bluuebunny/crossref_metadata_2025 huggingface dataset:
Post hoc survival analyses using RNAseq data: handle with care
Authors: Suresh Karthik , Psoter Kevin J.
Published: November 2022

With the advent of next-generation sequencing technologies, there has been a dramatic increase in the availability of paired clinical and transcriptomic data in a variety of disease states. For basic science researchers, this has provided a valuable opportunity for querying the impact of the transcript levels of a gene on disease survival in humans. However, there are a multitude of methodological and technical considerations to evaluate before embarking on these analyses. Herein, we provide a brief description of statistical considerations involved in these analyses, geared toward basic scientists who may not necessarily routinely use such statistical models as part of their studies.
Reflection of Plane Waves in Nonlocal Fractional-Order Thermoelastic Half Space
Authors: Sharma Surbhi , Kumari Sangeeta
Published: November 2022

The problem of plane waves in nonlocal fractional-order thermoelasticity has been studied. We have considered the x-y plane for the governing equation of nonlocal fractional thermoelasticity and solved these governing equations to calculate the equation in terms of frequency. This frequency shows that three sets of waves exist, in which two are coupled and one is uncoupled. The reflection coefficient of plane waves for classical theory and LS theory has been calculated. The effect of phase speeds, specific losses, and attenuation coefficients with respect to the frequency and nonlocal parameter for the two theories (LS theory and the classical theory of thermoelasticity) has been studied numerically for all propagating waves, and the same has been plotted graphically and explained thoroughly.
Application of Machine Learning Combined with Wireless Network in Design of Online Translation System
Authors: Li Jingyun
Published: November 2022

The importance of translation services has become increasingly prominent with the acceleration of economic globalization. Compared with human translation, machine translation is cheaper and faster, and therefore more suitable for the current era. The current mainstream machine translation method is neural machine translation, which employs machine methods to train on parallel corpora and create translation models. Research into neural machine translation has yielded a wealth of information. Learning and generalization abilities of neural networks have substantially enhanced the effectiveness of neural machine translation. This work applies machine learning and wireless network technology to build an online translation system for real-time translation. First, this work proposes a multigranularity feature fusion method based on a directed acyclic graph, which uses a directed acyclic graph to fuse different granularities as input and obtain a position representation. Secondly, this paper improves the Transformer model and proposes multigranularity position encoding and multigranularity self-attention. Then, on the basis of multigranularity features as input, this work introduces dynamic word vectors to improve the word embedding module, and uses the ELMo model to obtain dynamic word vector embeddings. Finally, this work builds a multigranularity feature-dynamic word vector machine translation model with above strategy, deploys it on server. Users can upload the content to be translated and download the translated content through the wireless network and realize an online translation system based on machine learning and wireless network.
Failure Mechanism of Anti-Inclined Karst Slope Induced by Underground Multiseam Mining
Authors: Wang Nanyun , Zhong Zuliang , Liu Xinrong , Gao Guofu
Published: November 2022

There occurred a lot of catastrophic landslides in Southwest China karst areas in recent years. This study numerically simulated the failure process of Pusa landslide by distinct element method (UDEC). The Voronoi diagram algorithm was used to discretize the rock blocks in the upper part of the mining area, and the erosion in sliding source area caused by heavy rainfall was simulated by increasing the block density and reducing the joint strength. Results obtained using UDEC matched the failure process recorded by UAV, and the subsidence of monitoring points on the slope surface was well coincident with the InSAR results. The DEM results are as follows: firstly, under the action of underground coal mining, the overlying strata of the mountain deform toward the goaf and the deformation of the stratum increase significantly with the caving of the roof stratum; and the deep karst fissures in the overlying stratum have an important influence on the deformation of the mountain; the upper strata form a subsidence zone along the fissures, expanding the range of tensile fissures. Secondly, due to the excavation and unloading of the rock masses at the leading edge of the sliding area, the extrusion deformation occurs to the outside of the slope, resulting in the critical instability of sliding area. Finally, with the strength decreasing of rock masses and structural planes by heavy rainfall, the stability of the mountain continues to decrease until the sliding area collapses.
A Novel Method for Network Intrusion Detection
Authors: Wang Hongmin , Wei Qiang , Xie Yaobin
Published: November 2022

Intrusion detection is one of the key research directions of network information security. In order to make up for the deficiencies of traditional security technologies such as firewall, encryption, and authentication, by analyzing the characteristics of network attacks and existing intrusion detection models, the advantages of triadic concept analysis and the application of fuzzy set theory in network intrusion detection are analyzed. The intrusion detection model FCTA based on triadic concept analysis is proposed, which promotes the further development of network intrusion detection. First, we analyze the characteristics of the data and use TF-IDF and Z-Score to normalize and standardize the data to construct a fuzzy triadic background containing quadratic characteristics. It is used to describe the triadic relationship between network connections, network connection characteristics, and intrusion types of network packets. Then, the (i)-induced operator is used to construct the fuzzy triadic concept set based on the fuzzy triadic background and transformed into a fuzzy attribute triadic concept set. Then, the new samples are classified by calculating the similarity between the new samples and the elements in the fuzzy attribute triadic concept set by using the Euclidean distance formula. In order to reduce the model space complexity, compression storage technology is adopted in the model building process.. Finally, by using the IDS-2018 dataset, the rationality and effectiveness of the FCTA model are demonstrated. The average accuracy and average intrusion detection rate of FCTA classification are much higher than BP neural network, SVM algorithm, and KNN algorithm, and the FCTA misjudgment rate is much lower than the BP neural network algorithm, the KNN algorithm, and the SVM algorithm; with the increase of data volume, the accuracy rate and intrusion detection rate increase significantly.
Majorization Properties for Certain Subclasses of Meromorphic Function of Complex Order
Authors: Khan Neelam , Arif Muhammad , Darus Maslina
Published: November 2022

By making use of q−differential operators, many distinct subclasses of analytic and meromorphic functions have already been defined and investigated from numerous perspectives. In this article, we investigated several majorization results for the class of meromorphic univalent functions of complex order, defined by q−differential operator. Moreover, we pointed out some new or known consequences of our results, which is in the form of corollaries.
Safety and Efficacy of Treatment with/without Ramucirumab in Advanced or Metastatic Cancer: A Meta-Analysis of 11 Global, Double-Blind, Phase 3 Randomized Controlled Trials
Authors: Tang Lingxue , Wang Tong , Zhang Qianqian , Yu Sheng , Li Wen , Yao Senbang , Cheng Huaidong
Published: November 2022

Ramucirumab, as a vascular endothelial growth factor receptor-2 inhibitor, was first approved in 2014 for treated advanced or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. This study deeply analyzed the efficacy and safety of advanced or metastatic cancer treated with ramucirumab, which included 11 global, double-blind, phase 3 randomized controlled trials with a total of 7410 patients. Subgroup analysis based on different cancer types showed that standard regimens plus ramucirumab significantly increased progression-free survival and overall survival compared with placebo groups in patients with advanced non-small-cell lung cancer (NSCLC), hepatocellular carcinoma, gastric cancer, or GEJ adenocarcinoma. Although a higher proportion of patients achieved overall response and disease control than those treated with placebo, the overall response was not statistically significant between the two groups in advanced NSCLC. Grade 3 or worse treatment-emergent adverse events (TEAEs) that occurred in at least 5% of patients were neutropenia (30.5% in the ramucirumab group vs. 23.5% in the placebo group), leucopenia (14.8% vs. 9.2%), weight decreased (14.2% vs. 8.0%), myalgia (11.7% vs. 7.7%), fatigue (10.9% vs. 7.7%), hypertension (9.2% vs. 2.3%), and anaemia (6.2% vs. 7.7%). In the TEAEs of special interest, the ramucirumab group had a significantly higher incidence of bleeding (mainly grade 1-2 epistaxis and gastrointestinal bleeding), hypertension, proteinuria, liver injury/failure (grade 1-2), venous thromboembolism (grade 1-2), and gastrointestinal perforation (grade ≧3) than the control group.
Evaluation of Krill Meal in Commercial Diets for Juvenile Swimming Crab (Portunus trituberculatus)
Authors: Guo Chen , Jin Min , Jiao Lefei , Xie Shichao , Zhang Xiangsheng , Luo Jiaxiang , Zhu Tingting , Zhou Qicun
Published: November 2022

An 8-week feeding trial was carried out to assess the effect of dietary krill meal on growth performance and expression of genes related to TOR pathway and antioxidation of swimming crab (Portunus trituberculatus). Four experimental diets (45% crude protein and 9% crude lipid) were formulated to obtain different replacements of fish meal (FM) with krill meal (KM); FM was replaced with KM at 0% (KM0), 10% (KM10), 20% (KM20), and 30% (KM30); fluorine concentration in diets were analyzed to be 27.16, 94.06, 153.81, and 265.30 mg kg-1, respectively. Each diet was randomly divided into 3 replicates; ten swimming crabs were stocked in each replicate (initial weight,

5.62
±
0.19
 
g

). The results indicated that crabs fed with the KM10 diet had the highest final weight, percent weight gain (PWG), and specific growth rate (SGR) among all treatments (

P
<
0.05

). Crabs fed with the KM0 diet had the lowest activities of total antioxidant capacity (T-AOC), total superoxide dismutase (SOD), glutathione (GSH), and hydroxyl radical scavenging activity and had the highest concentration of malondialdehyde (MDA) in the hemolymph and the hepatopancreas (

P
<
0.05

). In the hepatopancreas, the highest content of 20:5n-3 (EPA) and the lowest content of 22:6n-3 (DHA) were shown in crabs fed with the KM30 diet among all treatments (

P
<
0.05

). With the substitution level of FM with KM gradually increasing from 0% to 30%, the color of the hepatopancreas changed from pale white to red. Expression of tor, akt, s6k1, and s6 in the hepatopancreas was significantly upregulated, while 4e-bp1, eif4e1a, eif4e2, and eif4e3 were downregulated with dietary replacement of FM with KM increasing from 0% to 30% (

P
<
0.05

). Crabs fed with the KM20 diet had notably higher expression of cat, gpx, cMnsod, and prx than those fed with the KM0 diet (

P
<
0.05

). Results demonstrated that 10% replacement of FM with KM can promote growth performance and antioxidant capacity and notably upregulate the mRNA levels of genes related to TOR pathway and antioxidant of swimming crab.
Cuproptosis-Related LncRNA Signature for Predicting Prognosis of Hepatocellular Carcinoma: A Comprehensive Analysis
Authors: Chen Qiqi , Sun Tong , Wang Guorong , Zhang Mengyu , Zhu Yitian , Shi Xiaonan , Ding Zhishan
Published: November 2022

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and has a poor prognosis. Cuproptosis is a novel mode of cell death that has only recently been discovered. Considering the critical role of lncRNAs in liver cancer development, the aim of this study was to construct a prognostic signature based on cuproptosis-related lncRNAs (CRlncRNAs). We downloaded RNA-sequencing data and corresponding clinical information of patients with HCC from The Cancer Genome Atlas (TCGA) database. To verify the robustness of the model, we added an external validation set obtained from the Gene Expression Omnibus (GEO): GSE40144. In addition, we identified the cuproptosis-related genes (CRGs) based on previous reports. Pearson correlation analysis, univariate Cox regression, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were utilized to screen for genes associated with prognosis. On this basis, multivariate Cox regression and stepAIC were used to further construct and optimize the prognostic model. The simplified signature with the lowest Akaike information criterion (AIC) value was considered the prognostic signature. Seven different algorithms were used to perform immune infiltration analysis. The single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm was utilized to find the difference in immune function between the high- and low-risk groups. Finally, in vitro experiments were performed by quantitative real-time PCR (qRT–PCR) analysis using HCC cell lines to validate the expression of prognostic genes. We identified 3 lncRNAs (CYTOR, LINC00205, and LINC01184) as independent risk factors for HCC. The receiver operating characteristic (ROC) curves calculated that the AUC at 1, 3, and 5 years reached 0.717, 0.633, and 0.607, respectively. The expression levels of 41 immune checkpoints differed significantly between the high- and low-risk groups, and there were significant differences in sensitivity to immunotherapy between the high- and low-risk groups. The risk model could also serve as a promising predictor of immunotherapeutic response, which has been verified by the TIDE algorithm (

p
<
0.001

). Overall, we propose a signature related to CRlncRNAs that can be used to predict the prognosis of HCC patients, which was validated in external cohort and in vitro experiments.
Study on Blasting Characteristics of Soft-Hard Rock Strata Based on Energy Fields and Particle Expansion Loading Algorithm
Authors: Cui Jianbin , Xie Liangfu , Qin Yongjun , Liu Xuejun , Qiao Wei , Hu Zeyu , Wu Liming , Qiu Liewang , Huang Ke
Published: November 2022

Complex geological conditions often make the blasting effect difficult to control. In order to explore the influence of soft-hard rock strata on rock blasting characteristics, based on PFC2D software, combined with particle expansion loading algorithm, the numerical simulation blasting experiments are carried out. Firstly, the rationality of blasting method is verified by single-hole sandstone blasting experiment. Then, the soft-hard composite strata are established, and the single-hole blasting experiments of composite strata, with different distribution thickness of soft rock stratum and hard rock stratum, are carried out. The experimental results are analyzed from three perspectives: crack network state, internal stress of rock mass, and energy field. Results show that (i) the distance between the interface of soft-hard rock and the blasthole seriously affects the blasting effect. The law of crack number varying with the distance is obtained through further analysis. (ii) When detonated in the hard rock, if the structural plane is about 2 times the radius of crushing area from blasthole, the rock mass will be in a relatively high stress state due to the reflection and superposition of stress waves. (iii) When detonated in the hard rock, if the structural plane is about 2 times the radius of crushing area from blasthole, compared with pure hard rock case, the peak kinetic energy and peak friction energy are increased by about 15 times and 2.6 times, respectively, and the peak strain energy is attenuated by 18%.
Design of Sports Training Improvement and Evaluation Method under the Background of Big Data
Authors: Nie Baiqi
Published: November 2022

With the development of economic life, the phenomenon of poor health of human beings has gradually appeared, and sports training has also been paid more and more attention. In terms of improving the quality of sports training for students, physical education teachers must first make students aware of the importance of sports training. We should reasonably arrange sports training time, stimulate students’ interest and cultivation in sports, improve the results of sports training with scientific and efficient methods, and comprehensively improve the training quality of sports training. Therefore, the following work has been completed in this paper: (1) after searching and sorting out the relevant literature on the improvement and evaluation of sports training methods, this paper constructs a theoretical basis related to this topic. (2) The sports training promotion strategy and evaluation method are proposed, and the basic principles and structure of the DBN model are introduced. (3) We select the optimal parameters of the DBN model through experiments. We input the experimental data collected by big data into the trained model and compare the results with the evaluation results of experts. The experimental results show that the model in this paper has a high accuracy in evaluating the effectiveness of sports training improvement strategies.
Fixed-Time Fault-Tolerant Tracking Control of Fixed-Wing UAVs with Actuator Fault and Unmatched Disturbances
Authors: Wu Zhonghua , Zheng Shuaipeng
Published: November 2022

This paper presents a dynamic surface fixed-time fault-tolerant control strategy for the longitudinal dynamic model of fixed-wing unmanned aerial vehicles (UAVs). Firstly, a novel disturbance observer is constructed to precisely estimate the lumped disturbance. Secondly, without fractional power terms in the designed fixed-time fault-tolerant controller, the potential singular value problem is tactfully avoided, which often exists in the stability analysis of the traditional fixed-time controller design. Thirdly, a novel fixed-time filter is proposed to overcome the phenomenon of “differential explosion” in the backstepping control scheme. Lyapunov stability analysis guarantees that the tracking errors can converge to the neighborhood of the origin in the fixed time. The simulation results verify the effectiveness of the proposed control scheme.
Antitumor Effects of Delta (9)-Tetrahydrocannabinol and Cannabinol on Cholangiocarcinoma Cells and Xenograft Mouse Models
Authors: Leelawat Surang , Leelawat Kawin , Yimsoo Thunyatorn , Wunnakup Thaniya , Monton Chaowalit , Khamthong Nanthaphong , Madaka Fameera , Maha Athip , Songsak Thanapat
Published: November 2022

Cholangiocarcinoma (CCA) is a very aggressive tumor. The development of a new therapeutic drug for CCA is required. This study aims to evaluate the antitumor effect of ∆9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana (Cannabis sativa), and cannabinol (CBN), a minor, low-psychoactive cannabinoid, on CCA cells and xenograft mice. THC and CBN were isolated, and their identities were confirmed by comparing 1H- and 13C-NMR spectra and mass spectra with a database. Cell proliferation, cell migration, and cell apoptosis assays were performed in HuCCT1 human CCA cells treated with THC or CBN. The phosphorylation of signaling molecules in HuCCT1 cells was detected. To determine the effects of THC and CBN in an animal model, HuCCT1 cells were inoculated subcutaneously into nude mice. After the tumors reached an appropriate size, the mice were treated with THC or CBN for 21 days. Tumor volumes were monitored and calculated. The 1H- and 13C-NMR data of THC and CBN were almost identical to those reported in the literature. THC and CBN significantly inhibited cell proliferation and migration and induced apoptosis in HuCCT1 cells. The phosphorylation of AKT, GSK-3α/β, and ERK1/2 decreased in HuCCT1 cells treated with THC or CBN. CCA xenograft mice treated with THC showed significantly slower tumor progression and smaller tumor volumes than control mice. THC and CBN induced apoptosis in CCA by inhibiting the AKT and MAPK pathways. These findings provide a strong rationale for THC and CBN as therapeutic options for CCA.
Electroacupuncture Promotes Neuroplasticity of Central Auditory Pathway: An Auditory Evoked Potentials Study
Authors: Chang Chia-Hao , Lin Chia-Der , Hsieh Ching-Liang
Published: November 2022

Our previous studies found that electroacupuncture at the right Zhongzhu acupoint (TE3) can enhance auditory recovery in rats with noise-induced hearing loss. Here, we investigated the changes in auditory brainstem response (ABR) and long late latency (LLR) evoked potential to explain the mechanisms of electroacupuncture at TE3. The auditory evoked potentials were recorded, including ABR and LLR, at baseline and on day 3 (D3), D5, and D8 after baseline. The 2-Hz electroacupuncture at the right TE3 was applied on D3, D4, and D5 in the electroacupuncture group but not in the control group. In ABR, compared with the control group, the latency shift of waves I (0.298 ± 0.033 vs −0.045 ± 0.057 ms), III (0.718 ± 0.038 vs −0.163 ± 0.130 ms), and V (1.160 ± 0.082 vs −0.207 ± 0.138 ms) on D3 (all

p
 
<
 
0.01

) and of wave V (0.616 ± 0.433 vs −0.352 ± 0.209 ms,

p
 
<
 
0.05

) on D5 was greater in the electroacupuncture group than that in the control group. Moreover, the interpeak latency shift of I–III (0.420 ± 0.041 vs −0.118 ± 0.177 ms) and I–V (0.863 ± 0.088 vs −0.162 ± 0.156 ms) on D3 (both

p
 
<
 
0.05

) and of III–V (0.342 ± 0.193 vs −0.190 ± 0.110 ms) and I–V (0.540 ± 0.352 vs −0.343 ± 0.184 ms) on D5 (both

p
 
<
 
0.05

) was greater in the electroacupuncture group than that in the control group. In LLR, the latency shift of P0 was greater in the electroacupuncture group than in the control group on D3 (3.956 ± 2.975 vs −1.178 ± 1.358 ms,

p
 
<
 
0.01

) and D5 (2.200 ± 1.889 vs −0.311 ± 1.078 ms,

p
 
<
 
0.05

). These findings indicate that electroacupuncture at the right TE3 can modulate the neuroplasticity of the central auditory pathway, including the brain stem and the primary and secondary auditory cortex.
Novel Switched Configuration-Based Multilevel Inverter Topology for Industrial Applications
Authors: Krishnakumar V. , Anbarasan P. , Kumar K. Ramash , Venmathi M.
Published: November 2022

Multilevel inverters proved its capabilities nowadays operating in the symmetrical and asymmetrical source of voltages to bring output voltage nearly to a sinusoid. Several variations in topological strategies put forth better output quality with lesser harmonic distortion. However, it suffers from several issues predominantly such as more number of devices, higher blocking voltage, and power loss for higher voltage levels. This paper forays a fresh topology on switched configuration multilevel inverters with optimum dc sources, switches, voltage level, and filter requirements. The proposed topology has the flexibility to extend for higher voltage levels with make use of less switches. The proposed structure has been simulated in MATLAB/Simulink and validated the results in a laboratory setup.
Improving Upland Acid Soil Properties And Increasing Maize Yield By Phosphate Rock Application With Organic Acids
Authors: Sutriadi Mas Teddy , Anwar Syaiful , Mulyanto Budi , Darmawan  , Husnain  , Jaya Adi
Published: November 2022

Problems encountered in the management of upland acid soils, besides soil pH, are also low in phosphorus (P) content and less available to plants. The addition of organic acids (OAs) to the direct application of phosphate rock (PR) has not been widely studied yet and is expected to improve upland acid soil properties. The research aims to determine the effect of adding OAs on the direct application of PR to improve upland acid soil and increase maize yield. It was a greenhouse experiment using a randomized complete design in a factorial arrangement with three replications. The treatments consisted of four types of OA (citric, humic, succinic, and oxalic acid) and five OA concentration levels (0, 25, 50, 100, and 200 ppm). The hybrid maize (Zea mays L) was used as the test crop. The parameters observed were soil properties (pH, exchangeable H (H+), exchangeable Al (Al3+), exchangeable Ca (Ca2+), cation exchange capacity (CEC), available P (as P-Bray1)) and maize growth (plant heights and yield). The results show that the types of OA treatments had no significant effect on soil properties and maize yield; in contrast, the concentrations of OA levels were able to improve soil properties as indicated by a significant effect on pH, H+, Al3+, Ca2+, CEC, available P, and increased maize yield. An increase in soil pH due to the addition of OAs to the direct application of PR could increase Ca2+ and CEC and decrease Al3+ and H+, while increasing available P for plants. Although not significantly different, oxalic acid was able to improve the observed soil properties and maize yield, followed by citric, humic, and succinic acids. The maximum OA concentration was 126.9 ppm. We can say that the main finding of this research is that oxalic, citric, humic, and succinic acids at a concentration of 126 ppm can be applied to phosphate rock. In Indonesia, humic acid has been widely applied by farmers because it is easy to obtain. Therefore, it can be applied to phosphate rock.
The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors
Authors: Llano Elena , Todeschini Anne Laure , Felipe-Medina Natalia , Corte-Torres María D. , Condezo Yazmine B. , Sanchez-Martin Manuel , López-Tamargo Sara , Astudillo Aurora , Puente Xose S. , Pendas Alberto M. , Veitia Reiner A.
Published: November 2022

Adult-type granulosa cell tumors (AGCT) are the most common type of malignant ovarian sex cord–stromal tumors. Most AGCTs carry the somatic variant c.402C>G (p.C134W) affecting the transcription factor FOXL2. Germline dominant variants in FOXL2 are responsible for blepharophimosis syndrome, which is characterized by underdevelopment of the eyelid. In this work, we generated a mouse model harboring the C134W variant of FOXL2 to evaluate in vivo the poorly understood oncogenic role of FOXL2. The mutation was dominant regarding eyelid hypoplasia, reminiscent of blepharophimosis syndrome. Interestingly, Foxl2+/C134W female mice had reduced fertility and developed AGCTs through a progression from abnormal ovaries with aberrant granulosa cells to ovaries with stromal hyperplasia and atypia and on to tumors in adut mice. The genes dysregulated in mouse AGCTs exhibited the hallmarks of cancer and were consistent with a gain-of-function of the mutated allele affecting TGFβ signaling. A comparison of these data with previous results on human AGCTs indicated similar deregulated pathways. Finally, a mutational analysis of mouse AGCT transcriptomic data suggested the absence of additional driver mutations apart from FOXL2-C134W. These results provide a clear in vivo example in which a single mutational hit triggers tumor development associated with profound transcriptomic alterations.

Significance:

A newly generated mouse model carrying a FOXL2 mutation characteristic of adult-type granulosa cell tumors shows that FOXL2 C134W shifts the transcriptome towards a signature of granulosa cell cancer and drives tumorigenesis.
Longitudinal Changes in Immune Activation Serum Biomarkers Prior to Diagnosis and Risk of B-cell NHL Subtypes
Authors: Levin Lynn I. , Ramirez Christina M. , Liao Eileen L. , Guo Hongyu , Kim Bong K. , Marrogi Aizen J. , Magpantay Larry I. , Breen Elizabeth C. , Martínez-Maza Otoniel
Published: November 2022

Background:

To examine the contribution of B-cell activation molecules to B-cell follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), a prospective study was conducted using pre-diagnosis serial serum samples from the US Department of Defense Serum Repository.

Methods:

Each case (n = 142 FL, n = 211 DLBCL) was matched to two controls on age, gender, race, military branch, and blood collection dates. Immune activation molecules (IL1β, IL2, IL4, IL5, IL6, IL10, IL12, CXCL13, IL8, TNFα, IFNγ, GM-CSF, VEGF, sCD30, IgE) were quantified using ELISA or multiplex immunometric (Luminex) assay. Longitudinal data were analyzed using linear mixed modeling. As serial specimens were collected over several years before diagnosis, we evaluated the temporal dynamics of these markers.

Results:

Increased serum levels of sCD30, CXCL13, and to a lesser extent IL10, were associated with both FL and DLBCL in cases compared with controls, with a median follow-up of 5.5 years from the earliest specimen collection to diagnosis date. Significant increasing sCD30 and CXCL13 trajectories for FL and DLBCL subtypes were noted starting at the earliest time points and with IL10 levels increasing significantly at time points closer to diagnosis.

Conclusions:

These results suggest that sCD30, CXCL13, and IL10 may contribute to the etiology of FL and DLBCL and are potential biomarkers for these non–Hodgkin lymphoma subtypes.

Impact:

The increasing trajectories of the B-cell activation molecules, sCD30, CXCL13, and to a lesser extent IL10, may indicate early disease-induced effects or reflect the chronic stimulation of B-cells that promotes the development of FL and DLBCL subtypes.
The Conventional Dendritic Cell 1 Subset Primes CD8+ T Cells and Traffics Tumor Antigen to Drive Antitumor Immunity in the Brain
Authors: Bowman-Kirigin Jay A. , Desai Rupen , Saunders Brian T. , Wang Anthony Z. , Schaettler Maximilian O. , Liu Connor J. , Livingstone Alexandra J. , Kobayashi Dale K. , Durai Vivek , Kretzer Nicole M. , Zipfel Gregory J. , Leuthardt Eric C. , Osbun Joshua W. , Chicoine Michael R. , Kim Albert H. , Murphy Kenneth M. , Johanns Tanner M. , Zinselmeyer Bernd H. , Dunn Gavin P.
Published: November 2022

The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity.
CD73 Inhibits cGAS–STING and Cooperates with CD39 to Promote Pancreatic Cancer
Authors: Jacoberger-Foissac Célia , Cousineau Isabelle , Bareche Yacine , Allard David , Chrobak Pavel , Allard Bertrand , Pommey Sandra , Messaoudi Nouredin , McNicoll Yannic , Soucy Geneviève , Koseoglu Secil , Masia Ricard , Lake Andrew C. , Seo Heewon , Eeles Christopher B. , Rohatgi Neha , Robson Simon C. , Turcotte Simon , Haibe-Kains Benjamin , Stagg John
Published: November 2022

The ectonucleotidases CD39 and CD73 catalyze extracellular ATP to immunosuppressive adenosine, and as such, represent potential cancer targets. We investigated biological impacts of CD39 and CD73 in pancreatic ductal adenocarcinoma (PDAC) by studying clinical samples and experimental mouse tumors. Stromal CD39 and tumoral CD73 expression significantly associated with worse survival in human PDAC samples and abolished the favorable prognostic impact associated with the presence of tumor-infiltrating CD8+ T cells. In mouse transplanted KPC tumors, both CD39 and CD73 on myeloid cells, as well as CD73 on tumor cells, promoted polarization of infiltrating myeloid cells towards an M2-like phenotype, which enhanced tumor growth. CD39 on tumor-specific CD8+ T cells and pancreatic stellate cells also suppressed IFNγ production by T cells. Although therapeutic inhibition of CD39 or CD73 alone significantly delayed tumor growth in vivo, targeting of both ectonucleotidases exhibited markedly superior antitumor activity. CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Accordingly, large-scale pharmacogenomic analyses of human PDAC cell lines revealed significant associations between CD73 expression and gemcitabine chemoresistance. Strikingly, increased DNA damage in CD73-deficient tumor cells associated with activation of the cGAS–STING pathway. Moreover, cGAS expression in mouse KPC tumor cells was required for antitumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.
Rational Protein Design Yields a CD20 CAR with Superior Antitumor Efficacy Compared with CD19 CAR
Authors: Chen Ximin , Chen Laurence C. , Khericha Mobina , Meng Xiangzhi , Salvestrini Emma , Shafer Amanda , Iyer Neha , Alag Anya S. , Ding Yunfeng , Nicolaou Demetri M. , Chen Yvonne Y.
Published: November 2022

Chimeric antigen receptors (CAR) are fusion proteins whose functional domains are often connected in a plug-and-play manner to generate multiple CAR variants. However, CARs with highly similar sequences can exhibit dramatic differences in function. Thus, approaches to rationally optimize CAR proteins are critical to the development of effective CAR T-cell therapies. Here, we report that as few as two amino-acid changes in nonsignaling domains of a CAR were able to significantly enhance in vivo antitumor efficacy. We demonstrate juxtamembrane alanine insertion and single-chain variable fragment sequence hybridization as two strategies that could be combined to maximize CAR functionality, and describe a CD20 CAR that outperformed the CD19 CAR in antitumor efficacy in preclinical in vitro and in vivo assays. Precise changes in the CAR sequence drove dramatically different transcriptomic profiles upon antigen stimulation, with the most efficacious CAR inducing an enrichment in highly functional memory T cells upon antigen stimulation. These findings underscore the importance of sequence-level optimization to CAR T-cell function, and the protein-engineering strategy described here may be applied to the development of additional CARs against diverse antigens.

See related Spotlight by Scheller and Hudecek, p. 142
Localized Gastroesophageal Adenocarcinoma in the Elderly: Is Age a Factor Associated with Suboptimal Treatment?
Authors: Vassilakopoulou Maria , Chen Hsiang-Chun , Wang Xuemei , Harada Kazuto , Iwatsuki Masaaki , Das Prajnan , Blum Murphy Mariela , Matamoros Jr. Aurelio , Sagebiel Tara , Devine Catherine , Thomas Irene , Sanders Elizabeth M. , Shanbhag Namita , Rogers Jane E. , Lee Jeffrey H. , Weston Brian , Bhutani Manoop S. , Hofstetter Wayne , Nguyen Quynh-Nhu , Badgwell Brian D. , Ajani Jaffer A.
Published: November 2022

Introduction: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population. Methods: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model. Results: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0–3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model. Conclusion: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients’ general condition rather that age alone.
Changes of Choroidal Thickness in Children after Short-Term Application of 1% Atropine Gel
Authors: Zhou Yue , Zhu Yan , Huang Xiao Bo , Xiong Yao Jia , Guo Ya Li , Cai Qi , Wang Min , Gong Ye Xun , Cao Xin , Li Jun Jie , Cai Jian Ru , Song Yu , Sun Zhi Min
Published: November 2022

Introduction: The aim of the study was to assess changes in choroidal thickness (ChT) after administration of 1% atropine for 1 week in myopic, emmetropic, and hyperopic children. Methods: A total of 235 children aged 4–8 years, which included 46 myopia, 34 emmetropia, and 155 hyperopia patients, were recruited and divided into three groups according to the spherical equivalent with the use of 1% atropine twice a day for 1 week. The ChT was measured at baseline and 1 week. Results: In the myopia and emmetropia groups, following administration of 1% atropine gel, the ChT thickened significantly under the fovea (i.e., from 278.29 ± 53.01 μm to 308.24 ± 57.3 μm, p < 0.05; from 336.10 ± 78.60 μm to 353.46 ± 70.22 μm, p < 0.05, respectively), and at all intervals from the fovea, while in the hyperopia group, there was no significant difference in the ChT except the nasal side (p < 0.05). Conclusion: Topical administration of 1% atropine gel for 1 week significantly increased the subfoveal and parafoveal ChT in children with myopia and emmetropia. Atropine did not increase the ChT in hyperopic children, except on the nasal side.
Indocyanine Green Is a Safe and Effective Alternative to Radioisotope in Breast Cancer Sentinel Lymph Node Biopsy regardless of Patient Body Mass Index
Authors: Ng Samantha , Pitsinis Vassilis , Elseedawy Emad H. , Brown Douglas , Vinci Alessio , Jones Benjamin A. , Macaskill E. Jane
Published: November 2022

Introduction: A recent meta-analysis [Lancet Oncol. 2010;11:908–909] has confirmed high sensitivity of indocyanine green (ICG) fluorescence mapping for sentinel node detection in early breast cancer. Concerns have previously been raised regarding the efficacy in patients with high body mass index (BMI). Materials and Methods: All consecutive patients undergoing sentinel lymph node biopsies (SLNBs) for early breast cancer in NHS Tayside were included in a prospective audit of surgical and pathology findings. All patients included in the study received dual injection of patent blue dye and ICG. Approval was obtained from the local Caldicott guardian for collection and use of personal data. Results: Of 239 cases, all were female patients of mean age 62 years (range 27–93). In 4.2% (10/239) of cases, neither blue dye nor ICG was present in the axilla. Of the remaining 229 SLNB cases in this series, surgeons documented retrieval of 451 nodes, with a mean surgical nodal count per case of 1.97 (range 1–5) and pathological nodal count of 2.15 (range 0–7). Eighty three cases were performed in patients with BMI 30–39.9 and 21 cases with BMI ≥40, with nodal detection rates of 96.4% (80/83) and 95.2% (20/21), respectively, in these groups of patients. Twenty percent (48/229) of cases had nodal metastases on histopathology. Conclusions: This is a large single-center study which demonstrates the safety and accuracy of the combined ICG and blue dye technique for SLNB in breast cancer. This is represented by nodal detection rates and node positivity rates which are comparable to previous multicenter studies of standard SLNB regardless of BMI.
Endoscopic Stenting for Malignant Left-Sided Large-Bowel Obstruction in Patients with Colorectal Cancer: Evaluation according to Pathological Stage
Authors: Oh Yoon , Yoon Sunseok , Lim Sun Gyo , Oh Seung Yeop
Published: November 2022

Introduction: Self-expandable metallic stents (SEMSs) are widely used in patients with malignant left-sided large-bowel obstruction (MLLO) to convert an emergency situation into an elective one. However, the effects of endoscopic stenting on oncological outcomes remain unclear. This study aimed to analyze the oncological outcomes of SEMS placement in patients with MLLO stratified by pathological stage. Methods: We reviewed the data of patients with MLLO that were prospectively collected between January 2005 and December 2016. Patients were divided into those who underwent SEMS placement as a bridge to surgery and those who underwent emergency surgery. Disease-free survival (DFS) and overall survival (OS) were compared between groups, and their prognostic factors were determined by pathological stage. Results: SEMS placement and emergency surgery were performed in 130 and 45 patients, respectively. There was no difference in the 5-year DFS and OS rate between two groups. Subgroup analysis revealed a significant difference in the 5-year DFS and OS rate in patients with stage III MLLO, but was not observed in patients with stage II MLLO. Multivariate Cox regression analysis for stage III MLLO revealed endoscopic stenting (hazard ratio [HR], 2.051; 95% confidence interval [CI], 1.018–4.131; p = 0.044) as the only prognostic factor for DFS. Age, tumor differentiation, perineural invasion, and endoscopic stenting (HR, 3.189; 95% CI, 1.346–7.556; p = 0.008) were prognostic factors for OS. Conclusion: In terms of oncologic outcomes, endoscopic stenting might be more beneficial than ES in patients with stage III MLLO.
Increasing Societal Benefit From Cardiovascular Drugs
Authors: Tonelli Marcello , Straus Sharon
Published: November 2022

During the past few years, several innovative treatments for noncommunicable chronic disease have become available, including SGLT2i (sodium-glucose cotransporter-2 inhibitors), GLP-1a (glucagon-like-peptide 1 agonists), ARNI (angiotensin receptor-neprilysin inhibitors), and finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist. Each of these medications improves clinically relevant outcomes when added to existing therapies, and the indications for their use are rapidly expanding. Because existing drug regimens are already complex and costly, ensuring that society derives the maximal benefit from these new agents represents a major challenge. This Primer discusses how society can meet this challenge, which we address in terms of 5 principles: maximizing benefit, minimizing harm, optimizing uptake, increasing value for money, and ensuring equitable access. The Primer is most relevant for stakeholders in high-income countries, but the principles are broadly applicable to stakeholders in other settings, including low- and middle-income countries. We have focused the discussion on SGLT-2i, but the 5 principles herein could be used with reference to ARNI, finerenone, or any other health product.
Enjambement am Pentameterende
Authors: Brandenburg Yannick
Published: November 2022

This paper traces the enjambment techniques employed by Hellenistic and Latin authors at the end of the elegiac couplet. While the Alexandrians make deliberate use of enjambment at the end of the pentameter, in later Hellenistic and in Latin epigram there is a discernible movement toward a unity of syntax and metre, as testified by the poets’ tendency to avoid enjambment between distichs. The earliest Latin epigrammatists loyally render their Greek contemporaries’ aesthetics. Catullus, in his turn to Callimachean poetics, at times employs enjambment in this position, especially in elegy (as opposed to epigram). These techniques are largely abandoned by the Augustan poets, who rigidly introduce epigrammatic avoidance of enjambment into longer elegiac poems; among them, only Propertius in his fourth book rarely uses it as a stylistic means.
Checklist of Oribatid mites (Acari: Oribatida) of Ecuador
Authors: REVELO-TOBAR HAROL
Published: November 2022

The present checklist of the oribatid mites compiles all known published records of Ecuador with 479 species belonging to 232 genera and 89 families; 180 of these species were described from Ecuador. Oribatid mites were found in 15 of the 24 provinces that conform the Ecuadorian territory. In the provinces of Zamora Chinchipe, Galápagos, Loja, Cotopaxi, Pichincha and Napo, 95% of the species were recorded. 23.6% of these species are known only from Ecuador, 47.8% are distributed in Neotropical region, the remaining are Pantropical, semicosmopolitan and cosmopolitan. This high number of species makes Ecuador the country with the second largest number of species records in Latin America after Brazil.
Microstructure and Corrosion Characteristics According to the Si Content of Al–Ca-Si Alloys
Authors: Seo Dong-Wook , Kim Jun-Ho , Lee Myeong-Hoon , Lee Seung-Hyo
Published: November 2022

Aluminum is a general-purpose metal widely used in industrial fields owing to its excellent characteristics such as high specific strength, low density, excellent formability, and adequate corrosion resistance. However, Al has poor mechanical properties. To address this limitation,
trace elements such as Si, Mg, and Cu are added to form Al alloys; however, the corrosion resistance is often reduced. Therefore, the development of an Al alloy that exhibits satisfactory mechanical properties, castability, and corrosion resistance is necessary. To this end, Al–Ca-based
alloys were developed. The microstructures of these alloys were analyzed, and results indicated the formation of Al4Ca+Al2Si2Ca with a fine lamellar structure. The alloys in which Si was added to the Al–Ca-based alloy had more refined structures. Moreover,
AC4S7 exhibited a fine microstructure, formed a highdensity shallow pit, and served as a barrier to corrosion products, which is a major advantage. Electrochemical measurements were conducted, which demonstrated the positive influence of this structure in improving the corrosion resistance
of the alloy.