bluuebunny/crossref_metadata_2025 huggingface dataset:
T Cell Roles and Activity in Chronic Sclerosing Sialadenitis as IgG4-Related Disease: Current Concepts in Immunopathogenesis
Authors: Ibrahem Hazim Mahmoud
Published: June 2022

IgG4-related disease is a multiorgan immunological fibroinflammatory disorder characterized by lymphoplasmacytic infiltration and fibrosis in multiple organs accompanied by high serum IgG4 levels. The salivary glands are the most common organs involved in this disease. Recently, chronic sclerosing sialadenitis affecting salivary glands, formerly known as Küttner’s tumor, and Mikulicz’s disease have been classified as a class of IgG4-related diseases. The etiopathobiology of IgG4-related disease is not fully understood. It has recently been hypothesized that the inflammatory and fibrotic process and the increased serum IgG4+ levels in IgG4-related disease are the result of an interaction between B cells and T helper cells, suggesting that T cells may play a key role in the pathogenesis of this disease. The aim of this review is to discuss the proposed roles of different T cell subsets in the pathogenesis of IgG4-related disease focusing on their roles in immunopathogenesis of IgG4-related sialadenitis.
Research on Computer Intelligent Proofreading System for English Translation Based on Deep Learning
Authors: Ma Nannan
Published: June 2022

English, as a global language, is widely used in daily life, which leads to higher requirements for people’s language proficiency. Grammar, as an essential part of English, plays a significant role in language acquisition. Although the needs for English learning have become greater, the resources of English teaching are quite limited. Under this circumstance, it is imperative to apply information technology to alleviate the burden of lacking sufficient educational resources. The intelligent grammar correction system is in special needs. In this study therefore, the deep learning-based CNN and RNN bidirectional propagation model were utilized to construct a feedback filtering function, screen the suggested text, and select the high-quality suggested text for the retraining of the error correction model. The proofreading optimization algorithm and feedback filtering algorithm were used in practice to implement each functional module. The core function service module was designed with a cluster deployment scheme with high system performance and response speed to ensure system stability and availability. Experimental results demonstrate that the correct rate gradually increased with increasing the number of tests and finally stabilized at about 86%. The overall average correcting rate obtained from the present model was verified to be superior to that from the GRU model and the MGB model.
Network Security Situation Prediction Model Based on EMD and ELPSO Optimized BiGRU Neural Network
Authors: Zhang Biao , Jia Mingqi , Xu Jiazhong , Zhao Wanzhao , Deng Liwei
Published: June 2022

In order to improve the accuracy of network security situation prediction and the convergence speed of prediction algorithm, this paper proposes a combined prediction model (EMD-ELPSO-BiGRU) based on empirical mode decomposition (EMD) and improved particle swarm optimization (ELPSO) to optimize BiGRU neural network. Firstly, the network security situation data sequence is decomposed into a series of intrinsic mode function by EMD. Then, a particle swarm optimization algorithm (ELPSO) based on cooperative update of evolutionary state judgment and learning strategy is proposed to optimize the hyper-parameters of BiGRU neural network. Finally, a network security situation prediction model based on EMD-ELPSO-BiGRU is constructed to predict each intrinsic mode function, respectively, and the prediction results are superimposed to obtain the final network security situation prediction value. Simulation results show that ELPSO has better optimization performance, and EMD-ELPSO-BiGRU model has higher prediction accuracy and significantly improved convergence speed compared with other traditional prediction methods.
The Influence and Analysis of Multimedia Interaction on the Development of Dance
Authors: Wu Haijian , Leng Yan
Published: June 2022

Since ancient times, dance has been widely loved by people. The history of dance has a long history, and people’s pursuit of dance has never stopped. However, with the development of modern technology, traditional dance has been unable to keep up with the pace of the times. Therefore, this article studies the influence of multimedia interaction on the development of dance. This article proposes that multimedia interaction has a great influence on the status quo of dance development. This article aims to study the role of multimedia interaction in dance development. In the eleven years since 2010, the technology of stage effects has developed rapidly. As you can imagine, not only the stage effects can bring a visual feast, but also the development space of dancers has been greatly improved. It can be seen that multimedia interaction is of great significance to the development of dance; with the rapid development of science and technology, multimedia technologies such as computer networks are widely used in all walks of life. The application in the field of dance art is gradually popularized, in which dance teaching and stage performance methods have undergone great changes with the in-depth popularization of multimedia. Therefore, this article must analyze the influence of multimedia interaction on the development of dance.
The Association of Proning and Stroke among Deeply Sedated Critically Ill SARS-CoV-2 (COVID-19) Patients
Authors: Saberon Keith Moon Q. , Rosario Soliven Jo-Ann
Published: June 2022

There has been an increasing incidence of stroke cases among SARS-CoV-2 (COVID-19) patients who were deeply sedated and underwent proning positioning. We reviewed the association of proning and sedations used to the development of stroke, including demographic profiles of patients with COVID-19 infection in the critical care unit. There was a significant association seen among COVID-19 patients in the ICU who underwent proning to the development of stroke, with up to 15 times risk of having stroke (

p

value = 0.007) than those who were not proned during their course of ICU stay. Patients who were given propofol and fentanyl as sedation during proning for more than 24 hours was significantly associated with the development of stroke (

p

value = 0.004). Patient risk factors were also studied (age variability, hypertension, diabetes, smoking, and alcoholism) and showed that patients who were alcoholic beverage drinkers were significantly associated to the development of stroke during proning (

p

value = <0.001). The usual risk factors for stroke in the general population (hypertension, diabetes, and cigarette smoking) were not associated with stroke development during proning, strengthening the fact that proning during COVID-19 infection is an independent risk factor for the development of stroke thus needing stroke surveillance during the duration of proning.
Heating Properties of Graphene Oxide Nanosheets and Their Application in Clothing Design
Authors: Luan Xiaoli
Published: June 2022

Graphene oxide nanosheets are nanomaterials with a layered structure, which have good thermal conductivity and heat dissipation. This article aims to integrate it into clothing design to alleviate the existing contradictions in the development of the clothing market. In this article, an overview of clothing design is firstly suggested, and then the structure and properties of graphene oxide nanosheets are expounded. A comparative test was carried out in terms of style and mechanical properties. The results showed that the thermal conductivity of graphene oxide clothing materials was maintained at a maximum of about 37.8°C, and the heat dissipation performance could be maintained at a minimum of about 27.1°C, which fully verified its operability. Popularizing it in the current stage of clothing design can effectively improve the performance and comfort of clothing.
The Selection of Anode and Cathode Materials for Top Emission Organic Light-Emitting Diodes
Authors: Juang Fuh-Shyang , Patel Krishn Das , Huang Kuo-Chun , Juang Wen-Xaing , Chen Jeng-Yue , Hong Lin-Ann
Published: June 2022

In this study top emission organic light-emitting diodes (TE-OLED) were successfully fabricated on flexible PET/multilayer disordered silver nanonetwork (MDSN) substrate with conventional LiF/Al as a semitransparent cathode and Ag as a reflective anode. The effects of the hole injection layer, anode buffer layer, and an electron injection layer on the luminescence characteristics of TE-OLEDs were investigated. At first, the thickness of cathode Al is adjusted based upon the overall transmittance of the top-emission cathode and its conductivity. There is a high energy barrier for the hole between the work function of the anode Ag (4.2 eV) and the NPB highest occupied molecular orbital (HOMO) energy level (5.5 eV), which is not favorable for hole injection. This study tested four types of hole injection layer (HIL) materials. Finally, MoO3 was selected as an optimal HIL material, and the optimum thickness was adjusted, enabling the hole to be injected smoothly from the anode to the NPB and then to an emitting layer. The TE-OLED luminance reached 268 cd/m2. There is a high energy barrier between the work function of Ag and MoO3 HOMO (5.3 eV)—about 1.1 eV—which is still not conducive to the hole injection, so a thin layer of high work function metal Au (work function 5.1 eV) was added to the top of the anode silver, which more matches with the MoO3 energy level. It can make the hole easier to inject from the anode to MoO3 (HIL) and protect the silver from oxidation. At 8 V, the luminance is increased to 413.7 cd/m2, and the current efficiency is 0.81 cd/A. The luminance is significantly improved. An electron transport/hole blocking layer TPBi (10 nm) was added to enhance the electron transport capability and effectively block the holes with higher electron mobility and a higher HOMO energy level of TPBi. So that more holes can remain in the emitting layer and increase the chance of the electron-hole recombination to improve the luminance and current efficiency of TE-OLED. At 8 V, the luminance and current efficiency can reach 611.4 cd/m2 and 0.95 cd/A, respectively.
[Retracted] Application and Optimization of Wing Structure Design of DF‐2 Light Sports Aircraft Based on Composite Material Characteristics
Authors: Li Fenglei , Zhang Shengnian , Cheng Wanxiang
Published: June 2022

Compared with ordinary metal structures, advanced composite materials have the characteristics of high strength, high rigidity, and light weight. The use of composite materials in aircraft structures is currently a hot research topic. This research mainly discusses the optimization design of the composite wing structure of the DF‐2 light sports aircraft. This article takes the DF‐2 light sports aircraft planned to be produced by the company as the source. Based on its overall design basis, aerodynamic requirements, and the original wing structure design, according to the composite material aircraft structure design theory and method, the aircraft wing structure is carried out. Composite materials are materials with new properties that are composed of two or more materials with different properties at the macroscale by physical and chemical methods. Composite materials can be divided into functional composite materials and structural composite materials according to the nature of the application. Functional composites are materials with special functions, such as conductive composites, ablative materials, and frictional composites. At present, the main research is on structural composite materials, which are composed of two components: matrix material and reinforcing material. The new structural scheme design and structural strength analysis are designed to meet the structural strength requirements of the wing and the lightest weight. In this paper, according to the force transmission characteristics of different structural types of the wing, the characteristics of the load transmission are analyzed, and the shape parameters and load parameters of the wing structure design are used as initial conditions, and the quantitative analysis model of the wing structure is constructed according to the requirements of strength, stiffness, and stability. Through rapid mathematical modeling and analysis of the wing structure, the weight and efficiency of different configurations can be evaluated. Through the quantitative analysis model of the wing, the wing structure type can be quickly determined according to the wing parameters in the preliminary design, which makes the basis for the selection of the wing structure type. After optimization, the weight of the wing structure decreased from 0.966 kg to 0.803 kg, a decrease of 16.87%. The designability of composite materials is one of its major characteristics. By optimizing the layup angle, layup sequence, and dropout area, the performance indicators of the structure are finally improved. This research will promote the further development of the aerospace field.
Real-Time Trajectory Planning and Control for Constrained UAV Based on Differential Flatness
Authors: Wu Dongli , Zhang Hao , Liu Yunping , Fang Weihua , Wang Yan
Published: June 2022

The trajectory planning of UAV with nonholonomic constraints is usually taken as differential algebraic equation to solve the optimal control problem of functional extremum under the condition of inequality constraints. However, it can be challenging to meet the requirements of real-time for the high complexity. A differential flat theory based on B-spline trajectory planning can replace the optimal control problem with nonlinear programming and be a good means to achieve the efficient trajectory planning of an UAV under multiple dynamic constraints. This research verifies the feasibility of this theory with actual flight experiments.
Data Integration Method Design of Decision Spatial Information System
Authors: Li Daqian
Published: June 2022

With the development of technology, more and more enterprises have begun to use data integration analysis to make decisions. The decision spatial information system is an information system that provides decision support after analyzing and processing the spatial information. Data integration refers to a method of reasonably centralizing different or multisource data for data sharing, which can assist in decision management. This paper aims to study a more efficient data integration method for decision space information system. In this paper, an emergency information decision-making system for digital water network is designed, and a specific data integration algorithm is proposed. And the performance test of the early warning capability and power consumption of the system is carried out. The results show that the early warning time of the system designed in this paper is within 1 to 4 seconds, while the early warning time of the traditional system is within 1.5 seconds to 8 seconds. The power consumption of the system designed in this paper is not more than 25 W, while the traditional system power consumption is up to 50 W. The power consumption of the system in this paper is about half of the traditional system. Compared with the traditional system early warning capability, the system designed in this paper is significantly faster, the system power consumption is lower, and the system is more stable.
Analysis of Older Adults under Home Care in Taiwan’s Ageing Society
Authors: Chiu Jhih-Ling
Published: June 2022

As of January 2022, 16.91% of Taiwan’s population was over the age of 65, and a 2017 study indicated that 94.2% of patients who required long-term care in Taiwan received home care. This study produced a “post-home care patient information survey” to understand the characteristics of home care patients and the volume and results of home care and investigate the relationships between them. Different diagnoses were found to have no significant effect on the volume or results of home care. Positive correlations were found between the services patients required and the volume of home care and specific results. Volume and specific results were also positively correlated. The termination of home care was primarily due to medical needs (98.6%). As the Taiwanese population ages, home care must be improved, and the conditions for which patients can receive home care should be expanded. Care services should replace diagnoses in determining benefit standards for home care payments.
Comparison of Different Invasive Devices for the Treatment of Urinary Incontinence after Radical Prostatectomy
Authors: Salciccia Stefano , Viscuso Pietro , Bevilacqua Giulio , Tufano Antonio , Casale Paolo , De Berardinis Ettore , Di Pierro Giovanni Battista , Cattarino Susanna , Gentilucci Alessandro , Lourdes Lia Francesca , Ivan Di Giulio , Rosati Davide , Del Giudice Francesco , Sciarra Alessandro , Mariotti Gianna
Published: June 2022

Purpose. To compare different forms of invasive treatments for postradical prostatectomy (RP) urinary incontinence (UI) in terms of quantitative and qualitative parameters and continence recovery rate. Methods. We distinguished five categories of treatment: A = bulking agents, B = fixed slings, C = adjustable slings, D = circumferential compressor devices (artificial sphincter), and E = noncircumferential compressor devices (ProACT). A literature search was performed following the PRISMA guidelines. We performed a cumulative meta-analysis to explore the trend in the effect sizes across groups at postoperative follow-up. We compared the available treatment arms using standardized mean difference (SMD) and event rate (ER) for questionnaire results, number of pads/day, and percentage of pad-free patients. Evidence synthesis. 36 clinical trials were selected. At baseline, in the different populations, mean number of pad-day varied from 1.1 to 8.8, 24-hour pad weight varied extremely from 17.3 

g

to 747.0 

g

, and mean ICIQ-UI-SF questionnaire score varied from 4.8 to 18.6. Considering a random effect model among eligible studies, ER of continence recovery was 0.33 (95% CI −0.12–0.78), 0.63 (95% CI 0.55–0.71), 0.65 (95% CI 0.58–0.72), 0.50 (95% CI 0.34–0.66), and 0.53 (95%CI 0.36–0.70), respectively, in groups A, B, C, D, and E (I2 85.87%; Q 249.82—

P
>
0.01

) (test of group differences

P
=
0.22

). Conclusion. In our analysis, the use of adjustable and fixed slings is associated with the highest whereas the use of bulking agents is associated with the lowest recovery rate of continence after treatment. Results are conditioned by an elevated rate of heterogeneity in part explained with a high variability of consistence in urinary leakage at baseline among populations.
Synthesis and Characterization of a Novel Bentonite Composite Superabsorbent Resin Based on Starch
Authors: Li Dongfang , Guo Jing , Wang Xinru , Pei Lingnan , Li Wenjuan , Liu Yanxia , Deng Yongchang , Chen Zhu
Published: June 2022

A superabsorbent resin (SAR) is a functional polymer with a high water absorption capacity, which has been widely used in many fields. In this study, a modified aqueous solution polymerization process was adopted to synthesize a SAR. The optimum synthetical mass ratios of starch, bentonite, potassium persulfate (K2S2O8), and N,N′-methylene-bis-acrylamide to acrylic acid (AA) were 7.14%, 3.57%, 0.29%, and 0.057%, respectively, and the neutralization degree of AA was 50%. The molecular structure and the surface morphologies of the SAR were confirmed using Fourier transform infrared spectroscopy and scanning electron microscopy. The SAR had a water absorbency of 1300 mL/g in distilled water and 56 mL/g in 0.9 wt.% NaCl solution. The water absorption rate reached 72.65% of the maximum water absorption in 1 hour and swelled to equilibrium in 4 hours. The water retention rate was 45.86% after heating and evaporation at 150°C for 1 hour. The moisture absorption rate reached 28.2% after 10 days of placement. The modified technology provides a new synthetic method for production of SARs, which is characterized by a lack of nitrogen protection, the direct use of raw AA and potato starch, a simplified synthesis process, substantially improved efficiency, and lower production costs.
Statistical Characteristics of 3D MIMO Channel Model for Vehicle-to-Vehicle Communications
Authors: Saleem Asad , Xu Yan , Khan Rehan Ali , Rasheed Iftikhar , Jaffri Zain Ul Abidin , Layek Md Abu
Published: June 2022

Spatial and temporal characteristics of the propagation channel have a significant influence on multiantenna method applicability for fifth-generation- (5G-) enabled Internet of Things (IoT). In this paper, the statistical characteristics of a novel three-dimensional (3D) geometric-based stochastic model for next-generation vehicle-to-vehicle (V2V) multiple-input multiple-output (MIMO) communications under the nonisotropic scattering environment are investigated. In both line-of-sight (LoS) and non-line-of-sight (NLoS) conditions, the proposed model investigates the spatial, frequency, and temporal domain statistical distribution of multipath received signals by using the time-variant transfer function for indoor environments. The probability density function (PDF) of separation distance between the transceiver antennas, angle-of-arrival (AoA), and angle-of-departure (AoD) in the azimuth and elevation planes is derived by using closed-form expressions. For the space, time, and frequency correlation function (STF-CF), a precise analytical expression is derived based on MIMO antenna system. We further determine the effects of several model parameters on the V2V channel performance, such as tunnel width, antenna array spacing, Ricean

K

-factor, and moving velocity. The statistical characteristics of the MIMO channel model are validated by simulation results, confirming the flexibility and effectiveness of our proposed model in the tunnel scenario.
The Bioinformatic Study Uncovers Probable Critical Genes Involved in the Pathophysiology of Biliary Atresia
Authors: Chen Si , Wu Songli , Zhang Mingman
Published: June 2022

Background. Biliary atresia (BA) is an uncommon illness that causes the bile ducts outside and within the liver to become clogged in babies. If left untreated, the cholestasis causes increasing conjugated hyperbilirubinemia, cirrhosis, and hepatic failure. BA has a complicated aetiology, and the mechanisms that drive its development are unknown. The objective of this study was to show the role of probable critical genes involved in the pathophysiology of biliary atresia. Methods. We utilised the public Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE46960 to find differentially expressed genes (DEGs) in 64 biliary atresia newborns, 14 infants with various causes of intrahepatic cholestasis, and 7 deceased-donor children as control subjects in our study. The relevant information was looked into. The important modules were identified after functional enrichment, GO and KEGG pathway analyses, protein-protein interaction (PPI) network analyses, and GSEA analysis. Results. The differential expression analysis revealed a total of 22 elevated genes. To further understand the biological activities of the DEGs, we run functional enrichment analyses on them. Meanwhile, KEGG analysis has revealed significant enrichment of pathways involved in activating cross-talking with inflammation and fibrosis in BA. SERPINE1, THBS1, CCL2, MMP7, CXCL8, EPCAM, VCAN, ITGA2, AREG, and HAS2, which may play a significant regulatory role in the pathogenesis of BA, were identified by PPI studies. Conclusion. Our findings suggested 10 hub genes and probable mechanisms of BA in the current study through bioinformatic analysis.
Comparison of the Effects of Abdominal Massage and Oral Administration of Sweet Almond Oil on Constipation and Quality of Life among Elderly Individuals: A Single‐Blind Clinical Trial
Authors: Faghihi Amir , Zohalinezhad Mohammad Ebrahim , Najafi Kalyani Majid
Published: June 2022

Background. Constipation is a common digestive disorder in the elderly population, which has a considerable impact on various aspects of their lives. Traditional and complementary medicines are two common treatments for constipation. This study was aimed at comparing the effects of abdominal massage and oral administration of sweet almond oil on constipation and quality of life among elderly people. Methods. In this single‐blind study, 90 eligible elderly people were randomly selected according to ROME IV diagnostic criteria from October 2020 to May 2021 and were divided into three groups using block randomization (n = 30). In the oral consumption group, 126 ml sweet almond oil was administered during seven sessions held over two weeks (18 ml every other day). The abdominal massage group was provided with abdominal massage with the same amount of sweet almond oil during seven sessions in two weeks. Finally, the third group (i.e., the control group) received no interventions. Constipation was measured using the Constipation Assessment Scale (CAS) and the Bristol Stool Form Scale (BSFS) at baseline and on the 15th day of the intervention. Patient Assessment of Constipation‐Quality of Life (PAC‐QOL) was also applied before and after the intervention (day 15). The data were entered in to the SPSS 22 software and were analyzed using chi‐square t‐test, paired t‐test, independent t‐test, and ANOVA. p ≤ 0.05 was considered statistically significant. Results. The results revealed a significant decrease in the CAS score in the oral consumption group (i.e., oral administration of sweet almond oil; from 7.81 ± 2.62 to 1.15 ± 1.08, p < 0.0003) compared to the abdominal massage group (i.e., abdominal massage; from 8 ± 2.57 to 2.26 ± 1.81, p < 0.0002) and the control group (from 7.73 ± 2.53 to 6 ± 2.74, p < 0.0002). Additionally, the stool consistency score in BSFS was significantly higher in the oral consumption group in comparison to the two other groups (p < 0.0003) before and after the intervention. Furthermore, the quality of life score decreased more significantly in the oral consumption group (from 75.04 ± 7.66 to 28.15 ± 3.30, p < 0.0003) than in the abdominal massage group (from 81.15 ± 5.15 to 43.26 ± 4.13, p < 0.0001) and the control group (from 79.62 ± 4.76 to 62.31 ± 6.40, p < 0.0008). Conclusion. Since the oral administration of sweet almond oil and abdominal massage was highly influential in the participants’ constipation scores and quality of life, these cost‐effective methods with low complication rates are recommended to be used alongside other treatments in managing constipation among older adults.
CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease
Authors: Zhao Ning , Chopra Shalini , Trepka Kai , Wang Yung-Hua , Sakhamuri Sasank , Hooshdaran Nima , Kim Hyunjung , Zhou Jie , Lim Shion A. , Leung Kevin K. , Egusa Emily A. , Zhu Jun , Zhang Li , Foye Adam , Sriram Renuka , Chan Emily , Seo Youngho , Feng Felix Y. , Small Eric J. , Chou Jonathan , Wells James A. , Aggarwal Rahul , Evans Michael J.
Published: June 2022

Purpose:

With the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated whether the cell surface protein CUB domain-containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA-low subsets.

Experimental Design:

CDCP1 levels were evaluated using RNA sequencing from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post–enzalutamide- or abiraterone-treated mCRPC biopsies, 12 patient-derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor-bearing mice.

Results:

CDCP1 expression was observed in 90% of mCRPC biopsies, including small-cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared with PSMA. CDCP1 was expressed in 10 of 12 PDX samples. Bmax values of approximately 22,000, 6,200, and 2,800 fmol/mg were calculated for PC3, DU145, and C4–2B human prostate cancer cells, respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA-low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4–2B xenografts.

Conclusions:

The data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine whether CDCP1 is a viable drug target for patients with mCPRC.
Novel Radiomic Measurements of Tumor-Associated Vasculature Morphology on Clinical Imaging as a Biomarker of Treatment Response in Multiple Cancers
Authors: Braman Nathaniel , Prasanna Prateek , Bera Kaustav , Alilou Mehdi , Khorrami Mohammadhadi , Leo Patrick , Etesami Maryam , Vulchi Manasa , Turk Paulette , Gupta Amit , Jain Prantesh , Fu Pingfu , Pennell Nathan , Velcheti Vamsidhar , Abraham Jame , Plecha Donna , Madabhushi Anant
Published: June 2022

Purpose:

The tumor-associated vasculature (TAV) differs from healthy blood vessels by its convolutedness, leakiness, and chaotic architecture, and these attributes facilitate the creation of a treatment-resistant tumor microenvironment. Measurable differences in these attributes might also help stratify patients by likely benefit of systemic therapy (e.g., chemotherapy). In this work, we present a new category of computational image-based biomarkers called quantitative tumor-associated vasculature (QuanTAV) features, and demonstrate their ability to predict response and survival across multiple cancer types, imaging modalities, and treatment regimens involving chemotherapy.

Experimental Design:

We isolated tumor vasculature and extracted mathematical measurements of twistedness and organization from routine pretreatment radiology (CT or contrast-enhanced MRI) of a total of 558 patients, who received one of four first-line chemotherapy-based therapeutic intervention strategies for breast (n = 371) or non–small cell lung cancer (NSCLC, n = 187).

Results:

Across four chemotherapy-based treatment strategies, classifiers of QuanTAV measurements significantly (P < 0.05) predicted response in held out testing cohorts alone (AUC = 0.63–0.71) and increased AUC by 0.06–0.12 when added to models of significant clinical variables alone. Similarly, we derived QuanTAV risk scores that were prognostic of recurrence-free survival in treatment cohorts who received surgery following chemotherapy for breast cancer [P = 0.0022; HR = 1.25; 95% confidence interval (CI), 1.08–1.44; concordance index (C-index) = 0.66] and chemoradiation for NSCLC (P = 0.039; HR = 1.28; 95% CI, 1.01–1.62; C-index = 0.66). From vessel-based risk scores, we further derived categorical QuanTAV high/low risk groups that were independently prognostic among all treatment groups, including patients with NSCLC who received chemotherapy only (P = 0.034; HR = 2.29; 95% CI, 1.07–4.94; C-index = 0.62). QuanTAV response and risk scores were independent of clinicopathologic risk factors and matched or exceeded models of clinical variables including posttreatment response.

Conclusions:

Across these domains, we observed an association of vascular morphology on CT and MRI—as captured by metrics of vessel curvature, torsion, and organizational heterogeneity—and treatment outcome. Our findings suggest the potential of shape and structure of the TAV in developing prognostic and predictive biomarkers for multiple cancers and different treatment strategies.
EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma
Authors: Apfelbaum April A. , Wu Feinan , Hawkins Allegra G. , Magnuson Brian , Jiménez Jennifer A. , Taylor Sean D. , Wrenn Emma D. , Waltner Olivia , Pfaltzgraff Elise R. , Song Jane Y. , Hall Cody , Wellik Deneen M. , Ljungman Mats , Furlan Scott N. , Ryan Russell J.H. , Sarthy Jay F. , Lawlor Elizabeth R.
Published: June 2022

Purpose:

Propagation of Ewing sarcoma requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes Ewing sarcoma metastatic phenotypes, influences EWS::FLI1 transcriptional activity.

Experimental Design:

Existing tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR interference were employed to identify enhancers. CUT&RUN and RNA sequencing defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by gene set enrichment, flow cytometry, and migration assays.

Results:

We found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of Ewing sarcoma cells along a mesenchymal axis.

Conclusions:

Ewing sarcoma tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13.

See related commentary by Weiss and Bailey, p. 4360
Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases
Authors: Li Jing , Jiang Jun , Bao Xun , Kumar Vineet , Alley Stephen C. , Peterson Scott , Lee Anthony J.
Published: June 2022

Purpose:

This study evaluated the central nervous system (CNS) pharmacokinetics and target engagement of lapatinib, neratinib, and tucatinib in patients with cancer, using a physiologically based pharmacokinetic (PBPK) modeling approach.

Experimental Design:

Drug-specific parameters for in vitro metabolism, binding to plasma proteins and brain tissues, transcellular passive permeability, and interactions with efflux transporters were determined. Whole-body PBPK models integrated with a 4-compartment permeability-limited brain model was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration (Css,ave,br) to in vitro IC50 for HER2 inhibition, was used as a predictor of intracranial efficacy.

Results:

PBPK models predicted that following 1 cycle of standard dosing, tucatinib and lapatinib achieved similar Css,ave,br (14.5 vs. 16.8 nmol/L), while neratinib Css,ave,br (0.68 nmol/L) was 20-fold lower. Tucatinib and neratinib were equally potent for HER2 inhibition (IC50, 6.9 vs. 5.6 nmol/L), while lapatinib was less potent (IC50, 109 nmol/L). The model-predicted population mean TER in the human normal brain was 2.1 for tucatinib, but < 0.20 for lapatinib and neratinib.

Conclusions:

The PBPK modeling suggests that tucatinib induces sufficient HER2 inhibition (TER > 2.0) in not only brain metastases with a disrupted blood–brain barrier (BBB), but also micrometastases where the BBB largely remains intact. These findings, in line with available clinical pharmacokinetics and efficacy data, support the therapeutic value of tucatinib for treatment of brain metastases and warrant further clinical investigation for the prevention of brain metastases in patients with HER2-positive breast cancer.
Circulating Tumor DNA–Based MRD Assessment in Patients with CLL Treated with Obinutuzumab, Acalabrutinib, and Venetoclax
Authors: Fürstenau Moritz , Weiss Jonathan , Giza Adam , Franzen Fabian , Robrecht Sandra , Fink Anna-Maria , Fischer Kirsten , Schneider Christof , Tausch Eugen , Stilgenbauer Stephan , Ritgen Matthias , Schilhabel Anke , Brüggemann Monika , Eichhorst Barbara , Hallek Michael , Cramer Paula
Published: June 2022

Purpose:

With the advent of highly efficacious time-limited combination treatments of targeted agents in chronic lymphocytic leukemia (CLL), minimal residual disease (MRD) assessment has gained importance as a measure for therapeutic success and as a surrogate for progression-free survival. The currently most widely used method is multicolor flow cytometry, which detects circulating CLL cells in the peripheral blood. However, it seems to be less sensitive for the detection of MRD in the lymph node compartment.

Patients and Methods:

To evaluate whether a cell-free approach can overcome this limitation, we performed serial assessments of circulating tumor DNA (ctDNA) in patients with CLL treated with obinutuzumab, acalabrutinib, and venetoclax in the phase II CLL2-BAAG trial. Patient-specific variability, diversity, joining (VDJ) rearrangements as well as somatic driver mutations were tracked before, during and after treatment by digital droplet PCR in blood plasma. Furthermore, these were systematically compared to matched flow cytometry data.

Results:

In the 381 sample pairs, ctDNA and flow cytometry yielded highly concordant results. However, clone-specific ctDNA was detected in 44 of 152 samples (29%) that were assessed as undetectable MRD (uMRD) by flow cytometry (defined as less than one CLL cell in 10,000 normal leukocytes). 29 ctDNA-negative samples showed detectable MRD >10–4 by flow cytometry. Also, somatic driver mutations were detected with a similar sensitivity compared with patient-specific VDJ rearrangements in plasma. In patients with predominantly nodal residual disease, ctDNA compared favorably with 4-color flow cytometry and seemed to more accurately reflect the entire disease burden across compartments.

Conclusions:

On the basis of these findings, ctDNA-based MRD assessment appears to be a promising method to complement cell-based MRD approaches like flow cytometry that focus on circulating CLL cells in the peripheral blood.
Effect of Enteral Long-Chain Polyunsaturated Fatty Acids on Retinopathy of Prematurity: A Systematic Review and Meta-Analysis
Authors: Diggikar Shivashankar , Aradhya Abhishek Somasekhara , Swamy Ravi Shankar , Namachivayam Arunkumar , Chandrasekaran Manigandan
Published: June 2022

Background: Long-chain polyunsaturated fatty acids (LCPUFA) are critical for the maturation of the brain and retina. Retinopathy of prematurity (ROP) is a preventable cause of blindness in preterm infants. LCPUFA have anti-inflammatory, antioxidant, and antiangiogenesis effects. Supplementation of enteral LCPUFA might mitigate the incidence of ROP in these infants. Available limited randomized studies showed promising results. We aimed to assess the effect of enteral supplementation of LCPUFA on ROP in preterm infants. Methods: We followed PRISMA guidelines and searched MEDLINE, Cumulative Index of Nursing and Allied Health Literature, Embase, and Cochrane Registry from 1990 to 2021 for the studies that examined the effects of enteral LCPUFA and ROP in preterm infants. We included the studies that satisfied the predefined inclusion criteria. RevMan 5.3 software derived the forest plot of pooled relative risk. We assessed the quality of all the included studies using GRADE recommendations. Results: Nine studies were eligible for the meta-analysis involving 2,482 infants. Of the nine RCTs, six studies provided LCPUFA (DHA/AA) as a separate intervention in different concentrations, and three studies provided formula milk enriched with LCPUFA. In addition, five studies recruited infants below 32 weeks of gestational age. Supplementation of LCPUFA did not reduce the incidence of severe ROP (RR 0.71, 95% CI: 0.50–1.01, 5 studies, 1,822 infants) with very low CoE or any ROP (RR 0.95, 95% CI: 0.73–1.12, 6 studies, 1,177 infants) with very low CoE or ROP requiring treatment (RR 0.92, 95% CI: 0.62–1.38, 4 studies, 1,395 infants) with very low CoE. Regarding safety outcomes, enteral LCPUFA did not increase the risk of necrotizing enterocolitis or mortality. Discussion/Conclusion: Supplementation of enteral LCPUFA to preterm infants did not reduce ROP incidence; however, there was a trend toward benefit in mitigating severe form of ROP. More well-designed, large, randomized controlled studies are warranted.
Preoperative Risk Factors and Prognostic Impact of Postoperative Complications Associated with Total Gastrectomy
Authors: Nakazawa Nobuhiro , Sohda Makoto , Yamaguchi Arisa , Watanabe Takayoshi , Saito Hideyuki , Ubukata Yasunari , Kuriyama Kengo , Sano Akihiko , Sakai Makoto , Ogawa Hiroomi , Shirabe Ken , Saeki Hiroshi
Published: June 2022

Introduction: We evaluated the risk factors for patients with gastric cancer (GC) undergoing total gastrectomy (TG) that predict postoperative complications, including anastomotic leakage, postoperative pneumonia, and heart disease. Methods: We collected 106 patients who received TG for GC between May 2009 and May 2017 at Gunma University Graduate School of Medicine, including clinicopathologic, surgical, postoperative complication, laboratory test, and physiologic test data. Results: Of 106 patients, 92 (86.8%) had no complications, and 14 (13.2%) had complications. Univariate analyses revealed that a high American Society of Anaesthesiologists physical status (ASA-PS) and neutrophil-lymphocyte ratio (NLR) of ≥3.5 significantly correlated with postoperative complications. Multivariate analyses showed that high ASA-PS was an independent prognostic factor of postoperative complications. The cancer recurrence rate was 34.8% in the noncomplication group and 71.4% in the complication group. Conclusion: Patients with postoperative complications are prone to recurrence and poor prognosis. For patients with high-risk GC with poor ASA-PS and high NLR, more thorough perioperative management is essential.
How I Treat Localized Soft Tissue Sarcomas: Update on Diagnosis, Risk Stratification, and Treatment
Authors: Mazzocca Alessandro , Paternostro Flavia , Minelli Alessandro , Silletta Marianna , Greco Carlo , Valeri Sergio , Ramella Sara , Tonini Giuseppe , Vincenzi Bruno
Published: June 2022

Background: Adult-type soft tissue sarcomas (STSs) are rare tumors representing about 1% of all adult malignant tumors. Their extreme histological heterogeneity places them among the most challenging fields of diagnostic pathology. The variability of clinical and prognostic presentation between the various histotypes reflects the different management that should be followed on a case-by-case basis. These features make STSs the case in point of how important it is a centralized and multidisciplinary approach. Summary: Surgery represents the mainstay in the treatment of localized STSs. Recently, more and more studies are making efforts to understand what the contribution of chemotherapy and radiotherapy with neoadjuvant and adjuvant intent may be both in unselected and selected histological subgroups. In fact, despite the improvement in overall survival seen in the past few years thanks to the adoption of a more radical surgical approach, mortality remains relatively high and the 5-year overall survival is around 65%. Key Messages: In this review, we comment upon the treatment of localized STSs of the extremity, trunk wall, and retroperitoneum and how surgery, radiotherapy, and chemotherapy can be integrated with each other and individually tailored. Nomograms can assist clinicians in this complex therapeutic decision-making process, through the identification of patients at higher risk of death or disease relapse.
The Visceral-Fat-Area-to-Hip-Circumference Ratio as a Predictor for Insulin Resistance in a Chinese Population with Type 2 Diabetes
Authors: Zhang Shi , Huang Ya-Ping , Li Jing , Wang Wen-Hong , Zhang Min-Ying , Wang Xin-Cheng , Lin Jing-Na , Li Chun-Jun
Published: June 2022

Introduction: Adipose tissue deposited on the viscera is the main culprit in the development of insulin resistance (IR) and cardiometabolic diseases, whereas subcutaneous adipose tissue may have a protective role. This study aimed to propose a new predictive index – the visceral-fat area (VFA)-to-hip-circumference ratio (VHR) and explore its efficacy for prediction of IR in a Chinese population with type 2 diabetes mellitus. Methods: A total of 643 patients with newly diagnosed diabetes were enrolled in this study. Body composition, anthropometrical, and biochemical measurements were performed. IR was defined as homeostatic model assessment of IR (HOMA-IR) > 2.69. The association between VHR and IR was analyzed. Results: Regardless of gender, subjects in the IR group had higher VHR, body mass index (BMI), VFA, body fat percentage, systolic blood pressure, diastolic blood pressure (DBP), fasting blood glucose, fasting insulin, triglyceride (TG), uric acid (UA), homocysteine, and aminotransferases than those in the non-IR group. The other concomitant metabolic disorders were more common in the IR group. Further analysis showed that with the increase of VHR, the levels of HOMA-IR, BMI, VFA, DBP, TG, UA and the prevalence of nonalcoholic fatty-liver disease, hypertension, and hyperuricemia increased continuously (p trend <0.01). The linear trend test showed that VHR and IR remained closely correlated after adjusting for possible confounders (p trend <0.05). The receiver operating characteristic curve analysis showed that the area under the curve was 0.69, and the optimal cutoff of VHR was 0.89 (sensitivity 79.3%, specificity 61.5%). Conclusion: VHR was positively associated with IR regardless of gender, and it might be a reliable predictor for IR.