determined serologically or genetically, and 20 cancer susceptibility genes were used to classify probands as “mutation-positive” or “mutation-negative.” SIRs and 95% confidence intervals (CI) were calculated, comparing observed pancreatic cancer cases in the FDRs with the number expected in SEER-21 (reference population).

Results:

Overall, FDRs had 2-fold risk of pancreatic cancer (SIR = 2.00; 95% CI = 1.79–2.22). Pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.80; 95% CI = 2.81–5.02) than mutation-negative (SIR = 1.79; 95% CI = 1.57–2.04) probands (P < 0.001). The magnitude of risk did not differ by ABO blood group alone (SIRblood-group-O = 1.57; 95% CI = 1.20–2.03, SIRnon-O = 1.83; 95% CI = 1.53–2.17; P = 0.33). Among FDRs of probands with non-O blood group, pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.98; 95% CI = 2.62–5.80) than mutation-negative (SIR = 1.66; 95% CI = 1.35–2.03) probands (P < 0.001), but risk magnitudes were statistically similar when probands had blood group O (SIRmutation-positive = 2.65; 95% CI = 1.09–5.47, SIRmutation-negative = 1.48; 95% CI = 1.06–5.47; P = 0.16).

Conclusions:

There is a range of pancreatic cancer risk to FDRs according to probands' germline mutation status and ABO blood group, ranging from 1.48 for FDRs of probands with blood group O and mutation-negative to 3.98 for FDRs of probands with non-O blood group and mutation-positive.

Impact:

Combined ABO blood group and germline mutation status of probands can inform pancreatic cancer risk estimation in FDRs.
A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma
Authors: Girault Isabelle , Adam Julien , Shen Shensi , Roy Séverine , Brard Caroline , Faouzi Sara , Routier Emilie , Lupu Jéremy , Warren Sarah , Sorg Kristina , Ong SuFey , Morel Pascale , Scoazec Jean-Yves , Vagner Stéphan , Robert Caroline
Published: November 2021

Purpose:

Less than 50% of patients with melanoma respond to anti–programmed cell death protein 1 (anti–PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti–PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti–PD-1 therapy.

Experimental Design:

PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n = 66 and validation n = 71) of samples from patients with melanoma treated with anti–PD-1±anti–CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8+ cells density, and NanoString RNA signature, were also evaluated.

Results:

A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71–0.77). Progression-free and overall survival were significantly longer in patients with high PLA values (P = 0.00019 and P < 0.0001, respectively).

Conclusions:

The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti–PD-1 efficacy.
Multi-scale Pan-cancer Integrative Analyses Identify the STAT3-VSIR Axis as a Key Immunosuppressive Mechanism in Head and Neck Cancer
Authors: Katabathula Ramachandra , Joseph Peronne , Singh Salendra , Zhao Songzhu , Kumar Bhavna , Gaule Patricia , Pan Quintin , Old Matthew , Tuck David P. , Varadan Vinay
Published: November 2021

Purpose:

VSIR is a novel immune checkpoint protein whose expression on tumor cells across cancers remains largely uncharacterized. Here we purposed to decode the pan-cancer biologic and clinical significance of VSIR overexpression in the tumor compartment.

Experimental Design:

We performed multi-omics integrative analyses of 9,735 tumor samples to identify cancers with non-leukocytic expression of VSIR (VSIR High), followed by association with overall survival and immune cell infiltration levels. Orthogonal assessments of VSIR protein expression and lymphocytic infiltration were performed using quantitative immunofluorescence (QIF).

Results:

Integrative modeling identified a subset of cancer types as being enriched for VSIR High tumors. VSIR High tumors were associated with significantly poorer overall survival in immunogenic ovarian serous adenocarcinoma (SA) and oral cavity squamous cell carcinoma (SCC). QIF assessments in an independent validation cohort confirmed overexpression of VSIR as being associated with poorer overall survival within immunogenic oral cavity SCC. VSIR overexpression was associated with lower CD4 helper T-cell infiltration in both ovarian SA and oral cavity SCC, but did not impact CD8 T-cell infiltration. VSIR overexpressing tumors in both cancer types exhibited significantly higher STAT3 signaling activity. Pharmacologic inhibition of STAT3 signaling resulted in dose-dependent reduction of VSIR expression in ovarian SA and oral cavity SCC cells.

Conclusions:

The STAT3-VSIR axis is a potentially significant immunomodulatory mechanism in oral cavity and ovarian cancers, whose activation is associated with poorer survival and an immune microenvironment marked by decreased CD4 helper T-cell activity. The role of VSIR as a tumor-intrinsic modulator of resistance to immunotherapy warrants further exploration.
Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker
Authors: Rickelt Steffen , Neyaz Azfar , Condon Charlene , Whittaker Charles A. , Zaidi Ali H. , Taylor Martin S. , Abbruzzese Genevieve , Mattia Anthony R. , Zukerberg Lawrence , Shroff Stuti G. , Yilmaz Omer H. , Yilmaz Osman , Wu Elizabeth Y. , Choi Won-Tak , Jobe Blair A. , Odze Robert D. , Patil Deepa T. , Deshpande Vikram , Hynes Richard O.
Published: November 2021

Purpose:

There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus–related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus–related neoplasia and to predict neoplastic progression.

Experimental Design:

Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus–related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus–related neoplasia from 321 patients in three independent cohorts.

Results:

Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus–related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus–related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus–related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%.

Conclusions:

We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.
Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4+ Th1 Responses and Potential Use as a Cancer Vaccine
Authors: Basu Amrita , Albert Gabriella K. , Awshah Sabrina , Datta Jashodeep , Kodumudi Krithika N. , Gallen Corey , Beyer Amber , Smalley Keiran S.M. , Rodriguez Paulo C. , Duckett Derek R. , Forsyth Peter A. , Soyano Aixa , Koski Gary K. , Lima Barros Costa Ricardo , Han Heather , Soliman Hatem , Lee Marie Catherine , Kalinski Pawel , Czerniecki Brian J.
Published: November 2021

The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II–binding HER3 peptides, which can generate HER3-specific CD4+ Th1 antitumor immune responses. Using an overlapping peptide screening methodology, we identified nine MHC class II–binding HER3 epitopes that elicited specific Th1 immune response in both healthy donors and breast cancer patients. Most of these peptides were not identified by current binding algorithms. Homology assessment of amino acid sequence BLAST showed >90% sequence similarity between human and murine HER3/ERBB3 peptide sequences. HER3 peptide–pulsed dendritic cell vaccination resulted in anti-HER3 CD4+ Th1 responses that prevented tumor development, significantly delayed tumor growth in prevention models, and caused regression in multiple therapeutic models of HER3-expressing murine tumors, including mammary carcinoma and melanoma. Tumors were robustly infiltrated with CD4+ T cells, suggesting their key role in tumor rejection. Our data demonstrate that class II HER3 promiscuous peptides are effective at inducing HER3-specific CD4+ Th1 responses and suggest their applicability in immunotherapies for human HER3-overexpressing tumors.
Gridshells: integrating design with structural performance in early design stages, using formal and informal knowledge
Authors: Henriques Gonçalo Castro , Franco Juarez Moara
Published: November 2021

Gridshell has long interested the enthusiast of lightweight construction. The most popular examples date back to the 1960s; gridshell development requires mathematical, technical and material resources. These requirements limit gridshell development to special buildings, and their design to specialists requiring considerable time and budget to construct them. Digital processes of design, fabrication and assembly offer renewed possibilities to tackle these difficulties and to deepen the interaction among form, material and structural performance. This article documents a didactic experience regarding architectural and engineering gridshell design aimed at relative beginners, considering structural behaviour from early design stages. The research is included in a broader research about gridshells that seeks to gradually integrate formal and informal knowledge about form-finding, including empirical and theoretical research. The didactic experience is framed in a series of empirical constructions we are developing, and contributing to the collective debate about how to expand gridshell construction further.
Artefato metodológico do City Pattern: tradução computacional paramétrica de princípios de Christopher Alexander sobre forma e vida urbana
Authors: Cavalcanti Isabella Eloy , Mendes Leticia Teixeira , Barros Filho Mauro Normando Macêdo
Published: November 2021

O design computacional, especificamente a modelagem paramétrica, tem desempenhado um papel importante no alcance de formas complexas, otimizações e automatizações de processos de design. Além de usar a tecnologia paramétrica como ferramenta para gerar forma, este artigo tem como objetivo discutir o potencial da programação computacional como uma conexão entre a teoria e a atividade projetiva. Para ilustrar isso, este artigo apresentará a metodologia desenvolvida para traduzir a obra do arquiteto Christopher Alexander como base para o desenvolvimento de instrumentos computacionais de tomada de decisão que lidem com a complexidade entre a forma e a vida urbana. Para tanto, será apresentado o problema, o método Design Science Research como importante referência, a aplicação da metodologia de tradução dos padrões de Alexander e por fim o formato genérico das etapas, aplicável para tradução de outras bases teóricas.
Echocardiographic and Electrocardiographic Abnormalities Among Elderly Adults With Cardiovascular Disease in Rural South Africa
Authors: Ferro Enrico G. , Abrahams-Gessel Shafika , Jardim Thiago Veiga , Wagner Ryan , Gomez-Olive F. Xavier , Wade Alisha N. , Peters Ferande , Tollman Stephen , Gaziano Thomas A.
Published: November 2021

Background:

Sub-Saharan Africa is undergoing an epidemiological transition fueled by the interaction between infectious and cardiovascular diseases. Our cross-sectional study aimed to characterize the spectrum of abnormalities suggesting end-organ damage on ECG and transthoracic echocardiograms (TTE) among older adults with cardiovascular diseases in rural South Africa.

Methods:

The prevalence of ECG and TTE abnormalities was estimated; χ
2
analyses and multivariable logistic regressions were performed to test their association with sex, hypertension, and other selected comorbidities.

Results:

Overall, 729 ECGs and 155 TTEs were completed, with 74 participants completing both. ECG evaluation showed high rates of left ventricular hypertrophy (LVH, 36.5%) and T wave abnormalities (13.6%). TTE evaluation showed high rates of concentric LVH (31.6%), with moderate-severe (56.8%) diastolic dysfunction. Participants with hypertension showed more cardiac remodeling on ECG by LVH (45.4% versus 22.1%,
P
<0.01), and TTE by concentric LVH (42.5% versus 8.2%,
P
<0.01) and increased left ventricular mass (58.5% versus 20.4%,
P
<0.0001). In multivariable logistic regression, systolic blood pressure remained significantly associated with LVH on ECG (adjusted odds ratio, 1.03 per mm Hg [95% CI, 1.03–1.04],
P
<0.0001) and increased left ventricular mass on TTE (adjusted odds ratio, 1.04 per mm Hg [95% CI, 1.01–1.06],
P
=0.001). Male participants (n=326, 40.2%) were more likely than females (n=484, 59.8%) to show ECG abnormalities like LVH (45% versus 30.8%,
P
<0.01), whereas females were more likely to show TTE abnormalities like concentric LVH (40.8% versus 13.5%,
P
<0.01) and increased left ventricular mass (58.4% versus 23.1%,
P
<0.0001). Similar results were confirmed in multivariable models.

Conclusions:

Our findings suggest that cardiovascular diseases are widespread in rural South Africa, with a larger burden of hypertensive heart disease than previously appreciated, and define the severity of end-organ damage that is already underway. Local health systems must adapt to face the growing burden of hypertension, as suboptimal rates of hypertension diagnosis and treatment may dramatically increase the heart failure burden.
Survival in Patients With Suspected Myocardial Infarction With Nonobstructive Coronary Arteries: A Comprehensive Systematic Review and Meta-Analysis From the MINOCA Global Collaboration
Authors: Pasupathy Sivabaskari , Lindahl Bertil , Litwin Peter , Tavella Rosanna , Williams Michael J.A. , Air Tracy , Zeitz Christopher , Smilowitz Nathaniel R. , Reynolds Harmony R. , Eggers Kai M. , Nordenskjöld Anna M. , Barr Peter , Jernberg Tomas , Marfella Raffaele , Bainey Kevin , Sodoon Alzuhairi Karam , Johnston Nina , Kerr Andrew , Beltrame John F.
Published: November 2021

Background:

Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA.

Methods:

Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms “MI,” “nonobstructive,” “angiography,” and “prognosis” were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran’s Q and I
2
statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI.

Results:

The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%–4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%–3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%–4.1%] versus 5.6% [95% CI, 4.1%–7.0%]; odds ratio, 0.60 [95% CI, 0.52–0.70],
P
<0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%–5.9%]) compared with No-MI (0.7% [95% CI, 0.1%–1.3%]; odds ratio, 3.71 [95% CI, 0.58–23.61],
P
=0.09).

Conclusions:

In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI.

Registration:

URL:
https://www.crd.york.ac.uk/PROSPERO/
; Unique identifier: CRD42020145356.